RELATIONSHIP BETWEEN TRPM4 RS8104571 GENOTYPE, CIRCULATING TRPM4 AND SUR1, AND CLINICAL OUTCOME FOLLOWING TRAUMATIC BRAIN INJURY.

ABSTRACT: The variant single nucleotide polymorphism rs8104571 has been associated with poor outcomes following traumatic brain injury (TBI) and is most prevalent in those of African ancestry. This single nucleotide polymorphism (SNP) resides within a gene coding for the TRPM4 protein, which complexes with SUR1 protein to create a transmembrane ion channel and is believed to contribute to cellular swelling and cell death in neurological tissue. Our study evaluates the relationship between circulating TRPM4 and SUR1, rs8104571 genotype, and clinical outcome in TBI patients. Trauma patients with moderate to severe TBI were included in this retrospective study. rs8104571 genotyping and admission plasma TRPM4 and SUR1 quantification was performed with real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Adequate plasma for TRPM4 and SUR1 ELISA quantification was available for 289 patients, 54 of whom were African American (AA). Plasma TRPM4 concentration was increased in those with a variant rs8104571 allele compared to wild type when controlling for demographics and injury characteristics in the overall cohort (P = 0.04) and within the AA subgroup (P = 0.01). There was no significant association between plasma TRPM4 or SUR1 and clinical outcome (each P > 0.05). Plasma TRPM4 abundance increased with acute kidney injury severity (P = 0.02). The association between increased plasma TRPM4 and variant rs810457 supports an underlying mechanism involving increased neuroinflammation with a subsequent increase in the leakage of TRPM4 from the central nervous system into circulation. Alternative sources of plasma TRPM4 including the kidney cannot be excluded and may play a significant role in the pathophysiology of trauma as well.

Fibrinogen Fragment X Mediates Endothelial Barrier Disruption via Suppression of VE-Cadherin.

INTRODUCTION: Major traumatic injury is associated with early hemorrhage-related and late-stage deaths due to multiple organ failure (MOF). While improvements to hemostatic resuscitation have significantly reduced hemorrhage-related deaths, the incidence of MOF among trauma patients remains high. Dysregulation of vascular endothelial cell (EC) barrier function is a central mechanism in the development of MOF; however, the mechanistic triggers remain unknown. Accelerated fibrinolysis occurs in a majority of trauma patients, resulting in high circulating levels of fibrin(ogen) degradation products, such as fragment X. To date, the relationship between fragment X and EC dysregulation and barrier disruption is unknown. The goal of this study was to determine the effects of fragment X on EC barrier integrity and expression of paracellular junctional proteins that regulate barrier function. METHODS: Human lung microvascular endothelial cells (HLMVECs) were treated with increasing concentrations of fragment X (1, 10, and 100 µg/mL), and barrier function was monitored using the xCELLigence live-cell monitoring system. Quantitative PCR (qPCR) was performed to measure changes in EC expression of 84 genes. Immunofluorescent (IF) cytostaining was performed to validate qPCR findings. RESULTS: Fragment X treatment significantly increased endothelial permeability over time (P < 0.05). There was also a significant reduction in VE-cadherin mRNA expression in fragment X-treated HLMVECs compared to control (P = 0.01), which was confirmed by IF staining. CONCLUSIONS: Fragment X may induce EC hyperpermeability by reducing VE-cadherin expression. This suggests that a targeted approach to disrupting EC-fragment X interactions could mitigate EC barrier disruption, organ edema, and MOF associated with major trauma.

A 3-O-sulfated heparan sulfate dodecasaccharide (12-mer) suppresses thromboinflammation and attenuates early organ injury following trauma and hemorrhagic shock.

Introduction: Dysregulated inflammation and coagulation are underlying mechanisms driving organ injury after trauma and hemorrhagic shock. Heparan sulfates, cell surface glycosaminoglycans abundantly expressed on the endothelial surface, regulate a variety of cellular processes. Endothelial heparan sulfate containing a rare 3-O-sulfate modification on a glucosamine residue is anticoagulant and anti-inflammatory through high-affinity antithrombin binding and sequestering of circulating damage-associated molecular pattern molecules. Our goal was to evaluate therapeutic potential of a synthetic 3-O-sulfated heparan sulfate dodecasaccharide (12-mer, or dekaparin) to attenuate thromboinflammation and prevent organ injury. Methods: Male Sprague-Dawley rats were pre-treated subcutaneously with vehicle (saline) or dekaparin (2 mg/kg) and subjected to a trauma/hemorrhagic shock model through laparotomy, gut distention, and fixed-pressure hemorrhage. Vehicle and dekaparin-treated rats were resuscitated with Lactated Ringer's solution (LR) and compared to vehicle-treated fresh-frozen-plasma-(FFP)-resuscitated rats. Serial blood samples were collected at baseline, after induction of shock, and 3 hours after fluid resuscitation to measure hemodynamic and metabolic shock indicators, inflammatory mediators, and thrombin-antithrombin complex formation. Lungs and kidneys were processed for organ injury scoring and immunohistochemical analysis to quantify presence of neutrophils. Results: Induction of trauma and hemorrhagic shock resulted in significant increases in thrombin-antithrombin complex, inflammatory markers, and lung and kidney injury scores. Compared to vehicle, dekaparin treatment did not affect induction, severity, or recovery of shock as indicated by hemodynamics, metabolic indicators of shock (lactate and base excess), or metrics of bleeding, including overall blood loss, resuscitation volume, or hematocrit. While LR-vehicle-resuscitated rodents exhibited increased lung and kidney injury, administration of dekaparin significantly reduced organ injury scores and was similar to organ protection conferred by FFP resuscitation. This was associated with a significant reduction in neutrophil infiltration in lungs and kidneys and reduced lung fibrin deposition among dekaparin-treated rats compared to vehicle. No differences in organ injury, neutrophil infiltrates, or fibrin staining between dekaparin and FFP groups were observed. Finally, dekaparin treatment attenuated induction of thrombin-antithrombin complex and inflammatory mediators in plasma following trauma and hemorrhagic shock. Conclusion: Anti-thromboinflammatory properties of a synthetic 3-O-sulfated heparan sulfate 12-mer, dekaparin, could provide therapeutic benefit for mitigating organ injury following major trauma and hemorrhagic shock.

Influence of TRPM4 rs8104571 genotype on intracranial pressure and outcomes in African Americans with traumatic brain injury.

The TRPM4 gene codes for a membrane ion channel subunit related to inflammation in the central nervous system. Recent investigation has identified an association between TRPM4 single nucleotide polymorphisms (SNPs) rs8104571 and rs150391806 and increased intracranial (ICP) pressure following traumatic brain injury (TBI). We assessed the influence of these genotypes on clinical outcomes and ICP in TBI patients. We included 292 trauma patients with TBI. DNA extraction and real-time PCR were used for TRPM4 rs8104571 and rs150391806 allele discrimination. Five participants were determined to have the rs8104571 homozygous variant genotype, and 20 participants were identified as heterozygotes; 24 of these 25 participants were African American. No participants had rs150391806 variant alleles, preventing further analysis of this SNP. Genotypes containing the rs8104571 variant allele were associated with decreased Glasgow outcome scale-extended (GOSE) score (P = 0.0231), which was also consistent within our African-American subpopulation (P = 0.0324). Regression analysis identified an association between rs8104571 variant homozygotes and mortality within our overall population (P = 0.0230) and among African Americans (P = 0.0244). Participants with rs8104571 variant genotypes exhibited an overall increase in ICP (P = 0.0077), although a greater frequency of ICP measurements > 25 mmHg was observed in wild-type participants (P = < 0.0001). We report an association between the TRPM4 rs8104571 variant allele and poor outcomes following TBI. These findings can potentially be translated into a precision medicine approach for African Americans following TBI utilizing TRPM4-specific pharmaceutical interventions. Validation through larger cohorts is warranted.

Radiofrequency Ablation Remodels the Tumor Microenvironment and Promotes Neutrophil-Mediated Abscopal Immunomodulation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) presents a 5-year overall survival rate of 11%, despite efforts to improve clinical outcomes in the past two decades. Therapeutic resistance is a hallmark of this disease, due to its dense and suppressive tumor microenvironment (TME). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a promising local ablative and potential immunomodulatory therapy for PDAC. In this study, we performed RFA in a preclinical tumor-bearing KrasG12D; Trp53R172H/+; Pdx1:Cre (KPC) syngeneic model, analyzed local and abscopal affects after RFA and compared our findings with resected PDAC specimens. We found that RFA reduced PDAC tumor progression in vivo and promoted strong TME remodeling. In addition, we discovered tumor-infiltrating neutrophils determined abscopal effects. Using imaging mass cytometry, we showed that RFA elevated dendritic cell numbers in RFA-treated tumors and promoted a significant CD4+ and CD8+ T-cell abscopal response. In addition, RFA elevated levels of programmed death-ligand 1 (PD-L1) and checkpoint blockade inhibition targeting PD-L1 sustained tumor growth reduction in the context of RFA. This study indicates RFA treatment, which has been shown to increase tumor antigen shedding, promotes antitumor immunity. This is critical in PDAC where recent clinical immunotherapy trials have not resulted in substantial changes in overall survival.

How are Consumer Sleep Technology Data Being Used to Deliver Behavioral Sleep Medicine Interventions? A Systematic Review.

BACKGROUND: The rapid growth of consumer sleep technology demonstrates the population's interest in measuring sleep. However, the extent to which these devices can be used in the delivery of behavioral sleep interventions is currently unknown. The objectives of this systematic review were to evaluate the use of consumer sleep technology (wearable and mobile) in behavioral sleep medicine interventions, identify gaps in the literature and potential future directions. METHODS: We completed a scoping review of studies conducted in adult populations that used consumer sleep tracking technology to deliver sleep-related interventions. RESULTS: Our initial search returned 4,538 articles and 14 articles met our inclusion/exclusion criteria. Results demonstrated that wearable devices are being used for two main purposes: 1. To deliver treatment for insomnia and 2. Sleep monitoring as part of overall wellness programs. Half of the articles reviewed (n = 7) used consumer sleep technology in a cognitive behavioral therapy for insomnia. The majority of the studies reviewed (n = 10) were fully digital, without human intervention, and only two small studies evaluated interventions delivered with and without a sleep tracking device. CONCLUSIONS: These studies demonstrate opportunities to utilize consumer sleep trackers in insomnia treatment and wellness programs, but most new and innovative interventions are in the early, feasibility stages. Future research is needed to determine how to leverage wearables to improve existing behavioral sleep treatments and determine how this technology can engage patients and reduce barriers to behavioral sleep medicine interventions.

Circadian timing and alignment in healthy adults: associations with BMI, body fat, caloric intake and physical activity.

INTRODUCTION: Disruption of circadian rhythms is one of the proposed mechanisms linking late sleep timing to obesity risk but few studies have evaluated biological markers outside of the laboratory. The goal of this study was to determine the relationship between the timing and alignment of melatonin and sleep onset (phase angle) with body mass index (BMI), body fat and obesity-related behaviors. We hypothesized that circadian alignment (relationship of melatonin to sleep timing) rather than circadian (melatonin) timing would be associated with higher BMI, body fat, dietary intake and lower physical activity. SUBJECTS/METHODS: Adults with sleep duration ⩾6.5 h completed 7 days of wrist actigraphy, food diaries and SenseWear arm band monitoring. Circadian timing, measured by dim light melatonin onset was measured in the clinical research unit. Circadian alignment was calculated as the duration between dim light melatonin onset and average sleep onset time in the prior week (phase angle). Body fat was evaluated using dual-energy X-ray absorptiometry. Data were analyzed using bivariate correlations and multivariable regression analyses controlling for age, sex, sleep duration and evening light exposure. RESULTS: Participants included 97 adults (61 F, age 26.8±7.3 years) with average sleep duration 443.7 (s.d.=50.4) minutes. Average phase angle was 2.2 h (s.d.=1.5). Circadian alignment was associated with circadian timing (P<0.001) and sleep duration (P=0.005). In multivariable analyses, later circadian timing was associated with lower BMI (P=0.04). Among males only, circadian alignment was associated with percent body fat (P=0.02) and higher android/gynoid fat ratio (P=0.04). Circadian alignment was associated with caloric intake (P=0.049) carbohydrate intake (P=0.04) and meal frequency (P=0.03) among both males and females. CONCLUSION: Circadian timing and alignment were not associated with increased BMI or body fat, among healthy adults with ⩾6.5 h of sleep, but circadian alignment was associated with dietary intake. There may be sex differences in the relationship between circadian alignment and body fat.

Connecting the Dots: Linking Osteocyte Activity and Therapeutic Modulation of Sclerostin by Extending a Multiscale Systems Model.

The goal of this work was to extend a mathematical, multiscale systems model of bone function, remodeling, and health in order to explore hypotheses related to therapeutic modulation of sclerostin and quantitatively describe purported osteocyte activity within bone remodeling events. A pharmacokinetic model with first-order absorption and dual elimination pathways was used to describe the kinetics of romosozumab, a monoclonal antibody (mAb) against sclerostin. To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed. These models were subsequently linked to the systems model, with sclerostin signaling changes in resorption and formation through established osteocyte-mediated mechanisms. The model proposes relative contributions of the osteocyte to the RANKL pool, a major player in feedback signaling, and is used to explore hypotheses surrounding attenuation of anabolic activity after multiple doses of sclerostin mAbs, a phenomenon whose mechanism is poorly understood.

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration.

Focal adhesion turnover is a complex process required for cell migration. We have previously shown that the Ste20-like kinase (SLK) is required for cell migration and efficient focal adhesion (FA) turnover in a FA kinase (FAK)-dependent manner. However, the role of SLK in this process remains unclear. Using a candidate substrate approach, we show that SLK phosphorylates the adhesion adapter protein paxillin on serine 250. Serine 250 phosphorylation is required for paxillin redistribution and cell motility. Mutation of paxillin serine 250 prevents its phosphorylation by SLK in vitro and results in impaired migration in vivo as evidenced by an accumulation of phospho-FAK-Tyr397 and altered FA turnover rates. Together, our data suggest that SLK phosphorylation of paxillin on serine 250 is required for FAK-dependent FA dynamics.

[Refusal of care in the intensive care: how makes decision?]. / Non-admission en réanimation: comment décider?

OBJECTIVES: Decision-making bringing to an admission or not in intensive care is complex. The aim of this study is to analyze with an ethical point of view the making decision process leading to the refusal and its consequences. It is proposed a setting in prospect through the principles of beneficence, non-maleficience, respect for autonomy, justice, and the Leonetti law. PATIENTS AND METHODS: Prospective study in surgical reanimation at the University Hospital of Rouen over 9 months (November 2007-September 2008). Systematic collection for each non-admitted patient of the general characters, the methods of decision making, immediate becoming and within 48 h Constitution of two groups: patients for whom an admission in intensive care could be an unreasonable situation of obstinacy, and patients for whom an admission in reanimation would not be about unreasonable if it occurred. RESULTS: One hundred and fifty situations were analyzed. The potentially unreasonable character of an admission does not involve necessarily a refusal of care in intensive care. The question of the lack of place and equity in the access to the care is real but relative according to the typology of the patients. The research of the respect of the autonomy of the patient is difficult but could be facilitated. The Leonetti law does not appear to be able to be a framework with the situation of refusal of care in intensive care. CONCLUSION: It is not a question of going towards a systematic admission in intensive care of any patient proposed, but to make sure that so if there is a refusal, it is carried out according to a step ethically acceptable.

[Impact of Sfar experts' conference entitled "Modalities of sedation and/or analgesia in hospital setting"]. / Impact de la conférence d'experts intitulée "Modalités de la sédation et/ou de l'analgésie en situation extrahospitalière".

UNLABELLED: In 1999, the Société française d'anesthésie et de réanimation (Sfar) published guidelines regarding sedation in prehospital setting. The recommendated protocol for emergency intubation was the rapid sequence induction (RSI). The aim of this study was to assess the impact of these guidelines on clinical practices. PATIENTS AND METHODS: A restrospective observational study was conducted in three French mobile emergency and intensive care units. In 1998, 2000 and 2004, during periods of four months, charts from every interventions were analyzed. All the patients over 15 years of age needing to be intubated and not in cardiac arrest were included. The following data were collected: anaesthetic protocol used for intubation, drugs used for maintenance of sedation, circumstances requiring tracheal intubation and side effects related to tracheal intubation or sedation. An anonymous questionnary form was also sent to all physicians from the three units in order to assess sedation protocol used for emergency intubation, knowledge regarding the Sfar conference. RESULTS: Five hundred and thirty-one patients were included, and orotracheal intubation was performed in 84% of cases. RSI was administrated in 23% of cases in 1998, 45% in 2000 and 68% in 2004. Protocol for maintenance sedation complied the guidelines in 45% of cases in 1998, 68% in 2000 and 75% in 2004. Among the 62 physicians who answered the questionnary, 90% indicated they used RSI sequence for orotracheal intubation and 92% achieved sedation maintenance using midazolam fentanyl. CONCLUSION: The Sfar guidelines regarding sedation in prehospital setting seem to meet a good compliance in clinical practice.

Radio-guided surgery with the use of [99mTc-EDDA/HYNIC]octreotate in intra-operative detection of neuroendocrine tumours of the gastrointestinal tract.

PURPOSE: Radio-guided surgery (RGS) is an intra-operative localising technique which enables identification of tissue "marked" by a specific radiotracer injected before surgery. It is mainly used for sentinel node mapping and for detection of parathyroid adenomas and other tumours, including neuroendocrine tumours of the gastrointestinal tract (GEP-NET). The aim of this study was to determine whether intra-operative radio-detection with the use of [(99m)Tc-EDDA/HYNIC]octreotate, a new somatostatin analogue, is able to reveal an unknown primary and secondary sites, thereby improving surgical treatment and the final outcome of GEP-NET. METHODS: The study group included nine patients with suspected GEP-NET (four carcinoids, five pancreatic NET) localised with somatostatin receptor scintigraphy (with [(99m)Tc-EDDA/HYNIC]octreotate), who had negative results on other pre-operative imaging tests. At surgery, suspected tumours were measured in situ and ex vivo and precise exploration of the abdominal cavity was performed with the intra-operative scintillation detector (Navigator). RESULTS: Intra-operative gamma counting localised three carcinoids. In one patient SRS was false positive (owing to inflammatory infiltration). Compared with SRS, RGS revealed additional lymph node metastases in one case. RGS resulted in successful localisation of all pancreatic NET (the smallest lesion was 8 mm in diameter). CONCLUSION: [(99m)Tc-EDDA/HYNIC]octreotate SRS followed by RGS is a promising technique to improve the rate of detection and efficacy of treatment of GEP-NET, especially in the presence of occult endocrine tumours. The imaging properties of [(99m)Tc-EDDA/HYNIC]octreotate and the 1-day imaging protocol offer opportunities for more widespread application of this tracer followed by RGS in oncology.

99mTc-EDDA/HYNIC-octreotate in detection of atypical bronchial carcinoid.

UNLABELLED: Pulmonary carcinoids cause serious difficulties in imaging diagnostics in all stages of the disease. SRS holds great promise for detecting occult primary tu and metastatic lesions. (99m)Tc-EDDA/HYNIC-octreotate, a new scintigraphic agent, should significantly improve sensitivity of the diagnostics of carcinoids due to better affinity to SSR2 than (111)In-Octreoscan and the higher count rate obtained from (99m)Tc over (111)In. We present a case of a 40-year-old women operated on because of lung carcinoid tumour in 2002. The symptoms did not resolve after the operation and 5-OHIAA was still elevated. The thorax spiral CT revealed the focal lesion beneath carina. (111)In-Octreoscan and (99m)Tc-EDDA/HYNIC-octreotate SRS revealed two focal lesions in the mediastinum. (99m)Tc-EDDA/HYNIC-octreotate detected two additional lesions in the lower part of the right lung. Target/non-target count ratios of the lesions were as follows: (99m)Tc-EDDA/HYNIC-octreotate scans - 2,9, (111)In-Octreoscan- 2,1. PET-FDG examination revealed no pathology. Owing to severe bone pains and carcinoid symptoms the patient was referred for the 90Y-DOTA-octreotate treatment. CONCLUSIONS: SRS with a new 99mTc marked somatostatin analogue - octreotate allows for a more sensitive detection of metastatic leasions in carcinoid tumours. The usefulness of 18F-FDG PET, widely used as a powerful imaging technique in clinical oncology, is limited in detection of carcinoid tumours due to the low proliferative activity.

99mTc-EDDA/HYNIC-octreotate scintigraphy, an efficient method for the detection and staging of carcinoid tumours: results of 3 years' experience.

PURPOSE: At all stages of the disease, serious difficulties are encountered in the imaging diagnosis of carcinoids. Somatostatin receptor scintigraphy (SRS) holds great promise for detecting primary tumours and metastases. 99mTc-EDDA/HYNIC-octreotate should significantly improve the diagnosis of carcinoids in comparison with 111In-Octreoscan owing to the better affinity for SSR2 and the higher count rate. The aim of this study was to assess the diagnostic efficiency of 99mTc-EDDA/HYNIC-octreotate scintigraphy in the detection and staging of carcinoid tumours. METHODS: The study population comprised 75 patients (age 48.5+/-15.5 years): 46 with histological confirmation of carcinoid and 29 with suspected disease. 99mTc-EDDA/HYNIC-octreotate (740 MBq) SRS and CT were performed in all patients. Fifteen patients were examined with 111In-Octreoscan. RESULTS: High-quality 99mTc-EDDA/HYNIC-octreotate images were obtained in all cases, with maximum tumour tracer accumulation 4 h p.i. The mean target/non-target ratios for whole body (WB) and SPECT scans were, respectively, as follows: primary lesions: 4.5 and 10.2; metastases: liver, 3.1 and 12.3; abdominal focal lesions, 2.7 and 5.8; lung, 2.7 and 8.3; mediastinum, 3.4 and 7.6; bones, 6.8 and 19.0. 99mTc-EDDA/HYNIC-octreotate WB scans revealed more metastases than 111In-Octreoscan, with better individual separation. 99mTc-EDDA/HYNIC-octreotate SRS revealed new metastatic lesions in seven patients with confirmed carcinoid, and in four with dissemination the primary focus was found. Five patients qualified for radioguided surgery and 11 were referred to 90Y-DOTA-TATE therapy. The sensitivity of SRS in comparison with CT was higher for primary lesions and liver and abdominal lymph node metastases. In the subgroup of patients with suspected neuroendocrine tumours, two duodenal carcinoids, one thymic carcinoid and one ileal carcinoid were found. CONCLUSION: 99mTc-EDDA/HYNIC-octreotate, with high imaging quality, is an excellent alternative to 111In-Octreoscan for staging of carcinoids, and it seems to be the method of choice for detection of the primary focus in patients with metastases from an unknown primary tumour.

[Psychiatric and neuropsychological signs and symptoms in patients with fabry disease: literature review]. / Psychiatrische und neuropsychologische Auffälligkeiten bei Patienten mit Morbus Fabry: Literaturübersicht.

Fabry Disease (FD) is an X-linked lysosomal storage disorder (prevalence about 1 : 100 000) caused by a genetic defect associated with a lack of alpha-galactosidase A (alpha-GAL) enzyme activity. As a consequence, neutral glycosphingolipides can not be cleaved and metabolized, and accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. The most prominent symptoms comprise pain attacks and acroparesthesia, angiokeratoma, corneal opacity, renal and cardiac dysfunction, hypo- and anhidrosis, gastrointestinal symptoms, and cerebrovascular dysfunction with vertigo, headache, and cerebral ischemia. Characteristic symptoms of FD can occur in male and female patients with the same prevalence, while females with FD seem to be less severely affected. The course of untreated illness is progressive with considerable interindividual variability. Since 2001 two enzyme replacement therapies are approved which can possibly stop the disease progress and alleviate symptoms. The very few reports and clinical observations have shown that a very high proportion of FD patients develop neuropsychiatric symptoms. However, accurate data are lacking. Although the pathophysiologic mechanisms are quite unknown, it is surmised that sphingolipid deposits in the endothelium of small cerebral vessels lead to regional cerebral ischemia accompanied by neuropsychiatric symptoms and deficits. Furthermore, patients with FD are chronically distressed by pain attacks and additional somatic and psychological impairment. Frequently, pain attacks are triggered by psychosocial stress. The high interindividual variability can, thus, also be interpreted on the basis of existing stress and coping models. The present paper will review the presently available psychiatric and neuropsychological findings in FD and will discuss difficulties associated with classification and differential diagnosis of psychiatric disorders occurring in patients with FD.

White matter lesion severity in male and female patients with Fabry disease.

In male patients with Fabry disease (FD), significant age-related cerebral white matter lesions (WMLs) can be found. Although characteristic symptoms including cerebrovascular events are highly prevalent also in females with FD, cerebral structural changes have not been investigated in female FD patients yet. The authors quantified the WML load of 13 male and 14 age-matched female patients with FD and could demonstrate a comparably high frequency and severity of WMLs in both groups.

The right ventricle in Fabry disease.

AIM: Left ventricular (LV) hypertrophy is a common feature in Fabry disease-related progressive infiltrative hypertrophic cardiomyopathy and affects both men and women, but at different ages. To date, however, little is known about the role of right ventricular (RV) function in Fabry disease. Therefore, this study aimed to investigate the extent of RV involvement in patients with Fabry disease. METHODS: Echocardiographic examination of the right and left ventricle was carried out in 129 patients (80 women and 49 men) with Fabry disease. RESULTS: RV hypertrophy was present in 46 patients (35.7%). Of these patients, 13 showed signs of severely depressed right systolic function (tricuspid annulus movement < 10 mm and a prolonged RV pre-ejection period/pulmonary ejection time ratio) and six patients showed additional severe depression of parameters of diastolic function (pseudo-normal or restrictive RV filling pattems). Those patients with RV hypertrophy and severely compromised systolic and diastolic function had the highest LV masses (92 +/- 11.7 g/m(2.7)). CONCLUSION: RV involvement is common in Fabry disease and ultimately progresses to severe systolic and diastolic RV dysfunction. These findings might explain why patients with preserved LV function can develop clinical features such as reduced exercise capacity, organomegaly and lymphoedema.

Persistence of immunity to varicella-zoster virus after vaccination of healthcare workers.

OBJECTIVE: Varicella-zoster virus (VZV) vaccine is recommended to protect susceptible healthcare workers (HCWs) from serious disease and to prevent nosocomial spread of VZV. We evaluated clinical outcomes and serological responses in HCWs after immunization with live attenuated VZV vaccine. DESIGN: Vaccinees were immunized from 1979 to 1998 during VZV vaccine trials, as well as after licensure, and followed prospectively for 1 month to 20.6 (mean 4.6) years after vaccination. Sera were tested by fluorescent antibody to membrane antigen (FAMA), latex agglutination (LA), and enzyme-linked immunoassay (EIA) to detect VZV-specific antibodies. STUDY PARTICIPANTS: The median age of the 120 HCWs was 26 years; 51 (42%) were males. INTERVENTIONS: Ninety eight (82%) of these study subjects received vaccine prepared by Merck and 22 (18%) by SmithKline Beecham; 25, 81, and 14 vaccinees received one dose, two doses, and three doses, respectively. RESULTS: The crude attack rate was 10%; 12 of 120 HCWs developed chickenpox 6 months to 8.4 years after vaccination. The attack rates following household and hospital exposures were 18% (4/22) and 8% (6/72), respectively. All resulting illness was mild to moderate (mean 40 vesicles). Seroconversion after vaccination was documented by FAMA in 96% of HCWs, although 31% lost detectable antibodies. Compared with FAMA, LA and EIA were 82% and 74% sensitive and 94% and 89% specific, respectively. CONCLUSIONS: The VZV vaccine effectively protected HCWs from varicella, particularly from serious disease. Currently available serological tests are not optimal, and improved assays are needed.

Long-term seizure outcome and antiepileptic drug treatment in surgically treated temporal lobe epilepsy patients: a controlled study.

PURPOSE: To evaluate the long-term impact of surgical treatment on seizure outcome and antiepileptic drug (AED) use in patients with pharmacoresistant temporal lobe epilepsy (TLE). METHODS: Comparison of seizure outcome and AED us in operated-on TLE patients (n=148) and nonsurgically treated TLE patients (n=94) at a baseline visit and a follow-up visit after a mean period of 4.8 years. RESULTS: At follow-up, 44.6% of the surgical patients and 4.3% of the nonsurgical patients had been continuously seizure- free since the baseline visit (including the immediate postoperative period). A further 17.6% of the operated-on and 3.2% of the not operated-on patients had been seizure-free for at least the previous year; 37.8% of the surgical and 92.5% of the nonsurgical patients had had seizures during the previous 12 months (p < 0.001). Of the surgical patients, 8.8% versus none of the nonsurgical patients were AED free at follow-up; 55.4% versus 20.2% were receiving monotherapy, and 35.8% versus 79.8% were receiving polytherapy (p < 0.001). Mean number of AEDs and mean change in number of AEDs were significantly more favorable in operated-on than in non-operated-on patients. Further subgroup analysis revealed that not only the continuously seizure-free surgical patients, but also the operated-on patients with ongoing seizures took fewer AEDs than their respective non-operated-on counterparts. CONCLUSIONS: This controlled study for the first time provides comprehensive information on long-term seizure outcome and AED use in surgical TLE patients. It shows a more favorable seizure outcome and AED use in the surgically treated patients. The latter holds true even for the not seizure-free patient subgroup.