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The purpose of this study was to evaluate the delineation of nerve fiber bundles in the brainstem and optic radiation in infants associated with aging on T1WI, T2WI, and phase difference-enhanced (PADRE) images. We retrospectively reviewed 21 consecutive subjects

In amyotrophic lateral sclerosis (ALS), the "zebra sign" in the precentral gyrus on phase difference enhanced magnetic resonance imaging (PADRE) recently has been reported as a possible imaging biomarker for upper motor neuron (UMN) involvement. A previous study has shown that the "zebra sign" allowed us to differentiate patients with ALS from healthy subjects with excellent accuracy. We validated the usefulness of the sign for differentiating patients with ALS from healthy subjects and investigated whether the "zebra sign" can be observed other neurodegenerative disorders with UMN involvement. The "zebra sign" on PADRE was assessed in 26 patients with ALS, 26 with multiple system atrophy (MSA) and 26 healthy controls, and the sign was observed in 50%, 23%, and no subjects, respectively. ALS patients with the "zebra sign" demonstrated a higher UMN burden score than those without the sign. The "zebra sign" on PADRE is not specific to ALS, also present in MSA, but might reflect the degeneration of the UMN within the motor cortex in neurodegenerative disorders.

BACKGROUND AND PURPOSE: The transmantle sign is a characteristic MR imaging finding often seen in focal cortical dysplasia type IIb. The transmantle sign is typically hyperintense on T2WI and FLAIR and hypointense on T1WI. However, in some cases, it shows T1 high signal. We evaluated the imaging and pathologic findings to identify the causes of the T1 high signal in the transmantle sign. MATERIALS AND METHODS: We retrospectively reviewed the preoperative imaging data of 141 consecutive patients with histologically proved focal cortical dysplasia. We selected 25 patients with focal cortical dysplasia with the transmantle sign and divided them into groups based on the pathologic focal cortical dysplasia subtype and T1 signal of the transmantle sign. We evaluated the clinical, radiologic, and pathologic findings, including the number of balloon cells and dysmorphic neurons and the severity of gliosis or calcifications and compared them among the groups. RESULTS: Nine of the 25 patients had a T1-high-signal transmantle sign; the other 16 patients did not. All 9 patients with a T1-high-signal transmantle sign were diagnosed as type IIb (group A). Of the 16 patients with no T1-high-signal transmantle sign, 13 were diagnosed as having type IIb (group B), and the other 3 patients, as type IIa (group C). The number of balloon cells was significantly higher in group A than in the other groups, but there were no differences regarding dysmorphic neurons, the severity of gliosis, or calcifications. CONCLUSIONS: Approximately 6% (9/141) of this patient series had a T1-high-signal transmantle sign, and all were type IIb. The signal may reflect a rich density of balloon cells. This finding could support the differentiation of subtypes, especially type IIb.

Toxoplasma gondii can develop toxoplasmic encephalitis (TE) in immunodeficient conditions such as AIDS and after organ transplantation. While some cases of TE with malignant lymphoma were reported, these cases occurred immediately after chemotherapy or when their diseases were active. Here we report the first Case of TE that occurred in patient who was in partial remission (PR) of lymphoplasmacytic lymphoma (LPL) for two years. A 76-year-old man was referred to our institute because of disturbance of consciousness, right arm weakness and paresthesia. A computed tomography (CT) scan detected multiple nodules in his brain. Magnetic resonance imaging (MRI) of the head detected multiple gadolinium-enhancing parenchymal lesions with hyperintense signals on T2-and diffusion-weighted images, located in both cerebral and cerebellar hemispheres. Blood test and cerebrospinal fluid (CSF) findings were unremarkable. His rapidly deteriorating consciousness precluded a chance of brain biopsy. Considering the limited efficacy of antimicrobials and the imaging findings that could be compatible with the diagnosis of malignant lymphoma, we suspected central nerve system (CNS) recurrence of LPL. Although chemotherapy was initiated, he died of respiratory failure just after chemotherapy. A pathological autopsy showed his cause of death was TE. To our knowledge, this is the first case of TE in long-term PR of malignant lymphoma. TE should be suspected when patients with malignant lymphoma present unexplained neurologic symptoms regardless of their treatment efficacy of lymphoma. (226/250 words).

Background and purpose Recent studies suggest that the autoantibodies against adrenergic/muscarinic receptors might be one of the causes and potential markers of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The purpose of this study was to investigate the structural network changes related to autoantibody titers against adrenergic/muscarinic receptors in ME/CFS by performing a single-subject gray matter similarity-based structural network analysis. Methods We prospectively examined 89 consecutive right-handed ME/CFS patients who underwent both brain MRI including 3D T1-wighted images and a blood analysis of autoantibodies titers against β1 adrenergic receptor (β1 AdR-Ab), β2 AdR-Ab, M3 acetylcholine receptor (M3 AchR-Ab), and M4 AchR-Ab. Single-subject gray matter similarity-based structural networks were extracted from segmented gray matter images for each patient. We calculated local network properties (betweenness centrality, clustering coefficient, and characteristic path length) and global network properties (normalized path length λ, normalized clustering coefficient γ, and small-world network value δ). We investigated the correlations between the autoantibody titers and regional gray matter/white matter volumes, the local network properties, and the global network properties. Results Betweenness centrality showed a significant positive correlation with β1-AdR-Ab in the right dorsolateral prefrontal cortex. The characteristic path length showed a significant negative correlation with β2-AdR-Ab in the right precentral gyrus. There were no significant correlations between the antibody titers and the regional gray matter/white matter volumes, and the global network properties. Conclusions Our findings suggest that β1 AdR-Ab and β2 AdR-Ab are potential markers of ME/CFS.

Aims: The identification and appropriate management of commercial motor vehicle (CMV) drivers with unrecognized obstructive sleep apnea (OSA) is a major public health concern and priority; OSA among drivers has not been fully investigated in Japan, and a better understanding of this undiagnosed disease is warranted. Therefore, we evaluated the prevalence of OSA and the factors related to apnea–hypopnea index (AHI) in Japanese CMV drivers. Methods: This retrospective study included 1309 Japanese CMV drivers aged 40–69 years. All the subjects received type IV portable sleep monitors (PMs) with Epworth Sleepiness Scale (ESS) and a periodic health check including anthropometrical and laboratory measurements, and a questionnaire of medical history, smoking status, and life style, following which variables related to AHI were analyzed. Results: Of all the subjects, 23.9% had moderate to severe OSA (AHI ≥ 15). Age, body mass index (BMI), LogeHbA1c and diastolic blood pressure (DBP) showed significance with AHI in 1309 subjects. The following factors were found to have significant odds ratio (OR) for AHI of ≥ 15 in 1309 subjects: age, ESS, DBP, and LogeHbA1c. Conclusion: Notably, drivers with undiagnosed OSA exist. In these subjects, AHI was related to obesity, hypertension, and diabetes. For the early diagnosis and intervention of OSA, BMI, blood pressure, and HbA1c measurements may be helpful, particularly for drivers. Furthermore, when performing an objective assessment of the suspected OSA, evaluating these parameters during routine medical check-ups may be useful and feasible in the detection of drivers with latent OSA.

Microarrays containing 45 different lectins were analyzed to identify global changes in the glycosylation of serum glycoproteins from mice exposed to whole-body γ-radiation. The results showed that radiation exposure increased and decreased the relative amounts of α-2,3- and α-2,6-sialic acids, respectively. The expression of α-2,3- and α-2,6-sialyltransferase genes in the liver was analyzed to determine whether changes in their expression were responsible for the sialic acid changes. The increase in α-2,3-sialic acid correlated with St3gal5 upregulation after radiation exposure; however, a decrease in St6gal1 expression was not observed. Analysis of a PCR array of genes expressed in irradiated mouse livers revealed that irradiation did not alter the expression of most of the included genes. These results suggest that glycomic screening of serum glycoproteins using lectin microarrays can be a powerful tool for identifying radiation-induced changes in the post-translational addition of sugar moieties to proteins. In addition, the results indicate that altered sialylation of glycoproteins may be an initial response to acute radiation exposure.

The aim of the current study was to investigate the postoperative changes of high-signal lesions at the surgical margin on serial T2WI/FLAIR images in non-neoplastic patients. Seventy-one postoperative MR images in 27 patients (17 focal cortical dysplasia and 10 hippocampal sclerosis) who underwent surgery for intractable epilepsy were evaluated. T2WI/FLAIR-high-signal lesions in size and shape were visually assessed using a 3-point grading system. Associations of postoperative seizures or electroencephalography(EEG)spikes with advancing grade were also evaluated. As a result, follow-up showed enlarged T2WI/FLAIR-high-signal lesions in 6 of 27 patients (22%). The presence of post-operative seizures or EEG spikes was significantly associated with enlargement of the T2WI/FLAIR-high-signal lesion. Enlargement of the T2WI/FLAIR-high-signal lesion was observed in some non-neoplastic patients, and this finding might be correlated with remnant epileptogenesis.

Extensive large dumbbell-shaped hypoglossal schwannoma is extremely rare, and total resection is nearly impossible. We present a case of a 61-year-old male with a giant-size hypoglossal schwannoma with moderate tongue atrophy. The tumor extended from the enlarged hypoglossal canal to the brainstem intradurally and the high cervical region extradurally. Through the extreme lateral infrajugular transcondylar (ELITE) skull base approach, the tumor was totally removed in a single-stage operation. Single-stage total resection is feasible by an experienced skull base team utilizing transcondylar skull base techniques and high cervical dissection.

There is still no clear guideline for surgical treatment for patients with medically refractory trigeminal neuralgia (TN). When it comes to which surgical treatment to choose, microvascular decompression (MVD) or Gamma Knife surgery (GKS), we should know the long-term outcome of each treatment. We analyzed 179 patients undergoing MVD and 52 patients undergoing GKS followed for 1 year or longer. We evaluated the patient’s neurological status including pain relief, complications and recurrence. Results were assessed with Barrow Neurological Institute (BNI) pain intensity and facial numbness scores. Overall outcomes were compared between the two groups based on pain relief and complications. BNI pain intensity and facial numbness scores at the final visit were significantly lower in the MVD group than in the GKS group (P

The epidemiology of patients with traumatic brain injury (TBI) has changed dramatically over recent decades as a result of rapid advances in aging societies. We assessed the influence of age on outcomes of patients with TBI and sought to identify prognostic factors for in-hospital mortality of TBI among elderly patients.Using a nationwide database, we analyzed data from 5651 patients with TBI. Univariate analysis was conducted to compare patient demographics, neurologic status on admission, radiologic findings, systemic complication rates, length of hospital stay, in-hospital mortality, and home discharge rates between elderly and nonelderly groups. Multivariable analysis was conducted to determine prognostic factors for in-hospital mortality among elderly patients.Overall in-hospital mortality was significantly higher in elderly patients (12.8% vs. 19.3%; P0.001). In-hospital mortality of elderly patients with mild TBI increased significantly at7 days after admission, whereas that of elderly patients with moderate or severe TBI was significantly higher immediately after admission. Age (odds ratio [OR], 1.62; P = 0.024), male sex (OR, 1.30; P = 0.004), Japan Coma Scale score on admission (OR, 5.95, P0.001), and incidence of acute subdural hematoma (OR, 1.89; P0.001) were associated with in-hospital mortality in elderly patients with TBI.Elderly patients with TBI showed significantly higher in-hospital mortality. Delayed increases in in-hospital mortality were observed among elderly patients with mild TBI. Level of consciousness on admission was the strongest predictor of in-hospital mortality among elderly patients.

We used high-performance liquid chromatography to separate urine obtained from whole-body gamma-irradiated mice (4 Gy) before analyzing each fraction with matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry to identify radiation-responsive molecules. We identified two candidates: hepcidin antimicrobial peptide 2 (hepcidin-2) and peptide fragments of kidney androgen-regulated protein (KAP). We observed that peak increases of hepcidin-2 in urine were delayed in a dose-dependent manner (1 Gy and above); however, the amount of KAP peptide fragments showed no correlation with radiation dose. In addition, an increase in hepcidin-2 after exposure to relatively low radiation doses (0.25 and 0.5 Gy, respectively) was biphasic (at 8–48 h and 120–168 h, respectively, after irradiation). The increase in hepcidin-2 paralleled an increase in hepcidin-2 gene (Hamp2) mRNA levels in the liver. These results suggest that radiation exposure directly or indirectly induces urinary excretion of hepcidin-2 at least in part by the upregulation of Hamp2 mRNA in the liver.

Background— The existence of an atypical fast-slow (F/S) atrioventricular nodal reentrant tachycardia (AVNRT) including a superior (sup) pathway with slow conductive properties and an atrial exit near the His bundle has not been confirmed. Methods and Results— We studied 6 women and 2 men (age, 74±7 years) with sup-F/S-AVNRT who underwent successful radiofrequency ablation near the His bundle. Programmed ventricular stimulation induced retrograde conduction over a superior SP with an earliest atrial activation near the His bundle, a mean shortest spike-atrial interval of 378±119 milliseconds, and decremental properties in all patients. sup-F/S-AVNRT was characterized by a long-RP interval; a retrograde atrial activation sequence during tachycardia identical to that over a sup-SP during ventricular pacing; ventriculoatrial dissociation during ventricular overdrive pacing of the tachycardia in 5 patients or atrioventricular block occurring during tachycardia in 3 patients, excluding atrioventricular reentrant tachycardia; termination of the tachycardia by ATP; and a V-A-V activation sequence immediately after ventricular induction or entrainment of the tachycardia, including dual atrial responses in 2 patients. Elimination or modification of retrograde conduction over the sup-SP by ablation near the right perinodal region or from the noncoronary cusp of Valsalva eliminated and confirmed the diagnosis of AVNRT in 4 patients each. Conclusions— sup-F/S-AVNRT is a distinct supraventricular tachycardia, incorporating an SP located above the Koch triangle as the retrograde limb, that can be eliminated by radiofrequency ablation.

Background and purpose Chorea-acanthocytosis is clinically difficult to distinguish from Huntington's disease because these disorders have similar symptoms and MR imaging findings. We evaluated the usefulness of single-case voxel-based morphometry (VBM) analysis for differentiating the two diseases as well as VBM analysis. Materials and methods We examined five genetically proven chorea-acanthocytosis patients and 11 Huntington's disease patients to detect differences in the gray and white matter atrophic pattern by using single-case VBM analysis in each patient and their clinical findings. We also evaluated VBM analysis for a group comparison in both disease and control groups. Results The single-case VBM analysis results demonstrated a gray matter volume loss in caudate nucleus in all 16 patients. A characteristic symmetrical white matter volume loss was detected in globus pallidus, putamen, and thalamus on both sides in all the chorea-acanthocytosis patients, but this pattern of atrophy was not seen in any of the Huntington's disease patients. With the VBM analysis, a significant gray matter volume loss was noted in caudate nucleus on both sides in chorea-acanthocytosis patients compared with Huntington's disease patients, and a more extensive white matter volume loss around the basal ganglia and thalamus was observed in chorea-acanthocytosis patients compared to Huntington's disease patients, consistent with the single-case VBM analysis results. Genetic testing identified two novel pathogenic mutations, exon 1 c.16_22delGTGGTCG and exon 55 c.7736-7739delGAGA in a chorea-acanthocytosis patient. Conclusions Single-case VBM analysis may be useful to differentiate chorea-acanthocytosis from Huntington's disease with a focus on white matter atrophy.

To investigate the effect of saline flush on coronary CT angiography of proximal, middle, and distal coronary artery segments, using 320-row CT, and to compare two injection duration protocols as to amount of contrast in the right heart chambers.This retrospective study was approved by the local ethics committee, and the requirement for informed consent to participate in this study was waived. The final study group included 108 patients who underwent coronary CT angiography. The first 36 patients received contrast medium without saline flush (group 1); the next 36 patients received contrast medium for 14s and saline flush (group 2); the last 36 patients received contrast medium for 12s and saline flush (group 3). The CT number, noise, contrast-to-noise ratio (CNR), and number of segments with a CT number greater than 325 Hounsfield units (HU) were recorded for proximal, middle, and distal segments.The CT numbers and the CNR in groups 2 and 3 were significantly higher than that in group 1 (p0.005); the difference between groups 2 and 3 was not significant. The proportion of segments greater than 325HU improved with saline flush (p0.05), with a larger improvement in the distal segments.Saline flush improves enhancement and CNR of coronary arteries, particularly of distal segments, in coronary CT angiography using 320-row CT. An average contrast medium injection of 44mL was feasible using a saline flush.

The demand for establishment of high-throughput biodosimetric methods is increasing. Our aim in this study was to identify low-molecular-weight urinary radiation-responsive molecules using electrospray ionization Fourier transform mass spectrometry (ESI-FT MS), and our final goal was to develop a sensitive biodosimetry technique that can be applied in the early triage of a radiation emergency medical system. We identified nine metabolites by statistical comparison of mouse urine before and 8 h after irradiation. Time-course analysis showed that, of these metabolites, thymidine and either thymine or imidazoleacetic acid were significantly increased dose-dependently 8 h after radiation exposure; these molecules have already been reported as potential radiation biomarkers. Phenyl glucuronide was significantly decreased 8 h after radiation exposure, irrespective of the dose. Histamine and 1-methylhistamine were newly identified by MS/MS and showed significant, dose-dependent increases 72 h after irradiation. Quantification of 1-methylhistamine by enzyme-linked immunosorbent assay (ELISA) analysis also showed a significant increase 72 h after 4 Gy irradiation. These results suggest that urinary metabolomics screening using ESI-FT MS can be a powerful tool for identifying promising radiation-responsive molecules, and that urinary 1-methylhistamine is a potential radiation-responsive molecule for acute, high-dose exposure.

International audience; Mesio-temporal lobe epilepsy (MTLE), the most common drug-resistant epilepsy syndrome, is characterized by the recurrence of spontaneous focal seizures after a latent period that follows, in most patients, an initial insult during early childhood. Many of the mechanisms that have been associated with the pathophysiology of MTLE are known to be regulated by brain-derived neurotrophic factor (BDNF) in the healthy brain and an excess of this neurotrophin could therefore play a critical role in MTLE development. However, such a function remains controversial as other studies revealed that BDNF could, on the contrary, exert protective effects regarding epilepsy development. In the present study, we further addressed the role of increased BDNF/TrkB signaling on the progressive development of hippocampal seizures in the mouse model of MTLE obtained by intrahippocampal injection of kainate. We show that hippocampal seizures progressively developed in the injected hippocampus during the first two weeks following kainate treatment, within the same time-frame as a long-lasting and significant increase of BDNF expression in dentate granule cells. To determine whether such a BDNF increase could influence hippocampal epileptogenesis via its TrkB receptors, we examined the consequences of (i) increased or (ii) decreased TrkB signaling on epileptogenesis, in transgenic mice overexpressing the (i) TrkB full-length or (ii) truncated TrkB-T1 receptors of BDNF. Epileptogenesis was significantly facilitated in mice with increased TrkB signaling but delayed in mutants with reduced TrkB signaling. In contrast, TrkB signaling did not influence granule cell dispersion, an important feature of this mouse model which is also observed in most MTLE patients. These results suggest that an increase in TrkB signaling, mediated by a long-lasting BDNF overexpression in the hippocampus, promotes epileptogenesis in MTLE.

A rare resected case of hepatocellular carcinoma (HCC) invading the duodenum, the common bile duct (CBD), the gallbladder, and the pancreas is described. A 63-year-old man presented with a painful upper abdominal mass. Radiologic findings showed a 25-cm liver tumor arising from segment IV with an invasive extension to the hepatoduodenal ligament and pancreatoduodenal region, with a single intrahepatic metastasis. The patient successfully underwent a left hepatectomy in conjunction with a pylorus-preserving pancreatoduodenectomy (PD). As an unusual procedure, liver parenchymal transection was followed by PD to explore tumor resectability, because the overhanging liver mass precluded full hepatoduodenal ligament dissection. He was discharged without surgical complications, being free from antianalgesics, which had been used preoperatively. The main tumor was histologically diagnosed to be a poorly differentiated HCC with sarcomatous change invading the duodenum, the CBD, the gallbladder, and the pancreas. Unfortunately, aggressive hepatic and nodal recurrence, which was resistant to salvage chemotherapy, caused the patient's death at 8 months postoperatively. This is the first documented case of HCC with biliopancreatoduodenal invasion resected by hepatopancreatoduodenectomy. Literature review suggests a significant role of resection in selected patients with HCC with contiguous gastrointestinal tract invasion, particularly when the HCCs are naive without any forms of previous treatment. However, further surgical and nonsurgical experience is necessary to determine the oncological validity of aggressive surgery for HCC invading the biliopancreatoduodenal region.

Summary Purpose: Zinc is released in synaptic vesicles with glutamate, and modulates glutamatergic neurotransmission. In brain, the highest amount of zinc, detected by Timm staining, is in the mossy fiber (MF) system in the hippocampus. In the intrahippocampal kainate (KA) mouse model of mesial temporal lobe epilepsy, which is elicited by intrahippocampal KA, prominent MF sprouting develops rapidly within 2 weeks post-KA. However, the intensity of Timm staining is reduced gradually thereafter. The present study is designed to determine the mechanisms underlying this reduction of Timm staining. Methods: The changes in Timm staining, and VGluT1, Synapsin-1, and zinc transporter 3 (ZnT3) immunoreactivity (IR) were examined from 4–56 days post-KA. An analysis of glutamate release in the KA-injected hippocampus was conducted by microdialysis before and during the continuous injection of midazolam (MDZ). Results: At 56 days post-KA, Timm staining disappeared completely, whereas VGluT-1-, Synapsin-1-, and ZnT3-IR were increased in the sprouted MF boutons. However, when the seizures were suppressed by a continuous perfusion of MDZ, the glutamate release in the hippocampus decreased and Timm staining was recovered. Discussion: This study showed that the reduction of Timm staining is the result of decreased zinc content but not the loss of MF itself. The reduction is the result of the enhanced release of zinc relative to storage, and it should facilitate the glutamate excitation that might be related to the epileptogenesis and rapid advancement of the morphologic changes in this model.

International audience; PURPOSE: Granule cell dispersion (GCD) appears as a characteristic morphological feature of the mesial temporal lobe epilepsy (MTLE). It has been suggested that this phenomenon could be due to an increased neurogenesis in the dentate gyrus. However, this hypothesis is still debated and recent clinical and experimental studies have shown that neurogenesis is rather decreased in MTLE. To further determine the role of neural and astroglial cell generation in GCD we examined the consequences of aging and irradiation, which are known to reduce progenitor cells, in a mouse model of MTLE induced by intrahippocampal kainate (KA) injection. METHODS: We injected KA in hippocampus of three different types of mice; (1) young adult, (2) aged, and (3) irradiated mice. Newly generated cells were labeled by Bromodeoxyuridine (BrdU) and were characterized by immunohistochemistry. The extent of GCD was compared among the three animal groups. RESULTS: In young adult mice, BrdU-labeled neurons as well as doublecortin- and NeuroD-positive cells decreased progressively after KA injection whereas BrdU-labeled astrocytes and microglias increased. In aged and irradiated mice, where basal neurogenesis was already strongly reduced, GCD developed after KA injection to the same extent as in young adult mice. However, augmentation of the BrdU-labeled astrocytes after KA was less than 40% in irradiated mice in comparison to young and aged mice. CONCLUSIONS: Our data show that GCD occurs without neurogenesis. Furthermore GCD developed regardless of the degree of astroglial cell proliferation, suggesting that neural stem cell generation is not crucial for GCD.

We report a rare case of an epidermoid cyst originating from an intrapancreatic accessory spleen, in a 40-year-old Japanese man with no clinical symptoms. A cystic tumor in the pancreatic tail was detected incidentally by abdominal ultrasonography. The patient was referred to the KKR Tachikawa Hospital for further examination of the tumor. Preoperative imaging findings suggested that the tumor was an epidermoid cyst originating from an intrapancreatic accessory spleen. On both pre-and post-contrast computed tomography and magnetic resonance images, the solid compartment of the tumor had the same X-ray attenuation and intensity as the spleen. Upon surgical excision, the mass consisted of solid and cystic components that were macroscopically evident on the preoperative images. Microscopic analysis revealed that the solid component was an accessory spleen in the pancreatic tail, whereas the cystic component was lined with stratified epithelium representative of an epidermoid cyst. This is the thirteenth report (in English) of an epidermoid cyst originating from an intrapancreatic accessory spleen, and the first case to be diagnosed prior to surgery.

We proposed [11C]KF18446 as a selective radioligand for mapping the adenosine A2A receptors being highly enriched in the striatum by positron emission tomography (PET). In the present study, we investigated whether [11C]KF18446 PET can detect the change in the striatal adenosine A2A receptors in the rat after unilateral injection of an excitotoxin quinolinic acid into the striatum, a Huntington's disease model, to demonstrate the usefulness of [11C]KF18446. The extent of the striatal lesion was identified based on MRI, to which the PET was co-registered. The binding potential of [11C]KF18446 significantly decreased in the quinolinic acid-lesioned striatum. The decrease was comparable to the decrease in the potential of [11C]raclopride binding to dopamine D2 receptors in the lesioned striatum, but seemed to be larger than the decrease in the potential of [11C]SCH 23390 binding to dopamine D1 receptors. Ex vivo and in vitro autoradiography validated the PET signals. We concluded that [11C]KF18446 PET can detect change in the adenosine A2A receptors in the rat model, and will provide a new diagnostic tool for characterizing post-synaptic striatopallidal neurons in the stratum.

Recent studies in animal models have suggested that the mammalian target of rapamycin (mTOR) signaling pathway is involved in several features of mesio-temporal lobe epilepsy (MTLE), and that its inhibition could have therapeutic interests. However, it remains controversial whether mTOR activation is the cause or the consequence of MTLE. We previously showed in a mouse model of MTLE associated with hippocampal sclerosis that increased neuronal excitability and brain-derived neurotrophic factor (BDNF) overexpression contribute to the development of morphological features of this form of epilepsy. Here, we addressed whether mTOR activation promotes MTLE epileptogenesis via increasing neuronal excitability and/or BDNF expression or rather mediates neuroplasticity associated with hippocampal sclerosis. In mice injected intrahippocampally with kainate (1 nmol), we showed a biphasic increase of phospho-S6 (p-S6) ribosomal protein expression, the downstream product of the mTOR signaling pathway, in the dispersed granule cell layer (GCL) of the dentate gyrus with a second phase lasting up to 6 months. Chronic treatment with rapamycin suppressed p-S6 expression, granule cell dispersion and mossy fiber sprouting, but did not reduce cell loss, BDNF overexpression, glutamic acid decarboxylase (GAD)67 expression or the development of hippocampal paroxysmal discharges. Neuronal inhibition by midazolam (2 × 10 mg/kg, i.p.) abolished the increased expression of p-S6 in the dispersed GCL. Our data suggest that activation of the mTOR signaling pathway results from the increased neuronal excitation that develops in the GCL and may contribute to MTLE morphological changes. However, these data do not support the role of this pathway in the development of MTLE or its inhibition as a therapy for this form of epilepsy.

An 81-year-old man with long RP narrow QRS tachycardia underwent catheter ablation. Ventricular pacing reset the atrial cycle over a retrograde slow pathway, followed by termination of the tachycardia without atrial capture, confirming the diagnosis of fast-slow atrioventricular nodal reentrant tachycardia (AVNRT). The earliest atrial activation during tachycardia was found in the noncoronary sinus of Valsalva, where the first delivery of radiofrequency energy terminated and eliminated the inducibility of the tachycardia, by retrograde conduction block over the slow pathway. This is the first report of a fast-slow AVNRT, with successful ablation of the slow pathway from a noncoronary sinus of Valsalva.

Purpose: To study the changes in the distribution of postsynaptic benzodiazepine (BDZ) and presynaptic adenosine A 1 (AA 1 ) receptors in the superior colliculus (SC) and visual cortex (VC) of rats following monocular enucleation. Methods: The right eyes of 6-week-old Long-Evans rats were enucleated and ex vivo autoradiography was performed on the SC and VC obtained at different times up to 8 weeks after the enucleation. [ 14 C]deoxyglucose was used to detect glucose metabolism, and [ 11 C]flumazenil and [1-methyl- 11 C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine ([ 11 C]MPDX) were used to map BDZ and AA 1 receptors, respectively. The receptor-specific binding for 11 C was determined, and 11 C and 14 C activities were evaluated separately in the same tissue by a double tracing method. Results: The uptake of [ 14 C]deoxyglucose in the SC was depressed immediately after enucleation and gradually recovered. The binding of [ 11 C]flumazenil to BDZ receptors in the contralateral SC was increased at week 2, and then returned to the pre-enucleation levels. The uptake of [ 11 C]MPDX by the AA 1 receptors in the contralateral SC decreased by about 67% on day 5 after enucleation and remained low thereafter. In the contralateral VC, the uptake of [ 14 C]deoxyglucose decreased immediately after the enucleation followed by a gradual recovery, whereas the uptake of [ 11 C]flumazenil and [ 11 C]MPDX was not altered. Conclusions: The axon degeneration related decrease of the AA 1 receptor density resulted in a transient up-regulation of postsynaptic BDZ receptor density in monocularly enucleated adult rats. These results suggest that these radioligands can be used to study the distribution of the postsynaptic BDZ and presynaptic AA 1 receptors in the visual system and can probably be applied to the human visual system for positron emission tomography.

We present here the evidence of molecular and functional expression of LAT1 and LAT2, subunits of the large neutral amino acid transporter system L, in cultured brain capillary endothelial cells of the rat. By means of the RT-PCR method, transcripts of LAT1, LAT2 and heavy chain of 4F2 antigen (4F2hc) were detected in rat primary cultured brain capillary endothelial cells (BCECs) and immortalized subline, RBEC1. The uptake properties of RBEC1, such as [3H]leucine and l-[3H]DOPA uptake, were similar to those of primary cultured BCECs. So, RBEC1 may retain almost native properties of the large neutral amino acid uptake activities. [3H]Leucine uptake by RBEC1 showed two saturable components and the Km values of the high- and low-affinity components were 8.92 ± 3.18 and 119 ± 45 μm, respectively. The Km value of the high-affinity component agreed well with that of LAT1 and the amino acid transport selectivity of RBEC1 was similar to that of LAT1. Therefore, it is suggested that LAT1 is important at the blood-brain barrier of rats. Additionally, the Km value of the low-affinity component was similar to that of LAT2. These observations indicate that LAT1 and LAT2 are involved as transporters for large neutral amino acids at the blood-brain barrier. Additionally, we concluded that RBEC1 is useful as an in-vitro model for evaluation of the pharmacological relevance of system L at the blood-brain barrier.

In rat striata, DOPA released is a causal factor for glutamate release and resultant delayed neuron death by four-vessel occlusion. Nanomolar DOPA cyclohexyl ester (CHE), a potent and relatively stable competitive DOPA antagonist, protects these events. We tried to clarify whether DOPA CHE protects these events in hippocampal CA1 pyramidal cell layers most vulnerable against ischemia. Five to 10 min ischemia caused slight to mild glutamate release in 10 min samples during microdialysis and mild to severe neuron death 96 h after reperfusion. DOPA and dopamine were under assay limit in this design, but were basally detected by 20 min sampling and released by 20 min ischemia. In 10 min samples, intrahippocampal perfusion of 100 nM DOPA CHE 10 min before ischemia for 70 min did not inhibit glutamate release by 10 min ischemia, while it abolished glutamate release and protected delayed neuron death by 5 min ischemia. DOPA CHE is neuroprotective under a mild ischemic condition in rat hippocampus CA1.

We have evaluated the feasibility of using four positron emission tomography (PET) tracers for imaging the globus pallidus by ex vivo autoradiography in rats. The tracers investigated were [11C]KF18446, [11C]SCH 23390 and [11C]raclopride for mapping adenosine A2A, dopamine D1 and dopamine D2 receptors, respectively, and [18F]FDG. The highest uptake by the globus pallidus was found for [11C]SCH 23390, followed by [18F]FDG, [11C]KF18446 and [11C]raclopride. The receptor-specific uptake by the globus pallidus was observed in [11C]KF18446 and [11C]SCH 23390, but not in [11C]raclopride. Uptake ratios of globus pallidus to the striatum for [18F]FDG and [11C]KF18446 were approximately 0.6, which was twice as large as that for [11C]SCH 23390. In a rat model of degeneration of striatopallidal gamma-aminobutyric acid-ergic-enkephalin neurons induced by intrastriatal injection of quinolinic acid, the uptake of [11C]KF18446 by the striatum and globus pallidus was remarkably reduced. To prove the visualization of the globus pallidus by PET with [18F]FDG and [11C]KF18446, PET-MRI registration technique and advances in PET technologies providing high-resolution PET scanner will be required. The metabolic activity of the globus pallidus could then be measured by PET with [18F]FDG, and [11C]KF18446 may be a candidate tracer for imaging the pallidal terminals projecting from the striatum.

In vivo assessment of the adenosine A(2A) receptors localized in the striatum with positron emission tomography (PET) may offers us a new diagnostic tool for neurological disorders. We evaluated the potential of [7-methyl-(11)C](E)-8-(2,3-dimethyl-4-methoxystyryl)-1, 3,7-trimethylxanthine ([(11)C]KF21213) as a PET ligand for mapping adenosine A(2A) receptors in the central nervous system. KF21213 showed a high affinity for the adenosine A(2A) receptors in vitro (Ki = 3.0 nM) and a very low affinity for the A(1) receptors (Ki > 10,000 nM). In mice, the striatal uptake of [(11)C]KF21213 increased for the first 15 min and then gradually decreased, whereas the uptake in the reference regions such as the cortex and cerebellum rapidly decreased. The uptake ratio of striatum to cortex and striatum to cerebellum increased to 8.6 and 10.5, respectively, at 60 min postinjection. The striatal uptake was significantly blocked by co-injection of carrier KF21213 or each of three other A(2A) antagonists, but not by co-injection of A(1) antagonist. The specific uptake was not detected in the cortex or in the cerebellum. Ex vivo autoradiography and PET clearly visualized adenosine A(2A) receptors in the rat striatum. [(11)C]KF21213 was the most selective tracer for mapping adenosine A(2A) in the central nervous system by PET among the tracers proposed to date.

PET assessment of the adenosine A2a receptors localized in the striatum offers us a potential new diagnostic tool for neurological disorders. In the present study, we carried out in vitro receptor autoradiography of a newly developed PET ligand [11C]KF18446 ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthin e) with rat brain sections. [11C]KF18446 showed a high striatum/cortex binding ratio (5.0) and low nonspecific binding (10%), suggesting that [11C]KF18446 has characteristics comparable or slightly superior to [3H]CGS 21680 or [3H]SCH 58261, which are currently available representative A2a receptor ligands. Scatchard analysis indicated a Kd of 9.8 nM and a Bmax of 170 fmol/mm3 tissue in the striatum and a Kd of 16.4 nM and a Bmax of 33 fmol/mm3 tissue in the cortex. Seven xanthine-type and four nonxanthine-type adenosine receptor ligands with an affinity for the adenosine A2a receptors significantly reduced the in vitro binding of [11C]KF18446 to the brain section. The blocking effects were much stronger in the striatum than in the cortex, but did not necessarily parallel their affinity. On the other hand, four xanthine-type ligands and one nonxanthine-type ligand (SCH 58261) of the 11 ligands studied reduced the in vivo uptake of [11C]KF18446 in mice, but other ligands, including A1-selective and nonselective ligands and three nonxanthine-type A2a-selective antagonists did not. We conclude that [11C]KF18446 is a promising adenosine A2a receptor ligand for PET study.

Para-Hisian pacing, a useful method to differentiate conduction over an accessory pathway from conduction over the AV node, is assessed essentially by comparing the timing of local atrial electrograms between His-bundle captured beats and His-bundle noncaptured beats. We describe the case of a patient with a permanent form of junctional reciprocating tachycardia, in whom an atrial double potential was recorded only during the tachycardia at the right posterior septum. During para-Hisian pacing, a morphologic change in the atrial electrogram at the posterior septum was also identified, as well as a change in the retrograde atrial sequence. Since the morphologic change of atrial electrograms during para-Hisian pacing cannot be demonstrated in a patient without an accessory pathway, this new finding could be considered a new additional diagnostic criterion suggesting the presence of an accessory pathway.

Objective To identify target sites for radiofrequency ablation of ventricular tachycardia (VT) by entrainment mapping techniques in patients with arrhythmogenic right ventricular dysplasia. Methods Entrainment mapping and radiofrequency ablation of eight VTs was performed in seven patients. Radiofrequency ablation was applied at 31 reentry circuits sites that were classified based on findings during entrainment. Results By entrainment criteria the 31 sites were classified as: exit sites (n = 12), proximal sites (n = 6), and outer loop sites (n = 13). Radiofrequency current application terminated VT at 7 of 31 sites: 2 of 12 exit sites (17%), 4 of 6 proximal sites (67%), and 1 of 13 outer loop sites (8%). Conclusion Radiofrequency ablation terminated VTs most often at sites proximal to the exit as opposed to outer loop sites and exit sites (P = 0.05). The critical isthmus for ablation of VT in right ventricular dysplasia often may be distant to the exit.

The typical fourth criterion for transient entrainment is defined when both a sudden shortening in conduction interval to and a distinct change in electrogram morphology at a bipolar recording site are demonstrated while performing overdrive pacing of a reentrant tachycardia from a single pacing site at two different constant rates. The purpose of this article was to test the hypothesis that if an intracardiac recording site showing both orthodromic and antidromic capture with entrainment pacing is located suitably distant from the circuit, sudden shortening in conduction interval to that site may occur without any significant change in the bipolar electrogram morphology (i.e., atypical form of the fourth criterion). Atrial overdrive pacing of orthodromic tachycardia was performed in 20 patients with either left anterior (12 patients) or left posterior (8 patients) accessory pathways. We investigated the effects of overdrive pacing from the proximal or distal coronary sinus, specifically effects on the electrogram interval and the electrogram morphology at the right atrial appendage. Overdrive pacing of orthodromic tachycardia from the proximal coronary sinus was performed in 10 of the 12 patients with left anterior accessory pathways; those 10 patients demonstrated the first entrainment criterion at the right atrial appendage site. Overdrive pacing of orthodromic tachycardia at still shorter cycle lengths demonstrated a sudden shortening in conduction interval to the right atrial appendage site. Despite shortening in conduction interval the morphology of the right atrial appendage electrogram was completely or almost identical to that during orthodromic tachycardia, indicating an atypical form of the fourth criterion. This criterion was not demonstrated in patients with left posterior accessory pathways. Thus, atypical fourth entrainment criterion was demonstrated during overdrive pacing of orthodromic tachycardia from the proximal coronary sinus only in patients with left anterior accessory path ways. Demonstration of atypical fourth criterion seems largely dependent on the location of the accessory pathway, the pacing, and the recording sites.

We investigated the effects of KF19514 (5-phenyl-3-(3-pyridyl)methyl-3H-imidazo[4,5-c][1,8]naphthyridin-4 (5H)-one) on bronchoconstriction and allergic inflammation in guinea pigs and on tumor necrosis factor-alpha production in mice. KF19514 inhibited phosphodiesterase 4 (IC50 = 0.40 microM) and phosphodiesterase 1 (IC50 = 0.27 microM) derived from canine tracheal smooth muscles. KF19514 relaxed contracted tracheal smooth muscle and had a potent inhibitory effect on antigen-induced bronchoconstriction (EC50 = 0.058 microM) in vitro. Intravenous administration of KF19514 inhibited histamine-induced bronchoconstriction (ID50 = 2.8 microg/kg i.v.). Moreover, oral administration of KF19514 inhibited anaphylactic bronchoconstriction (ID50 = 0.2 mg/kg p.o.), and eosinophil infiltration in airway stimulated with platelet-activating factor (PAF) or antigen. KF19514 also produced a significant inhibition of tumor necrosis factor-alpha production in mice (ID50 = 0.023 mg/kg p.o.). Finally, KF19514 completely inhibited antigen-induced hyperreactivity at 0.1 mg/kg p.o. These results demonstrate that KF19514 may have efficacy in the treatment of asthma.

To investigate the hypothesis that 5-alpha-reductase inhibitors exert early ameliorative effects on voiding and storage symptoms in men with lower urinary tract symptom-associated benign prostatic hyperplasia.This was a prospective study involving the participation of eight outpatient clinics in Chiba Prefecture, Japan. The patients received dutasteride (0.5 mg) once daily orally for 24 weeks as an add-on to their ongoing therapy with an alpha-1 blocker. The study patients recorded their urinary symptoms every day for 14 days after starting dutasteride. The International Prostate Symptom Score, prostate volume, uroflowmetry results, and residual urine volume were checked at 3 and 6 months after starting dutasteride.A total of eighty-eight patients participated in the present study; 74 were eligible for analysis of the early effects of dutasteride. The median age was 69.6 years (range 54-89), the median prostate volume was 50.3 mL (range 24.7-103.3) and the median International Prostate Symptom Score was 17.6 (range 8-35). The proportion of patients with International Prostate Symptom Score improvements (≥3 points, or ≥25%) or 3 points or more decreased International Prostate Symptom Score were defined effective, 37 (50.0%) and 47 (63.5%) experienced improvement at 1 month after administration, respectively.This is the first prospective clinical study to show the early beneficial effects of 5-alpha-reductase inhibitors for lower urinary tract symptom-associated benign prostatic hyperplasia. Patients with severe symptoms were found to be responsive to dutasteride. The influence of the placebo effect was not denied. Further study is necessary.

Acute myocardial infarction (AMI) remains one of the most serious heart diseases and elucidation of its pathogenesis and advances in treatment strategies have been desired. In 2009, to understand the status of AMI in Fukushima Prefecture for improving treatment outcomes, a new AMI registration survey system was conducted throughout the prefecture. A total of 1,556 cases were registered in the initial 2 years from 2009 to 2010. The hospital-based overall incidence of AMI in Fukushima Prefecture was 37.9 people per population of 100,000 per year. Mortality from AMI within 30 days of onset was 10.2%. We report herein the actual situation of AMI onset and treatment in Fukushima Prefecture based on the initial results of the survey.

A 6-hr continuous infusion of 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenos ine (CGS21680), a selective A2a-adenosine agonist, into the subarachnoid space underlying the ventral surface region of the rostral basal forebrain, which has been defined as the prostaglandin (PG) D2-sensitive sleep-promoting zone, at rates of 0.02, 0.2, 2.0, and 12 pmol/min increased slow-wave sleep (SWS) and paradoxical sleep (PS) in a dose-dependent manner up to 183% and 202% of their respective baseline levels. The increments produced by the infusion of CGS21680 at 0.2 and 2.0 pmol/min were totally diminished when the rats had been pretreated with an i.p. injection of (E)-1,3-dipropyl-7-methyl-8-(3,4-dimethoxystyryl)xanthine (KF17837; 30 mg/kg of body weight), a selective A2-adenosine antagonist. In contrast, the infusion of N6-cyclohexyladenosine (CHA), a selective A1-adenosine agonist, at 2 pmol/min significantly suppressed SWS before causing an increase in SWS, and a decrease in PS was also markedly visible. Essentially the same effects of CGS21680 and CHA were observed when these compounds were administered to the parenchymal region of the rostral basal forebrain through chronically implanted microdialysis probes. Thus, we clearly showed that stimulation of A2a-adenosine receptors in the rostral basal forebrain promotes SWS and PS. Furthermore, i.p. injections of KF17837 at 30 and 100 mg/kg of body weight dose-dependently attenuated the magnitude of the SWS increase produced by the infusion of PGD2 into the subarachnoid space of the sleep-promoting zone, thus indicating that the A2a-adenosine receptors are crucial in the sleep-promoting process triggered by PGD2.

An 11C-labeled selective adenosine A2A antagonist, (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-[11C]-methylxanthine ([11C]KF17837), was prepared by reaction of (E)-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine and [11C]methyl iodide with decay-corrected radiochemical yield of 19-50%, radiochemical purity of99%, sp. act. of 17-100 GBq/mumol and preparation time of 20-25 min. In mice, the myocardium showed the highest (13.4% ID/g) at 5 min after i.v. injection, which decreased gradually with time. The specific myocardial uptake was visualized by gamma-camera. In the brain region the radioactivity level was higher in the A2A receptors-rich striatum than in the cortex and cerebellum. The specific striatal uptake in rats was clearly demonstrated by PET. These results have shown that [11C]KF17837 is a potential PET radioligand for mapping the adenosine A2A receptors in the heart and brain.

A patient with reentrant ventricular tachycardia exhibited both the orthodromic and antidromic resetting responses at a single intracardiac recording site during programmed extrastimulation of ventricular tachycardia. The transition from orthodromic to antidromic resetting with extrastimulation demonstrated a sudden shortening in conduction interval to an electrogram recording site and unexpected identical morphology of the spontaneous and captured electrograms at that site, indicating atypical antidromic resetting. This newly observed resetting phenomenon with programmed extrastimulation suggests that the fourth entrainment criterion with overdrive pacing may likely be demonstrated in an atypical form; that is, a sudden shortening in conduction interval to an electrogram recording site may occur without any significant change in the bipolar electrogram morphology at that site when overdrive pacing is performed during tachycardia from a single pacing site at two different constant rates.

During retrograde conduction through an accessory pathway (AP) or the atrioventricular (AV) node, earlier activation of the distal recording site than a more proximal site of the coronary sinus (CS) generally indicates retrograde conduction via a distally located AP. Thus, after successful ablation of a left-sided AP, if the distal CS recording site is activated earlier than a more proximal site retrogradely, it is considered to suggest-in the absence of His-bundle recording or more frequently in the setting of poor recording of the low septal right atrial electrogram-a conduction via a second AP (located more distally), and not conduction via the AV node. Yet, we hypothesized that retrograde conduction through the AV node may activate the far distal site of the CS (CSD) earlier than a more proximal site, as the anterior atrial wavefront, coming retrogradely from the AV node and traveling along the anterior mitral annulus, could reach the CSD earlier than a more proximal site. To test this we studied 18 patients with intact retrograde conduction via the AV node, but without evidence of an AP. The CSD was recorded by means of a quadripolar catheter (interelectrode distance of 2-5 mm); retrograde activation sequence at the distal (CSD1-2) versus proximal (CSD3-4) bipolar recording site was determined during ventricular stimulation. In 12 of 18 patients the CSD1-2 recording site was activated 5-10 ms earlier than the CSD3-4 recording site, in 3 of 18 patients the CSD1-2 site was activated 5 ms later than the CSD3-4 site; in the remaining 3 patients both recording sites were depolarized simultaneously. The results indicate that the CSD was often depolarized earlier than a more proximal site by impulses that conducted to the atria retrogradely via the AV node while the quadripolar recording catheter was placed at the CSD. This observation, although not well documented previously, suggests that the sequence of retrograde atrial activation in the CS should be studied carefully in consideration of the actual location of the mapping catheter in order to correctly diagnose the presence or absence of conduction via an AP.

PURPOSE The objective of this assessment is to identify prognostic factors of recurrence and disease progression of primary superficial transitional cell carcinoma of the bladder. PATIENTS AND METHODS TUR-Bt was performed in 150 patients with initial superficial bladder cancer, of which pathological diagnosis was pTa or pT1 transitional cell carcinoma. The recurrence and progression free survival was examined. The clinicopathological factors analyzed were as follows: grade, pT, tumor size, tumor number and tumor form. RESULTS Median follow-up period was 39 months (range 3-184). The age distribution was from 25 to 98 years old with the average of 67. The patients were 122 males and 28 females. Recurrence was observed in 72 patients. The 5-year recurrence free rate for all cases were 41.6%. The factors found to be of significance for the prognosis for recurrence were tumor size (1 cm

Evacuated feces after intraperitoneal administration of selective adenosine receptor antagonists were evaluated in rats. The selective adenosine A 1 receptor antagonists, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (100–300 μg/kg i.p.) and ( R )-7,8-dihydro-8-ethyl-2-(3-noradamantyl)-4-propyl-1 H -imidazo[2,1- i ]purin-5(4 H )-one (KF20274) (30–300 μg/kg i.p.), significantly increased defacation, whereas the selective adenosine A 2 receptor antagonist 4-amino-8-chloro-1-phenyl[1,2,4]triazolo[4,3- a ]quinoxaline (CP-66,713) failed to cause a significant increase at up to 10 mg/kg i.p. The defacation caused by DPCPX (100 μg/kg) was markedly alleviated by (2 S )- N 6 -(2- endo -norbornyl)adenosine (( S )-ENBA) (30–300 μg/kg s.c.), a selective adenosine A 1 receptor agonist, but not influenced by 2-[ p -(2-carboxyethyl)phenethylamino]-5′- N -ethylcarboxamidoadenosine (CGS 21680) (30–1000 μg/kg s.c.), a selective adenosine A 2 receptor agonist. These results suggest that endogenous adenosine plays a physiological role in sustained inhibition of defecation via adenosine A 1 receptors.

Objectives. This study attempted to determine the prevalence and electrocardiographic (ECG) lead distribution of T wave “humps” (T2, after an initial T wave peak, T1) among families with long QT syndrome and control subjects.Background. T wave abnormalities have been suggested as another facet of familial long QT syndrome, in addition to prolongation of the rate-corrected QT interval (QTc), that might aid in the diagnosis of affected subjects.Methods. The ECGs from 254 members of 13 families with long QT syndrome (each with two to four generations of affected members) and from 2,948 healthy control subjects (age ≥ 16 years, QTc interval 0.39 to 0.46 s) were collected and analyzed. Tracings from familes with long QT syndrome were read without knowledge of QTc interval or family member status (210 blood relatives and 44 spouses).Results. We found that T2 was present in 53%, 27% and 5% of blood relatives with a “prolonged” (≥ 0.47 s), “borderline” (0.42 to 0.46 s) and “normal” (≤0.41 s) QTc interval, respectively (p < 0.0001), but in only 5% and 0% of spouses with a borderline and normal QTc interval, respectively (p = 0.06 vs. blood relatives). Among blood relatives with T2, the mean [±SD] maximal T1T2 interval was 0.10 ± 0.03 s and correlated with the QTc interval (p < 0.01); a completely distinct U wave was seen in 23%. T2 was confined to leads V2and V3in 10%, whereas V4, V5, V6or a limb lead was involved in 90% of blood relatives with T2. Among blood rotatives with a borderline QTc interval, 50% of those with versus 20% of those without major symptoms manifested T2 in at least one left precordial or limb lead (p = 0.05). A T2 amplitude > 1 mm (grade III) was observed, respectively, in 19%, 6% and 0% of blood relatives with a prolonged, borderline and normal QTc interval with T2 in at least one left precordial or limb lead. Among the 2,948 control subjects, 0.6% exhibited T2 confined to leads V2and V3, and 0.9% had T2 involving one or more left precordial lead (but none of the limb leads). Among 37 asymptomatic adult blood relatives with QTc intervals 0.42 to 0.46 s, T2 was found in left precordial or limb leads in 9 (24%; 5 with limb lead involvement) versus only 1.9% of control subjects with a borderline QTc interval (p < 0.0001).Conclusions. These findings are consistent with the hypothesis that in families with long QT syndrome, T wave humps involving left precordial or (especially) limb leads, even among asymptomatic blood relatives with a borderline QTc interval, suggest the presence of the long QT syndrome trait.

KF17837 is a novel selective adenosine A2A receptor antagonist. Oral administration of KF17837 (2.5, 10.0 and 30.0 mg/kg) significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680 (10 micrograms), in a dose-dependent manner. KF17837 also reduced the catalepsy induced by haloperidol (1 mg/kg i.p.) and by reserpine (5 mg/kg i.p.). These anticataleptic effects were exhibited dose dependently at doses from 0.625 and 2.5 mg/kg p.o., respectively. Moreover, KF17837 (0.625 mg/kg p.o.) potentiated the anticataleptic effects of a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 25 mg/kg i.p.) plus benserazide (6.25 mg/kg i.p.). These results suggested that KF17837 is a centrally active adenosine A2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A2A receptor antagonists. Furthermore, KF17837 may be a useful drug in the treatment of parkinsonism.

To determine the optimal temperature for catheter heat mapping without damaging cardiac tissue, we studied the electrophysiologic and histologic responses of the atrioventricular (AV) conduction system exposed to a specific range of temperatures. In 18 closed-chest dogs, an electrode catheter with a thermistor, tip was positioned transvenously at the AV junction. Radiofrequency current (RFC) was applied in incremental temperature steps until transient 2nd-degree AV block was induced. Catheter tip temperature (CTT) was measured at each step. RFC was immediately discontinued when AV block occurred. AV conduction was evaluated before and 4 weeks after the procedure. Acute transient 2nd-degree AV block was induced in 45 applications, during which the average CTT was 48.7 +/- 2.7 degrees C. In another 40 applications in which 2nd degree AV block was not induced, the average CTT was significantly lower [46.3 +/- 2.5 degrees C] (p0.001). Eleven of 16 dogs showed acute 2nd-degree AV block, but had normal AV conduction at 4 weeks (Group A). In the other 5 dogs, 1st-degree AV block was seen at 4 weeks (Group B). The lowest CTTs in Groups A and B were 45 and 49 degrees C, respectively. Histologic findings in 2 dogs from Group A revealed that 10-15% (by area) of the AV node was fibrotic. These findings suggest that the induction of fully reversible AV block can be achieved by titration of RFC, during the application of RFC to the AV junction. In conclusion, RF energy was used to produce a tip temperature of between 45 degrees C and 49 degrees C, which induced reversible and significant interruption of conduction of in tissue in the AV junction, and presumably also in target sites in clinical RF ablation.

A series of quinolinecarboxylic acid derivatives has been previously described as a new class of 5-HT3 receptor antagonists due to deviation of a carbonyl moiety from the place of an aromatic ring in their minimum-energy conformations. These derivatives were evaluated in a wrap-restraint stress-induced defecation model in rats. Reference compounds, ondansetron (1), granisetron (2), and YM060 (4), potently inhibited a stress-induced increase in stools excreted from fed rats (ID50 = 0.27, 0.12, and 0.0052 mg/kg, po, respectively). However, quinoline derivatives exhibited different activities depending on structural class. 4-Hydroxyquinoline-3-carboxylic acid derivatives 5 and 6a possess high affinity for the 5-HT3 receptor (Ki = 6.1 and 1.5 nM, respectively) and exhibit potent activity in the Bezold-Jarisch (B-J) reflex test (ED50 = 0.0017 and 0.000 10 mg/kg, i.v., respectively), but they did not effectively inhibit the increase in fecal pellet output at the dose of 1 mg/kg, po. On the other hand, most of 1-substituted 2-oxoquinoline-4-carboxylates 10 showed less potent activity in the B-J reflex test than 1 or 2 but inhibited restraint stress-induced defecation more potently than 1 or 2. The ID50 value of endo-8-methyl-8- azabicyclo[3.2.1]oct-3-yl 1-isobutyl-2-oxo-1,2-dihydro-4- quinolinecarboxylate 10e was 0.013 mg/kg, po. With respect to the selected compounds 6a and 10e, effects of 5-HT- and thyrotropin-releasing hormone (TRH)-induced defecation, castor oil-induced diarrhea and wrap-restraint stress-induced colonic propulsion in rats were examined. These 5-HT3 receptor antagonists did not effectively inhibit castor oil-induced diarrhea, which has been reported not to be mediated via the 5-HT3 receptor. Although 10e showed 800-fold decreased potency compared with 4 in the B-J reflex test, 10e exhibited activity as potent as 4 in 5-HT- and TRH-induced defecation assays; 10e exhibited 7-fold increased potency compared with 4 in wrap-restraint stress-induced colonic propulsions. From these results, 10e appears to interact selectively with 5-HT3 receptors in the gastrointestinal system and might be effective in the therapy of irritable bowel syndrome (IBS).

Adenosine A2a receptors have been localized to GABAergic striatopallidal neurons, but their functional role is unknown. To address this question, the modulation of endogenous GABA release by adenosine A2a receptors was examined in slices of rat globus pallidus. The selective adenosine A2a receptor agonist CGS-21680 (3.0-10 nM) significantly increased electrically stimulated release (overflow) of GABA, with 10 nM CGS-21680 resulting in a 44% increase compared with the control. Both the nonselective adenosine receptor antagonist 8-phenyltheophylline (10 microM) and the selective A2a receptor antagonist KF-17837 (100 nM) abolished the CGS-21680-induced increase in GABA overflow. Higher concentrations of CGS-21680 (0.10-1.0 microM) decreased GABA overflow by approximately 25%. 8-Phenyltheophylline (10 microM) antagonized these effects, whereas KF-17837 (100 nM) did not, suggesting actions of CGS-21680 on other adenosine receptors at these concentrations. These results demonstrate that activation of adenosine A2a receptors augments electrically stimulated release of GABA from globus pallidus slices and suggest a mechanism by which adenosine may modulate GABAergic output from the striatopallidal efferent system.

A series of 5-(4-aryl- or 4-arylcarbonylpiperazin-1-yl)-5-deoxy-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared in order to obtain orally active, nitrate-type vasodilators with reduced side effects. Our drug design was based on a small reduction in the lipophilicity compared to that of 5-deoxy-5-[4-(3-phenylthiopropyl)piperazin-1-yl]-1,4: 3,6-dianhydro-L-iditol 2-nitrate (1, KF14124). Compounds 4h (aryl = benzimidazol-2-yl), 4i (arylcarbonyl = nicotinoyl), and 4w (arylcarbonyl = 3-furoyl) showed potent anti-ischemic activity in a lysine-vasopressin-induced angina pectoris model (rats), and their structure-activity relationships are discussed. Compound 4i exhibited potent vasodilation of the coronary artery in anesthetized dogs and also exhibited potent preload reduction in a heart failure model (dogs) as compared with isosorbide dinitrate (2), nicorandil (3), and KF14124 (1). Furthermore, 4i showed much weaker acute lethal toxicity and less central nervous system depression than 1 in mice. Thus, 4i (KW-3196) is under development as a vasodilator and a drug for treating angina pectoris.

Although the anterior and posterior boundaries of cavotricuspid isthmus-dependent atrial flutter (AFL) are reported to be located at the tricuspid annulus and sinus venosa region or crista terminalis, the exact upper turnaround point of the AFL circuit remains unclear. The aim of this study was to determine the upper turnaround site of the AFL circuit by means of three-dimensional (3D) mapping and entrainment pacing.Subjects were 21 patients with counter-clockwise AFL in whom high-density mapping of the high right atrium (RA) and superior vena cava (SVC) orifice was performed with an electroanatomical or non-contact mapping system. Entrainment pacing was performed around the SVC-RA junction.In 20 of the 21 patients, the wavefront from the septal RA split into two wavefronts: one that traveled anterior to the SVC and another that traveled to the posterior RA where it was blocked. In the remaining patient, the wavefront from the septal RA split into two wavefronts: one that propagated through the anterior portion of the SVC orifice and another that propagated transversely across the posterior portion of the SVC orifice. The two wavefronts joined in the lateral RA. Entrainment pacing from the SVC-RA junction demonstrated that the anterior boundary was within the circuit in all patients, but the posterior boundary also constituted a circuit in four patients.We surmise that the upper turnaround site of the AFL circuit is located in the anterior portion of the SVC-RA junction in the majority of patients with AFL.