Alterations in hepatic kinase activity following whole body gamma-irradiation of mice

The chronological activation of the signaling molecules following whole body gamma-irradiation was investigated in mouse liver. The activity of two kinases, tyrosine kinase and protein kinase C (PKC), was found to respond differently to gamma-irradiation. Tyrosine kinase was found to respond to much lower doses of irradiation (10 cGy), whereas PKC was found to be activated at comparatively higher doses (3 Gy). Tyrosine kinase showed a sharp activation at 30 min and then a decline to normal values at 1 h. Activation of PKC was apparent at as early as 15 min of irradiation and showed a maximal increase at 30 min. This was followed by a decline to normal values at 1 h. The response of the whole organ was found to be different from that of reported effects on a single cell. These results suggest that the data obtained from the single-cell studies would have limited application in the experiments involving the whole animal. Interruption of these signals at various steps is currently being used to manipulate tumor response to radiotherapy. In such cases, the difference in response of a single cell and a whole animal must be considered.     

Assessment of oral bioavailability and preclinical pharmacokinetics of DRF-6196, a novel oxazolidinone analogue, in comparison to linezolid.

The aim of this study was to determine the bioavailability of a novel oxazolidinone, DRF-6196, in mice and rats following intravenous (i.v) and oral dosing and to compare the pharmacokinetics with those obtained following linezolid dosing. Blood samples were drawn at predetermined intervals up to 24 h post-dose after either DRF-6196 or linezolid administration. The concentrations of DRF-6196 and linezolid in various plasma samples were determined by a HPLC method. Following oral administration maximum concentrations of DRF-6196 were achieved within 0.5 h irrespective of the species. While the doses increased in the ratio of 1 : 3 : 10, mean Cmax and AUC(0-infinity) values in mice for DRF-6196 increased in the ratio of 1 : 3.87 : 8.53 and 1 : 2.51 : 9.24, respectively. Both the Cmax and AUC(0-infinity) values increased almost proportional to the dose administered in mice. Following i.v administration, the concentration of DRF-6196 declined in a bi-exponential fashion with terminal elimination half-life of 1.5 h irrespective of the species. The systemic clearance and volume of distribution of DRF-6196 in mice were 1.14 L/h/kg and 0.66 L/kg, respectively after i.v administration, while the respective values in rats were 0.61 L/h/kg and 0.41L/kg, respectively. Elimination half-life ranged between 0.8-1.5 h. Absolute oral bioavailability of DRF-6196 was found to be 80-96% across the test dose range. Although plasma levels of DRF-6196 were lesser compared to linezolid in the initial hours, it may not have any consequences on the clinical effectiveness of the molecule.     

Household Debt and Relation to Intimate Partner Violence and Husbands' Attitudes Toward Gender Norms: A Study Among Young Married Couples in Rural Maharashtra,India

Objective

Evidence has linked economic hardship with increased intimate partner violence (IPV) perpetration among males. However, less is known about how economic debt or gender norms related to men''s roles in relationships or the household, which often underlie IPV perpetration, intersect in or may explain these associations. We assessed the intersection of economic debt, attitudes toward gender norms, and IPV perpetration among married men in India.

Methods

Data were from the evaluation of a family planning intervention among young married couples (n=1,081) in rural Maharashtra, India. Crude and adjusted logistic regression models for dichotomous outcome variables and linear regression models for continuous outcomes were used to examine debt in relation to husbands'' attitudes toward gender-based norms (i.e., beliefs supporting IPV and beliefs regarding male dominance in relationships and the household), as well as sexual and physical IPV perpetration.

Results

Twenty percent of husbands reported debt. In adjusted linear regression models, debt was associated with husbands'' attitudes supportive of IPV (b=0.015, p=0.004) and norms supporting male dominance in relationships and the household (b=0.006, p=0.003). In logistic regression models adjusted for relevant demographics, debt was associated with perpetration of physical IPV (adjusted odds ratio [AOR] = 1.4, 95% confidence interval [CI] 1.1, 1.9) and sexual IPV (AOR=1.6, 95% CI 1.1, 2.1) from husbands. These findings related to debt and relation to IPV were slightly attenuated when further adjusted for men''s attitudes toward gender norms.

Conclusion

Findings suggest the need for combined gender equity and economic promotion interventions to address high levels of debt and related IPV reported among married couples in rural India.Intimate partner violence (IPV) perpetrated by male partners or husbands occurs in high proportions globally as well as in low- to middle-income countries such as India.^1,2 One recent multi-country household study found that 37% of men in India reported having ever perpetrated physical violence against a female intimate partner in their lifetime. The health burden of IPV has been well demonstrated, with significant effects on women''s sexual and reproductive health (e.g., increased sexually transmitted infections, unintended pregnancy, and poor pregnancy outcomes),^3–5 mental health (e.g., anxiety, depression, and substance use),^6,7 as well as a multitude of other poor health outcomes among women and their children (e.g., maternal and child malnutrition and infant death).^8,9Recent research among women has identified economic hardship (e.g., financial dependence on male partners and economic instability) as increasing women''s vulnerability to IPV.^10,11 Although studies have found an association between economic stressors and reports of male IPV perpetration,^12–16 no research has examined debt in relation to these outcomes.Debt and other economic decisions in the context of marriage, particularly in rural India, are largely under the control of husbands. Taking on debt may be associated with economic hardship, heightening stress levels among men, and, in turn, IPV. Also, previous work documenting the association between economic hardship and increased IPV perpetration by males^12–15 has largely been explained by perceptions related to men''s roles financially within the family (e.g., men who do not feel that they are providing financially for their families may perceive that they are not fulfilling their roles as husbands/males, and this perception related to lack of role fulfillment may escalate into violence). Given that a decision to take on debt appears to be largely controlled by men in this context and likely tied to their perceived role of providing financially for the family, a man''s decision to take out loans may be determined, in part, by their support of masculine gender norms (e.g., a man''s role in the family and male dominance and control in the household). In addition, given previous work highlighting the association between masculine gender norms and a number of risk behaviors among boys and men (e.g., substance and tobacco use and behaviors resulting in unintentional injury),^17–21 such gender norms may also be linked to taking on risks associated with debt, as well as debt-acquiring behaviors (e.g., spending money on nonessential goods such as alcohol).Gender norms pertaining to IPV, relationships, and the household are also important driving factors in terms of understanding men''s behaviors related to IPV. Cross-cultural research has shown that societies with greater gender inequities in social norms and policies have a higher prevalence of IPV.²¹ In the context of India and elsewhere, women''s low status in families and high levels of societal tolerance and acceptance of IPV promote IPV.²²More research is needed to understand economic hardship, and debt specifically, in relation to attitudes toward gender norms and IPV perpetration. Many studies have hypothesized that stress related to economic hardship and debts increases IPV perpetration;^12–15 however, less research has sought to understand the role of attitudes supportive of men''s more traditional gender norms in relationships or households in contributing to decisions to take on debt as well as in terms of explaining its association with increased IPV perpetration. Increased understanding of the mechanisms that explain associations between economic hardship/debt and IPV is needed to inform prevention approaches, particularly given the increasing number of economic promotion interventions being implemented globally and throughout India.Thus, the primary objective of the current study was to assess household debt in relation to husbands'' support of gender-inequitable norms and norms promoting IPV as well as husbands'' use of IPV against wives. The secondary objective of this study was to assess whether or not gender-based attitudes are important factors in debt and IPV, as well as in explaining an association between debt and increased risk for IPV perpetration among husbands.     

Hepatosplenic T Cell Lymphoma

A 26 year old lady came with intermittent fever since eight months. She also complained of abdominal pain and decreased appetite for six months. She had swelling of feet and distension of abdomen due to ascites since one month. There was history of jaundice one month back. On radiological examination, hepatomegaly with dilated portal vein, massive splenomegaly and ascites without any lymphadenopathy was noted. Chest X-ray was normal. Blood examination and bone marrow studies were inconclusive. We received her liver biopsy, which showed normal architecture and sinusoidal infiltration by a monomorphic population of small to intermediate sized lymphoid cells. Portal tracts were free of such infiltrate. These lymphoid cells were LCA, CD3, CD43 positive and negative for CD20, CD34, CD4, CD8 and c-kit. Based on all these features, a diagnosis of Hepatosplenic T cell lymphoma was made. She was treated symptomatically, however she died within two months of diagnosis.     

Glutaric aciduria type I and kynurenine pathway metabolites: A modified hypothesis

Glutaric aciduria type I is an inborn error of organic acid metabolism that demonstrates a particular temporal vulnerability (acute encephalopathic episodes in infancy) and a spatial vulnerability (acute striatal necrosis, focused on the putamen). Excitotoxic mechanisms involving 3-hydroxyglutaric acid as the major neurotoxin have been suggested. This paper proposes a role for metabolites of the kynurenine pathway in the pathogenic process and modifies the hypothesis of Heyes. Deficiency of glutaryl-CoA dehydrogenase blocking the glutarate pathway and activation of indoleamine 2,3-dioxygenase in macrophages/monocytes by intercurrent inflammation may increase flux down the kynurenine pathway towards the production of quinolinic acid. Quinolinic acid is neurotoxic and is an endogenous agonist at N-methyl-D-aspartate receptors. Synergistic excitation of these receptors by quinolinic acid and 3-hydroxyglutaric acid, which alone does not have sufficient potency, may be involved in the pathogenesis of striatal necrosis.     

Differential activation of kinases in ex vivo and in vivo irradiated mice lymphocytes

Various kinases, such as tyrosine, protein kinase C (PKC) and MAP kinase, play important role in the cellular response to radiation, but little is known about the specific response in the whole animal. Most studies, except a few, are based on single cells. There is a paucity of data where signaling following whole body irradiation is concerned. In this study a comparison has been made between the activities of these kinases following ex vivo and in vivo irradiation. Tyrosine kinase activity showed no difference in the lymphocytes irradiated ex vivo or in vivo. A significant differential dose-dependent response could be observed in PKC activity. PKC was seen to be activated at the higher dose, i.e., 1 Gy in, in vivo irradiated lymphocytes, whereas in ex vivo irradiated lymphocytes, PKC was seen to be activated at the lower dose, i.e., 0.1 Gy. MAP kinase activity was seen to decrease with an increasing dose in ex vivo irradiated lymphocytes. In vivo MAP kinase activity was seen to increase as the dose increased, with maximum activation at 3 Gy. These kinases are being used to manipulate the tumor response to radiotherapy. Thus it is essential to study the behavior of the above kinases in the whole animal because the difference in response of a single cell to the whole animal may be different.