Can urinary excretion rate of malondialdehyde, uric acid and protein predict the severity and impending death in perinatal asphyxia?

Background

Perinatal asphyxia (PA) associated with multi-organ damage is a leading cause of neonatal mortality and morbidity. We evaluated if urinary malondialdehyde:creatinine (UMDA:Cr), uric acid:creatinine (UUA:Cr) and protein:creatinine (UP:Cr) vary with the severity of PA and if these parameters can predict the impending death in PA.

Methods

Study included 20 asphyxiated and 20 healthy newborn males. Hypoxic-ischemic encephalopathy (HIE) staging, APGAR (activity, pulse, grimace, appearance and respiration) score and urinary protein, uric acid, creatinine and MDA were evaluated.

Results

UMDA:Cr, UUA:Cr and UP:Cr were significantly higher and correlated with APGAR and HIE in PA. By regression analysis also, urinary parameters were found to have significant association with HIE stage and APGAR in PA. Receiver operating characteristics (ROC) curve of UP:Cr, UUA:Cr and UMDA:Cr showed area under curve of 0.896 (p = 0.003), 0.859 (p = 0.008) and 0.849 (p = 0.010) with cut-off value of 9.04 mg, 2.34 mg and 3.49 µg/mg of creatinine respectively that can optimally predict the impending death in PA. SDS-PAGE of unconcentrated urine detected both high (73 kDa and 68 kDa) and low molecular weight proteins (52 kDa, 47 kDa, 25 kDa and 20 kDa) in PA but not in controls.

Conclusion

Urinary excretion rate of uric acid, MDA and proteins is higher and has potential to act as biochemical markers for severity evaluation and death prediction in PA.     

Effects of in utero arsenic exposure on child immunity and morbidity in rural Bangladesh

Chronic exposure to arsenic, a potent carcinogen and toxicant, via drinking water is a worldwide public health problem. Because little is known about early-life effects of arsenic on immunity, we evaluated the impact of in utero exposure on infant immune parameters and morbidity in a pilot study. Pregnant women were enrolled at 6–10 weeks of gestation in Matlab, a rural area of Bangladesh, extensively affected by arsenic contamination of tubewell water. Women (n = 140) delivering at local clinics were included in the study. Anthropometry and morbidity data of the pregnant women and their children, as well as infant thymic size by sonography were collected. Maternal urine and breast milk were collected for immune marker and arsenic assessment. Maternal urinary arsenic during pregnancy showed significant negative correlation with interleukin-7 (IL-7) and lactoferrin (Ltf) in breast milk and child thymic index (TI). Urinary arsenic was also positively associated with fever and diarrhea during pregnancy and acute respiratory infections (ARI) in the infants. The effect of arsenic exposure on ARI was only evident in male children. The findings suggest that in utero arsenic exposure impaired child thymic development and enhanced morbidity, probably via immunosuppression. The effect seemed to be partially gender dependent. Arsenic exposure also affected breast milk content of trophic factors and maternal morbidity.     

A validated UV spectrophotometric method for estimation of nebivolol hydrochloride in bulk and pharmaceutical formulation

A simple, sensitive and accurate UV spectrophotometric method was developed for the assay of nebivolol hydrochloride in raw material and tablets. Validation of the method yielded good results concerning range, linearity, precision and accuracy. The absorbance was measured at 282 nm for nebivolol hydrochloride tablet solution. The linearity range was found to be 5-50 microg/mL for the drug. It was found that the excipients present in the commercial formulation did not interfere with the method.     

A validated UV spectrophotometric method for determination of duloxetine hydrochloride

A simple, sensitive and accurate UV spectrophotometric method was developed for the assay of duloxetine hydrochloride in raw material and capsules. Validation of the method yielded good results concerning range, linearity, precision and accuracy. The absorbance was measured at 290 nm for duloxetine capsule solution. The linearity range was found to be 5-50 microg/mL for the drug. It was found that the excipients in the commercial formulation did not interfere with the methods.     

Lead effects on development and function of bone marrow-derived dendritic cells promote Th2 immune responses

Although lead (Pb) has significant effects on the development and function of macrophages, B cells, and T cells and has been suggested to promote allergic asthma in mice and humans, Pb modulation of bone marrow (BM)-derived dendritic cells (DCs) and the resultant DC effects on Th1 and Th2 development have not been examined. Accordingly, we cultured BM cells with murine granulocyte macrophage-colony stimulating factor (mGM-CSF)+/-PbCl(2). At day 10, culture supernatant (SN) and non-adherent cells were harvested for analysis. Additionally, day 10 non-adherent BM-DCs were harvested and recultured with mGM-CSF+LPS+/-Pb for 2 days. The day 10 Pb exposure significantly inhibited BM-DC generation, based on CD11c expression. Although fewer DCs were generated with Pb, the existing Pb-exposed DCs had significantly greater MHC-II expression than did the non-Pb-exposed DCs. However, these differences diminished upon LPS stimulation. After LPS stimulation, CD80, CD86, CD40, CD54, and MHC-II were all up-regulated on both Pb-DCs and DCs, but Pb-DCs expressed significantly less CD80 than did DCs. The CD86:CD80 ratio suggests a Pb-DC potential for Th2 cell development. After LPS stimulation, IL-6, IL-10, IL-12 (p70), and TNF-alpha levels significantly increased with both Pb-DCs and DCs, but Pb-DCs produced significantly less cytokines than did DCs, except for IL-10, which further supports Pb-DC preferential skewing toward type-2 immunity. In vitro studies confirm that Pb-DCs have the ability to polarize antigen-specific T cells to Th2 cells. Pb-DCs also enhanced allogeneic and autologous T cell proliferation in vitro, and in vivo studies suggested that Pb-DCs inhibited Th1 effects on humoral and cell-mediated immunity. The Pb effect was mainly on DCs, rather than on T cells, and Pb's modification of DC function appears to be the main cause of Pb's promotion of type-2-related immunity, which may relate to Pb's enhanced activation of the Erk/MAP kinase pathway.     

Behavioral Deficits Induced by Somatostatin-Positive GABA Neuron Silencing Are Rescued by Alpha 5 GABA-A Receptor Potentiation

IntroductionDeficits in somatostatin-positive gamma-aminobutyric acid interneurons (SST+ GABA cells) are commonly reported in human studies of mood and anxiety disorder patients. A causal link between SST+ cell dysfunction and symptom-related behaviors has been proposed based on rodent studies showing that chronic stress, a major risk factor for mood and anxiety disorders, induces a low SST+ GABA cellular phenotype across corticolimbic brain regions; that lowering Sst, SST+ cell, or GABA functions induces depressive-/anxiety-like behaviors (a rodent behavioral construct collectively defined as “behavioral emotionality”); and that disinhibiting SST+ cells has antidepressant-like effects. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions, α5-GABAA receptor positive allosteric modulators (α5-PAMs), achieved antidepressant-like effects. Together, the evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in mood disorders and that rescuing SST+ cell function via α5-PAM may represent a targeted therapeutic strategy.MethodsWe developed a mouse model allowing chemogenetic manipulation of brain-wide SST+ cells and employed behavioral characterization 30 minutes after repeated acute silencing to identify contributions to symptom-related behaviors. We then assessed whether an α5-PAM, GL-II-73, could rescue behavioral deficits.ResultsBrain-wide SST+ cell silencing induced features of stress-related illnesses, including elevated neuronal activity and plasma corticosterone levels, increased anxiety- and anhedonia-like behaviors, and impaired short-term memory. GL-II-73 led to antidepressant- and anxiolytic-like improvements among behavioral deficits induced by brain-wide SST+ cell silencing.ConclusionOur data validate SST+ cells as regulators of mood and cognitive functions and demonstrate that bypassing low SST+ cell function via α5-PAM represents a targeted therapeutic strategy.     

Small cell neuroendocrine carcinoma of nose and paranasal sinuses: a study of three cases with short review of the literature

Primary small cell neuroendocrine carcinoma (SNEC) of nose and paranasal sinuses is an extremely rare malignant tumour known for its aggressive clinical course, high rate of recurrence and poor prognosis. Only 69 cases have been reported in world literature till March, 2006. This tumour usually occurs in elderly persons with main complaints being nasal obstruction, epistaxis, loss of visual acuity, exophthalmos, local pain and rarely tender swelling over the sinuses. Computerized tomography scan (CT) is essential to assess the size, extent of the tumour, evidence of bone destruction and infiltration to orbit and brain. Due to its rarity, the understanding of pathogenesis of the disease, diagnosis and ideal treatment have been difficult. The origin of the tumour is believed from basal cells of the olfactory mucosa. The present study deals with three cases of SNECs of nose and paranasal sinuses in elderly males, their clinical presentations, CT scan findings, histopathological diagnosis with short review of literature.     

Physiological concentrations of dopamine inhibit the proliferation and cytotoxicity of human CD4+ and CD8+ T cells in vitro: a receptor-mediated mechanism.

OBJECTIVE: Dopamine, a catecholamine neurotransmitter, influences growth and proliferation of lymphocytes. Pharmacological doses of dopamine have been shown to modulate T cell functions significantly, but no information is available on the effect of physiological concentrations of circulating dopamine on CD4+ and CD8+ T cell functions. This information may be of importance since significantly elevated plasma dopamine levels were observed in humans during uncoping stress, and suppression of T cell functions during stress is a well-known phenomenon. However, the mechanism inducing the suppression of T cell functions during stress is not yet clear. In the present investigation, we evaluated the effect of the dopamine level attained in the plasma of individuals with uncoping stress on the proliferation and cytotoxicity of CD4+ and CD8+ T cells in vitro. METHODS: T cell subpopulations were separated by panning. The effect of dopamine on IL-2-induced cell proliferation in vitro was evaluated by [3H]thymidine incorporation and cytotoxicity by 51Cr release, receptors by radioligand binding, cAMP by an assay kit and apoptosis by DNA fragmentation. RESULTS: At these elevated physiological concentrations, dopamine was found to inhibit significantly the proliferation and cytotoxicity of CD4+ and CD8+ T cells in vitro. This dopamine-mediated inhibition of proliferation was more marked on CD8+ T cells than on CD4+ T cells. The underlying mechanism was found to be D1 class of dopamine-receptor-mediated stimulation of intracellular cAMP. CONCLUSION: Results may be of significance to understand the role of peripheral dopamine in human neuroimmune communication in terms of physiological homeostasis in health and disease.