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Intracranial hematomas (IHs) occur commonly after severe traumatic brain injury, but their effects on outcomes in patients with prolonged disorders of consciousness (DoC) following coma (i.e., unresponsive wakefulness syndrome and minimally conscious state) are unknown.In this multicenter longitudinal study, we compared clinical outcomes and serum neurofilament light chain (NFL) levels of 52 patients with traumatic DoC with (n = 35) and without (n = 17) IH in the acute phase. Patients were evaluated with the Coma Recovery Scale-Revised (CRS-R) at enrollment (1-3 months post-injury) and with the CRS-R, extended Glasgow Outcome Scale (GOSE), and Functional Independence Measure (FIM) at 6 months post-injury. At the same timepoints, serum NFL levels were compared between patients with and without IHs and with those of 52 sex- and age-matched healthy controls.Patients with and without IH did not differ in terms of DoC or CRS-R scores at admission, or clinical outcomes (death, unresponsive wakefulness syndrome, minimally conscious state, or emergence from minimally conscious state) or CRS-R, GOSE, or FIM scores 6 months post-injury. NFL levels were significantly higher in patients than in controls at admission and 6 months post-injury (both p 0.0001), but they did not differ between patients with and without IH.This study showed that IHs do not affect clinical outcomes or markers of axonal degeneration in patients with traumatic DoC.

Growing evidence suggests that pathophysiological mechanisms leading to neurodegeneration and neuronal loss take place during the chronic phase of a severe traumatic brain injury (TBI). In this study we evaluated a well-established marker of brain injury, the neuron-specific enolase (NSE), in the serum of 51 patients with severe TBI (86% males, mean age 33.8 ± 11.1 years). All patients' samples were available from a previous study and the mean time between TBI and blood sample collection was 23.2 ± 31.5 months (28 patients were evaluated within 12 months of TBI and 23 patients were evaluated ≥12 months after TBI). Patients' NSE levels were compared with those obtained from 30 age and sex-matched healthy controls (87% males, 33.7 ± 11.3 years). We found that NSE levels were significantly lower in patients (median 3.2 ng/mL; 25th, 75th percentile 2.5, 5.1) than in healthy controls (median 4.1 ng/mL; 25th, 75th percentile 3.1, 7.5) (

The mechanisms involved in secondary brain injury after the acute phase of severe traumatic brain injury (TBI) are largely unknown. Ongoing axonal degeneration, consequent to the initial trauma, may lead to secondary brain injury. To test this hypothesis, we evaluated the cerebrospinal fluid (CSF) level of neurofilament light chain (NF-L), a proposed marker of axonal degeneration, in 10 patients who developed a severe disorder of consciousness after a TBI, including 7 in a minimally conscious state and 3 with unresponsive wakefulness syndrome (time since brain injury, 309 ± 169 days). CSF NF-L level was measured with a commercially available NF-L enzyme-linked immunosorbent assay. CSF NF-L level was very high in all 10 patients, ranging from 2.4- to 60.5-fold the upper normal limit (median value, 4458 pg/mL; range, 695-23,000). Moreover, NF-L level was significantly higher after a severe TBI than in a reference group of 9 patients with probable Alzheimer's disease, a population with elevated levels of CSF NF-L attributed to neuronal degeneration (median value, 1173 pg/mL; range, 670-3643; p 0.01). CSF NF-L level was correlated with time post-TBI (p = 0.04). These results demonstrate prolonged secondary brain injury, suggesting that patients exhibit ongoing axonal degeneration up to 19 months after a severe TBI.

Background: Traumatic brain injury (TBI) is a major risk factor for Alzheimer’s disease (AD). Although the mechanisms that lead to AD after a TBI are unclear, we hypothesize that changes in amyloid-β (Aβ) metabolism and abnormal tau phosphorylation are reasonable candidates.Objective: To investigate Aβ and tau dynamics in the chronic phase of TBI.Methods: We evaluated Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) levels in the cerebrospinal fluid (CSF) of 15 patients who developed a prolonged disorder of consciousness after a severe TBI (mean time from TBI 271.6 ± 176.5 days).Results: Reduced Aβ1-42 levels (median 258 pg/ml, range 90–833.6) were observed in 14/15 patients (93.3%) with severe post-TBI disorders of consciousness. These CSF analysis data did not correlate with time since TBI or with the patients’ level of consciousness as determined by the Coma Recovery Scale Revised. Normal t-tau levels (median 95.2 pg/ml, range 52–256.9) were found in all patients. Normal p-tau levels (...

Traumatic brain injury (TBI) is a major risk factor for Alzheimer's disease. Recent studies suggest that amyloid-beta (Aβ) deposit can be detected several years after TBI. However, it is unknown whether post-TBI Aβ deposits arise from short-term changes in Aβ metabolism or reflect a long-term sequela. To answer this question, we evaluated the cerebrospinal levels of Aβ several months after a severe TBI. The participants of this study were eight consecutive patients who developed a disorder of consciousness after a TBI, including seven in a minimally conscious state and one with unresponsive wakefulness syndrome (mean age: 35.4±14.2 years, mean time since brain injury 297.9±189.8 days). Cerebrospinal Aβ1-42 peptide was measured using a commercially available Aβ enzyme-linked immunoassay kit. Reduced Aβ1-42 levels were observed in seven of eight (87.5%) patients with severe post-TBI disorders of consciousness, with the magnitude of reduction among these seven patients ranging from 27 to 75.1% of the lower normal limit. These results point to prolonged changes in Aβ metabolism after a TBI and they suggest a potential mechanism of long-term neurotoxicity.

Traumatic brain injury (TBI) is a major risk factor for Alzheimer disease (AD). Although the mechanisms that lead to AD after a TBI are largely unknown, changes in amyloid- β (A β ) metabolism and abnormal tau phosphorylation are probably involved. In this study, we evaluated A β 1 - 42 , total tau (t-tau), and phosphorylated tau (p-tau) levels in the cerebrospinal fluid (CSF) of 15 patients who developed a prolonged disorder of consciousness after a severe TBI (mean time from TBI 271.6 ± 176.5 days; range 92–578 days). Reduced A β 1 - 42 levels (cohort median value 258 pg/ml, range 90–833.6 pg/ml) were observed in 14/15 patients (93.3%) with severe post-TBI disorders of consciousness. Normal t-tau levels (median 95.2 pg/ml, range 52–256.9 pg/ml) were found in all patients. Normal p-tau levels (median 22.2 pg/ml, range 14–72 pg/ml) were observed in 14/15 patients, while 1 patient had a p-tau level slightly increased. In conclusion, the present findings show that reduced CSF A β levels are not paralleled by significant changes in t-tau and p-tau levels; these results suggest that treatments aimed to prevent chronic neurodegeneration and AD risk after a severe TBI may be better targeted on A β than tau.

a Department of Biological Sciences, Wichita State University, Wichita, Kansas, USA b OASI Istituto per la ricerca sul ritardo mentale e l’involuzione cerebrale, Troina, Sicily, Italy c Department of Biopathology and Biomedical Methodology, University of Palermo, Palermo, Sicily, Italy d Department of Psychology, University of Rome, and Fondazione Santa Lucia IRCCS, Rome, Italy e McGill University—Montreal Children’s Hospital Research Institute, Montreal, Que., Canada f Laboratory of Cerebral Metabolism, National Institute of Mental Health, Bethesda, MD, USA

We previously produced evidence that the human mammary-carcinoma cell line 8701-BC expresses several metalloproteinases (MMP-1, -2, -9, and -10) and their tissue inhibitors. In order to obtain a better understanding of the environmental control over gelatinolytic activities, we have tested the enzyme production of 8701-BC cells, at time intervals after plating on different collagen substrates, i.e., types I, III, IV, V and OF/LB, used as films in culture dishes. Proteinase activities, released in the conditioned culture media, were tested by zymography on SDS-PAGE, and by quantificative analyses, using 14C carboxy-methylated transferrin as substrate in a liquid incubation medium. Enzymatic activities varied with time and were inversely related to cell densities, with minimum values at cell confluence. The enzymatic activity was positively supported by collagen substrates, with a maximal increase in activity when OF/LB collagen was used. In addition to the known MMPs, we found a proteinase with an Mr of about 20 kDa, which displayed higher activity at 48 hr after cell plating and gradually decreased with cell increment. In contrast to the other MMPs, this proteinase is inhibited by soybean trypsin inhibitor, but it does not display a complete identity with trypsin, since it does not digest casein and is not inhibited by other serine proteinase inhibitors. © 1995 Wiley-Liss, Inc.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that influences neuronal plasticity throughout life. Emergence from a vegetative state (VS) after a traumatic brain injury (TBI) implies that the brain undergoes plastic changes. A common polymorphism in the BDNF gene—BDNF Val66Met (referred to herein as BDNFMet)—impairs cognitive function in healthy subjects. The aim of this study was to determine whether the BDNFMet polymorphism plays a role in the recovery of consciousness and cognitive functions in patients in a VS after a TBI. Fifty-three patients in a VS 1 month after a TBI were included in the study and genotyped for the BDNFMet polymorphism. Scores of levels of cognitive functioning (LCF) at 1, 3, 6, and 12 months post-TBI were retrospectively compared in patients without (Val group), and with (Met group), the BDNFMet polymorphism. The BDNFMet polymorphism was detected in 20 out of the 53 patients. The mean LCF scores in the Val and Met groups were 1.6 – 0.5 and 1.4 – 0.5 at 1 month, 2.3 – 0.7 and 2.5 – 1.2 at 3 months, 3.3 – 1.7 and 3.5 – 1.7 at 6 months, and 4 – 1.9 and 3.9 – 1.8 at 12 months, respectively ( p > 0.05). The percentages of patients in the Val and Met groups who emerged from the VS were 36.4% and 30% at 3 months, 66.3% and 70% at 6 months, and 70% and 87.5% at 12 months ( p > 0.05), respectively. These findings provide evidence that the BDNFMet polymorphism is not involved in cognitive improvement in patients with a VS following TBI. Future studies should focus on the role of other BDNF polymorphisms in the recovery from a VS.

Aromatic antiepileptic drugs (phenytoin, carbamazepine, oxcarbazepine, and phenobarbital) are frequently associated with cutaneous eruptions. A cell-mediated pathogenic mechanism has been demonstrated in most of such reactions on the basis of positive responses to patch tests and/or lymphocyte transformation tests. Therefore, such tests are useful tools for evaluating anticonvulsant hypersensitivity reactions. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patient's lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in a large percentage of patients with hypersensitivity reactions to aromatic anticonvulsants. Although several hypersensitivity reactions to sequential exposure to more than one aromatic anticonvulsant (i.e., clinical cross-reactivity) have been reported, there are few studies performed with patch tests and/or lymphocyte transformation tests assessing immunologic cross-reactivity, and their data are contradictory. In any case, considering studies performed in samples of at least 10 patients, the immunologic cross-reactivity rate among aromatic anticonvulsants appears to be low. On the other hand, the reported rate of the toxic cross-reactivity (i.e., assessed by lymphocyte toxicity assays) is high. Further in vivo and in vitro studies in large samples of subjects are needed to evaluate cross-reactivity among aromatic anticonvulsants.

PIPERACILLIN (PP) is a wide-spectrum bactericidal ureidopenicillin. There have been a number of reports of cutaneous adverse reactions to PP, particularly in patients affected by cystic fibrosis. A cellmediated immunopathogenic mechanism has been demonstrated (on the basis of patch-test or delayed intradermal-test positivity) in only two cases of maculopapular reactions to PP (1,2). This report describes two cases of cutaneous reactions to PP that appear to have been caused by delayed hypersensitivity. Patient 1: A 38-year-old male immediately after a hemorrhoidectomy had been started on PP (Avocin 4 g/day intramuscularly), and after 6 days of treatment a generalized erythematous rash developed. The antibiotic was discontinued and after 7 days of corticosteroid therapy the skin lesions resolved. Patient 2: This 42-year-old male had undergone surgery for cranial trauma. Avocin (4 g/day intramuscularly) was administered during the postoperative period and a generalized maculopapular rash developed on the fourth day. The drug was then discontinued, and corticosteroid therapy was started. The rash resolved within 10 days, leaving generalized scaling. Neither patient had a personal or family history of allergic diseases. Two and seven months later, respectively, the patients underwent skin tests with penicilloylpolylysine (Allergopen, Reinbeck, Germany), minor determinant mixture (Allergopen), benzylpenicillin (BP), ampicillin (AM), amoxicillin (AX) and PP, as well as cefaclor and ceftriaxone, as previously described (3). AM, AX and PP were used at concentrations of 1 and 20 mg/ml in 0.9% NaCl, cephalosporins at 2 mg/ml. Both patients presented skin-test negativity after 20 min, and delayed intradermal reactions (after 24 h in case 1 and 48 h in case 2) only to AM, AX and PP: erythematous, indurated wheals larger than 10 mm, which began to fade after 72 h. Intradermal tests with PP were negative in 10 healthy control subjects, 4 of whom had previously tolerated PP. Patch tests were done with BP, AM, and AX (5% in petrolatum), as well as with PP, cefaclor and ceftriaxone (200 mg/ml in 0.9% NaCl) as previously described (3). Only those with AM, AX and PP were positive at the 48and 72h readings (patient 1:+++for all haptens; patient 2:+for all haptens). Single-blind challenges with BP (1000 000 IU), ceftriaxone (1 g) and cefaclor (500 mg) were also performed, the first two intramuscularly and the last orally. Increasing doses (0.01, 0.1 and 1.0 of the respective therapeutic doses indicated in parentheses) were administered at 1 week intervals, and were well tolerated. The characteristics of these two cases (i.e., cutaneous reactions appearing more than 48 h after the initiation of therapy, as well as patch-test and delayed intradermal-test positivity) are indicative of delayed hypersensitivity to PP. Patch tests and delayed-reading intradermal tests are a simple and effective means of diagnosing this type of reaction. Both of the previously described subjects displayed allergologic-test negativity to penicillin determinants as well as to AM and AX (1,2). Thus, their reactions were probably caused by a selective sensitization to PP; however, they were not challenged with other blactams to assess such selectivity. Our patients presented positive reactions to AM and AX, as well as to PP, but there were no reactions to penicillin determinants or to cephalosporins. The cross-reactivity between PP and the aminopenicillins may reflect the presence of antigenic structures shared by the side-chains of all three semisynthetic penicillins. However, considering that subjects tolerated cefaclor (an aminocephalosporin which shares the aminobenzyl side chain with AM and AX) recognition of the penicillin thiazolidin ring also appears to be important.

The extracellular matrix (ECM) is known to play an active role in numerous biological processes such as differentiation, apoptosis and cancer. Extensive alterations of epithelial basement membranes and of interstitial ECM are known to occur during the progression of most invasive carcinomas. Collagen, which represents the major component of the interstitial ECM, is primarily involved in the stromal changes at the site of tumor cell invasion. We have previously described the occurrence in breast and colon cancer ECM of an oncofetal form of collagen, characterized by an acidic chain distinct from those of type I and III collagen. In the present paper, we bring evidence that alpha2(I) collagen chains in colon cancer tissues expressing the acidic chains, are either overmodified or absent, both as protein and as regular mRNA transcripts. The results obtained strongly suggest that: i) the disorganisation of the collagen architecture and the phenomenon of fibril dispersion, which accompanies the lysis of basement membrane, is not only due to the enzymatic degradation of the collagen fibres, but presumably also to changes of the collagen molecules deposited in the stroma; ii) the neosynthesis of collagen occurring at tumor-host interface is deeply deregulated, and therefore to be considered the result of altered collagen gene expression correlated with the tumor progression, rather than as a mere defensive reaction of the host cells.

We investigated the mechanisms that regulate the efficacy of agonists in the arginine-vasopressin (AVP)/oxytocin (OT) receptor system. In this paper, we present evidence that AVP, a full agonist of the vasopressin receptors, acts as a partial agonist on the oxytocin receptor. We also found that AVP becomes a full agonist when two aromatic residues of the oxytocin receptor are replaced by the residues present at equivalent positions in the vasopressin receptor subtypes. Our results indicate that these two residues modulate the response of the oxytocin receptor to the partial agonist AVP.

We have recently identified an oncofetal-laminin binding collagen (OF/LB) composed of three alpha chains, with the apparent molecular mass of about 100 kDa each, but bearing different pI. One of the chains appears markedly acidic in a bidimensional electrophoretic system, where the NEPHGE is used as first dimension separating gel, while the two more basic chains have similar migration as alpha 1(III) and alpha 1(I) collagen chains, respectively. Sequence analyses have been performed on CNBr-peptides, derived from pepsinized triple helical molecules and on tryptic fragments obtained after in gel digestion of the acidic band. The research of sequence homology with computerized databases indicated that the acidic chain represents a gene product distinct from either type I, type III and other known collagen chains, while the identity of the other two chains remains to be fully determined.

Human breast and colon carcinoma tissues contain a form of collagen, not described before, composed of alpha 1 chains of similar size (approximately 100 kDa) but different charge. The three constitutive chains, separated by two-dimensional electrophoresis, are a unique acidic component, undetectable in other collagen types, with an apparent isoelectric point of 4-5, and two more basic components displaying the same electrophoretic behavior as alpha 1(III) and alpha 1(I), respectively. The acidic chain is structurally distinct from alpha 1(I) and displays a cyanogen bromide-derived fragment of similar size to CB5(III). This collagen in its native state is resistant to trypsin and metalloproteinase 3, while it is fully degraded by metalloproteinases 1 and 9. Moreover, this collagen appears able to bind to laminin, as tested by affinity chromatography. The biological significance of our data is related to the finding of this collagen form not only in the tumor tissue tested but also in embryonic-fetal tissues (bovine skin and intestine and human umbilical cord). For its peculiar laminin-binding ability and occurrence in tumoral and embryonic-fetal tissues, we propose to temporarily term this new collagen form OF/LB collagen (onco-fetal, laminin-binding collagen). The presence of OF/LB collagen during development and cancer, and its absence in normal adult tissues, make this protein a potential stromal marker of malignancy.

Background A cell-mediated immunopathogenic mechanism has been demonstrated in only a few cases of cutaneous reactions to systemically administered cephalosporins. Objective The aim was to investigate the pathogenic mechanism of a maculopapular rash experienced by a subject during cefazolin therapy. Methods and Results Prick, intradermal, and patch tests were carried out using penicillin determinants, ampicillin, amoxicillin, cefazolin, cephalothin, cefuroxime, ceftazidime, and ceftriaxone. Those tests for penicillin G and its determinants, as well as for ampicillin and amoxicillin, were negative. The patient displayed patch-test and delayed intradermal-test positivity to all the cephalosporins tested. No specific immunoglobulin E antibodies were found for penicillins or cefazolin. The lymphocyte-transformation-test results were negative for all the penicillins tested and showed a positive concentration-effect curve for cefazolin, ceftazidime, and ceftriaxone at concentrations up to 50 μg/mL. At 100 μg/mL the responses decreased with all the cephalosporins tested. Challenges with penicillin G and amoxicillin were well tolerated, but the challenge with cefazolin was positive. Conclusions The data of this case demonstrate delayed hypersensitivity to cefazolin. Patch tests and delayed-reading intradermal tests can be a simple and effective means of diagnosing this type of reaction. Both in vivo and in vitro studies indicate that the responses were directed toward a determinant shared by all cephalosporins, but not by penicillins. The concentration of the cephalosporins used for the in vitro lymphocyte stimulation was critical, because at the concentrations normally used to test other β-lactams the response decreased. This phenomenon may be attributable to an immunosuppressive, rather than toxic, effect.

A patient with maculopapular reactions to iopamidol needed to undergo angiography for a cerebral arteriovenous malformation. In vivo and in vitro tests were performed with ionic and nonionic contrast media, including iopamidol and iobitridol. All results were positive, demonstrating delayed hypersensitivity. The patient received 6-α-methylprednisolone and cyclosporine 1 week before and 2 weeks after four angiograms were obtained with the use of iobitridol, which was well tolerated. © RSNA, 2002