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Antiphospholipid Antibodies in Children with Age-Dependent Epileptic Encephalopathy.Purpose:Antiphospholipid antibodies (aPLs) have been found in the serum of patients with several neurologic disorders. Serum aPLs were detected in 19–26% of adult patients both with chronic epilepsy and with newly diagnosed seizure disorders. In children with partial epilepsy, Angelini et al. (1998) found aPLs in 13% of these cases. We studied the serum aPLs in 31 children with age-dependent epileptic encephalopathy: early infantile epileptic encephalopathy with suppression burst (EIEE), West syndrome (WS), and Lennox–Gastaut syndrome (LGS).Methods:Two children with EIEE, 20 with WS, and nine with LGS in the Pediatric Unit of Nihon University Itabashi Hospital were enrolled in the study. Inclusion criteria were (a) reliable diagnosis of age-dependent epileptic encephalopathy, (b) no signs or symptoms consistent with clinical immune system disorders and collagen diseases, and (c) negative for anticardiolipinβ2-glycoprotein I antibodies. Anticardiolipin antibodies (aCLs) of serum immunoglobulin G (IgG class) were measured with the enzyme-linked immunosorbent assay (ELISA) method. A value of aCL<10 U/ml is within normal limits. All of the subjects were classified in two groups. The patients in group A were diagnosed within 3 years, and those in group B were diagnosed beyond 3 years.Results:In the two patient with EIEE, the peak values of aCL were 57.9 and 35.6 U/ml. In patients with WS, the positive rate for the peak aCL levels was 91.7%, and the mean (±SD) level was 40.4± 39.2U/ml in group A, whereas the corresponding figures were 25% and12.7± 17.0 U/ml in group B. In patients with LGS, the positive rate for the peak aCL levels was 100%, and the mean level was 20.3± 6.6U/ml in group A, whereas the corresponding figures were 50% and 11.0± 12.2 U/ml in group B. We divided all the patients into a seizure-free group and a seizure-uncontrolled group. The mean peak value was 15.2± 17.8 in the seizure-free group and 38.8± 35.1 in the seizure-uncontrolled group.Discussion:A high positive rate of aPLs was found among patients with WS, characterized by early onset and long duration of epilepsy. These patients were poor responders to antiepileptic drugs (AEDs). Immunomodulatory therapies (intravenous Igs) have been shown to be effective in some children with this type of intractable epilepsy. Conversely, aPLs were more frequent among patients with localization–related epilepsies than in those with idiopathic generalized epilepsies. Several AEDs such as carbamazepine and phenytoin have been implicated as activators of antinuclear antibody production and drug-induced systemic lupus erythematosus. These antibodies are usually associated with autoimmune disorders such as primary antiphospholipid syndrome in rheumatic and connective tissue disorders. Two main pathogenic mechanisms have been proposed to explain the relationship between positive aPLs and neurologic symptoms (i.e., thrombotic and ischemic events within the CNS, and immune-mediated cellular damage from neuronal synaptic membrane attack). It has been shown that aPLs can disrupt neuronal function by directly acting on nerve terminals and reducingγ-aminobutyric acid-receptor–mediated chloride currents, suggesting a direct and reversible mechanism through which aPLs might lower the seizure threshold. It has also been postulated that antibodies to endothelium frequently coexist with aPLs and may induce apoptosis within the CNS. The high prevalence of positive aPLs in children with epilepsy indicates that immunologic dysfunction is associated with epilepsy, in at least some children. Conversely, aCL may appear after viral infections, and we speculate that some viral infections may be related to the age-dependent epileptic encephalopathyConclusions:The level of aPLs is related to disease severity and seizure frequency in patients with age-dependent epileptic encephalopathy, and aPLs may be useful to indicate prognosis and treatment effect. Regional Hyperperfusion in Temporal Lobe Seizures with Dystonic Posturing, Evaluated by Ictal–Interictal Subtraction SPECT.Purpose:Ictal hyperperfusion areas evaluated by multimodality registration methods may demonstrate anatomic localization of ictal symptoms. Dystonic posturing (DP) is one of the most reliable lateralizing indicators for temporal lobe epilepsy (TLE). Areas of regional hyperperfusion associated with DP in TLE were evaluated by using ictal–interictal subtraction single-photon emission computed tomography (SPECT).Methods:Twenty-three patients were randomly selected from 97 TLE patients who underwent operations between 1988 and 2000 in Shizuoka Medical Institute of Neurological Disorders (National Epilepsy Center). All ictal events were noted by reviewing long-term video-EEG monitoring records (by Y.I. and M.M.). The patients were divided into three groups according to the ictal symptoms: group D with unilateral DP, group H with elevated muscle tonus but without DP, and group N without DP or alternation of muscle tonus. For SPECT (Headtome set-070, Shimazu, Tokyo) sampling, each patient was injected with the same tracer during the ictal and interictal periods. Ictal and interictal SPECT and thin-slice magnetic resonance imaging (MRI; Sierra 1.5-T; General Electric, Milwaukee, WI, U.S.A.) were input into the automatic multimodality registration program (Dr. View/Linux, Asahikasei, Tokyo) to generate ictal–interictal subtraction images of SPECT on MRI for individual patients. Ictal hyperperfusion areas were evaluated by K.M. and M.T.Results:Six patients belonged to group D, nine patients to group H, and eight patients to group N. Statistically significant hyperperfusion was observed in the putamen (five patients in group D, two in group H and group N; p<0.01). Other ictal symptoms (such as autonomic symptoms, oral automatism, ocular or head deviation or both) showed no statistically significant differences except unilateral upper-limb automatism (four patients in group D, one in group H, and none in group N; p<0.01). Other factors such as age, sex, duration of illness, presence of MRI lesion or SPECT tracer (nine patients with[123I]-IMP and 14 with[99mTc]-ECD) were not statistically significant.Conclusions:A strong correlation between DP and putaminal hyperperfusion was demonstrated. Some patients showed a wide hyperperfusion area extending from the mesial temporal lobe to the putamen that may correspond to the propagation of epileptic discharges. Hyperactivity of the putamen is suggested to be associated with contralateral dystonic posturing. Epilepsy with Psychosis: Endocrine Psychic Syndrome.Case 1:A 9-year-old girl has had paroxysmal episodes of microspia and complex partial seizures without aura since age 8 years. She experienced visual hallucinations such as the strange face of an old lady and six moving ballerinas at age 9 years. In addition, she experienced auditory hallucination of a voice, something invisible coming close to her, and the feeling of fear. She broke her sister's comic book in a quick temper. Electroencephalogram (EEG) showed repetitive spikes on the left occipital and posterotemporal regions during both the psychotic state and remission. Brain magnetic resonance imaging (MRI) showed no definite abnormality. Brain single-photon emission computed tomography (SPECT) showed a subtle change in hypoperfusion in the left hemisphere. No definite differences were found during both states in EEG or SPECT. Her psychotic symptoms appeared after a lucid period of 30 min to 2 days and are followed by habitual complex partial seizures. It seemed that the psychotic symptoms of case 1 developed after seizures. We therefore considered that her symptoms correlated with the postictal stage, so-called postictal psychosis. However, her biochemical studies showed hyperthyroidism. Her psychotic symptoms disappeared soon after taking thiamazole.Case 2:A 21-year-old woman experienced complex partial seizures and secondarily generalized tonic–clonic seizures since age 2 years. She was admitted to the pediatrics department for recurrent vomiting. After admission, she complained that a ghost disturbed her eating. She experienced hearing voices of neighbors, delusions of reference and persecution, and delusions of speech with bizarre and grotesque features. In addition, she showed irritation, agitation, and violent behavior to her family. The EEG showed theta waves on bilateral frontocentroparietotemporal regions during psychosis. The same findings of EEG were observed during remission. Brain MRI showed a high-intensity area in the right cingulate gyrus. Brain SPECT showed hypoperfusion in the right mesial and lateral temporal regions during both states. However, hyperperfusion in bilateral frontal cortex were observed during psychosis. No correlation was noted between her psychotic symptoms and seizure activity or medication. We therefore considered that her psychotic symptoms resembled interictal chronic psychosis. However, her biochemistry data and the Ellsworth-Howard test showed pseudohypoparathyroidism type II. Her psychotic symptoms disappeared after treatment with a vitamin D analogue. We were able to discontinue all antipsychotic drugs.Conclusions:More than 150 years ago, von Basedow first described psychotic illness in a patient with exophthalmic goiter. Brownlie et al. reported psychosis associated with thyrotoxicosis. Eight among their 18 patients experienced hallucination, and 10 cases, including two schizophreniform cases, had good prognosis after an adequate treatment. Conversely, Hey et al. reported a case of Capgras syndrome in association with pseudohypoparathyroidism. This patient had mental retardation, epilepsy, and schizophrenia-like symptoms. Because of psychosis, he had a history of electroconvulsive therapy. Pollard et al. reported a 13-year-old Asian girl who showed hysterical paralysis and a rapid-cycling mood disorder. The mood disorder responded to treatment of pseudohypoparathyroidism with a vitamin D analogue.Although endocrine psychic syndrome is not unusual, epileptic psychosis combined with endocrine disease, as in our cases, is confusing as to whether the symptoms mimicked postictal or chronic psychosis. We propose to reconsider the association of psychiatric problems with endocrine disease when we encounter epilepsy patients with psychosis. Single Small Enhancing CT Lesions (SSECTL) in Epilepsy in India.Purpose:Single small enhancing CT lesions (SSECTLs) are extremely common in Indian epilepsy patients seen for the first time with seizures. Various hypotheses exist regarding their etiology, ranging from tuberculomas to neurocysticercosis, on the basis of histology and excisions done in a small percentage of cases. It also has been observed that these lesions disappear spontaneously over a short period after treatment with antiepileptic drugs (AEDs), causing doubts about their etiology and raising questions regarding management. The present study was carried out to observe such patients with SSECTLs with respect to persistence or disappearance of these lesions with AED treatment alone.Methods:All the new patients who attended our neurology clinics, with seizures, generalized or focal, were studied for the purpose of the present study. Apart from historical details and the seizure characteristics, complete neurologic examinations were done and recorded in specified form. Routine blood counts, erythrocyte sedimentation rate, urine examination, blood biochemistry, chest radiograph, and EEG were carried out. Computed tomography (CT) scan was done at the first instance and repeated after≥10–12 weeks of AED wherever possible. All the patients were given AEDs alone.Results:All the patients with first-ever seizures during the study period formed the subjects of this study; 43.5% of the patients had normal scans, whereas in 56.5%, the scans were abnormal. Of the patients, 12.9% had specific abnormalities, which included meningioma (5), gliosis (21), atrophy (21), multiple neurocysticercosis (43), and multiple infarcts (18), among others. 40.4% of patients showed nonspecific abnormalities on their scans such as low attenuation (51), high-attenuation disks (67), high-attenuation rings (241), generalized edema (56), and calcified spots (75). A follow-up scan was possible in 219 cases. Of these, 131 (59.8%) showed complete resolution, whereas 53 (24.2%) had significant resolution, but 35 (16%) remained unresolved.Discussion:The appearing and disappearing CT scan lesions in epilepsy in India have been an enigma. Initially these were thought to be tuberculous granulomas, as tuberculosis is one of the commonest diseases prevalent in this region. Disappearance of these lesions or healing by calcification by antituberculosis therapy (ATT) was taken as evidence for the hypothesis of tuberculosis. When some of these patients had to discontinue ATT because of adverse drug reactions, it was noted that these lesions disappear also without ATT. Subsequently, some histopathologic studies were conducted, with an evidence of neurocysticercosis in some of these patients, which resolved with cysticidal drugs. However, a majority of these patients who neither had ATT nor cysticidal therapy had their lesions resolve spontaneously on follow-up CT scans. Our study also supports the hypothesis. However, a small number of cases were seen in which these lesions either do not resolve or increase on follow-up CT scans. It is probable that these lesions do not represent one single etiology, and they must be managed appropriately.Conclusions:The SSECTL are one of the most common findings on CT in patients of epilepsy in India. These lesions resolve spontaneously without any specific treatment such as ATT or cysticidal therapy in the majority of patients. Therefore, there is an ample justification in treating them initially with AEDs only. A Neuropathological Study on the Limbic System in Dentatorubral-Pallidoluysian Atrophy.Purpose:Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by progressive myoclonic epilepsy (PME), dementia, and cerebellar ataxia. According to the age at onset, DRPLA is classified into juvenile, early-adult, and late-adult types. In the juvenile type, PME is most frequently observed, whereas seizures or PME sometimes and rarely occurs in early- and late-adult types. In general, glutamate transporters and calcium-binding proteins (parvalbumin and calbindin-D28K) are believed to reflect glutamate neurotoxicity and functions of theγ-aminobutyric acid (GABA)ergic inhibitory interneurons in the limbic system, respectively. To investigate epileptogenesis in DRPLA, we examined the expressions of glutamate transporters and calcium-binding proteins in the limbic system in autopsy cases of DRPLA.Methods:Fourteen autopsy cases of clinicopathologically confirmed DRPLA, comprising nine cases of juvenile type with PME and five cases of late-adult type without PME, as well as 10 age-matched controls, were studied. Immunohistochemistry was performed on serial sections of the temporal lobe including the hippocampus, amygdaloid complex, and entorhinal cortex, by using mouse monoclonal antibodies to parvalbumin and calbindin-D28K (Sigma-Aldrich, St. Louis, MO, U.S.A.) and rabbit polyclonal antibodies to excitatory amino acid transporters 1 (EAAT1), EAAT2, and EAAT3 (Wako Pure Chemicals Industries, Japan). The degree of immunoreactivity was evaluated by semiquantitative visual inspection.Results:The number of interneurons immunoreactive for parvalbumin or calbindin-D28K seemed to be lower in cases of the juvenile type of DRPLA with PME compared with that in cases of late-adult type of DRPLA not manifesting PME. Reduction of calbindin-D28K–immunoreactive neurons appeared to be more prominent than that of parvalbumin-immunoreactive neurons. It is noteworthy that four of five cases of the juvenile type, in which seizure occurred before puberty and the amygdaloid complex could be examined, and one case of the adult type completely lacked the amygdaloid immunoreactivity for parvalbumin or calbindin-D28K. The amygdaloid lesion is likely to be related to PME in DRPLA as either a cause or a result. Conversely, the expression of glutamate transporters seemed to be mildly affected. Three cases of juvenile type and one case of adult type showed a reduced expression of EAAT1 or EAAT2 or both in the entorhinal cortex, hippocampus, or amygdaloid complex. The expression of neuronal glutamate transporter EAAT3 was comparatively preserved in most of the remaining neurons in all subjects.Conclusions:An active debate has continued on the subject of whether the cerebral or subcortical lesions are more involved in the epileptogenesis in DRPLA. Neuropathologically, various brainstem changes, such as atrophy of the brainstem tegmentum, have been delineated. Previously we performed neuropathologic analysis of the brainstem in the same subjects and failed to find any PME-specific lesions. The current study showed that the GABAergic interneurons were altered more definitively in cases of juvenile type manifesting PME, whereas glutamate transport might not be severely disturbed in the limbic system in DRPLA. Recently, neuroradiologic studies have shown the presence of cerebral cortical atrophy in DRPLA. Furthermore, the extensive involvement of cerebral cortical neurons was demonstrated by immunohistochemistry against mutant atrophin-1, a responsible protein for DRPLA, particularly in the juvenile type. Taking these findings together, we speculate that the occurrence of PME in DRPLA may be related to the lesions of the cerebral cortex, including the limbic system. We also believe that further functional analysis of the cerebral cortex is useful to examine treatment for the usually intractable PME in DRPLA. Prevalence and Localizing Value of Emotional Facial Paresis in Medically Refractory Temporal Lobe Epilepsy.Purpose:The selection of patients with medically refractory temporal lobe epilepsy (TLE) for surgery depends on the concordance of data from clinical, electroencephalographic (EEG), radiologic, and neuropsychological evaluation. Although the clinical examination is often normal, contralateral emotional facial paresis (EFP) has been observed in patients with medically refractory mesial TLE (MTLE). Emotional facial paresis refers to unilateral lower facial weakness during emotional expression such as smiling, along with normal voluntary facial movements. We intended to determine the frequency of occurrence of EFP and its lateralizing significance in identifying appropriate candidates for anterior temporal lobectomy (ATL) with amygdalohippocampectomy.Methods:We investigated the prevalence, predictive value, and associations of EFP among 50 consecutive patients who underwent ATL during the period from November 1999 to July 2001 and satisfied the following criteria: (a) magnetic resonance imaging (MRI) findings consistent with mesial temporal sclerosis (MTS) and concordant interictal and ictal EEG data; and (b) seizure free or≥90% seizure reduction for≥6 months after ATL. Fifty age- and sex-matched normal subjects acted as controls. Facial asymmetry was assessed at rest and during volitional movements. EFP was looked for during conversation, by provoking a smile. The whole examination undertaken during the video-EEG monitoring was available for review. To ascertain observer bias, two investigators (A.J. and J.C.) independently examined the first 20 patients for the presence or absence of emotional facial paresis. The interobserver agreement was 80% with a kappa value of 0.63. Subsequently, one investigator (A.J.) assessed all subjects, and controversies were resolved by reexamination along with J.C. or K.R. We used standard deviation to define the dispersion, andttest (two-tailed) and Fisher's exact test to evaluate the significance of the association of different clinical characteristics between patient and control groups, and between patients with and without emotional facial paresis.Results:The patients comprised 27 male and 23 female subjects. The age at ATL ranged from 14 to 55 years, and the mean duration of epilepsy before ATL was 17.8 years. When compared with eight (16%) of 50 control subjects, 36 (72%) of 50 MTLE patients exhibited unilateral EFP; the difference was highly significant (p<0.0001). The presence of contralateral EFP correctly predicted the side of ATL in 86.1% of patients. Patients with EFP had a longer duration of epilepsy compared with those without this sign (19.2± 8.0 vs. 14.4± 6.1 years; p= 0.048). We did not find any significant association between EFP and the following clinical characteristics: age at epilepsy onset, age at ATL, gender, and antecedent history of febrile seizures. Both the patients and the control subjects had EFP more frequently involving the right side of the face. Of the eight control subjects who had EFP, seven had it on the right. Whereas 13 (54.2%) of 24 patients with right MTLE had EFP (on the left side in 11), 23 (88.5%) of 26 with left MTLE had emotional facial paresis (right side in 20; p= 0.011).Conclusions:Our observations confirm that EFP contralateral to the side of MTS is a valuable localizing sign in correctly predicting the epileptogenic temporal lobe. To our knowledge, the significant association we observed between left MTLE and more frequent occurrence of emotional facial paresis has not been previously documented. The value of EFP in localizing the ictal-onset zone in patients with bilateral MTS is uncertain. We hypothesize that the presence of an intact right hemisphere and pathologic changes more extensive than MTS may be required for EFP to be readily manifest. Convulsive Episodes in Patients with Group A Xeroderma Pigmentosum.Purpose:Xeroderma pigmentosum is an autosomal recessive disease characterized by sunlight hypersensitivity, freckles, and skin cancers. In addition to these skin lesions, patients with group A xeroderma pigmentosum (A-XP) show progressive and severe neurologic complications of unknown causes. However, few A-XP patients with seizure disorders have been reported in the literature (Mimaki et al., 1988), and no systematic search for seizure disorders in A-XP patients has been performed. We aimed to clarify the incidence of convulsive episodes in patients with A-XP.Methods:We investigated the history of convulsive episodes of 33 A-XP patients in our institute by reviewing the medical charts or conducting interviews with caregivers.Results:Five patients had episodes of convulsions at age 12 years (YoT, male), 13 (MA, female), 14 (HM, female), 16 (YY, female), and 19 and 21 (YaT, male) years. YoT and YY were siblings, and they had another healthy brother who had no history of convulsive episodes. Their parents also had no history of convulsions. Among family members of MA, HM, and YaT, no seizure disorder was identified. YoT, MA, HM, and YY exhibited brief episodes of loss of consciousness with cessation of movement. Valproate acid (VPA) was effective for these episodes. YaT had a brief cessation of respiration at age 19 years, which disappeared after phenobarbital (PB) administration. PB was discontinued by the family after 6 months of treatment, and he (YaT) had a generalized tonic seizure with left upper extremity focality at age 21 years. He has been taking PB again, and no further episode appeared for the past 4 years. A few low-voltage theta rhythms were the dominant background activities of drug-induced sleep EEG recordings of these five patients. Except HM, no apparent epileptic discharge was found on interictal EEG recordings. HM showed periodic high-voltage sharp waves at bilateral frontal regions on drug-induced sleep EEG recording when she was 15 years old. Except MA, no A-XP patient had an episode of febrile seizure. MA had a single febrile seizure when she was 4 years old.Conclusions:Because these five patients exhibited recurrent afebrile seizures, we diagnosed them as having epilepsy. However, we could not identify the precise type of epilepsy, in part because of few EEG findings. A-XP patients exhibit marked diffuse brain atrophy after age 5 years (Ohinata et al., 2002), which makes it difficult to obtain apparent epileptic discharges on routine EEG recordings. From the clinical standpoint, YaT is considered to have symptomatic localization-related epilepsy, showing complex partial seizures at age 19 years with secondary generalization at 21 years. The other four patients might exhibit complex partial seizures (due to localization-related epilepsy) or atypical absence seizures (due to generalized epilepsy), but few typical EEG findings, making it difficult to differentiate the types of epilepsy. Nevertheless, we diagnosed five (15%) of 33 A-XP patients as having symptomatic epilepsy. In contrast, we found only one (3%) patient with a history of febrile seizures. In the general population,∼3% of all people living to age 80 years in the United States will be diagnosed with epilepsy (Westbrook, 2000). The cumulative incidence of febrile seizures in Europe and the United States is 2–5%, and that in Japan is 8–10% (Maeda, 2001). Taking these figures together, in comparison with the general Japanese population, Japanese A-XP patients show a lower incidence of febrile seizures, whereas they exhibit a higher prevalence of epilepsy. Neurohumoral Behavior of Epilepsy with Neurocysticercosis in Nepal.Purpose:Epilepsy due to neurocysticercosis (NC) is common in Nepal. The 120 epilepsy cases with NC confirmed by magnetic resonance imaging (MRI),Diagnostic and Statistical Manual of Mental DisordersIV, and International League Against Epilepsy criteria were subjected to enzyme-linked immunosorbent assay (ELISA) testing for comparative study of serum anti-cysticercus antibody levels between epilepsy with various types of NC before and after treatment with antihelminthic, correlation with therapeutic efficacy of cysticide, and identification of a prognostic indicator. Comparative MRI studies of the brain were done with various types of NC before and after treatment to evaluate drug efficacy, resolution rate of the cerebral lesion, and correlation with antibody titer.Methods:Ninety persons with epilepsy with single benign parenchymal NC and 30 with multiple benign parenchymal NC were subjected to ELISA before and 1 month after the unified treatment regimen with albendazole, 15 mg/kg/body wt daily, for 8 days, and oral cortisone. Comparative studies of serum antibody titers and correlation between mean optical density (OD) and therapeutic efficacy of cysticide before and after treatment were done to evaluate the therapeutic efficacy. Assessment of antibody titer was done to understand the efficacy of treatment and to find an indicator of prognosis. MRI scan of the brain was done before and 8 days after the treatment to assess the resolution of the cerebral lesion and correlation with antibody titer.Results:The sensitivity of ELISA for serum anti-cysticercus antibodies in epilepsy with multiple benign parenchymal NC was 93.3%, showing strong positivity in contrast to epilepsy with single benign parenchymal NC, with a sensitivity of 77.8%. Comparative studies of the sensitivity of ELISA between epilepsy with single and multiple benign parenchymal NC before treatment were significant (F= 15.47; p≤ 0.0001). The mean ODs of epilepsy cases with single benign parenchymal NC before and after treatment were mean, 1.387; SD, 0.433; and m, 0.314 SD, 0.102, respectively (F= 430.31; p= 0.0001). In contrast, the ODs of epilepsy with multiple benign parenchymal NC were m, 1.757; SD, 0.321; and m, 0.482; SD, 0.164, respectively (p= 0.0001). The differences between the OD of epilepsy with single (m, 0.314; SD, 0.102) and multiple benign parenchymal NC (m, 0.482; SD, 0.164) before and after treatment were highly statistically significance (F= 43.93; p= 0.0001). MRI study after treatment for epilepsy with various types of NC revealed that of 90 epilepsy cases with single benign parenchymal NC, 94.4% resolved completely, 2.2% resolved partially, and 3.3% showed no change, whereas, of 30 epilepsy cases with multiple benign parenchymal NC, 40% resolved completely, 30% resolved partially, and 30% showed no change. The comparative therapeutic responses to albendazole in epilepsy cases with single benign parenchymal NC and multiple benign parenchymal NC revealed that the former responded better than the latter (i.e., the cure and resolution rate was 94.4% vs. 40% for epilepsy with single benign parenchymal NC vs. multiple benign parenchymal NC). Epilepsy with single benign parenchymal NC having low serum OD showed better response to treatment, in contrast to epilepsy with multiple benign parenchymal NC having higher serum OD.Conclusions:Epilepsy with NC is the biologic marker of poverty and poor sanitation in the community of an undeveloped country. The low serum OD in epilepsy with single benign parenchymal NC showed a better response to the treatment in contrast to epilepsy with multiple benign parenchymal NC having higher serum OD. These results indicate that low serum antibody titer of epilepsy with NC predicts good prognosis and better therapeutic efficacy of antihelminthic treatment. The evaluation of the serum antibody titer of epilepsy with NC may be used for the diagnosis, assessment of therapeutic efficacy of antihelminthic treatment, and prediction of prognosis. Probable Molecular Dysfunction by Autoantibodies Against NMDA-Receptor GluRℇ2 in Epilepsies After Acute Encephalitis.Purpose:Glutamate receptors (GluRs) in the central nervous system play an important role in the excitatory synapse and have been implicated in neurodegenerative diseases and symptomatic epilepsy. After Rogers et al. reported that autoantibodies against GluR3 were involved in some cases of Rasmussen encephalitis, studies focused on other neurologic diseases with a possible causal relation to autoantibodies against GluRs. In 1999, we found autoantibodies against theN-methyl-d-aspartate (NMDA) GluRℇ2 subunit in sera and CSF from patients with chronic progressive epilepsia partialis continua, Rasmussen encephalitis, and other diseases. To elucidate the pathophysiologic mechanisms of intractable epilepsy after acute encephalitis or encephalopathies, we studied the autoantibodies in sera and CSF from such patients.Methods:With the tetracycline-induction system, we established stable NIH3T3 transformant cell lines expressing the NMDA-type GluRℇ2 subunit. Cell extracts of the transformants were transferred to nitrocellulose membranes to detect the presence of antibodies against GluRℇ2. The membrane was exposed to sera from patients and was stained by second antibodies coupled to alkaline phosphatase. Four peptides (an N-terminal, and three C-terminal fragments) were synthesized from GluRℇ2 cDNA by using bacterial fusion protein vectors. Homogenates of the transformants and bacteria were transferred to nitrocellulose membranes, and the membranes were incubated with the patients' sera or CSF, and stained by second antibodies coupled to alkaline phosphatase. Fifteen patients with epilepsies after acute encephalitis (influenza virus; two patients, herpes simplex virus; two, varicella zoster virus; one, others) and three after acute encephalopathies (influenza vaccination, others) were studied. Ages at onset were from 2 to 36 years (0–5 years, eight patients; 6–10 years, four; 11–15 years, three; older than 16 years, three). Cerebral palsy was found in eight patients, and mental retardation (IQ<70) in 11 of 18 patients. Seizure outcome ranged from seizure free (five patients), monthly (four), weekly (five), to daily (three).Results:Immunoglobulin G (IgG) and IgM autoantibodies against the NMDA GluRℇ2 subunit were positive in 13 and 12, respectively, of 18 patients. IgM autoantibodies disappeared in two patients, and IgG autoantibodies changed from absence to presence in three patients evolutionally. Two patients continued to have the autoantibodies even several years after acute encephalitis. Production of autoantibodies against GluRℇ2 was related significantly to episodes of convulsive status epilepticus in the acute stage of encephalitis (p= 0.19; Spearman's correlation coefficient by rank test) and insignificantly to cell counts and protein levels in CSF, duration of unconsciousness, and the latency of first convulsion from onset. Comparing neuropsychological outcomes between patients with and without the autoantibodies, the autoantibodies were causally related to mental retardation (p<0.03, Mann–WhitneyUtest), motor impairment (p<0.03,χ2 for independent test), and seizure frequencies (p<0.03, Spearman's correlation coefficient by rank test). The epitopes of the autoantibodies existed mainly in the c-terminal of GluRℇ2 molecules. In five patients (broader type), both n- and c-terminals were epitopes of the autoantibodies; in eight (narrow type), only c-terminals were epitopes. Comparing the relations between broadness of epitopes and clinical factors, no significant correlation was found for age at onset (p= 0.11, Spearman's correlation coefficient by rank test), concentration of proteins in CSF (p= 0.07, Spearman's test), and latency of convulsion from the onset of illness (p= 0.09, Spearman's test). The broadness of epitopes was not related to neuropsychological outcomes but was related to lower cell counts in CSF. The spectra of epitopes were broader in CSF than in sera.Conclusions:Production of the autoantibodies might be related to destruction of brain tissue by a convulsive status and might contribute to severe neuropsychological outcomes. Relationship Between Clinical Characteristics and Magnetoencephalographic Findings in Typical and Atypical Benign Childhood Epilepsy with Centrotemporal Spikes.Purpose:Benign childhood epilepsy with centrotemporal spikes (BECT) is an electroclinical syndrome characterized by partial sensorimotor seizures (sylvian seizures: SSs) with centrotemporal spikes (rolandic discharges: RDs). Typically the prognosis is excellent with remission before age 16 years. However, some patients with BECT initially seem to evolve into atypical or complicated types, one of which has been called atypical benign partial epilepsy of childhood (ABPC) by Aicardi. Recently, the search for the predictor of evolution into atypical or complicated types was attempted. In this article, we use the termcomplicated BECT(CECT) to include atypical or complicated types. We report the detailed analysis of the generator of RDs in BECT and CECT by using magnetoencephalography (MEG).Methods:Sixteen children with BECT undertook MEG examination; seven were excluded because of insufficient numbers of RDs for analysis, leaving nine patients. All three patients with CECT were characterized as having frequent atonic seizures (negative myoclonus) or hemifacial or hand twitching, with continuous spike–waves during slow wave sleep in EEG, and also mental deterioration. MEG activity was recorded during sleep by using a whole-head 204-channel neuro-magnetometer (Neuromag-204) with simultaneous EEG recordings. Locations and directions of estimated dipoles of high-amplitude MEG sharp waves were displayed on magnetic resonance images. The data were sampled at 300 Hz with a 160-Hz low-pass filter and analyzed under 45-Hz low-pass filter and 1- to 3-Hz high-pass filter. Analysis of three types of MEG spikes was performed: current dipoles of the first of the highest or lowest peak. Therefore, a uniform pattern of MEG spikes was analyzed individually.Results:In nine (56.3%) of 16 patients with BECT and all three (100%) patients with CECT, sufficient numbers of MEG spikes (>30 spikes in several sampling sequences for about several minutes each) were detected for analysis. Five typical BECT patients had only SSs during sleep, typical unilateral RDs, and over a 2-year seizure-free period, except one patient. These patients had typical MEG spikes characterized by current dipoles showing relatively limited localization and regular directions. The remaining four patients with BECT had clinical characteristics other than SSs, such as refractory SSs, perioral twitching during wakefulness, febrile convulsions after epilepsy onset, and fewer RDs on EEG while remaining significant in number on MEG. These patients showed less concentrated MEG spikes and moderately irregular dipole directions. In all three patients with CECT, current dipoles were scattered widely around rolandic areas, showing more irregular directions.Conclusions:Although we have not developed sequential MEG data of individual patients, our MEG findings may suggest an intermediate type of BECT as a continuum between typical BECT and CECT. Scattering of epileptic foci from the restricted rolandic areas may be due to some immaturity of neuronal systems. Multifocal activated cortical areas, including excessively inhibitory or excitatory neuronal generators, may induce CECT evolution and neuropsychological dysfunction. This kind of mechanism may play a role in the formation of secondary bilateral synchrony, which is considered to cause generalized spike–waves in some cases of BECT. If sequential MEG data in the very early stages of BECT onset are obtainable individually, evolution to complicated BECT may be predictable. Our MEG findings suggest an intermediate type of BECT as a continuum between typical BECT and CECT or ABPC. If current dipoles are scattered and showing more irregular directions, even in the early stage of CECT, MEG study may be a quick predictor of complications. MEG may be able to explain the mechanism of evolution of typical BECT to complicated BECT. Safe Pregnancy in Epilepsy: Registry of Epilepsy and Pregnancy Initiative in India.Background:Care for women with epilepsy (WWE) is suboptimal in most countries. The Government of India has recently eased the legal constraints to marriage for WWE. The proportion of married among WWE is comparable to that in the community, according to a survey in Kerala State. WWE in developing countries face several difficulties. Health services are sparse and expensive. Many of them have malnutrition, anemia, or intercurrent infections. Social stigma is another major handicap.Objective:Indian Registry of Epilepsy and Pregnancy (IREP) is established to monitor reproductive functions in WWE and facilitate their optimal care under prevailing conditions.Methods:The first registry in India was started at Trivandrum (TVM) in 1998. A consensus protocol was developed in a workshop held in Trivandrum in 1998. Preconception management focuses on diagnosis, antiepileptic drug (AED) therapy, if required, and initiation of folate supplementation. We use a higher dose of folate (5 mg daily) to obviate any nutritional deficiency. The early antenatal care includes estimation of serumα-fetoprotein (16 weeks) and malformation-targeted ultrasonography (18 weeks). The couple is provided extensive counseling on the diverse aspects of epilepsy and pregnancy. It is often necessary to counsel close relatives also, as many couples live in joint families. Two intramuscular injections of vitamin K (10 mg) are recommended in the last 6 weeks of pregnancy, as oral vitamin K preparations are not widely available. Three months after delivery, babies are screened for malformations by physical examination, echocardiography and abdominal ultrasonography. We assess development and language at 1 and 3 years, respectively. Similar registries were set up on the east coast (Vishakhapattanam-VZG, 1999) and North India (Ludhiana-LDH, 2000). These registries are following a unified protocol and joined together to form IREP. Three new centers are being established in other parts of India. IREP is now pooling data with the European Registry of Epilepsy and Pregnancy.Results:As of January 2002, 547 WWE (mean age, 24 years) were enrolled (TVM, 386; VZG, 125; LDH, 36), and 320 had completed pregnancies (TVM, 224; VZG, 66; LDH, 30). AEDs included carbamazepine,141; phenytoin, 98; phenobarbitone, 83; valproate, 63; clobazam, 12; clonazepam, seven; and lamotrigine, seven. Preconception or first trimester folate supplementation was high in TVM (83%) but low in VZG (33%) and LDH (17%). There were 38 (11.9%) cases with malformations (including two terminations). Nervous system malformations included spina bifida and meningomyelocele (three). There were 20 cases of cardiac defects, including tetrology of Fallot, coarctation of the aorta, patent ductus, septal defects, and patent foramen ovale; some of latter had closed subsequently. Other malformations involved the skeleton (seven), genitourinary system (four), and anterior abdominal wall (three). Babies from one center (TVM) showed mild delay in motor and mental development at age 1 year, when compared with matched normal babies.Conclusions:The spectrum and prevalence of birth defects observed in this study are comparable to those in reports from elsewhere. Ultrasonography and echocardiography has enabled us to detect malformations like hydronephrosis, cyst in liver, and small septal defects. It is debatable whether patent foramen ovale should be recognized as an anomaly or otherwise, as several of them closed subsequently. This initiative has sensitized the medical fraternity to the special needs of WWE and has contributed to improving the standards of care for them. Wada Test and Interictal[ 18F]FDG-PET in Unilateral Temporal Lobe Epilepsy.Purpose:To investigate the association between regional glucose metabolism obtained with interictal[18F]fluorodeoxyglucose positron emission tomography (18FDG-PET) and material-specific memory measured with the Wada test in patients with unilateral temporal lobe epilepsy.Methods:We investigated 47 consecutive patients with intractable, unilateral temporal lobe epilepsy (26 left and 21 right) who underwent presurgical evaluation including interictal18FDG-PET and the Wada test. Nine patients had non-left dominance for language (one right and eight mixed); the remainder were left dominant. To obtain regional glucose metabolism, we worked with 14 groups of regions of interest (ROIs) in either hemisphere. We calculated the PET asymmetry index (PET-AI) for each group of ROIs by using the formula: (L− R)/(L+ R)× 200, where L or R represents averaged glucose metabolism in each ROI on the left or right hemisphere. In addition, we created a“general asymmetry factor,” which is the mean of all the 14 PET-AIs, to diminish general effects of unilateral hemispheric hypometabolism that are commonly seen in patients with unilateral temporal lobe epilepsy. To estimate unilateral memory, we used recognition memory paradigms in the Wada test based on words, faces, and pictures and obtained three material-specific memory scores for each hemisphere. The memory asymmetry index (memory-AI) for each material was calculated by using the formula: (L− R)/6× 100, where L or R represents material-specific memory scores performed on the left or right hemisphere. In our statistical analysis, we created a linear regression model to predict the memory-AI for each material by combining the PET-AI for each ROI with the general asymmetry factor. The model was compared between subgroups according to the side of focus or the language dominance.Results:The associations between the PET-AI and the memory-AI did not significantly differ between patients with left and right foci. In four combinations of PET-AI and memory-AI, the associations were significantly different between the subgroups according to language dominance. Only patients with non-left language dominance showed positive correlation of PET-AI with memory-AI: PET-AI for the lateral frontal region with memory-AI for words (t=−3.39; p= 0.002) or for pictures (t=−2.29; p= 0.027); PET-AI for the anterior inferior temporal region and memory-AI for faces (t=−2.48; p= 0.017); and memory-AI for words and PET-AI for the anterior superior temporal regions (t=−1.99; p= 0.053).Conclusions:When we analysed the subgroups according to the side of focus, we found no significant associations between the PET-AI in any brain area and the memory-AI for any material. In contrast, when we analyzed the subgroups according to language dominance, we found four significant associations between hypometabolism in certain areas and material-specific memory deficits, and this was observed only in patients with non-left language dominance. Our results suggest that in patients with unilateral, drug-resistant temporal lobe epilepsy, functional anatomy of memory also is influenced by language dominance. Muscle Activity During Non-REM Sleep in Patients with Infantile Spasms.Purpose:Under physiologic conditions, muscle activity is abolished during rapid-eye-movement (REM) sleep but is sustained in non-REM sleep. We found a disturbance of muscle activity during REM sleep in patients with infantile spasms (ISs) (Kohyama et al., 2000). In the current study, we examined muscle activity during non-REM sleep in patients with ISs.Methods:Twelve IS patients (ages, 53–83 postconceptional weeks; mean, 64.1), who had not previously been treated, were enrolled in the study. Nine of 12 patients had a good prognosis on convulsions. One all-night polysomnography was performed for each patient, and the percentage of chin muscle atonia during non-REM sleep (%ATNR) was calculated. Seven neurologically unaffected infants (ages, 55–81 postconceptional weeks; mean, 70.4 weeks) served as age-matched controls.Results:%ATNR in IS patients ranged from 5.5 to 33.4 (mean, 19.0). The mean value was higher than that in the controls (13.8; range, 3.4–29.4), although no significant difference was obtained (p= 0.27).Conclusions:Petre-Quadens (1972) reported the normal %ATNR value in 10 children aged three months to 5 years as 14.7%. In comparison with this value, Fukuyama et al. (1979) reported elevation of %ATNR in IS patients. They also reported that the mean %ATNR value in three patients who showed unfavorable response to adrenocorticotropic hormone (ACTH; 45.3; range, 32.0–63.8) was higher than that in five IS patients with a favorable response to ACTH therapy (37.6; range, 17.7–55.1). Interestingly, Petre-Quadens (1972) also reported elevation of a similar index in children with mental retardation. Brain insults may result in the elevation of %ATNR. In the current study, however, we failed to demonstrate a significant difference in %ATNR between IS patients and age-matched controls. Petre-Quadens (1972) also observed the average %ATNR in young adults (aged 15–25 years) to be 2.4% and hypothesized that this index declines with age progression. However, based on a study with healthy young children, we found no age-related decrease of %ATNR (Furushima et al., 2002). The cited works including the current study were based on visual inspection of muscle activity, and so far, no consistent results have been obtained on %ATNR. Recently, Werth et al. (2002) analyzed chin muscle activity during non-REM sleep by using computer analysis, and found that chin muscle atonia during non-REM sleep appeared at a constant rate of 10–15% throughout the night in healthy young adults. They also examined %ATNR in patients with narcolepsy and observed that the latency to chin muscle atonia during non-REM sleep was shorter in narcoleptics (0.7± 1.1 min) than in normal controls (48.8± 28.9 min). They speculated that atonia during non-REM represents a measurement of REM propensity. The brainstem cholinergic and monoaminergic systems are involved in the state-dependent muscle activity control. Cholinergic agents microinjected into the brainstem elicit muscle-tone suppression, and the disfacilitation of serotonergic system is considered to be involved in the decrease of excitability of the hypoglossal motoneuron. %ATNR is easily measured on routine EEG recordings, with the only addition of the measurement of chin muscle tone. %ATNR is a potentially useful index reflecting the balance between the brainstem cholinergic and monoaminergic activities. Broad clinical application of %ATNR with the development of a computerized analyzing system is expected to provide new insights into the assessment of cholino-monoaminergic activities in the brainstem. [ABSTRACT FROM AUTHOR]

The article lists several papers related to immune system that are to be published in the December 2004 issue of the journal "Immunology." Some of the papers are "Phenotypic and Functional Heterogeneity of Porcine Blood Monocytes and Its Relation With Maturation," by Sonia Chamorro, Concepcion Revilla, Belen Alvarez, Fernando Alonso, Angel Ezquerra, Javier Dominguez; "Influence of Pathological Progression on the Balance Between Cellular and Humoral Immune Responses in Bovine Tuberculosis," Michael Welsh, Rodat Cunningham, David Corbett, R. Martyn Girvin, James McNair, Robin Skuce, David Bryson, John Pollock.

Lists forthcoming papers on immunology published in the October 2005 issue of the journal "Immunology." "Relationship Between SPRY and B30.2 protei domains: Evolution of a Component of Immune Defense?" by David Rhodes, Bernard de Bono and John Trowsdale; "Putting the NK Cell in Its Place," by Geraldine O'Connor, Orla Hart and Clair Gardiner; "Tolerosome Induced Oral Tolerance Is MHC Restricted," by Esbjorn telemo, S. Ostman and M. Taube; Others.

Immunosenescence, also known as immune aging, refers to the degeneration, compensation, and reconstruction of the immune system with aging. Immune aging is an important factor in the increased susceptibility of the elderly to infectious diseases, malignant tumors, and a variety of chronic diseases and has long been a hotspot in geriatrics and immunology research. In this paper, the characteristics and progression of immune aging are briefly reviewed for clinicians' reference. [ABSTRACT FROM AUTHOR]

The colon is the largest compartment of the immune system, with innate immune cells exposed to antigens in the environment. However, the mechanisms by which the innate immune system is instigated are poorly defined in colorectal cancer (CRC). Here, a population of CD16+ neutrophils that specifically accumulate in CRC tumor tissues by imaging mass cytometry (IMC), immune fluorescence, and flow cytometry, which demonstrated pro‐tumor activity by disturbing natural killer (NK) cells are identified. It is found that these CD16+ neutrophils possess abnormal cholesterol accumulation due to activation of the CD16/TAK1/NF‐κB axis, which upregulates scavenger receptors for cholesterol intake including CD36 and LRP1. Consequently, these region‐specific CD16+ neutrophils not only competitively inhibit cholesterol intake of NK cells, which interrupts NK lipid raft formation and blocks their antitumor signaling but also release neutrophil extracellular traps (NETs) to induce the death of NK cells. Furthermore, CD16‐knockout reverses the pro‐tumor activity of neutrophils and restored NK cell cytotoxicity. Collectively, the findings suggest that CRC region‐specific CD16+ neutrophils can be a diagnostic marker and potential therapeutic target for CRC. [ABSTRACT FROM AUTHOR]

Posttranslational modifications play a crucial role in governing cellular functions and protein behavior. Researchers have implicated dysregulated posttranslational modifications in protein misfolding, which results in cytotoxicity, particularly in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease. These aberrant posttranslational modifications cause proteins to gather in certain parts of the brain that are linked to the development of the diseases. This leads to neuronal dysfunction and the start of neurodegenerative disease symptoms. Cognitive decline and neurological impairments commonly manifest in neurodegenerative disease patients, underscoring the urgency of comprehending the posttranslational modifications' impact on protein function for targeted therapeutic interventions. This review elucidates the critical link between neurodegenerative diseases and specific posttranslational modifications, focusing on Tau, APP, α‐synuclein, Huntingtin protein, Parkin, DJ‐1, and Drp1. By delineating the prominent aberrant posttranslational modifications within Alzheimer disease, Parkinson disease, and Huntington disease, the review underscores the significance of understanding the interplay among these modifications. Emphasizing 10 key abnormal posttranslational modifications, this study aims to provide a comprehensive framework for investigating neurodegenerative diseases holistically. The insights presented herein shed light on potential therapeutic avenues aimed at modulating posttranslational modifications to mitigate protein aggregation and retard neurodegenerative disease progression. [ABSTRACT FROM AUTHOR]

Immune dysregulation is a pivotal factor in the onset and progression of various diseases. In cancer, the immune system's inability to discern and eliminate abnormal cells leads to uncontrolled tumor growth. When faced with resilient pathogens or harmful toxins, the immune system encounters challenges in clearance and neutralization. Achieving a delicate balance of pro‐inflammatory and anti‐inflammatory signals is essential in managing a range of disorders and diseases. Like in other biomedical research domains, nanotechnology has provided innovative approaches for rebalancing host immunity. Among the plethora of nanotechnology‐based interventions, the concept of cell membrane‐coated nanoparticles holds significant potential for immunomodulatory applications owing to their biomimetic properties that allow for precise interaction with the compromised immune system. This review thoroughly examines the potential of novel nanosystems for immune modulation. The exploration covers crucial elements, including the origins and characteristics of cell membranes, the methods employed for their procurement and coating, physicochemical/biological characterization techniques, and enhancement of their therapeutic efficacy via functionalization. Subsequently, case studies‐based analysis of utilizing these bioinspired nanosystems in tackling different conditions caused by immune disturbance has been comprehensively discussed. [ABSTRACT FROM AUTHOR]

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Regulatory T cells (Tregs) are essential for maintaining immune homeostasis by serving as negative regulators of adaptive immune system effector cell responses. Reduced production or function of Tregs has been implicated in several human autoimmune diseases. The cytokine interleukin 2 plays a central role in promoting Treg differentiation, survival, and function in vivo and may therefore have therapeutic benefits for autoimmune diseases. mRNA‐6231 is an investigational, lipid nanoparticle‐encapsulated, mRNA‐based therapy that encodes a modified human interleukin 2 mutein fused to human serum albumin (HSA‐IL2m). Herein, we report the development of a semi‐mechanistic kinetic‐pharmacodynamic model to quantify the relationship between subcutaneous dose(s) of mRNA‐6231, HSA‐IL2m protein expression, and Treg expansion in nonhuman primates. The nonclinical kinetic‐pharmacodynamic model was extrapolated to humans using allometric scaling principles and the physiological basis of pharmacological mechanisms to predict the clinical response to therapy a priori. Model‐based simulations were used to inform the dose selection and design of the first‐in‐human clinical study (NCT04916431). The modeling approach used to predict human responses was validated when data became available from the phase I clinical study. This validation indicates that the approach is valuable in informing clinical decision‐making. [ABSTRACT FROM AUTHOR]

Despite being some of the most anecdotally well‐known roads to pathogenesis, the mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation of the cellular immune system and the characteristic development of autoantibodies have been linked to oxidative stress. Typical clinical manifestations, such as joint swelling and deformities and inflammation of the skin and internal organs, have also been connected directly or indirectly to redox mechanisms. The differences in generation and restraint of oxidative stress provide compelling evidence for the broad variety in pathology among rheumatic diseases and explain some of the common triggers and discordant manifestations in these diseases. Growing evidence of redox mechanisms in pathogenesis has provided a broad array of new potential therapeutic targets. Here, we explore the mechanisms by which oxidative stress is generated, explore its roles in autoimmunity and end‐organ damage, and discuss how individual rheumatic diseases exhibit unique features that offer targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

As the penetration of wind generation increases, the uncertainty it brings has imposed great challenges to power system operation. To cope with the challenges, tremendous research work has been conducted, among which two aspects are of most importance, that is, making immune operation strategies and accessing the power system's capability to accommodate the variable energy. Driven and inspired by the latter problem, this paper will discuss the power system's capability to accommodate variable wind generation in a probability sense. Wind generation, along with its uncertainty is illustrated by a polyhedron, which contains prediction, risk, and uncertainty information. Then, a three-level optimisation problem is presented to estimate the lower probability bound of power system's capability to fully accommodate wind generation. After reformulating the inner max-min problem, or feasibility check problem, into its equivalent mixed-integer linear program (MILP) form, the bisection algorithm is presented to solve this challenging problem. Modified IEEE systems are adopted to show the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

Osteoporosis disease is caused by hormonal changes, vitamin D, and calcium deficiency. With current technologies, the identification of osteoporosis requires many tests with the support of medications. Bone mineral density is a typical measure implemented using a DEXA scan which can be very costly. Such high technology equipment is usually not accessible for remote people, and thus a low‐cost screening system is very appealing. This article proposes an osteoporosis prediction system that effectively determines its possibility of occurrence based on essential factors such as smoking habits and calcium level so that the people at high risk can be referred to access the DEXA scanner. Our proposed system is implemented by an improved version of the artificial immune system, enabling care providers to take precautionary measures at the right time to avoid the early development of osteoporosis. The experiments demonstrated a promising result of 94% prediction accuracy that proved its usefulness in identifying people with potential osteoporosis in the future. [ABSTRACT FROM AUTHOR]

Summary: Plants have evolved a multi‐layered immune system to fight off pathogens. However, immune activation is costly and is often associated with growth and development penalty. In crops, yield is the main breeding target and is usually affected by high disease resistance. Therefore, proper balance between growth and defence is critical for achieving efficient crop improvement. This review highlights recent advances in attempts designed to alleviate the trade‐offs between growth and disease resistance in crops mediated by resistance (R) genes, susceptibility (S) genes and pleiotropic genes. We also provide an update on strategies for optimizing the growth–defence trade‐offs to breed future crops with desirable disease resistance and high yield. [ABSTRACT FROM AUTHOR]

Some biological phenomena offer clues to solving real-life, complex problems. Researchers have been studying techniques such as neural networks and genetic algorithms for computational intelligence and their applications to such complex problems. The problem of security management is one of the major concerns in the development of eBusiness services and networks. Recent incidents have shown that the perpetrators of cybercrimes are using increasingly sophisticated methods. Hence, it is necessary to investigate non-traditional mechanisms, such as biological techniques, to manage the security of evolving eBusiness networks and services. Towards this end, this paper investigates the use of an Artificial Immune System (AIS). The AIS emulates the mechanism of human immune systems that save human bodies from complex natural biological attacks. The paper discusses the use of AIS on one aspect of security management, viz. the detection of credit card fraud. The solution is illustrated with a case study on the management of frauds in credit card transactions, although this technique may be used in a range of security management applications in eBusiness. [ABSTRACT FROM AUTHOR]

The primary objective of this meta‐analysis was to provide the comprehensive understanding of the intricate correlation that existed between immune senescence and its effects on the advancement of lung cancer as well as recovery of cutaneous wounds. By conducting this systematic review of six rigorous studies utilizing databases such as PubMed and Web of Science, this research examined the multitude of facets pertaining to immune aging and consequences it bear on the health outcomes. The incorporated studies encompassed wide range of geographical and methodological viewpoints, with the specific emphasis on non‐small‐cell lung cancer and diverse scenarios related to wound recovery. This analysis synthesized discoveries regarding therapeutic responses, cellular and molecular mechanisms and impact of lifestyle factors on immune senescence. The findings suggested that immune senescence has substantial impact on the effectiveness of treatments for lung cancer and cutaneous wounds healing process; therefore, targeted therapies and holistic approaches may be able to mitigate these effects. By following the revised PRISMA guidelines, this meta‐analysis guarantee thorough and ethically sound methodology for amalgamating pre‐existing literature. The study concluded by emphasizing the critical nature of comprehending immune senescence in the context of clinical practice and proposed avenues for further investigation to enhance health results among the elderly. [ABSTRACT FROM AUTHOR]

Innate immune adaptor proteins are critical components of the innate immune system that propagate pro‐inflammatory responses from their upstream receptors, and lead to pathogen clearance from the host. Bacterial pathogens have developed strategies to survive inside host cells without triggering the innate immune surveillance in ways that are still not fully understood. Here, it is reported that Pseudomonas aeruginosa induces its quorum sensing mechanism after macrophage engulfment. Further investigation of its secretome identified a quorum sensing regulated product, LasB, is responsible for innate immune suppression depending on the MyD88‐mediated signaling. Moreover, it is showed that this specific type of pathogen‐mediated innate immune suppression is due to the enzymatic digestion of the death domains of the innate immune adaptors, mainly MyD88, and attributed to LasB's large substrate binding groove. Lastly, it is demonstrated that the secretion of LasB from P. aeruginosa directly contributed to MyD88 degradation within macrophages. Hence, it is discovered an example of bacterial quorum sensing‐regulated cellular innate immune suppression by direct cleavage of immune adaptors. [ABSTRACT FROM AUTHOR]

Clinical pharmaceutical trials aimed at modulating the immune system in Alzheimer's Disease have largely focused on either dampening down central proinflammatory innate immunity or have manipulated adaptive immunity to facilitate the removal of centrally deposited beta amyloid. To date, these trials have had mixed clinical therapeutic effects. However, a number of clinical studies have demonstrated disturbances of both systemic and central innate immunity in Alzheimer's Disease and attention has been drawn to the close communication pathways between central and systemic immunity. This paper highlights the need to take into account the potential systemic effects of drugs aimed at modulating central immunity and the possibility of developing novel therapeutic approaches based on the manipulation of systemic immunity and its communication with the central nervous system., (© 2011 Blackwell Publishing Ltd.)

We are frequently exposed to potentially harmful microbes of various types on a daily basis. Our immune system is an amazing collection of unique organs and cells that defends us from hazardous germs as well as certain diseases. It plays a crucial role in protecting the body against external invaders, including bacteria, viruses, and parasites. Maintaining a healthy immune system requires consuming a balanced diet that provides a variety of macro‐ and micronutrients. By consuming sufficient amounts of water, minerals such as zinc and magnesium, micronutrients, herbs, and foods rich in vitamins C, D, and E, and adopting a healthy lifestyle, one can enhance their health and immunity, and prevent infections. This article provides a comprehensive review of the scientific literature on common foods known for their potential to boost human immunity. The review begins by discussing the various components of the immune system and their functions. It then delves into the current understanding of how nutrition can influence immune response, highlighting the importance of a well‐balanced diet in supporting optimal immune function. The article presents an extensive analysis of a range of common foods that have been studied for their immune‐boosting properties. These foods include fruits, vegetables, whole grains, and animal‐based foods. Each food category is explored in terms of its specific nutrients and bioactive compounds that contribute to immune support. Foods such as milk, eggs, fruits, leafy greens, and spices like onion, garlic, and turmeric contain beneficial compounds that can enhance the immune system's function, activate and inhibit immune cells, and interfere with multiple pathways that eventually lead to improved immune responses and defense. The available literature on the issue was accessed via online resources and evaluated thoroughly as a methodology for preparing this manuscript. [ABSTRACT FROM AUTHOR]

Intestinal flora is very important for improving the development of the immune system in newborns. Maternal diet during pregnancy and lactation is one of the key factors affecting the growth and development of offspring. The objective of the present study was to examine whether supplementation of maternal diet with milk oligosaccharides and Bifidobacterium could influence the development of the intestinal flora and immune system of neonatal mice. In total, 30 pregnant Institute of Cancer Research (ICR) mice were randomly divided into six groups: a control group (basal diet) and five intervention groups (basal diet supplemented with different doses of 2′‐fucosyllactose [2′‐FL] and Bifidobacterium Bb12) during the pregnancy period. All female mice were monitored for physical health during gavage. After delivery, the number of mice in each litter, any deformity, and the development of the offspring were recorded. The spleen, blood, and fecal samples of six groups of 10–12 day‐old offspring were collected. The results demonstrated that maternal milk oligosaccharides and probiotics conferred protective effects against lipopolysaccharide (LPS)‐induced immunosuppression in mice offspring by significantly enhancing the immune organ indexes, splenocyte proliferation, immunoglobulin (immunoglobulin G, A, M) production as well as improving the macrophage phagocytosis (p <.05). The abundance of Lactobacilli and Bifidobacteria in the feces of offspring mice in the intervention groups was significantly higher than that of the offspring mice in the control group (p <.05). These findings suggest that the combination of 2′‐FL and Bifidobacterium Bb12 displayed synergistic interactions between the two components that could promote the development of the immune system of the offsprings and improve their microbiota through maternal ingestion. [ABSTRACT FROM AUTHOR]

Bacterial or fungal membrane vesicles, traditionally considered as microbial metabolic wastes, are secreted mainly from the outer membrane or cell membrane of microorganisms. However, recent studies have shown that these vesicles play essential roles in direct or indirect communications among microorganisms and between microorganisms and hosts. This review aims to provide an updated understanding of the physiological functions and emerging applications of bacterial membrane vesicles, with a focus on their biogenesis, mechanisms of adsorption and invasion into host cells, immune stimulatory effects, and roles in the much‐concerned problem of bacterial resistance. Additionally, the potential applications of these vesicles as biomarkers, vaccine candidates, and drug delivery platforms are discussed. [ABSTRACT FROM AUTHOR]

Background and Aims: The global Coronavirus‐2 outbreak has emerged as a significant threat to majority of individuals around the world. The most effective solution for addressing this viral outbreak is through vaccination. Simultaneously, the virus's mutation capabilities pose a potential risk to the effectiveness of both vaccines and, in certain instances, newly developed drugs. Conversely, the human body's immune system exhibits a robust ability to combat viral outbreaks with substantial confidence, as evidenced by the ratio of fatalities to affected individuals worldwide. Hence, an alternative strategy to mitigate this pandemic could involve enhancing the immune system's resilience. Methods: The research objective of the review is to acquire a comprehensive understanding of the role of inflammation and immunity in COVID‐19. The pertinent literature concerning immune system functions, the impact of inflammation against viruses like SARS‐CoV‐2, and the connection between nutritional interventions, inflammation, and immunity was systematically explored. Results: Enhancing immune function involves mitigating the impact of key factors that negatively influence the immune response. Strengthening the immune system against emerging diseases can be achieved through nonpharmaceutical measures such as maintaining a balanced nutrition, engaging in regular exercise, ensuring adequate sleep, and managing stress. Conclusion: This review aims to convey the significance of and provide recommendations for immune‐strengthening strategies amidst the ongoing COVID‐19 pandemic. Key points: Coronavirus‐2 outbreak is a global threat.Human immune system has the potential to fight against viral outbreaks effectively.Virus's mutation can reduce the efficacy of vaccines and drugs.Minimizing factors that adversely affect the immune response can improve immunity.The immune‐strengthening strategies are important during the COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • P2X7 receptors are involved in the production of pro-inflammatory cytokines, such as Il-1β, by central and peripheral immune cells. Il-1β has been implicated as an important mediator of inflammation. Therefore, the P2X7 receptor is an attractive therapeutic target for inflammatory diseases. WHAT THIS STUDY ADDS • Findings in pharmacokinetics, pharmacodynamics, safety and tolerability of a P2X7 receptor modulator, GSK1482160, from the first human study for the molecule are described. A pharmacokinetic/pharmacodynamic model for LPS-stimulated ATP-induced Il-1β production in blood allowed the integration of all relevant data and provided in vivo evidence of the nature of the drug-receptor interaction. The model has the potential to be used to simulate future trials. AIMS This paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. METHODS Escalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1β production in blood were evaluated. RESULTS Drug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1β as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study ( n= 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose. CONCLUSION The model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Squires et al. (2012) Influenza research database: an integrated bioinformatics resource for influenza research and surveillance. Influenza and Other Respiratory Viruses 6(6), 404-416. Background The recent emergence of the 2009 pandemic influenza A/H1N1 virus has highlighted the value of free and open access to influenza virus genome sequence data integrated with information about other important virus characteristics. Design The Influenza Research Database (IRD, http://www.fludb.org) is a free, open, publicly-accessible resource funded by the U.S. National Institute of Allergy and Infectious Diseases through the Bioinformatics Resource Centers program. IRD provides a comprehensive, integrated database and analysis resource for influenza sequence, surveillance, and research data, including user-friendly interfaces for data retrieval, visualization and comparative genomics analysis, together with personal log in-protected 'workbench' spaces for saving data sets and analysis results. IRD integrates genomic, proteomic, immune epitope, and surveillance data from a variety of sources, including public databases, computational algorithms, external research groups, and the scientific literature. Results To demonstrate the utility of the data and analysis tools available in IRD, two scientific use cases are presented. A comparison of hemagglutinin sequence conservation and epitope coverage information revealed highly conserved protein regions that can be recognized by the human adaptive immune system as possible targets for inducing cross-protective immunity. Phylogenetic and geospatial analysis of sequences from wild bird surveillance samples revealed a possible evolutionary connection between influenza virus from Delaware Bay shorebirds and Alberta ducks. Conclusions The IRD provides a wealth of integrated data and information about influenza virus to support research of the genetic determinants dictating virus pathogenicity, host range restriction and transmission, and to facilitate development of vaccines, diagnostics, and therapeutics. [ABSTRACT FROM AUTHOR]

CCL25/TECK and CCL28/MEC are CC chemokines primarily expressed in thymic dendritic cells and mucosal epithelial cells. The cognate receptors of CCL25 and CCL28, CCR9 and CCR10, respectively, are mainly expressed on T and B lymphocytes. In human, mouse and pig, CCL25 and CCL28 play a key role in the segregation and the compartmentalization of the mucosal immune system through recruitment of immune cells to specific locations. However, little is known about their role in the ontogeny of the mucosal immune system during fetal development. In the present paper, we report the cloning and the sequencing of ovine CCL25, CCL28, CCR9 and CCR10 and the subsequent assessment of their mRNA expression by q-polymerase chain reaction in several tissues, including thymus, gut-associated lymphoid tissue and mammary gland, from young and adult sheep and in the fetal lamb during the development of the immune system. CCL25 mRNA was highly expressed in thymus and gut while CCL28 mRNA was more expressed in large intestine, trachea, tonsils and mammary gland, especially at the end of gestation. These results are consistent with observations in other species suggesting similar roles for these chemokines in sheep. In fetuses, mRNA of CCL25, CCL28 and their receptors are expressed early in the thymus and mucosal tissues, including the small intestine and the nasal mucosa. Furthermore, their expression increased towards the end of gestation. Consequently, we hypothesize that CCL25 and CCL28 play an important role in the lymphocyte colonization of fetal tissues, enabling the development of a functional immune system. [ABSTRACT FROM AUTHOR]

Increasing attention is being given to the use of adult rather than embryonic stem cells, both for research and for the development of transplantation treatments for human disease. In particular, mesenchymal bone marrow stem cells have been studied extensively because of their ability to self-renew and to give rise to various differentiated cell types, and because of the relative ease with which they can be obtained and cultured. In addition, the possibility of labelling stem cells with green fluorescent protein before transplantation has opened new and promising perspectives for their use in basic research. Because no structural or ultrastructural description of adult mesenchymal stem cells is available in the literature, this paper describes their morphology as revealed by light, confocal and electron microscopy, focusing on cells that are particularly suitable for transplantation studies, i.e. those derived from rat bone marrow transfected with green fluorescent protein. The results provide a basis for experimental studies of the differentiation of these cells in normal and pathological tissues. [ABSTRACT FROM AUTHOR]

Blalock JE (University of Alabama, Birmingham, USA). The immune system as the sixth sense (Minisymposium).J Intern Med2005;257:126–138.One of the truly remarkable discoveries in modern biology is the finding that the nervous system and immune system use a common chemical language for intra- and inter-system communication. This review will discuss some of the pivotal results that deciphered this chemical language. Specifically the nervous and immune systems produce a common set of peptide and nonpeptide neurotransmitters and cytokines that act on a common repertoire of receptors in the two systems. The paper will also review more recent studies that have delineated hardwired and humoral pathways for such bidirectional communication. This is discussed in the context of the idea that the sharing of ligands and receptors allows the immune system to serve as the sixth sense that notifies the nervous system of the presence of entities, such as viruses and bacteria, that are imperceptible to the classic senses. Lastly, this review will suggest ways to apply the newfound knowledge of the sixth sense to understand a placebo effect and to treate human disease. [ABSTRACT FROM AUTHOR]

Cellular senescence is a cell surveillance mechanism that arrests the cell cycle in damaged cells. The senescent phenotype can spread from cell to cell through paracrine and juxtacrine signalling, but the dynamics of this process are not well understood. Although senescent cells are important in ageing, wound healing and cancer, it is unclear how the spread of senescence is contained in senescent lesions. In the absence of the immune system, senescence could theoretically spread infinitely from one cell to another, but this contradicts experimental evidence. To investigate this issue, we developed both a minimal mathematical model and a stochastic simulation of senescence spread. Our results suggest that differences in the number of signalling molecules secreted between subtypes of senescent cells can limit the spread of senescence. We found that dynamic, time‐dependent paracrine signalling prevents the uncontrolled spread of senescence, and we demonstrate how model parameters can be determined using Bayesian inference in a proposed experiment. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) is the predominant mycotoxin that originated toxicity in broilers through oxidative damage, intestinal barrier dysfunction, reduced immune system and dysfunction of microorganisms and enzymes in target organs. The intestine is the first AFB1 target organ destroyed after the bird's body is induced. This review summarises the current knowledge of the negative results of AFB1‐induced intestinal damage on broiler production. It was conducted in accordance with the relevant studies in the cited literatures being retrieved from PubMed, Google Scholar, Science Direct and Web of Science. First, AFB1 can change the intestinal barrier function by destroying the intestinal architecture, tissue and cell integrity of the gut epithelium. Second, AFB1 can damage the immune barrier function of the gastrointestinal mucosa. Third, the microbiota of birds interacts closely with the ingested aflatoxin. Finally, because broilers are tremendously sensitive to AFB1 contamination, the poisonous and noxious effects of this mycotoxin in the broiler industry cause millions of dollars in losses every year. This review briefly discussed that the AFB1, which affects the intestines of broiler chickens, was reduced the immune apparatus, antioxidant protection system, gastric system, and broiler production status and its impact on human health. Therefore, this review will improve our perception of the important intestine in a bird's health and the adverse effect of AFB1. [ABSTRACT FROM AUTHOR]

With increasing rates of cesarean section worldwide and international guidelines advising pre‐incision antibiotics, neonatal exposure to pre‐birth antibiotics is higher than ever before. Emerging evidence has raised concern regarding the impact of such antibiotics on the neonatal intestinal microbiota, immune system development and health conditions later in life. This narrative review investigates current protocols for intrapartum prophylactic antibiotics in cesarean section, how this and other factors may affect the neonatal intestinal microbiota and whether intrapartum antibiotics used for cesarean section are linked to the development of allergic disease. [ABSTRACT FROM AUTHOR]

SUMMARY: Plant cells possess a two‐layered immune system consisting of pattern‐triggered immunity (PTI) and effector‐triggered immunity (ETI), mediated by cell surface pattern‐recognition receptors and intracellular nucleotide‐binding leucine‐rich repeat receptors (NLRs), respectively. The CONSTITUTIVE EXPRESSION OF PR GENES 5 (CPR5) nuclear pore complex protein negatively regulates ETI, including ETI‐associated hypersensitive response. Here, we show that CPR5 is essential for the activation of various PTI responses in Arabidopsis, such as resistance to the non‐adapted bacterium Pseudomonas syringae pv. tomato DC3000 hrcC‐. In a forward‐genetic screen for suppressors of cpr5, we identified the mediator protein MED4. Mutation of MED4 in cpr5 greatly restored the defective PTI of cpr5. Our findings reveal that CPR5 plays opposite roles in regulating PTI and ETI, and genetically regulates PTI via MED4. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID‐19) pandemic increased food insecurity among US households, however, little is known about how infants, who rely primarily on human milk and/or infant formula, were impacted. We conducted an online survey with US caregivers of infants under 2 years of age (N = 319) to assess how the COVID‐19 pandemic impacted breastfeeding, formula‐feeding and household ability to obtain infant‐feeding supplies and lactation support (68% mothers; 66% White; 8% living in poverty). We found that 31% of families who used infant formula indicated that they experienced various challenges in obtaining infant formula, citing the following top three reasons: the formula was sold out (20%), they had to travel to multiple stores (21%) or formula was too expensive (8%). In response, 33% of families who used formula reported resorting to deleterious formula‐feeding practices such as diluting formula with extra water (11%) or cereal (10%), preparing smaller bottles (8%) or saving leftover mixed bottles for later (11%). Of the families who fed infants human milk, 53% reported feeding changes directly as a result of the pandemic, for example, 46% increased their provisioning of human milk due to perceived benefits for the infant's immune system (37%), ability to work remotely/stay home (31%), concerns about money (9%) or formula shortages (8%). Fifteen percent of families who fed human milk reported that they did not receive the lactation support they needed and 4.8% stopped breastfeeding. To protect infant food and nutrition security, our results underscore the need for policies to support breastfeeding and ensure equitable and reliable access to infant formula. Key messages: One in three families who fed infants formula reported using one or more deleterious formula‐feeding practices during the coronavirus disease 2019 pandemic, likely due to formula shortages and financial strain.Of the families who fed infants human milk, 15% reported difficulties accessing lactation support directly as a result of the pandemic, although 46% of families reported increased provision of human milk.Flexible government programmes and policies are needed to ensure equitable access to lactation support and infant formula during crises. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a complex process of gathering sub-endothelial plaques decreasing lumen of the blood vessels. This disorder affects people of all ages, but its progression is asymptomatic for many years. It is regulated by many typical and atypical factors including the immune system response, a chronic kidney disease, a diet rich in lipids, a local inflammatory process and a local oxidative stress that is here one of the key factors. In this study, a Petri net model of atherosclerosis regulation is presented. This model includes also some information about stoichiometric relationships between its components and covers all mentioned factors. For the model, a structural analysis based on invariants was made and biological conclusions are presented. Since the model contains inhibitor arcs, a heuristic method for analysis of such cases is presented. This method can be used to extend the concept of feasible t-invariants. [ABSTRACT FROM AUTHOR]

The thoracic duct or efferent prescapular duct was cannulated in four fetal calves aged 121-259 days post-conception. The duration of lymph flow ranged from 2 to 20 days and the mean flow rates sustained over these collection periods varied from 54 to 488 ml/hr. Lymphocyte output ranged from 44 × 106 cells/hr in thoracic duct lymph from a 121-day fetus to 3.9 × 108 cells/hr in efferent prescapular lymph from a 259-day fetus. The circulating lymphocyte pool in fetal calves of about 120 and 190 days gestational age was calculated to contain, respectively, 4 × 108 cells and 2 × 1010 cells. The proportion of lymphocytes bearing surface immunoglobulin detected in fetal lymph ranged from 2.1% to 8.7%. Recirculating lymphocytes from fetal calves produced strong proliferative responses when stimulated by T-cell mitogens but responded poorly to B-cell mitogens. Fetal lymphocytes also responded to stimulation by allogeneic cells and stimulated other cells to proliferate during mixed lymphocyte culture. When stimulated with Con A, fetal lymphocytes secreted IL-2 to a degree that was indistinguishable from the secretory behaviour of lymphocytes from adult animals. The results presented in this paper show that chronic lymphatic fistulae can be established successfully in fetal calves to give access to recirculating lymphocytes. This provides a new experimental approach for studying the development of the bovine immune system. [ABSTRACT FROM AUTHOR]

In this paper we describe production of alloantisera specific for determinants encoded by I-J gene loci expressed on macrophages. B10.A(3R) (l-Jb) mice were hyperimmunized with pure populations of macrophages grown in vitro from bone marrow stem cells of congenic B10.A(5R) mice. The antisera contained predominantly IgM antibody that was non-adherent to protein-A-Sepharose with a minor component of IgGI, and IgG2a antibodies that were adherent to protein.A-Sepharose. The protein- A non-adherent antibody completely blocked the in vitro generation of humoral immune responses to sheep erythrocytes by spleen cell from B10.A(5R) mice and from inbred strains that share the I-Jk haplotypes, but did not alter the responses of spleen cells of the I-Jb haplotype. In the presence of complement. both protein-A adherent and protein-A non-adherent antibodies eliminated the capacity of B10.A(5R) spleen cells to generate humoral and proliferative responses, but the functional activity of B10.A(3R) cells was unaffected. These data indicate the I-Jk specificity of the antisera. The capacity of the anti-macrophage antibody to block humoral immune induction was removed by absorption with bone marrow-derived macrophages from B10.A(5R) mice, but not from B10.A(3R) mice. Further, the B10.A(5R) macrophages completely restored the humoral responses of antibody- and complement-treated B10.A(5R) spleen cells, but B10.A(3R) macrophages showed only partial restoration that was consistent with a factor-mediated allogeneic effect. These data demonstrate the specificity of our anti-I-J sera for macrophages and indicate that bone marrow-derived macrophages express surface I-J encoded molecules. [ABSTRACT FROM AUTHOR]

This paper describes the induction of delayed-type hypersensitivity (DH) in the mouse and guinea-pig to haptenated liposomes. The tripeptide- enlarged hapten 3-(p-azobenzenearsonate)-N-acetyl- L-tyrosylglycylglycine (A) was coupled to phosphatidylethanolamine (PE) and incorporated into liposomal membranes (A PE-liposomes). In mice DH was measured as footpad swelling and in guinea pigs by skin testing. To induce hapten A-specific DH in mice with A-PE- liposomes the application of the cationic, surface- active lipid, dimethyl dioctadecyl ammonium bromide (DDA) was necessary. The use of Freund's complete adjuvant (FCA) did not result in the induction of DH to hapten A. In guinea-pigs, however, FCA and DDA had equally good adjuvant properties in the induction of DH. The time course of the DH and the optimal time interval between immunization and elicitation were determined for the mouse system. Also, the effect of dose and epitope density was studied in that system. Cyclophosphamide treatment, before immunizing mice with A-PE-liposomes and DDA, resulted in greatly impaired DH, probably caused by the short lifetime of the integrity of liposomes after intracutaneous administration to mice. The results make it very likely that presentation of hapten A in a liposomal or micellar structure is required to induce a cellular immune response to this hapten in mice. [ABSTRACT FROM AUTHOR]

In the present paper it is shown that the non-species specific determinant of the antigenic thymus-brain system previously detected in murine and human brain also exists in human thymus. However, in contrast to the situation in mice and rats this antigenic structure is not expressed on suspended thymic lymphocytes, but is associated with thymic tissue largely depleted of thymic lymphocytes. Moreover, this determinant is also detectable in human lymph nodes. Besides the non-species-specific antigenic determinant human thymus and brain also share a species-specific determinant. In contrast to the non species specific determinant this structure is also displayed by suspended thymic lymphocytes, certain peripheral blood lymphocytes and bone marrow cells. The non-species-specific determinant detected in human thymus is borne by a structure, which physico-chemically resembles the thymus-brain antigen isolated from murine brain and thymus as well as from human brain. Although the structure bearing the species specific antigenic determinant has a similar apparent molecular weight both antigens could be separated by ion exchange chromatography indicating their molecular diversity. [ABSTRACT FROM AUTHOR]

Mouse bone marrow is capable of a distinct plaque-forming cell (PFC) response after i.v. immunization with the thymus-independent antigen E. coli lipopolysaccharide (LPS). Both during the primary and secondary response to i.v. administered LPS the spleen contained the majority of PFC until about 5 days after immunization. In the course of the reaction the number of PFC in the bone marrow rose to a level which surpassed the level in the spleen. This paper deals with the regulating influence of the spleen on the primary and secondary anti-LPS PFC response in the bone marrow. Splenectomy prior to the first injection of 5 μg LPS i.v. initially did not affect the bone marrow PFC response. However, at the 7th day after immunization the PFC response in the bone marrow fell to only 10 per cent of the bone marrow PFC activity in sham-splenectomized mice. In contrast to the primary response no regulating influence of the spleen on the bone marrow PFC activity could be demonstrated during the secondary response. The influence of splenectomy on the appearance of B-memory cells in the bone marrow depended on the priming dose. The appearance of LPS-specific B-memory cells in the bone marrow was not affected by splenectomy at priming doses of LPS as high as 1 and 0.1 μg. On the other hand splenectomy before 0.01 μg LPS i.v. reduced, and splenectomy prior to 0.001 μg LPS i.v. completely prevented the appearance of B-memory cells in the bone marrow. [ABSTRACT FROM AUTHOR]

This work concerns the involvement of brown adipose tissue in the immune system of the rat. Wistar rats were thymectomized, adipectomized (surgical extirpation of the interscapular brown adipose tissue), thymectornited and adipectomized, and. sham,operated at birth, only 8-week-old females being employed in the experiment The production of antibody to bovine serum albumin (BSA). and sheep red blood cells (SRBC), delayed skin reactions to BSA, rejection of thyroid allograft implanted under the kidney capsule, and development of experimental allergic encephalomyelitis were investigated. Neonatal adipectomy did not affect the production of anti-BSA and anti-SRBC antibodies. On the other hand, delayed skin reactions to BSA, rejection of thyroid allograft, and incidence and severity of allergic encephalomyelitis were much more pronounced In adipectomized animals. It has been postulated that the immune function of brown adipose tissue is an expression of the secretory activity of the tissue. Since the immunosuppressive effect of neonatal thymectomy on demyelinating disease was neutralized by neonatal adipectomy, and vice versa, and since thymectomy rendered ineffective the immunopotentiating influence of adipectomy on this disease, as demonstrated in thymo-adipectomized rats, it was concluded that the brown adipose tissue is a natural antagonist of the thymus in cell-mediated immunity. This paper also describes the extra thymuses which were situated in the vicinity of the thyroid and parathyroid lobes of 23.2 per cent of rats. [ABSTRACT FROM AUTHOR]

A mean of 6.9 per cent of small lymphocytes in peripheral blood preparations and between 1.8 and 2.4 per cent of small lymphocytes in lymph node, spleen, bone marrow and thymus preparations from unimmunized guinea-pigs bound 125I-labelled purified protein derivative of mammalian tuberculin (mammalian PPD). The percentage of these cells fluctuated but did not alter substantially after immunization with BCG or with BCG emulsified with human thyroglobulin (HTg) in Freund's incomplete adjuvant (FIA). Blocking experiments indicated that the binding of 125I-labelled mammalian PPD was specific and there was tentative evidence that the lymphocyte receptors may be IgG. A comparison is drawn between the observed time course of 125I-labelled mammalian PPD- binding small lymphocytes and the response of lymphocytes sensitive to strong histocompatibility antigens, and it is proposed that the propensity of certain anti- gens to induce a delayed hypersensitivity-type response is related to the presence of substantial numbers of antigen-binding cells in unimmunized animals. A noteworthy incidental finding was an unexplained depression in the cellular and humoral responses to mammalian PPD in guinea-pigs that had been immunized with HTg-BCG-FIA emulsion. [ABSTRACT FROM AUTHOR]

Oestrogen (E2) has been suggested to be responsible for the female preponderance for systemic lupus erythematosus (SLE) and for exacerbations of disease during pregnancy. In lupus-prone (NZB × NZW) F1 (NZB/W) mice, sex hormones also influence disease progression, thus long-term treatment of NZB/W mice with high doses oloestradiol increases the mortality in immune-complex mediated disease. We have previously demonstrated that E2 suppression of delayed-type hypersensitivity (DTH) to oxazolone (OXA) in NZB/W mice is inherited from the healthy NZW (H-2i) and not from the autoimmune NZB (H-2d) parental strain. In this paper we have analysed the influence of E2 on DTH and antibody responses to OXA in backcrosses of NZB/W mice and the NZB and NZW parental strains. Suppressed DTH was found in 15/16(94%) of female (NZB/W × NZW) F1 (NZB/ W/W) mice treated with E2. In contrast, only 32/63 (51%) of (NZB/W × NZB)F1 (NZB/W/B) mice treated with E2 displayed suppressed DTH reactivity. These two findings are compatible with a single, rather than multiple, dominant gene inherited from the NZW strain encoding for E2-mediated suppression of DTH in NZB/W mice. FACS analysis, using a monoclonal antibody recognizing the H.2z but not the H-2d locus, identified the H-2 expression (H-2dd and Hdz) of the NZB/W/B backerosses and revealed that E2 suppression of DTI-I is not linked to the H-2 haplotype of the backcrosses. Furthermore, E2 treatment of NZB/W/W mice, but not of NZB/W/B mice, significantly enhanced the serum levels of anti-OXA antibodies of both IgG and IgM classes. Based on our results it is tempting to speculate whether similar genetic factors for E2 sensitivity of the immune system may be of importance for the female predominance of human SLE. [ABSTRACT FROM AUTHOR]

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an essential component of the innate immune system and is central to the identification of abnormal DNA leakage caused by ionising radiation (IR) damage. Cell‐intrinsic cGAS–STING initiation has been revealed to have tremendous potential for facilitating interferon synthesis and T‐cell priming. Targeting the cGAS–STING axis has been proposed as a strategy to improve radiosensitivity or enhance immunosurveillance. However, due to the complex biology of the irradiated tumour microenvironment and the extensive involvement of the cGAS–STING pathway in various physiological and pathological processes, many defects in this strategy limit the therapeutic effect. Here, we outline the molecular mechanisms by which IR activates the cGAS–STING pathway and analyse the dichotomous roles of the cGAS–STING pathway in modulating cancer immunity after radiotherapy (RT). Then, based on the crosstalk between the cGAS–STING pathway and other signalling events induced by IR, such as necroptosis, autophagy and other cellular effects, we discuss the immunomodulatory actions of the broad cGAS–STING signalling network in RT and their potential therapeutic applications. Finally, recent advances in combination therapeutic strategies targeting cGAS–STING in RT are explored. [ABSTRACT FROM AUTHOR]

Background: To date, it is unknown why some individuals develop late‐onset inflammatory adverse events after treatment with fillers. These events may result from various factors, including an immunological response of the adaptive immune system. Objective: In a pilot study, we looked for evidence that is there a relation between late‐onset inflammatory adverse events and the presence of immune cells surrounding the injected filler. Methods and Materials: We included 47 patients, of whom 20 experienced late‐onset inflammatory adverse events to different fillers (inflammatory group) and 27 who did not (reference group). A biopsy was taken from the area of the adverse event. Hematoxylin–eosin staining and immunohistochemistry analysis with CD3 (T‐cells) and CD68 (macrophages) on paraffin tissue sections was used to assess the biopsies. Results: Immune cells were found in biopsies obtained from 18 of 47 patients: Nine biopsies from the inflammation group and nine from the reference group. All these 18 cases showed CD68‐positive immune cells. Virtually no CD3‐positive immune cells were found. Conclusion: Our results indicate that there is no T‐cell activity in biopsies from areas with late‐onset adverse events after filler injections. The macrophages found in the biopsies are probably not responsible for the inflammatory response. [ABSTRACT FROM AUTHOR]

Gram‐negative bacteria form spherical blebs on their cell periphery, which later dissociate from the bacterial cell wall to form extracellular vesicles. These nano scale structures, known as outer membrane vesicles (OMVs), have been shown to promote infection and disease and can induce typical immune outputs in both mammal and plant hosts. To better understand the broad transcriptional change plants undergo following exposure to OMVs, we treated Arabidopsis thaliana (Arabidopsis) seedlings with OMVs purified from the Gram‐negative plant pathogenic bacterium Xanthomonas campestris pv. campestris and performed RNA‐seq analysis on OMV‐ and mock‐treated plants at 2, 6 and 24 h post challenge. The most pronounced transcriptional shift occurred at the first two time points tested, as reflected by the number of differentially expressed genes and the average fold change. OMVs induce a major transcriptional shift towards immune system activation, upregulating a multitude of immune‐related pathways including a variety of immune receptors. Comparing the response of Arabidopsis to OMVs and to purified elicitors, revealed that OMVs induce a similar suite of genes and pathways as single elicitors, however, pathways activated by OMVs and not by other elicitors were detected. Pretreating Arabidopsis plants with OMVs and subsequently infecting with a bacterial pathogen led to a significant reduction in pathogen growth. Mutations in the plant elongation factor receptor (EFR), flagellin receptor (FLS2), or the brassinosteroid‐insensitive 1–associated kinase (BAK1) co‐receptor, did not significantly affect the immune priming effect of OMVs. All together these results show that OMVs induce a broad transcriptional shift in Arabidopsis leading to upregulation of multiple immune pathways, and that this transcriptional change may facilitate resistance to bacterial infection. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a complex systemic catabolism syndrome characterized by muscle wasting. It affects multiple distant organs and their crosstalk with cancer constitute cancer cachexia environment. During the occurrence and progression of cancer cachexia, interactions of aberrant organs with cancer cells or other organs in a cancer cachexia environment initiate a cascade of stress reactions and destroy multiple organs including the liver, heart, pancreas, intestine, brain, bone, and spleen in metabolism, neural, and immune homeostasis. The role of involved organs turned from inhibiting tumor growth into promoting cancer cachexia in cancer progression. In this review, we depicted the complicated relationship of cancer cachexia with the metabolism, neural, and immune homeostasis imbalance in multiple organs in a cancer cachexia environment and summarized the treatment progress in recent years. And we discussed the molecular mechanism and clinical study of cancer cachexia from the perspective of multiple organs metabolic, neurological, and immunological abnormalities. Updated understanding of cancer cachexia might facilitate the exploration of biomarkers and novel therapeutic targets of cancer cachexia. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that resolution of inflammation is a critical and dynamic endogenous process for host tissues defending against external invasive pathogens or internal tissue injury. It has long been known that autoimmune diseases and chronic inflammatory disorders are characterized by dysregulated immune responses, leading to excessive and uncontrol tissue inflammation. The dysregulation of epigenetic alterations including DNA methylation, posttranslational modifications to histone proteins, and noncoding RNA expression has been implicated in a host of inflammatory disorders and the immune system. The inflammatory response is considered as a critical trigger of epigenetic alterations that in turn intercede inflammatory actions. Thus, understanding the molecular mechanism that dictates the outcome of targeting epigenetic regulators for inflammatory disease is required for inflammation resolution. In this article, we elucidate the critical role of the nuclear factor‐κB signaling pathway, JAK/STAT signaling pathway, and the NLRP3 inflammasome in chronic inflammatory diseases. And we formulate the relationship between inflammation, coronavirus disease 2019, and human cancers. Additionally, we review the mechanism of epigenetic modifications involved in inflammation and innate immune cells. All that matters is that we propose and discuss the rejuvenation potential of interventions that target epigenetic regulators and regulatory mechanisms for chronic inflammation‐associated diseases to improve therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Background: So far, limited studies have focused on the role of Macrophages (MQs) in the development or progression of celiac disease (CD). Researchers believe that increasing knowledge about the function of MQs in inflammatory disorders plays a critical role in finding a new treatment for these kinds of diseases. Main body: CD is a permanent autoimmune intestinal disorder triggered by gluten exposure in predisposed individuals. This disorder happens due to the loss of intestinal epithelial barrier integrity characterized by dysregulated innate and adaptive immune responses. MQs are known as key players of the innate immune system that link innate and adaptive immunity. MQs of human intestinal lamina propria participate in maintaining tissue homeostasis, and also intestinal inflammation development. Previous studies suggested that gliadin triggers a proinflammatory phenotype (M1 MQ) in human primary MQs. Moreover, M2‐related immunosuppressive mediators are also present in CD. In fact, CD patients present an impaired transition from pro‐inflammatory to anti‐inflammatory responses due to inappropriate responses to gliadin peptides. Conclusion: The M1/M2 MQs polarization balancing regulators can be considered novel therapeutic targets for celiac disease. [ABSTRACT FROM AUTHOR]

Objective: Podcasts are increasingly utilized as educational tools within emergency medicine (EM). As EM residency programs seek to incorporate asynchronous educational material, it is important to ensure we are covering the full breadth of EM core content. This study sought to describe the distribution of EM core content among three popular EM podcasts. Methods: We performed a retrospective study of the distribution of podcast topics among three popular EM podcasts from July 2011 to June 2021. We evaluated the podcast episode content and alignment with the EM core content, as defined by the Model of the Clinical Practice of Emergency Medicine (MCPEM) and American Board of Emergency Medicine (ABEM) examination distribution. Data are presented descriptively. Results: We identified 2759 podcast episodes, consisting of 7413 total topics and 2498.7 hours of content. The most frequently covered topics were "signs, symptoms, and presentations" (20.1% of total hours vs. 7.9% of MCPEM and 10.0% of ABEM exam) and "procedures and skills integral to the practice of emergency medicine" (14.8% of total hours vs. 8.1% of MCPEM and 8.0% of ABEM exam). The least frequently covered topics was were "immune system disorders"(0.5% of total hours vs. 2.0% of MCPEM and 2.0% of ABEM exam),"environmental disorders"(0.8% of total hours vs. 2.4% of MCPEM and 2.0% of ABEM exam), "obstetrics and gynecology" (1.0% of total hours vs. 5.4% of MCPEM and 3.0% of ABEM exam), and "cutaneous disorders" (0.9% of total hours vs. 4.3% of MCPEM and 3.0% of ABEM exam). Conclusions: Our findings suggest an imbalance of MCPEM core content in three popular EM podcasts. [ABSTRACT FROM AUTHOR]

Immunoprotection and oxygen supply are vital in implementing a cell therapy for type 1 diabetes (T1D). Without these features, the transplanted islet cell clusters will be rejected by the host immune system, and necrosis will occur due to hypoxia. The use of anti‐rejection drugs can help protect the transplanted cells from the immune system; yet, they also may have severe side effects. Cell delivery systems (CDS) have been developed for islet transplantation to avoid using immunosuppressants. CDS provide physical barriers to reduce the immune response and chemical coatings to reduce host fibrotic reaction. In some CDS, there is architecture to support vascularization, which enhances oxygen exchange. In this review, we discuss the current clinical and preclinical studies using CDS without immunosuppression as a cell therapy for T1D. We find that though CDS have been demonstrated for their ability to support immunoisolation of the grafted cells, their functionality has not been fully optimized. Current advanced methods in clinical trials demonstrate the systems are partly functional, physically complicated to implement or inefficient. However, modifications are being made to overcome these issues. [ABSTRACT FROM AUTHOR]

Vaccination is one of the greatest achievements in biomedical research preventing death and morbidity in many infectious diseases through the induction of pathogen‐specific humoral and cellular immune responses. Currently, no effective vaccines are available for pathogens with a highly variable antigenic load, such as the human immunodeficiency virus or to induce cellular T‐cell immunity in the fight against cancer. The recent SARS‐CoV‐2 outbreak has reinforced the relevance of designing smart therapeutic vaccine modalities to ensure public health. Indeed, academic and private companies have ongoing joint efforts to develop novel vaccine prototypes for this virus. Many pathogens are covered by a dense glycan‐coat, which form an attractive target for vaccine development. Moreover, many tumor types are characterized by altered glycosylation profiles that are known as "tumor‐associated carbohydrate antigens". Unfortunately, glycans do not provoke a vigorous immune response and generally serve as T‐cell‐independent antigens, not eliciting protective immunoglobulin G responses nor inducing immunological memory. A close and continuous crosstalk between glycochemists and glycoimmunologists is essential for the successful development of efficient immune modulators. It is clear that this is a key point for the discovery of novel approaches, which could significantly improve our understanding of the immune system. In this review, we discuss the latest advancements in development of vaccines against glycan epitopes to gain selective immune responses and to provide an overview on the role of different immunogenic constructs in improving glycovaccine efficacy. [ABSTRACT FROM AUTHOR]

Extracellular communication is critical to the function of an organism. Exosomes, small lipid extracellular vesicles, have been recently appreciated to participate in this vital function. Within these vesicles lie critical bioactive molecules including mRNAs, proteins, and a plethora of noncoding RNAs, including microRNAs (miRNAs). Exosomal miRNAs have been shown to be produced by, trafficked between, and function in many distinct donor and recipient cell types, including cells of the immune system. For instance, loss of these critical communicators can alter the cellular response to endotoxin, and when tumor cells lose the ability to secrete these vesicles, the immune system is able to effectively suppress tumor growth. This review will highlight key findings on the known communication to and from the immune system, highlighting exosomal miRNA research in macrophages, dendritic cells, B lymphocytes, and T cells. Additionally, we will focus on three major areas of exosomal studies that involve immune responses including mucosal barriers, adipose tissue, and the tumor microenvironment. These environments are heterogeneous and dynamic, and rapidly respond to the microbiota, metabolic shifts, and immunotherapies, respectively. It is clear that exosomal miRNAs play pivotal roles in regulating cross‐talk between cells in these tissues, and this represents a novel layer of cellular communication proving critical in human health and disease. [ABSTRACT FROM AUTHOR]