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.

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.

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.

Effect of Zidovudine and its interaction with rocuronium on neuromuscular transmission.

Neuromuscular weakness is often found in patients receiving zidovudine therapy due to mitochondrial damage. Effect of zidovudine was evaluated in indirectly and directly stimulated isolated rat phrenic nerve hemidiaphragm preparations, by cumulative dose response curve with square wave pulses, 0.5 ms duration of 2 Hz at every 10 s. To understand the observed effect of zidovudine, interaction studies were carried out with rocuronium. Dose response curve of rocuronium was compared in the absence and in the presence of 1.2 and 12 mmol/ml zidovudine. In another set of experiment, intact animals were treated with zidovudine 50 and 100 mg/kg for 15 days and phrenic nerve hemidiaphragm was obtained for in vitro experiment. Effect of zidovudine (30 mmol/ml) on twitch responses inhibited by dantrolene 50 µmol/ml, magnesium chloride 8 mmol/ml, rocuronium 10 µmol/ml, succinylcholine 25 µmol/ml and lignocaine 600 µmol/ml was studied. Zidovudine (3-30 mmol/ml) significantly augmented the twitch responses up to 80 and 40% in indirectly and directly stimulated preparations, respectively (P<0.05). Zidovudine did not show significant interaction with rocuronium in any group as per dose response curve and inhibitory concentration 5%, inhibitory concentration 50% and inhibitory concentration 95% of rocuronium. Zidovudine (30 mmol/ml) augmented the twitch responses inhibited by dantrolene, magnesium chloride and rocuronium. It reduced the time for complete block of succinylcholine (P<0.05). Zidovudine affects the neuromuscular transmission. No conclusive interaction between rocuronium and zidovudine was found.

Neuromuscular blocking effect of fluoxetine and its interaction with rocuronium.

As selective serotonin reuptake inhibitors have an inhibitory effect on nicotinic acetylcholine receptors, they may affect the neuromuscular transmission and interact with neuromuscular blockers. This study was designed to observe the effect of fluoxetine on neuromuscular transmission and its interaction with rocuronium using the rat phrenic nerve hemidiaphragm and rabbit head drop methods. Rat phrenic nerve hemidiaphragms were mounted and stimulated using a train of four pulses (TOF). The effect of fluoxetine was studied on both indirectly and directly stimulated basal twitch responses by plotting cumulative dose response curves (DRCs). DRCs of rocuronium were obtained in the absence, and presence of 5 µm and 20 µm fluoxetine to study its interaction. ED5 , ED50 and ED95 values of rocuronium DRCs in absence and presence of fluoxetine were calculated. Fluoxetine significantly inhibited twitch responses in both indirect and directly stimulated preparations. Fluoxetine (20 µm) caused an increase in the potency of rocuronium such that the ED50 and ED95 values of rocuronium DRCs were significantly decreased. Partially inhibited twitch responses by fluoxetine (100 µm) were not reversed by neostigmine (3.3 µm) or 3,4 diaminopyridine (0.25 µm). Rabbits were given fluoxetine 0.25 mg kg(-1) and 1 mg kg(-1) orally for 15 days, and on 15th day, rocuronium infusion was given, and time for head drop was recorded. The time of head drop was significantly reduced in fluoxetine pretreated as compared to control group. Fluoxetine blocks the neuromuscular transmission and increases the potency of rocuronium-induced neuromuscular block.

Dopamine release in the basal ganglia.

Dopamine (DA) is a key transmitter in the basal ganglia, yet DA transmission does not conform to several aspects of the classic synaptic doctrine. Axonal DA release occurs through vesicular exocytosis and is action potential- and Ca²âº-dependent. However, in addition to axonal release, DA neurons in midbrain exhibit somatodendritic release by an incompletely understood, but apparently exocytotic, mechanism. Even in striatum, axonal release sites are controversial, with evidence for DA varicosities that lack postsynaptic specialization, and largely extrasynaptic DA receptors and transporters. Moreover, DA release is often assumed to reflect a global response to a population of activities in midbrain DA neurons, whether tonic or phasic, with precise timing and specificity of action governed by other basal ganglia circuits. This view has been reinforced by anatomical evidence showing dense axonal DA arbors throughout striatum, and a lattice network formed by DA axons and glutamatergic input from cortex and thalamus. Nonetheless, localized DA transients are seen in vivo using voltammetric methods with high spatial and temporal resolution. Mechanistic studies using similar methods in vitro have revealed local regulation of DA release by other transmitters and modulators, as well as by proteins known to be disrupted in Parkinson's disease and other movement disorders. Notably, the actions of most other striatal transmitters on DA release also do not conform to the synaptic doctrine, with the absence of direct synaptic contacts for glutamate, GABA, and acetylcholine (ACh) on striatal DA axons. Overall, the findings reviewed here indicate that DA signaling in the basal ganglia is sculpted by cooperation between the timing and pattern of DA input and those of local regulatory factors.

Immunocytochemical identification of proteins involved in dopamine release from the somatodendritic compartment of nigral dopaminergic neurons.

We examined the somatodendritic compartment of nigral dopaminergic neurons by immunocytochemistry and confocal microscopy, with the aim of identifying proteins that participate in dopamine packaging and release. Nigral dopaminergic neurons were identified by location, cellular features and tyrosine hydroxylase immunoreactivity. Immunoreactive puncta of vesicular monoamine transporter type 2 and proton ATPase, both involved in the packaging of dopamine for release, were located primarily in dopaminergic cell bodies, but were absent in distal dopaminergic dendrites. Many presynaptic proteins associated with transmitter release at fast synapses were absent in nigral dopaminergic neurons, including synaptotagmin 1, syntaxin1, synaptic vesicle proteins 2a and 2b, synaptophysin and synaptobrevin 1 (VAMP 1). On the other hand, syntaxin 3, synaptobrevin 2 (VAMP 2) and SNAP-25-immunoreactivities were found in dopaminergic somata and dendrites Our data imply that the storage and exocytosis of dopamine from the somatodendritic compartment of nigral dopaminergic neurons is mechanistically distinct from transmitter release at axon terminals utilizing amino acid neurotransmitters.

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.

Masquerade: a malignant arrhythmia masquerading as benign.

Pseudoatrial flutter has been reported to have benign causes, but this is the first report of a malignant arrhythmia presenting as a benign arrhythmia. An 82 year old patient presented with ventricular tachycardia and electrical artefact appearing as atrial flutter. In this case, comparing the morphology of the QRS complexes in the rhythm strip with those in lead II showed the arrhythmia to be ventricular in origin and points to the importance of comparing all leads of the ECG before arriving at a diagnosis.

Follow up of 318 cases of diabetes mellitus.

Ignorance, apathy, desire to get free advice, investigation and treatment is prevalent in diabetics. Most diabetics (69.63%) are uncontrolled whether on diet, single oral drug or combination of oral drugs or insulin. Ischemic heart disease was commonest complication. Neuritis was present in the one fourth of the followed up cases and was more prevalent in uncontrolled cases. Hypertension increases with the duration of diabetes and was twice more prevalent after duration of more than 5 years. Eye changes were present in about 50% of the people examined. Abnormality increases with the duration of diabetes.

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.

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.

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.

Nosocomial pneumonia in the pediatric trauma patient: a single center's experience.

OBJECTIVES: To evaluate a single center's experience with the frequency rate, patterns of occurrence, and impact on outcome of nosocomial pneumonia in the critically injured child. DESIGN: Retrospective review of prospectively collected data. SETTING: Level I university trauma center with a pediatric trauma intensive care unit. PATIENTS: A total of 523 consecutive critically injured children admitted to the pediatric intensive care unit during an 80-month interval. MEASUREMENTS AND RESULTS: Thirty-five episodes of nosocomial pneumonia were identified in 29 children (frequency rate of 5.5%). The mean age of the children was 9.2 yrs, and the mean Injury Severity Score was 27 +/- 9. In 91% of patients (26 children), nosocomial pneumonia was associated with mechanical ventilation. This represented a 13% frequency rate in injured children who were ventilated during the study period. The most common organisms recovered were Staphylococcus aureus (21%), Haemophilus influenzae (19%), Pseudomonas (11%), and Enterobacter (11%). Early pneumonia (diagnosed < or = 7 days after injury) was predominantly caused by Haemophilus species. In contrast, Enterobacter and/or Pseudomonas were isolated primarily in late pneumonia (diagnosed >7 days after injury). Staphylococcus was prominent throughout the hospitalization. Overall, children with nosocomial pneumonia were more severely injured (Injury Severity Score 27 vs. 17, p < .001) and had a longer hospital stay (26 vs. 7 days, p < .001). Despite this, mortality (6.9% vs. 7.9%, p = NS) was not significantly different from injured children without pneumonia. CONCLUSIONS: In this study of a single pediatric trauma center, nosocomial pneumonia occurred in a small but significant percentage of injured children. The frequency rate increased two- to three-fold with mechanical ventilation. Microbiology varied with day of onset. In contrast to the adult, mortality did not seem to be significantly altered by this complication. Analysis of additional pediatric trauma centers is encouraged to confirm these characteristics of nosocomial pneumonia in the injured child.

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.

Pharmacomechanical thrombolysis with use of the brush catheter in canine thrombosed femoropopliteal arterial PTFE bypass grafts.

PURPOSE: To assess the efficacy, acute endothelial changes, and distal arterial emboli after use of the Cragg thrombolytic brush catheter in mature thrombosed polytetrafluoroethylene (PTFE) femoropopliteal arterial grafts in canines. MATERIALS AND METHODS: PTFE femoropopliteal arterial grafts were implanted in 10 canines and were allowed to mature for approximately 4 weeks. The grafts were thrombosed by mechanical means and allowed to remain thrombosed for 24-72 hours. Through a left carotid cut-down, standard Seldinger arterial puncture was performed, followed by catheterization of the thrombosed graft. A soft, low-speed, brush (6 mm in diameter) aided by preprocedure pulse-spray urokinase infusion was utilized for thrombolysis. The native vessels, just proximal and distal to the anastomosis, were evaluated microscopically for endothelial damage. Arteriography was used for assessment of distal embolus. RESULTS: All grafts were successfully thrombosed before thrombolysis. One graft could not be traversed with a wire and catheter and was, therefore, not treated. Immediate preprocedure pulse-spray urokinase infusion in the remaining nine grafts did not reconstitute antegrade flow in any instance and left significant amounts of residual thrombus in all treated grafts. Mechanical brush thrombolysis reconstituted antegrade flow in all nine treated grafts and complete graft thrombolysis was obtained in most. This was accomplished in a mean time of less than 4 minutes. Emboli were noted angiographically in 67% of cases. Histologic studies showed vessel wall damage limited to the intima or media in 67% of anastomoses. CONCLUSION: This method offers a simple and rapid means of recanalizing thrombosed PTFE femoropopliteal arterial grafts in the studied model. This technique provides a means of rapidly "debulking" most intragraft thrombi. This may result in a shorter course of thrombolytic infusion. Potential benefits may include shortening the total treatment time and decreasing morbidity and cost associated with percutaneous thrombolysis. The occurrence of distal emboli in a majority of cases is a concerning limitation of this technique.