A circadian study of liver antioxidant enzyme systems of female Fischer-344 rats subjected to dietary restriction for six weeks.

We examined the influences of dietary restriction (DR) on the circadian profile of liver catalase (CAT), glutathione peroxidase (GPx), and interacting systems required for removal of H₂O₂ (support systems), in 18-week old female Fischer 344 rats fed 60% of their ad libitum (AL) diet for six weeks. Food was presented to the DR animals during the early light-span. Regardless of diet, enzyme levels were generally consistent with circadian patterns. In CR animals, maximum activities often occurred at the time of food presentation. CAT and GPx activities generally were significantly higher in DR animals than in AL animals at the time of feeding. When assessing glucose-6-phosphate dehydrogenase (G6PDH) activity using saturating substrate (NADP⁺) concentrations, higher activities were seen at all times of day in the AL animals; however, when activity was measured in the presence of lower (i.e., physiologic) NADP⁺ concentrations, the reverse was true. In contrast, glutathione reductase (GR) activity was not influenced by DR. Cytosolic levels of NADPH peaked and were higher in DR than in AL rodents prior to feeding. NADH levels were not influenced by diet, but did manifest a significant circadian pattern with a maximum occurring toward the middle of the dark span. These data suggest that even at a young age and following only a relatively brief duration of DR, there exists an enhanced enzymatic capability in rats subjected to DR to remove free radicals generated as a consequence of normal oxidative metabolism. Further, these data support emerging trends suggesting metabolic regulation of antioxidant defense systems in response to free radical generation.     

Neonatal screening for haemoglobin variants using filter paper-dried blood specimens.

Neonatal screening for haemoglobinopathies utilizing cord blood samples is well established, although it has a high miss rate and has the inherent problem of possible misdiagnosis from maternal contamination of the sample. The use of dried Guthrie card samples which are taken at six days of age avoids these problems and has the advantage of using an established system of sample collection. Controversy exists as to the method of choice for analysis of dried samples, this study of 2406 samples found that Iso-electric focusing (IEF) analysis of dried specimens gives excellent correlation when compared with cellulose acetate/citrate agar electrophoresis of liquid cord blood samples. The IEF results were clear and relatively simple to interpret even when the samples had been stored at room temperature for 4 weeks. The commercial enzyme linked immunosorbent assay (ELISA) screening test JOSHUA reliably determines the presence or absence of haemoglobin S in dried specimens. It could therefore be used as a relatively cheap and simple method for the confirmation of sickle cell trait in neonatal screening programmes based on dried specimens.     

Tumor-related hyponatremia

Hyponatremia is an important and common electrolyte disorder in tumor patients and one that has been reported in association with a number of different primary diagnoses. The correct diagnosis of the pathophysiological basis for each patient is important because it significantly alters the treatment approach. In this article, we review the epidemiology and presentation of patients with hyponatremia, the pathophysiologic groups for the disorder with respect to sodium and water balance and the diagnostic measures for determining the correct pathophysiologic groups. We then present the various treatment options based on the pathophysiologic groups including a mathematical approach to the use of hypertonic saline in management. In cancer patients, hyponatremia is a serious comorbidity that requires particular attention as its treatment varies by pathophysiologic groups, and its consequences can have a deleterious effect on the patient's health.     

Etiology of distinct membrane excitability in pre- and posthearing auditory neurons relies on activity of Cl? channel TMEM16A

The developmental rehearsal for the debut of hearing is marked by massive changes in the membrane properties of hair cells (HCs) and spiral ganglion neurons (SGNs). Whereas the underlying mechanisms for the developing HC transition to mature stage are understood in detail, the maturation of SGNs from hyperexcitable prehearing to quiescent posthearing neurons with broad dynamic range is unknown. Here, we demonstrated using pharmacological approaches, caged-Ca²⁺ photolysis, and gramicidin patch recordings that the prehearing SGN uses Ca²⁺-activated Cl⁻ conductance to depolarize the resting membrane potential and to prime the neurons in a hyperexcitable state. Immunostaining of the cochlea preparation revealed the identity and expression of the Ca²⁺-activated Cl⁻ channel transmembrane member 16A (TMEM16A) in SGNs. Moreover, null deletion of TMEM16A reduced the Ca²⁺-activated Cl⁻ currents and action potential firing in SGNs. To determine whether Cl⁻ ions and TMEM16A are involved in the transition between pre- and posthearing features of SGNs we measured the intracellular Cl⁻ concentration [Cl⁻]_i in SGNs. Surprisingly, [Cl⁻]_i in SGNs from prehearing mice was ∼90 mM, which was significantly higher than posthearing neurons, ∼20 mM, demonstrating discernible altered roles of Cl⁻ channels in the developing neuron. The switch in [Cl⁻]_i stems from delayed expression of the development of intracellular Cl⁻ regulating mechanisms. Because the Cl⁻ channel is the only active ion-selective conductance with a reversal potential that lies within the dynamic range of SGN action potentials, developmental alteration of [Cl⁻]_i, and hence the equilibrium potential for Cl⁻ (E_Cl), transforms pre- to posthearing phenotype.The dynamic range of neuronal action potentials (APs) resides within voltages that are outside the reversal potentials (E_rev) of most ion currents except Cl⁻ currents, making Cl⁻ conductance the most versatile one in a course of a single AP. Neurons use this adaptable feature of Cl⁻ conductance with respect to the resting membrane potential (RMP) of neurons to confer synaptic plasticity by altering intracellular Cl⁻ (Cl⁻_i) homeostasis during development. This process transforms depolarizing GABA/glycinergic-mediated responses in immature to hyperpolarizing responses in mature neurons (1, 2). A similar synaptic switch has been described in auditory brainstem neurons, where the mature GABA/glycinergic-induced inhibitory neurotransmission contributes strongly toward the computation of interaural level and time differences required for sound source localization (3–6). The depolarization mediated by GABA/glycine in early postnatal development may increase intracellular Ca²⁺ concentration ([Ca²⁺]_i), which is predicted to promote synapse stabilization in the CNS (1). We hypothesized that besides synaptic plasticity one mechanism that alters the firing phenotype of developing neurons is via changes in intracellular Cl⁻ concentration ([Cl]_i) and activation of voltage and Ca²⁺-activated Cl⁻ channels (CaCCs).CaCCs are encoded by anoctamin 1 and 2 (ANO1 and 2), also known as transmembrane member 16A and B (TMEM16A and B) genes, which are expressed in epithelia and smooth muscle cells (7, 8) and in sensory cells such as nociceptive dorsal root ganglion neurons (9, 10), cilia of olfactory cells (11), and in rods and cones (12). The prevailing functions of CaCCs are ascribed to the amplification of pain sensation (10), cone responses (12), and olfactory signal transduction (13, 14), although recent reports using TMEM16B knockout mice suggest that CaCCs may play a limited role in signal amplification of olfactory transduction (11). TMEM16A has been identified in the cochlea in a cell-type-specific manner, showing robust labeling in basal cells of the stria vascularis and efferent endings of the auditory nerve (15), but its role in the inner ear has not been determined.The trademark of the developing auditory neuron is the rhythmic and burst-patterned spontaneous AP (SAP), which is thought to shape synapse formation and refinement in the brainstem (16, 17). In the inner ear, inputs from Ca²⁺-mediated SAPs from developing hair cells (HCs) sculpt the firing patterns of spiral ganglion neurons (SGNs) (18, 19). However, SGNs evolve from depolarizing hyperexcitable to hyperpolarized mature neurons with a wide dynamic range (20). Mechanisms underlying the remarkable changes in SGN phenotype during development are not well understood. Here, we demonstrate the origin and molecular mechanisms of the transition from primordial to mature auditory neurons. SGNs undergo marked alterations in intracellular Cl⁻ concentration ([Cl⁻]_i) handling during development and in doing so transform a predominantly inwardly driven Cl⁻ current into outwardly directed current through activation of TMEM16 channels.     

Epithelioid granuloma in the iris of a lepromatous leprosy patient; an unusual finding

This case report depicts a case of histopathologically confirmed polar lepromatous (LL) leprosy with a bacterial index of 4+. He experienced recurrent episodes of erythema nodosum leprosum (ENL) in the first 5 years after diagnosis. Skin smears became negative after 6 years of dapsone monotherapy and have remained negative since that time. At 23 years after diagnosis, the patient had developed cataracts and underwent intracapsular cataract extractions with broad-based iridectomies. In one of the iris specimens, histopathologic examination revealed a focal granuloma composed of epithelioid cells. Subsequently a lepromin skin test showed a positive Mitsuda reaction with a borderline tuberculoid histopathology. This clearly illustrates the immunological upgrading of a polar lepromatous patient, perceived first in the iris tissue.     

Type 2 diabetes in adult Nigerians: a study of its prevalence and risk factors in Port Harcourt, Nigeria

OBJECTIVES: This study aimed to assess the prevalence rates of type 2 diabetes and to determine potential associated risk factors of the disease in Port Harcourt, Nigeria. RESEARCH DESIGN AND METHODS: Five hundred and two (502) subjects aged above 40 years, obtained by a two-stage cluster sampling technique participated in this survey. Casual (random) plasma glucose estimations were done for all subjects after relevant personal data were obtained. Subjects with casual plasma glucose (CPG) > or =7.0 mmol/l had oral glucose tolerance tests (OGTT) done. Fasting and 2 h post glucose load blood samples were analyzed for plasma glucose levels. RESULTS: Thirty-four (34) subjects had diabetes, giving a crude prevalence rate of 6.8% (CI=4.6-9.0%), and standardized rate of 7.9%. The crude prevalence rates were 7.7 and 5.7% for males and females, respectively. Of the 34 diabetic subjects seen, 14 (41.2%) of them were not previously known to have diabetes; 83.7% of these were asymptomatic. Body mass index (BMI) > or = 25 kg/m2 and WHR > or = 0.85, family history of diabetes, physical inactivity, heavy consumption of alcohol, older age as well as high social status and Hausa-Fulani or Ibibio origin were associated with significantly higher prevalence of type 2 diabetes. CONCLUSION: The prevalence of type 2 diabetes in Port Harcourt is relatively high. Changing lifestyle associated with industrialization may explain this. A significant proportion of the diabetic subjects are asymptomatic and undiagnosed. The risk factors as shown in our study clearly emphasize the point that type 2 diabetes is to a large extent a preventable disease.