Sepsis in patients with haematological versus solid cancer: a retrospective cohort study.

OBJECTIVES: This study aims to examine the outcome of haematological and patients with solid cancer presenting with sepsis to the emergency department (ED). DESIGN: Single-centred, retrospective cohort study. Setting conducted at an academic emergency department of a tertiary hospital. PARTICIPANTS: All patients >18 years of age admitted with sepsis were included. INTERVENTIONS: Patients were stratified into two groups: haematological and solid malignancy. PRIMARY AND SECONDARY OUTCOME: The primary outcome of the study was in-hospital mortality. Secondary outcomes included intensive care unit (ICU) mortality, ICU and hospital lengths of stay and mechanical ventilation duration. RESULTS: 442 sepsis cancer patients were included in the study, of which 305 patients (69%) had solid tumours and 137 patients (31%) had a haematological malignancy. The mean age at presentation was 67.92 (±13.32) and 55.37 (±20.85) (p<0.001) for solid and liquid tumours, respectively. Among patients with solid malignancies, lung cancer was the most common source (15.6%). As for the laboratory workup, septic solid cancer patients were found to have a higher white blood count (12 576.90 vs 9137.23; p=0.026). During their hospital stay, a total of 158 (51.8%) patients with a solid malignancy died compared with 57 (41.6%) patients with a haematological malignancy (p=0.047). There was no statistically significant association between cancer type and hospital mortality (OR 1.15 for liquid cancer p 0.58). There was also no statistically significant difference regarding intravenous fluid administration, vasopressor use, steroid use or intubation. CONCLUSION: Solid tumour patients with sepsis or septic shock are at the same risk of mortality as patients with haematological tumours. However, haematological malignancy patients admitted with sepsis or septic shock have higher rates of bacteraemia.

Pediatric emergency department utilisation during Ramadan: a retrospective cross-sectional study.

OBJECTIVE: To investigate the impact of Ramadan on patient characteristics, diagnoses and metrics in the paediatric emergency department (PED). DESIGN: Retrospective cross-sectional study. SETTING: PED of a tertiary care centre in Lebanon. PATIENTS: All paediatric patients. EXPOSURE: Ramadan (June 2016 and 2017) versus the months before and after Ramadan (non-Ramadan). MAIN OUTCOME MEASURES: Patient and illness characteristics and PED metrics including peak patient load; presentation timings; length of stay; and times to order tests, receive samples and report results. RESULTS: We included 5711 patients with mean age of 6.1±5.3 years and 55.4% males. The number of daily visits was 28.3±6.5 during Ramadan versus 31.5±7.3 during non-Ramadan (p=0.004). The peak time of visits ranged from 18:00 to 22:00 during non-Ramadan versus from 22:00 to 02:00 during Ramadan. During Ramadan, there were significantly more gastrointestinal (GI) and trauma-related complaints (39.0% vs 35.4%, p=0.01 and 2.9% vs 1.8%, p=0.005). The Ramadan group had faster work efficiency measures such as times to order tests (21.1±21.3 vs 24.3±28.1 min, p<0.0001) and to collect samples (50.7±44.5 vs 54.8±42.6 min, p=0.03). CONCLUSIONS: Ramadan changes presentation patterns, with fewer daily visits and a later peak time of visits. Ramadan also affects illness presentation patterns with more GI and trauma cases. Fasting times during Ramadan did not affect staff work efficiency. These findings could help EDs structure their staffing to optimise resource allocation during Ramadan.

Clinical Outcome of Septic Patients With Heart Failure With Preserved Ejection Fraction Presenting to the Emergency Department of a Tertiary Hospital: A Retrospective Cohort Study.

Background: Patients with heart failure with preserved ejection fraction (HFpEF) may be at a higher risk of mortality from sepsis than patients without heart failure. Objective: The aim of this study is to compare sepsis-related morbidity and mortality between patients with HFpEF and patients without heart failure presenting to the emergency department (ED) of a tertiary medical center. Design: Single-center retrospective cohort study conducted at an academic ED between January 1, 2015 and December 31, 2018. Patients: Patients with a diagnosis of sepsis were included. Main Measures: Bivariate and multivariate analyses were performed to look at differences in demographics, infection, and treatment parameters as well as outcomes of patients with sepsis. The primary outcome of the study was in-hospital mortality. Secondary outcomes included ED mortality, lengths of stay, and treatment differences between both groups. Key Results: A total of 1,092 patients presented with sepsis to the ED, of which 305 (27.93%) had HFpEF. There was no significant difference in in-hospital mortality between the two groups (40.7% vs. 37.4%; p = 0.314). However, there was a significant increase in ED mortality for septic HFpEF patients compared to non-heart failure patients (2.4 vs. 0.4%; p = 0.003). Septic HFpEF patients presenting to the ED were older than non-heart failure patients (76.84 vs. 68.44 years old; p < 0.0001). On the other hand, there was no significant increase in the use of vasopressors in the first 24 h between both groups. There was a significantly higher rate of intubation in the first 48 h for septic HFpEF patients (17.5 vs. 8.9%; p < 0.0001). Finally, there was significantly less intravenous fluid requirement at 6 h (1.94 L vs. 2.41L; p < 0.0001) and 24 h (3.11 L vs. 3.54L; p = 0.004) for septic patients with HFpEF compared to non-heart failure patients. Conclusion: Septic HFpEF patients experienced an increase in ED mortality, intubation, and steroid use compared to septic non-heart failure patients.

Relative Hyperlactatemia in the Emergency Department.

Objective: The clinical interpretation of lactate ≤ 2.00 mmol/L in emergency department (ED) patients is not well-characterized. This study aims to determine the optimal cutoff value for lactate within the reference range that predicts in-hospital mortality among ED patients. Methods: This was a retrospective study of adult patients presenting to a tertiary ED with an initial serum lactate level of <2.00 mmol/L. The primary outcome was in-hospital mortality. Youden's index was utilized to determine the optimal threshold that predicts mortality. Patients above the threshold were labeled as having relative hyperlactatemia. Results: During the study period, 1,638 patients were included. The mean age was 66.9 ± 18.6 years, 47.1% of the population were female, and the most prevalent comorbidity was hypertension (56.7%). The mean lactate level at presentation was 1.5 ± 0.3 mmol/L. In-hospital mortality was 3.8% in the overall population, and 16.2% were admitted to the ICU. A lactate level of 1.33 mmol/L was found to be the optimal cutoff that best discriminates between survivors and non-survivors. Relative hyperlactatemia was an independent predictor of in-hospital mortality (OR 1.78 C1.18-4.03; p = 0.02). Finally, relative hyperlactatemia was associated with increased mortality in patients without hypertension (4.7 vs. 1.1%; p = 0.008), as well as patients without diabetes or COPD. Conclusion: The optimal cutoff of initial serum lactate that discriminates between survivors and non-survivors in the ED is 1.33 mmol/L. Relative hyperlactatemia is associated with increased mortality in emergency department patients, and this interaction seems to be more important in healthy patients.

Lactate/Albumin Ratio as a Predictor of In-Hospital Mortality in Septic Patients Presenting to the Emergency Department.

Background: The aim of this study is to evaluate the prognostic value of the Lactate to Albumin (L/A) ratio compared to that of lactate only in predicting morbidity and mortality in sepsis patients. Methods: This was a single-center retrospective cohort study. All adult patients above the age of 18 with a diagnosis of sepsis who presented between January 1, 2014 and June 30, 2019 were included. The primary outcome was in-hospital mortality. Results: A total of 1,381 patients were included, 44% were female. Overall in-hospital mortality was 58.4% with the mortalities of sepsis and septic shock being 45.8 and 67%, respectively. 55.5% of patients were admitted to the intensive care unit. The area under the curve value for lactate was 0.61 (95% CI 0.57-0.65, p < 0.001) and for the L/A ratio was 0.67 (95% CI 0.63-0.70, p < 0.001). The cutoff generated was 1.22 (sensitivity 59%, specificity 62%) for the L/A ratio in all septic patients and 1.47 (sensitivity 60%, specificity 67%) in patients with septic shock. The L/A ratio was a predictor of in-hospital mortality (OR 1.53, CI 1.32-1.78, p < 0.001). Conclusion: The L/A ratio has better prognostic performance than initial serum lactate for in-hospital mortality in adult septic patients.

Health care workers in conflict and post-conflict settings: Systematic mapping of the evidence.

BACKGROUND: Health care workers (HCWs) are essential for the delivery of health care services in conflict areas and in rebuilding health systems post-conflict. OBJECTIVE: The aim of this study was to systematically identify and map the published evidence on HCWs in conflict and post-conflict settings. Our ultimate aim is to inform researchers and funders on research gap on this subject and support relevant stakeholders by providing them with a comprehensive resource of evidence about HCWs in conflict and post-conflict settings on a global scale. METHODS: We conducted a systematic mapping of the literature. We included a wide range of study designs, addressing any type of personnel providing health services in either conflict or post-conflict settings. We conducted a descriptive analysis of the general characteristics of the included papers and built two interactive systematic maps organized by country, study design and theme. RESULTS: Out of 13,863 identified citations, we included a total of 474 studies: 304 on conflict settings, 149 on post-conflict settings, and 21 on both conflict and post-conflict settings. For conflict settings, the most studied counties were Iraq (15%), Syria (15%), Israel (10%), and the State of Palestine (9%). The most common types of publication were opinion pieces in conflict settings (39%), and primary studies (33%) in post-conflict settings. In addition, most of the first and corresponding authors were affiliated with countries different from the country focus of the paper. Violence against health workers was the most tackled theme of papers reporting on conflict settings, while workforce performance was the most addressed theme by papers reporting on post-conflict settings. The majority of papers in both conflict and post-conflict settings did not report funding sources (81% and 53%) or conflicts of interest of authors (73% and 62%), and around half of primary studies did not report on ethical approvals (45% and 41%). CONCLUSIONS: This systematic mapping provides a comprehensive database of evidence about HCWs in conflict and post-conflict settings on a global scale that is often needed to inform policies and strategies on effective workforce planning and management and in reducing emigration. It can also be used to identify evidence for policy-relevant questions, knowledge gaps to direct future primary research, and knowledge clusters.

Non-communicable diseases research output in the Eastern Mediterranean region: an overview of systematic reviews.

BACKGROUND: Rates of non-communicable diseases (NCDs) are rapidly rising in the Eastern Mediterranean Region (EMR). Systematic reviews satisfy the demand from practitioners and policy makers for prompt comprehensive evidence. The aim of this study is to review trends in NCD systematic reviews research output and quality by time and place, describe design and focus, and examine gaps in knowledge produced. METHODS: Using the Montori et al. systematic reviews filter, MeSH and keywords were applied to search Medline Ovid, Cochrane Central and Epistemonikos for publications from 1996 until 2015 in the 22 countries of the EMR. The 'Measurement Tool to Assess Systematic Reviews', AMSTAR, was used to assess the methodological quality of the papers. RESULTS: Our search yielded 2439 papers for abstract and title screening, and 89 papers for full text screening. A total of 39 (43.8%) studies included meta-analysis. Most of the papers were judged as being of low AMSTAR quality (83.2%), and only one paper was judged as being of high AMSTAR quality. Whilst annual number of papers increased over the years, the growth was mainly attributed to an increase in low-quality publications approaching in 2015 over four times the number of medium-quality publications. Reviews were significantly more likely to be characterized by higher AMSTAR scores (±SD) when meta-analysis was performed compared to when meta-analysis was not performed (3.4 ± 1.5 vs 2.6 ± 2.0; p-value = 0.034); and when critical appraisal of the included studies was conducted (4.3 ± 2.3 vs 2.5 ± 1.5; p-value = 0.004). Most of the reviews focused on cancer and diabetes as an outcome (25.8% and 24.7%, respectively), and on smoking, dietary habits and physical activity as exposures (15.7%, 12.4%, 9.0%, respectively). There was a blatant deficit in reviews examining associations between behaviors and physiologic factors, notably metabolic conditions. CONCLUSIONS: Systematic reviews research in the EMR region are overwhelmingly of low quality, with gaps in the literature for studies on cardiovascular disease and on associations between behavioral factors and intermediary physiologic parameters. This study raises awareness of the need for high-quality evidence guided by locally driven research agenda responsive to emerging needs in countries of the EMR.

Illness cognition and health anxiety in parents of children with cancer.

Purpose: Health anxiety is a clinical entity characterized by a pathological fear of illness. Illness cognition refers to persistent positive or negative thoughts an individual has towards illness. Evidence has shown that patients with chronic conditions who possess negative illness cognitions experience greater social, emotional, and physical difficulties than patients with positive illness cognitions. This study aims to measure the prevalence of health anxiety in a population of parents of children with cancer, and investigate the association between positive and negative illness cognitions and health anxiety. Methods: We interviewed 105 parents of children with cancer and administered Arabic versions of the Illness Cognition Questionnaire - Parent Version and the Short Health Anxiety Inventory. Results: The mean parental age was 37.7 years with the majority of participants being mothers (78.1%) and married (94.3%) and with 35.2% having completed university education. The average age of the child with cancer was 8.4 years, with the largest proportion of children suffering from leukemia. The prevalence of health anxiety among parents of children with cancer was 21%. The following two dimensions of illness cognition were significantly associated with health anxiety: Helplessness (B = 0.222, p = 0.021) and lower Acceptance (B = -0.242, p = 0.008). Other variables associated with health anxiety were perceived inadequate income (B = -0.238, p = 0.021) and personal illness or illness of a family member/close friend (B = 0.251, p = 0.013). Conclusions: Parents of children with cancer may experience health anxiety. Predictors of health anxiety include feelings of helplessness, lower acceptance, inadequate income, and extended family illnesses.

Effect of Gender on Postoperative Morbidity and Mortality Outcomes: A Retrospective Cohort Study.

Full extent of gender differences on postoperative outcomes has never been studied on large scale, specifically postoperative complications. This study aims to assess the effect of gender on 30-day morbidity and mortality after major surgery. A retrospective cohort study was carried out using data of patients undergoing major surgeries from the American College of Surgeons' National Surgical Quality Improvement Program database between 2008 and 2011. Demographics, pre- and perioperative risk factors, as well as 30-day morbidities, both overall and specific, were reviewed. The 30-day mortality data were also assessed. Multivariate logistic regression analyses, basic (Adj1) and extended (Adj2), were used to assess the association between gender and outcomes. Out of 1,409,131 patients, 57.2 per cent were females. Females had lower prevalence of most system-specific risk variables. Overall morbidities were also lower in females versus males, even after adjustment for variables [total overall morbidity: ORadj2 = 0.9 (0.89-0.92), P < 0.0001] except in some cases such as after cardiac surgeries [ORadj2 = 1.29 (1.14-1.44), P < 0.0001] and vascular surgeries [ORadj2 = 1.14 (1.10-1.18), P < 0.0001], where overall morbidities of females were higher. Specific morbidities were also lower in females than in males in all types of complications except central nervous system-related postoperative complications [ORadj2 = 1.15 (1.08-1.22), P < 0.0001] and return to the operating room [ORadj2 = 1.06 (1.04-1.08), P < 0.0001]. The 30-day mortality rate for females was lower than males [ORadj2 = 0.99 (0.96-1.03), P = 0.94]. Female gender was associated with less perioperative morbidity and mortality versus males, but they did worse after cardiovascular procedures and had more central nervous system-related complications. These outcomes should be taken into consideration by surgeons and should be evaluated further in future studies.

The Effect of Preoperative Pneumonia on Postsurgical Mortality and Morbidity: A NSQIP Analysis.

BACKGROUND: Currently, only indirect evidence suggests that preoperative pneumonia is a significant risk factor for poor postsurgical outcomes. Although this relationship is clinically intuitive, this is the first study that aims to quantify the extent to which pneumonia impacts morbidity and mortality. The objective of this study was to determine the impact of preoperative pneumonia on 30-day mortality and morbidity among both elective and emergency surgical patients. METHODS: We conducted a retrospective cohort study using 2008-2012 data from the American College of Surgeons National Surgical Quality Improvement Program database. Patients with preoperative pneumonia were matched to controls without preoperative pneumonia. Patient demographics and postoperative outcomes were extracted from the database, including 30-day mortality, specific morbidities (wound, cardiac, respiratory, urinary, central nervous system, thromboembolism and sepsis), composite morbidity, number of blood transfusions and number of patients that returned to the OR. Mortality and composite morbidity were further stratified. RESULTS: We obtained data for 137,174 patients, of whom 6933 (0.50%) had preoperative pneumonia. Overall, 6111 were successfully matched to 24,444 patients with no pneumonia. Postoperative mortality and composite morbidity were both higher in patients with pneumonia than in those without pneumonia, with an odds ratio of 1.37 (95% CI 1.26-1.48) and 1.68 (95% CI 1.58-1.79), respectively. CONCLUSION: Preoperative pneumonia significantly increased the rate of postoperative morbidity and mortality across several surgical settings and patient groups. It is our recommendation that elective surgery be delayed until after the pneumonia resolves.

Small Bowel Obstruction Secondary to a Metamucil Bezoar: Case Report and Review of the Literature.

Bezoar-induced small bowel obstruction is a rare entity. It should be highly suspected in patients with gastric hypomotility disorders, psychiatric conditions, prior abdominal or bariatric surgery, or improper intake of medication. Their diagnosis is quite challenging and surgical exploration remains the best treatment of choice to ensure the viability of the small bowel tissue and relieve the obstruction. This is a case of a 48-year-old female with no previous abdominal surgery who presented with acute abdominal pain. The patient's history was remarkable for the daily ingestion of 1.5 teaspoons of Metamucil with minimal amount of water. Computed tomography scan demonstrated dilated small bowel loops and a transition zone at the level of the mid jejunum. On laparoscopy, the patient was found to have a hard mass in the mid jejunum amenable to gentle fragmentation and breakdown. Metamucil bezoars are due to the solidification of psyllium-based substances in the gastrointestinal tract. The usual management of small bowel obstruction induced by a bezoar is exploratory laparotomy with enterotomy and primary anastomosis. Laparoscopic intervention has gained popularity among surgeons with good outcome and lower morbidity. In this unusual case, the small bowel obstruction induced by the Metamucil bezoar was safely treated with laparoscopic fragmentation alone.

Life threatening presentation of thoracic duct injury post thyroid surgery; a case report.

BACKGROUND: Injury to thoracic duct is a rare potential complication of time-honored conventional thyroidectomy. Nevertheless, it can be a cause of significant morbidity, and sometimes life-threatening. PATIENT FINDINGS: A 78-year-old female patient with a previous surgical history of thyroid lobectomy for nodular disease presented with primary hyperparathyroidism, and a nodule in the remaining thyroid lobe. The patient underwent completion thyroidectomy and parathyroidectomy. Less than 24h post operatively, the patient developed progressive shortness of breath and neck swelling requiring immediate intubation and re-exploration. A large amount of chyle was drained and an injured thoracic duct was identified and ligated. SUMMARY: In experienced hands thyroid surgery is safe. Nevertheless, factors such as the type of pathology and its extent, the level of surgery, and re-operative surgery increase the risk of postoperative complications. Immediate surgical exploration is necessary when patients present with neck swelling and respiratory distress. In our case, a high output chyle leak in a confined space was life threatening. CONCLUSION: Timely re-exploration following thyroid surgery and thorough knowledge of the anatomy of neck structures is crucial in sparing patients potential morbidity and/or mortality.

Preoperative INR and postoperative major bleeding and mortality: A retrospective cohort study.

Little research has been done on the current cut-off international normalized ratio (INR) value of 1.5 for patients undergoing surgery. The objectives of this study are to assess the association between INR and postoperative major bleeding and mortality in patients undergoing surgery and to identify an ideal pre-operative INR for surgical patients. We analyzed data from the American College of Surgeons' National Surgical Quality Improvement Program database between 2008 and 2011 (636,231 patients). The primary outcomes were major bleeding and mortality at 30 days postoperatively. Multivariate logistic regression analyses were carried out to assess these associations. Compared to an INR of <1, the adjusted odds ratio (aOR) for major bleeding was 1.22 (95 % CI 1.18-1.25) for INR 1-1.49, 1.48 (95 % CI 1.40-1.56) for INR 1.5-1.9, and 1.49 (95 % CI 1.39-1.60) for INR ≥2. The aOR for mortality at 30 days post-operation compared to INR of <1 was 1.51 (95 % CI 1.41-1.62), 2.31 (95 % CI 2.12-2.52), and 2.81 (95 % CI 2.56-3.10) for INR 1-1.49, 1.5-1.9, and ≥2, respectively. The ideal pre-operative INR value to predict an increased risk for major bleeding was 1.10 and 1.13 for mortality. In conclusion, preoperative INR is significantly and independently associated with postoperative major bleeding and mortality.

The effect of cataract surgery on blue-yellow and standard-pattern visual-evoked potentials.

PURPOSE: Blue-yellow visual-evoked potentials (BY-VEPs) may be used for diagnostics of functional ganglion cell damage in glaucoma and other ocular diseases. In this study we investigated the impact of lenticular opacities on BY- and standard pattern reversal VEPs by examining patients before and after cataract surgery. METHODS: Eighteen patients with moderate cataract were included in a prospective study. Transient on/off isoluminant blue-yellow 2° checks were used for short-wavelength stimulation (BY-VEP), transient large 1° (M1) and small 0.25° (M2) black-white checks for standard pattern reversal VEPs. VEPs were acquired before (24 ± 30 days) and after cataract surgery (14 ± 16 days). The contralateral eye was used as a control. RESULTS: Amplitude and latency of M1 and M2 peaks did not change significantly from before to after surgery. The amplitude of the BY-VEPs did not change significantly after cataract surgery (pre-surgery, -7.42 ± 3.43 µV, post-surgery, -7.93 ± 3.65 µV, p = 0.42), yet the latency of the main negative peak showed a significant decrease (pre-surgery, 143.9 ± 12.9 ms, post-surgery, 133.2 ± 7.7 ms, p = 0.0006). The BCVA improvement was significant from before to after cataract surgery (pre-surgery, 0.344 ± 0.125 LogMAR, post-surgery, 0.224 ± 0.179 LogMAR, p = 0.013) yet not correlated to the absolute decrease in latency of the BY-VEP after surgery (r = 0.309, p = 0.22). No significant changes were found in the contralateral eye. CONCLUSIONS: The BY-VEP is sensitive to lenticular opacities of the human lens, presumably due to the increased short-wavelength absorption in the aging eye. This fact should be considered when applying BY-VEPs for diagnostics.

Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures.

BACKGROUND: Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE. METHODOLOGY/PRINCIPAL FINDINGS: A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS. CONCLUSIONS/SIGNIFICANCE: The present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy.

Nuclear localization of a novel human syntaxin 1B isoform.

The syntaxins are proteins associated with various intracellular membrane compartments. They are major participants in a large variety of physiological processes where membrane fusion occurs, including exocytosis. We have identified a novel syntaxin isoform generated by alternative splicing of the human STX1B gene. In contrast with the canonical syntaxins, this isoform (STX1B-DeltaTMD) lacked the classical C-terminal transmembrane domain and localized to the nucleus of various tumoral and non-tumoral cell types including human brain cortical neurons in vivo. The reversible blockade of STX1B-DeltaTMD nuclear import demonstrated that nuclear import occurred via a Ran-dependent pathway. A specific and glycine-rich C-terminus of 15 amino acids served as an unconventional nuclear localization signal. STX1B-DeltaTMD colocalized with Lamin A/C and NuMA (NUclear Mitotic Apparatus protein) in interphasic nuclei, and with NuMA and gamma-tubulin in the pericentrosomal region of the mitotic spindle in dividing cells. In a series of 37 human primary brain tumors, the ratio of STX1B-DeltaTMD to Lamin A/C transcripts was a significant prognostic marker of survival, independent of tumor staging. The characterization of STX1B-DeltaTMD as the first nucleoplasmic syntaxin with no transmembrane domain, illustrates the importance of alternative splicing in the emergence of unsuspected properties of the syntaxins in human cells, in both physiological and pathological conditions.

Familial generalized epilepsy in Bulgarian Roma.

AIMS: Gypsy communities constitute cultural and frequently inbred genetic isolates. Several genetic neurological disorders have been identified in these communities. Epilepsy appears as a fairly frequent medical condition among Bulgarian Gypsies, and many patients can be related to large pedigrees that may then be studied by conventional genetic linkage analyses. PATIENTS AND METHODS: We identified two large Wallachian Gypsy families from the Plovdiv and Varna regions of Bulgaria, with detailed clinical questionnaires and examination, and EEG recordings for many. Genetic linkage analysis was performed using microsatellite markers spaced across the human genome. RESULTS: Although phenotypes were not always easy to identify, epilepsy appears in both families as a dominant, or pseudo-dominant trait, with the characteristics of idiopathic generalized epilepsy with onset at various ages, with infrequent, generalized tonic-clonic seizures, some associated with fever in childhood, but without sensitivity to fever in later life. While few markers yielded LOD scores > 2, no locus showed significant linkage, assuming autosomal dominant or recessive modes of inheritance. CONCLUSION: Idiopathic generalized epilepsy, with a marked familial character, has not been reported to date in Bulgarian Gypsies. Both pedigrees studied here present with an identifiable epilepsy type inherited as a Mendelian trait. Despite the current lack of significant linkage, these families may constitute interesting ground for further genetic studies, on condition that more patients and families can be recruited. [Published with supplemental data on DVD].

SRPX2 mutations in disorders of language cortex and cognition.

The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.

Large-scale expression study of human mesial temporal lobe epilepsy: evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex.

Human mesial temporal lobe epilepsies (MTLE) are the most frequent form of partial epilepsies and display frequent pharmacoresistance. The molecular alterations underlying human MTLE remain poorly understood. A two-step transcriptional analysis consisting in cDNA microarray experiments followed by quantitative RT-PCR validations was performed. Because the entorhinal cortex (EC) plays an important role in the pathophysiology of the MTLE and usually discloses no detectable or little cell loss, resected EC and each corresponding lateral temporal neocortex (LTC) of MTLE patients were used as the source of disease-associated and control RNAs, respectively. Six genes encoding (i) a serotonin receptor (HTR2A) and a neuropeptide Y receptor type 1 (NPY1R), (ii) a protein (FHL2) associating with the KCNE1 (minK) potassium channel subunit and with presenilin-2 and (iii) three immune system-related proteins (C3, HLA-DR-gamma and CD99), were found consistently downregulated or upregulated in the EC of MTLE patients as compared with non-epileptic autopsy controls. Quantitative western blot analyses confirmed decreased expression of NPY1R in all eight MTLE patients tested. Immunohistochemistry experiments revealed the existence of a perivascular infiltration of C3 positive leucocytes and/or detected membrane attack complexes on a subset of neurons, within the EC of nine out of eleven MTLE patients. To summarize, a large-scale microarray expression study on the EC of MTLE patients led to the identification of six candidate genes for human MTLE pathophysiology. Altered expression of NPY1R and C3 was also demonstrated at the protein level. Overall, our data indicate that local dysregulation of the neurotransmission and complement systems in the EC is a frequent event in human MTLE.