Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.

Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.

Detection of evoked acetylcholine release in mouse brain slices.

The study of transmitter interactions in reward and motor pathways in the brain, including the striatum, requires methodology to detect stimulus-driven neurotransmitter release events. Such methods exist for dopamine, and have contributed to the understanding of local and behavioral factors that regulate dopamine release. However, factors that regulate release of another key transmitter in these pathways, acetylcholine (ACh), are unresolved, in part because of limited temporal and spatial resolution of current detection methods. We have optimized a voltammetric method for detection of local stimulus-evoked ACh release using enzyme-coated carbon-fiber microelectrodes and fast-scan cyclic voltammetry. These electrodes are based on the detection of H2O2 generated by the actions of acetylcholine esterase and choline oxidase, and reliably respond to ACh in a concentration-dependent manner. Methods for enzyme coating were optimized for mechanical stability that allowed for their use in ex vivo brain slices. We report here the first quantitative assessment of extracellular ACh concentration after local electrical stimulation in dorsal striatum in slices from control mice. The selective detection of ACh under these conditions was confirmed by showing that the response detected in the control slices was absent in slices from mice bred to lack ACh synthesis in the forebrain. These electrodes represent a new tool to study ACh and ACh-dopamine interactions with micrometer spatial resolution.

Anemia Offers Stronger Protection Than Sickle Cell Trait Against the Erythrocytic Stage of Falciparum Malaria and This Protection Is Reversed by Iron Supplementation.

BACKGROUND: Iron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodium falciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection. METHODS: This observational cohort study occurred in a malaria-endemic region where sickle-cell trait is also common. We studied fresh RBCs from anemic children (135 children; age 6-24months; hemoglobin <11g/dl) participating in an iron supplementation trial (ISRCTN registry, number ISRCTN07210906) in which they received iron (12mg/day) as part of a micronutrient powder for 84days. Children donated RBCs at baseline, Day 49, and Day 84 for use in flow cytometry-based in vitro growth and invasion assays with P. falciparum laboratory and field strains. In vitro parasite growth in subject RBCs was the primary endpoint. FINDINGS: Anemia substantially reduced the invasion and growth of both laboratory and field strains of P. falciparum in vitro (~10% growth reduction per standard deviation shift in hemoglobin). The population level impact against erythrocytic stage malaria was 15.9% from anemia compared to 3.5% for sickle-cell trait. Parasite growth was 2.4 fold higher after 49days of iron supplementation relative to baseline (p<0.001), paralleling increases in erythropoiesis. INTERPRETATION: These results confirm and quantify a plausible mechanism by which anemia protects African children against falciparum malaria, an effect that is substantially greater than the protection offered by sickle-cell trait. Iron supplementation completely reversed the observed protection and hence should be accompanied by malaria prophylaxis. Lower hemoglobin levels typically seen in populations of African descent may reflect past genetic selection by malaria. FUNDING: National Institute of Child Health and Development, Bill and Melinda Gates Foundation, UK Medical Research Council (MRC) and Department for International Development (DFID) under the MRC/DFID Concordat.

Sinus of Valsalva fistula with quadricuspid aortic valve, a first reported association.

Quadricuspid aortic valve and sinus of Valsalva fistula are rare congenital anomalies. We report the first case of association of these two congenital anomalies in an adult patient and the important role of Magnetic Resonance Imaging (MRI) in establishing and confirming the correct diagnosis and helping in planning the treatment.

Prevalence of hibernating myocardium in patients with severely impaired ischaemic left ventricles.

OBJECTIVE: Severe impairment of left ventricular (LV) contraction is associated with an adverse prognosis in patients with ischaemic heart disease. Revascularisation may improve the impaired LV contraction if hibernating myocardium is present. The proportion of patients likely to benefit from this intervention is unknown. Therefore, the prevalence of hibernating myocardium in patients with ischaemic heart disease and severe impairment of LV contraction was assessed. DESIGN: From a consecutive series of patients undergoing coronary angiography for the investigation of chest pain or LV impairment, all patients with ischaemic heart disease and an LV ejection fraction (LVEF) < or = 30% were identified. These patients underwent positron emission tomography (PET) to detect hibernating myocardium, identified by perfusion metabolism mismatch. SETTING: A teaching hospital directly serving 500,000 people. RESULTS: Of a total of 301 patients, 36 had ischaemic heart disease and an LVEF < or = 30%. Twenty-seven patients had PET images, while nine patients were not imaged because of emergency revascularisation (three), loss to follow up (one), inability to give consent (four), and age < 50 years (one, ethics committee guidelines). Imaged and non-imaged groups were similar in LV impairment, demographic characteristics, and risk factor profile. Fourteen patients (52% of the imaged or 39% of all patients with ischaemic heart disease and LVEF < or = 30%) had significant areas of hibernating myocardium on PET. CONCLUSION: It is possible that up to 50% of patients with ischaemic heart disease and severely impaired left ventricles have hibernating myocardium.

Alterations in the concentration of an apolipoprotein E-containing subfraction of plasma high density lipoprotein in coronary heart disease.

The concentrations of high density lipoprotein (HDL) subfractions in 100 healthy male subjects were compared with 100 newly presenting patients with myocardial infarction (MI) within 12 h of the onset of chest pain. A subfraction of HDL enriched in apolipoprotein E (apo E), separated by heparin-Sepharose affinity chromatography, was present in lower concentrations (P < 0.001) in the plasma of the coronary patients than in the control subjects. This finding was confirmed by a lower content (P < 0.02) of apo E, measured by ELISA, in the total HDL fraction isolated from the coronary patients. Gradient gel electrophoresis of the total HDL demonstrated that the coronary patients had a significantly decreased concentration of the large HDL particles, HDL2b, of mean diameter 10.57 nm and a higher concentration of the smaller-sized HDL3, especially HDL3c, of mean diameter 7.62 nm. The coronary patients had a lower concentration of HDL cholesterol than the control subjects, attributable to the HDL2 fraction, with no difference in HDL2a between the two groups. There was no difference in the concentration of plasma cholesterol or triglyceride. The distribution of apo E phenotypes was similar in the two groups. HDL2b produced the highest discriminant power between the two groups, followed by apo E-rich HDL, HDL2 and HDL3c Plasma cholesterol correlated strongly with apo E-rich HDL for control subjects but not for MI survivors. This study demonstrates that the inverse relationship between HDL cholesterol and coronary risk shown in epidemiological studies is attributable to the large, apo E-containing HDL subspecies which under some circumstances are implicated in cholesterol removal by reverse cholesterol transport. This study also suggests that the concentration of the large, apo E-containing HDL may provide a sensitive predictor for subjects at risk of developing coronary heart disease.

The role of intravenous cholangiography in pre-operative assessment for laparoscopic cholecystectomy.

With the advent of laparoscopic cholecystectomy, pre-operative identification of calculi in the common bile duct has become increasingly important. In patients without clinical or biochemical evidence of common bile duct calculi, debate continues as to the value of intravenous cholangiography (IVC) as a screening modality for the detection of unsuspected choledocholithiasis. In a prospective series of 180 patients, IVC was used to assess the common bile duct in 113 patients at low risk of choledocholithiasis, 51 patients at high risk underwent endoscopic retrograde cholangiography (ERC) and sphincterotomy if indicated, and in 16 patients, for a variety of reasons, no pre-operative cholangiography was performed. 31% of those who had ERC and two (1.8%) of those who had IVC had duct calculi. These data do not support the routine use of IVC in patients with no evidence of common bile duct calculi and its routine use has been discontinued.

Neonatal necrotizing enterocolitis: the long-term perspective.

Ten years' experience with neonatal necrotizing enterocolitis (NNEC) was reviewed retrospectively to determine long-term survival and quality of life and to analyze risk factors associated with in-hospital mortality. Institutional records were queried to identify all neonates who required emergent surgical intervention for NNEC. These records were then reviewed and survivors' families interviewed by phone to determine patient status, persistent gastrointestinal problems, and overall quality of life. Once identified, long-term survivors (LTSs) were compared to in-hospital deaths by the analysis of birth weight, gestational age, time interval from birth to diagnosis, indications for laparotomy, and extent of intestinal involvement. Between 1986 and 1996, 69 patients required surgical intervention for NNEC. Eleven patients were lost to follow-up. Of the remaining 58 patients, 31 were ultimately discharged home, with 28 patients having survived an average of 4.18 years. The acute, or in-hospital, mortality rate was 39.1 per cent. Infants who died did so within an average of 23 days postoperatively, and those who were discharged home required an average of 121 days of inpatient convalescence. Twenty-one of the 28 LTSs achieved a normal quality of life with no persistent health problems. One patient required a hepatic-intestinal transplant, and another six had minor problems with frequent diarrhea. Average birth weight, age at NNEC diagnosis, and gestational age were not significantly different between LTSs and those with acute deaths. Aggressive in-hospital care is warranted for infants with NNEC. The excellent quality of life achieved in 75 per cent of survivors implies that the expense of heroic surgical care for these seriously ill premature infants is a worthwhile investment.

The efficacy of focused abdominal sonography for trauma (FAST) as a screening tool in the assessment of injured children.

PURPOSE: Focused abdominal sonography for trauma (FAST) is rapidly gaining acceptance as an effective and accurate way to determine significant abdominal injury. The authors analyzed their experience in 94 children with blunt torso trauma (BTT) to assess FAST accuracy in identifying operative lesions and utility in avoiding additional diagnostic studies. METHODS: The authors' pediatric trauma registry was queried to identify all children with BTT who underwent FAST as part of their initial trauma assessment. Accuracy was determined by calculating sensitivity and specificity using as true positives those children with lesions requiring operative intervention. Utility was analyzed by reviewing the need for additional diagnostic or therapeutic intervention in those patients with negative FAST findings and negative clinical examination findings. RESULTS: Three of these 94 children had lesions that required laparotomy. One was FAST positive (sensitivity, 33.3%). One of two FAST-negative patients was a child in extremis from a suspected thoracic aortic disruption, and the other was a child with an intestinal disruption in whom peritoneal signs developed 24 hours after injury. Of 89 FAST-negative children, 20 underwent abdominal computed tomography (CT) at the surgeon's request. Eight of these patients were found to have minor visceral injury that required no further treatment. The remaining 69 included the child with the aortic disruption and 68 patients whose hospital course was uneventful and required no additional intervention. CONCLUSIONS: From the practical perspective of indicating need for operative intervention in BTT, FAST has a high specificity (95%); however, it is not particularly sensitive (33%). This excellent specificity in combination with clinical examination underscores FAST utility by avoiding unnecessary diagnostic intervention in 72% of the patients in this study.

Pediatric cervical spine injuries: defining the disease.

BACKGROUND/PURPOSE: Pediatric cervical spine injuries are uncommon. Most previous studies have been hampered by the small number of patients available for evaluation. The purpose of this study is to determine the incidence and characteristics of pediatric cervical spine injury utilizing a multiinstitutional pediatric trauma database, and to assess the impact of age and level of spine injury on mortality rate. METHODS: All children with cervical spine injury entered into the National Pediatric Trauma Registry over a consecutive 10-year period were identified. Patients were stratified by age, mortality, presence or absence of bony injury, level of cervical spine injury, and presence of neurologic deficit. Data were analyzed utilizing Student's t test for continuous variables and chi(2) analysis for categorical variables. Statistical significance was accepted at the P less than .05 level. RESULTS: From a database of 75,172 injured children, 1,098 were identified with cervical spine injury, overall incidence 1.5%. The mean age of the study group was 11 +/- 5 years, and 61% were boys. Nine hundred eight children (83%) had bony spine injury. Distribution of bony injury among upper cervical spine, lower cervical spine, or both was 52%, 28%, and 7%, respectively. The remaining 13% comprised unspecified levels of injury. Upper cervical spine injuries were prevalent among all age groups (42%, age < or = 8; 58%, age > 8), whereas lower spine injuries predominated in older children (85%, age > 8). One third of children in the study group had neurologic injury, and half of these had no radiographic evidence of bony injury. Ninety-four children (24%) had a complete cord injury, and the remaining 76% had an incomplete spinal cord injury. One hundred eleven children (23%) with upper spine injury died compared with 11 children (4%) with lower spine injury. Mortality rate was highest (48%) in those with atlanto-occipital dislocation. CONCLUSIONS: From this, the largest experience with pediatric cervical spine injury, several conclusions can be drawn. (1) Cervical spine injury occurs in 1.5% of injured children. (2) Upper cervical spine injuries are not limited to younger children but are equally prevalent in both age groups. (3) Associated mortality rate is nearly 6-fold higher in patients with upper cervical injury. (4) Seventeen percent of children with cervical spine trauma show no radiologic anomaly, yet 50% of children with cervical spinal cord injury have no initial radiologic abnormalities. (5) Of those in whom cervical spine injury is associated with a neurologic deficit, the deficit is complete in 24% of children.

Infectious complications in critically injured children.

PURPOSE: Infection will complicate the care of a significant number of injured adults. Trauma is the leading cause of mortality in the pediatric population, yet little information is available regarding the incidence of infection in this group. This study evaluates infectious complications in the critically injured child. METHODS: All children admitted to the pediatric intensive care unit from an urban level-1 trauma center during an 80-consecutive-month period were studied. Infection was defined by Centers for Disease Control criteria and was identified by a retrospective review of the medical records. Demographic and clinical information, including microbiologic data, were compiled for all study patients. Data were analyzed using Student's (t)test or chi2 analysis where appropriate. RESULTS: Five hundred twenty-three children were at risk for infection during the study period. Seventy-eight infections were documented in 53 children (incidence, 10.1%). Nosocomial infections accounted for 78% of these with a majority (85%) being device associated. Common infections in this group included lower respiratory (n = 35), primary bloodstream (n = 10), and urinary tract (n = 7). Trauma-related infections were primarily wound (n = 9), intraabdominal (n = 3), or central nervous system (n = 3). Bacterial pathogens predominated, and the most frequent microorganisms recovered were Staphylococcus aureus, Pseudomonas sp, and Haemophilus sp. Children with infectious complications were more severely injured (injury severity score [ISS] 24 versus 17, P < .001) and had a longer hospital stay (21 days v 6 days, P < .001) compared with children without infection during the same period. Overall mortality rate for the study group was 5.7% and was not significantly different from children without infection. CONCLUSIONS: Infection is a significant source of morbidity in the critically injured child. Nosocomial infections predominate, and a majority of these are device related, emphasizing the need for continued vigilance toward prevention in this high-risk group.

Computed tomography (CT) appearances of acute pancreatitis presenting as polyarthropathy with subcutaneous fat necrosis.

A case of severe acute pancreatitis presenting with polyarthropathy and subcutaneous nodules but no abdominal pain is described. Abdominal CT showed multiple subcutaneous soft tissue densities which on histological examination were identified as areas of fat necrosis consistent with pancreatic disease. Such CT appearances have not been described previously.

Complications in 8793 cases of diabetes mellitus 14 years study in Bombay Hospital, Bombay, India.

Complications in 8793 hospitalised cases of diabetes in 14 years were present in 81.8 percent. It was equal in both sexes. They did not depend upon religious dietary habits or on economic condition/status of the patient. Hypertension was present in 42.2%. Ischaemic heart diseases in 27.2%. C.V.A. in 9.2% and gangrene and peripheral vascular diseases in 4.2%. Acute & chronic U.T.I. was in 31.4% and uraemia in 4.5% and K.W. Syndrome in 2.5%. In Infection Tuberculosis was in 5.9% and pyogenic skin infection in 4.1%. Vascular and renal complications increased with the duration of diabetes and with age in type II diabetes.

Prevalence of cerebrovascular accident in 4349 diabetic cases.

1. Prevalence of cerebrovascular accident in 4349 cases of diabetes admitted in the Bombay Hospital, Bombay between 1967 and 1975 was in 411 (9.45 percent) cases. 2. Number of males predominated, but was of no significance as compared to the occurrence of cerebrovascular in females. 3. Highest number of cases were in the age group of 61-70 years (statistically significant), which was a decade higher than the age of (51-60 years) maximum number of admitted cases in 4349 cases. The mortality increases with age, highest in age above 70 years-statistically significant. 4. The type and site of cerebrovascular accident had no relation to the age group or sex, duration and severity of diabetes. 5. Cerebrovascular accident was much less in the last 3 months of the year and was highest in the month of June, and is of no statistical significance. 6. Cerebrovascular accident was more prevalent in mild type diabetes, but mortality was higher in severe type of diabetes. 7. Cerebrovascular accident was prevalent in all types of blood pressure, but had highest mortality in severe hypertension. 8. Occurrence of CVA had no relation with the duration of diabetes.

Obesity. Effective and safe management.

Rapidly rising prevalence of weight in Indians in cities and upper strata of society in villages and towns is a problem of health in India. It also adds substantially to future morbidity and mortality and will increase the health costs. It is a public health problem. In other countries it is a national problem. It increase cost of treatment of the nation. It is individual matter in India. Hence the treatment of chronic diseases like hypertension diabetes, hyperlipidemia is not being effectively carried out in India due to burden of cost of treatment on individual. Lack of education and funds prevent continuous treatment. It is problem of education of public and a support from authorities. Those who are aware should not neglect their own health. Prevention of obesity should be the goal in life.

Cirrhosis of liver with ascites treatment based on principles of ayurved.

A case of ascites with cirrhosis of liver due to chronic malaria and nutritional deficiency was treated with 20 ml of imferron with improvement and is alive for a period of six years after first treatment with iron.

Falls in elderly.

Falls are common in elderly. They cause morbidily, mortality and financial hardship. They can be prevented with minimum cost. All steps should be taken. Remove the cause or causes as far as it is possible in the environment.

Hypertension in elderly.

Treatment of hypertension is necessary to prevent morbidity i.e. complications and early mortality. Adherence to the treatment is imperative. Education of the patient is a must on the part of the physician. Continuous regular treatment is economical than that of its complications.

GERD like symptoms as seen in a village.

Twenty cases of protozoal infection presented with symptoms suggesting GERD. Treatment with antacids and H2 blockers was unsuccessful in giving them relief. As they had also protozoal infection, treatment with anti-protozoal drugs gave them complete relief in the follow up period of one year after the end of treatment. Hence we have named these conditions simulating peptic ulcer GERD as pseodogerd or protozoal GERD. It is suggested that the person presenting with the symptoms of GERD in our area should be investigated for protozoal infection or should be given treatment of protozoal infection rather than that of peptic ulcers. It is also suggested that the length of treatment of protozoal infection should not be less than one month and not for three or 7 days as suggested in western text books.

Tetanus: study of 8,697 cases.

Records of 8,697 cases of tetanus seen over a period of 14 years are analysed. Overall mortality was 48.0%. Mortality in neonatal group was 86.38% whereas that in non-neonatal group it was 40.18%. Disease was seen more frequently in male than in female. Mortality in male was lower than in female. Incidence was highest in the first decade of life. Mortality was lowest (about 33%) in first two decades (excluding neonatal group). Mortality in neonatal group was highest (86.38%). Mortality was inversely related to length of incubation period. In cases with incubation period of 7 days or less, mortality was 58.26% in non-neonates and 94.15% in neonates. Mortality was very low (2.14%) in 2,100 cases who did not develop spasms. In cases with spasms mortality was inversely related to the length of period of onset. Temperature of 100 degrees F within first 24 hours of admission was an adverse factor and these cases had higher mortality. Cases were divided into five grades according to the severity. Mortality in each grade was significantly different from that in the other. Mortality was lower in otogenic tetanus while it was higher in post-abortion and post-injection tetanus. Tetanus following penetrating injury carried higher mortality whereas tetanus following abrasions had lower mortality. With head and face as the site of infection, mortality was low while it was high when the site of infection was a trunk. Results were similar with dose of A.T.S. ranging between 5,000 and 60,000 i.u. and tetanus immune globulin, whereas mortality was high with higher and lower dose of A.T.S. or with no A.T.S. Respiratory spasms, respiratory failure, respiratory complications and circulatory failure were the common causes of death.