Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer's Disease?

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in older people. AD is associated with the loss of synapses, oxidative stress, mitochondrial structural and functional abnormalities, microRNA deregulation, inflammatory responses, neuronal loss, accumulation of amyloid-beta (Aß) and phosphorylated tau (p-tau). AD occurs in two forms: early onset, familial AD and late-onset, sporadic AD. Causal factors are still unknown for a vast majority of AD patients. Genetic polymorphisms are proposed to contribute to late-onset AD via age-dependent increases in oxidative stress and mitochondrial abnormalities. Recent research from our lab revealed that reduced levels of Rlip76 induce oxidative stress, mitochondrial dysfunction and synaptic damage, leading to molecular and behavioral phenotypes resembling late-onset AD. Rlip76 is a multifunctional 76 kDa protein encoded by the RALBP1 gene, located on chromosome 18. Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione-electrophile conjugates. Rlip is evolutionarily highly conserved across species and is ubiquitously expressed in all tissues, including AD-affected brain regions, the cerebral cortex and hippocampus, where highly active neuronal metabolisms render the cells highly susceptible to intracellular oxidative damage. In the current article, we summarize molecular and cellular features of Rlip and how depleted Rlip may exacerbate oxidative stress, mitochondrial dysfunction and synaptic damage in AD. We also discuss the possible role of Rlip in aspects of learning and memory via axonal growth, dendritic remodeling, and receptor regulation. We conclude with a discussion of the potential for the contribution of genetic polymorphisms in Rlip to AD progression and the potential for Rlip-based therapies.

Disparities in Breast Cancer Survivors in Rural West Texas.

OBJECTIVES: Breast cancer is the second highest female mortality rate in Texas for all races and ethnicities, except for Hispanics. Interestingly, Hale County is a rural underserved county in West Texas which experiences a lower rate of cancer, has higher age-adjusted mortality rates (26.2/100 000), on average, compared to all of Texas (23.1/100 000). The purpose of this study was to determine the relationship between sociodemographic variables and breast cancer outcomes in underserved Hale County which contributed to the highest mortality rate in Texas. METHODS: Hale County breast cancer data (1995-2014) were obtained from the Texas Cancer Registry. Statistical methods independent samples t-test, Kaplan-Meier curve, and Cox proportional hazard were used to describe the significant relationship between survival time, sociodemographic, and prognostic variables. RESULTS: Women with breast cancer in Hale County were more likely to be White non-Hispanics (n = 266, 65.5%) and had the highest longevity (2753.6 ± 2073.5 days). White Hispanics experienced the worst survival (2369.6 ± 2060.2 days) and were more likely to develop a serious grade of cancer. Significant relationships were found between the stage of cancer and insurance status with survival time for both White non-Hispanics and White Hispanics (P < .001). Patients in grades II and III were found to be significantly (P < .01) associated with breast cancer death, and grades II and III which had around five-fold and eleven-fold increased risk of death, respectively, compared with the referent group, grade I. CONCLUSION: Determining the impact of sociodemographic variables on breast cancer outcome is essential to addressing issues of geographic disparities and integrating such variables may guide relevant policy interventions to reduce breast cancer's incidence in rural underserved communities in West Texans.

Rlip depletion prevents spontaneous neoplasia in TP53 null mice.

TP53 (p53) is a tumor suppressor whose functions are lost or altered in most malignancies. p53 homozygous knockout (p53-/-) mice uniformly die of spontaneous malignancy, typically T-cell lymphoma. RALBP1 (RLIP76, Rlip) is a stress-protective, mercapturic acid pathway transporter protein that also functions as a Ral effector involved in clathrin-dependent endocytosis. In stark contrast to p53-/- mice, Rlip-/- mice are highly resistant to carcinogenesis. We report here that partial Rlip deficiency induced by weekly administration of an Rlip-specific phosphorothioate antisense oligonucleotide, R508, strongly inhibited spontaneous as well as benzo(a)pyrene-induced carcinogenesis in p53-/- mice. This treatment effectively prevented large-scale methylomic and transcriptomic abnormalities suggestive of inflammation found in cancer-bearing p53-/- mice. The remarkable efficiency with which Rlip deficiency suppresses spontaneous malignancy in p53-/- mice has not been observed with any previously reported pharmacologic or genetic intervention. These findings are supported by cross-breeding experiments demonstrating that hemizygous Rlip deficiency also reduces the spontaneous malignancy phenotype of p53+/- mice. Rlip is found on the cell surface, and antibodies directed against Rlip were found to inhibit growth and promote apoptosis of cell lines as effectively as Rlip siRNA. The work presented here investigates several features, including oxidative DNA damage of the Rlip-p53 association in malignant transformation, and offers a paradigm for the mechanisms of tumor suppression by p53 and the prospects of suppressing spontaneous malignancy in hereditary cancer syndromes such as Li-Fraumeni.

Quality of life after coronary artery bypass graft & percutaneous transluminal coronary angioplasty: A follow up study from India.

Coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are treatments of choice for coronary artery disease. Quality of life (QoL) is an important factor in determining optimum treatment. This study was aimed to compare changes in QoL, six months post procedure, between CABG and PTCA, and to understand the confounding effect of various contributing factors. Thirty stable angina patients each in CABG and PTCA groups, were followed up for six months. QoL was assessed with WHO-QoL-BREF. Depression was rated on the Hamilton Depression Rating Scale. Changes in QoL and depression within and between CABG and PTCA groups were compared. Multinomial logistic regression was used to measure the predictive strength of treatment type (CABG and PTCA) on QoL, controlling for significant confounders. Although scores of QoL and depression significantly changed over time in both the groups, time×group interaction did not reach to a significance. Significant confounding effects of diabetes (P<0.01), hypertension (P<0.05) and diet restriction (P<0.05) were found. Controlling for confounding effects of these factors, group distribution to PTCA, compared to CABG, significantly predicted greater improvements in QoL (P<0.01).

A New Derivatization Reagent for HPLC-MS Analysis of Biological Organic Acids.

Small molecules containing carboxylic acid functional groups are ubiquitous throughout biology, playing vital roles in biological chemistry ranging from energy metabolism to cellular signaling. This paper describes a new derivatization reagent, 4-bromo-N-methylbenzylamine, which was selected for its potential to derivatize mono-, di- and tri-carboxylic acids, such as the intermediates of the tricarboxylic acid (TCA) cycle. This derivatization procedure facilitated the use of positive electrospray ionization (ESI) tandem mass spectrometry (MS/MS) detection of derivatized species allowing for clear identification thanks to the easily recognizable isotope pattern of the incorporated bromine. A liquid chromatography (LC)-MS/MS method was developed which provided limits of detection between 0.2 and 44 µg L-1 in under 6 min, depending on the analyte and total analysis time. This method was successfully applied in both in vitro and in vivo models.

Modulation of myocardial injury and collagen deposition following ischaemia-reperfusion by linagliptin and liraglutide, and both together.

Studies have indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce infarct size after myocardial ischaemia. Whether these agents modify cardiac remodelling after ischaemia is unclear. Furthermore, it is not known if combination of the two types of drugs is superior to either agent alone. We investigated the modulatory effect of the DPP-4 inhibitor linagliptin alone, the GLP-1 activator liraglutide alone, or the two agents together on myocardial infarct size, left ventricular contractile function and cardiac remodelling signals after a brief period of left coronary artery (LCA) occlusion. C57BL/6 mice were treated with vehicle, the DPP-4 inhibitor linagliptin, the GLP-1 activator liraglutide, or both agents together for 5 days, and then subjected to LCA occlusion (1 h) and reperfusion (3 h). Ischaemia-reperfusion increased reactive oxygen species (ROS) generation and expression of NADPH oxidase (p47(phox), p22(phox) and gp91(phox) subtypes), collagens, fibronectin and proinflammatory cytokines (interleukin 6, tumour necrosis factor α and monocyte chemoattractant protein-1) in the LCA-supplied regions. Pre-treatment with linagliptin or liraglutide reduced infarct size, protected cardiomyocytes from injury and preserved cardiac contractile function in a similar fashion. It is interesting that profibrotic (collagen deposition) signals were expressed soon after ischaemia-reperfusion. Both linagliptin and liraglutide suppressed ROS generation, NADPH oxidase and proinflammatory signals, and reduced collagen deposition. Addition of linagliptin or liraglutide had no significant additive effect above and beyond that of liraglutide and linagliptin given alone. In conclusion, linagliptin and liraglutide can improve cardiac contractile function and indices of cardiac remodelling, which may be related to their role in inhibition of ROS production and proinflammatory cytokines after ischaemia.

Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling.

4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione-peroxidase activity and that these enzymes can also detoxify LPO end-products such as 4HNE. Available evidence from earlier studies together with results of recent studies in our laboratories strongly suggests that LPO products, particularly hydroperoxides and 4HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the alpha-class GSTs through the regulation of the intracellular concentrations of 4HNE. We demonstrate that 4HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal kinase (JNK) and caspase-3 activation. Cells exposed to mild, transient heat or oxidative stress acquire the capacity to exclude intracellular 4HNE at a faster rate by inducing GSTA4-4 which conjugates 4HNE to glutathione (GSH), and RLIP76 which mediates the ATP-dependent transport of the GSH-conjugate of 4HNE (GS-HNE). The balance between formation and exclusion promotes different cellular processes - higher concentrations of 4HNE promote apoptosis; whereas, lower concentrations promote proliferation. In this article, we provide a brief summary of the cellular effects of 4HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTA4-4. Taken together, 4HNE is a key signaling molecule and that GSTs being determinants of its intracellular concentrations, can regulate stress-mediated signaling, are reviewed in this article.

The moderating effects of perceived social worth and organizational virtuousness on the relationship between emotional labor, precarious work, and organizational commitment among ASHA workers in India.

Accredited Social Health Activists (ASHAs) in India are the subjects of this study, which explores the complex relationships between emotional labor (EL) and unstable work environments and how these relationships affect organizational commitment (OC). The study also looked at how organizational virtuousness (OV) and perceived social value mediated the relationship between precarious work (PW), EL, and OC. This study included a total sample size of N = 467 ASHA personnel from a variety of healthcare settings. Hierarchical regression analysis was used to look at the moderating effects using the Hayes Process Macro. The findings suggest that there are noteworthy negative associations between EL, PW, and the OC of ASHA workers. Nevertheless, OV and perceived social worth (PSW) emerged as significant moderators. More precisely, elevated levels of PSW and OV mitigated the adverse effects of PW and EL on the OC of ASHA workers.

Workplace ostracism influencing turnover intentions: Moderating roles of perceptions of organizational virtuousness and authentic leadership.

Workplace Ostracism is known to be a physically and emotionally painful experience. Even if it has a temporary and minor impact, it strongly predicts employee turnover intentions. Therefore, the purpose of this paper is to examine the moderating effects of perceptions of Organizational Virtuousness (OV) and Authentic Leadership (AL) in explaining the relationship between Workplace Ostracism (WO) and employees' Turnover Intentions (TI). Data were collected from 686 full-time employees using a non-probabilistic convenience sampling in India's Information Technology (IT) companies. The reliability and validity of scales were assessed using confirmatory factor analysis. Multiple hierarchical regression modeling was used to test the proposed hypotheses using IBM SPSS 23.0 with Process Macro 3.5. The present study's findings suggest that workplace ostracism is significantly related to employees' turnover intentions. Furthermore, perceptions of organizational virtuousness and authentic leadership moderated the relationship between workplace ostracism and employee turnover intentions. Employee turnover is a gigantic problem for IT firms in India. The present study offers valuable insights to managers to create awareness of workplace ostracism. Implementing managerial strategies rooted in positive psychology can help organizations create a more inclusive, supportive, and psychologically healthy work environment. This, in turn, can reduce the occurrence of workplace ostracism and turnover intentions.

The role of RLIP76 in oxidative stress and mitochondrial dysfunction: Evidence based on autopsy brains from Alzheimer's disease patients.

Several converging lines of evidence from our group support a potential role of RLIP76 (AKA Rlip) in neurodegenerative disorders, including Alzheimer's Disease (AD). However, the role of Rlip in Alzheimer's and other neurodegenerative diseases is not well understood. The purpose of the present study is to determine the role of Rlip in the brains of AD patients and control subjects. To achieve our goals, we used frozen tissues and formalin-fixed paraffin-embedded postmortem brains from AD patients of different Braak stages and age-matched control subjects. Our immunohistology and immunoblotting blotting analysis revealed that expression of Rlip protein gradually and significantly decreased (p = 0.0001) with AD progression, being lowest in Braak stage IV-V. Rlip was colocalized with Amyloid beta (Aß) and phosphorylated tau (p-Tau) as observed by IHC staining and co-immunoprecipitation studies. Lipid peroxidation (4-HNE generation) and H2O2 production were significantly higher (p = 0.004 and 0.0001 respectively) in AD patients compared to controls, and this was accompanied by lower ATP production in AD (p = 0.0009). Oxidative DNA damage was measured by 8-Hydroxyguanosine (8-OHdG) in tissue lysates by ELISA and COMET assay. AD 8-OHdG levels were significantly higher (p = 0.0001) compared to controls. COMET assay was performed in brain cells, isolated from frozen postmortem samples. The control samples showed minimal DNA in comets representing few DNA strand breaks (<20 %), (score-0-1). However, the AD group showed an average of 50 % to 65 % of DNA in comet tails (score-4-5) indicating numerous DNA strand breaks. The difference between the two groups was significant (p = 0.001), as analyzed by Open Comet by ImageJ. Elevated DNA damage was further examined by western blot analysis for phosphorylated histone variant H2AX (γH2AX). Induction of γH2AX was very significant (p < 0.0001) and confirmed the presence of double-strand breaks in DNA. Overall, our results indicate an important role for Rlip in maintaining neuronal health and homeostasis by suppressing cellular oxidative stress and DNA damage. Based on our findings, we cautiously conclude that Rlip is a promising therapeutic target for Alzheimer's disease.

Assessing specific items of Indian VSMS: Perspective of medical and rehabilitation professionals.

Background: Adaptive behavior plays a crucial role in daily functioning, involving a complex interplay between individuals and their environment. In India, the Vineland Social Maturity Scale (VSMS) has been the preferred assessment tool for measuring adaptive behaviors, despite its age of over 85 years. However, periodic evaluation is necessary to ensure its continued relevance. Aim: This study aims to critically evaluate selected items of the Indian version of the VSMS. Materials and Methods: A survey form was developed through a focus group discussion (FGD), comprising 20 items from the Indian adaptation of the VSMS. The form was converted into a Google Form and distributed to medical and rehabilitation specialists across India. The responses were collected, recorded, and analyzed in an Excel sheet. Results: Of the 107 responses received, 14 were incomplete and excluded, leaving 93 complete for analysis. The analysis revealed that less than half of the surveyed items and domains received ratings of disagreement from over a quarter of the respondents concerning their frequency, relevance, and diagnostic value. Conclusion: This study underscores the need for a dynamic approach to defining and assessing adaptive behavior, especially in the Indian context. It highlights the importance of revising existing scales, incorporating technology-related items, and considering societal and cultural norms shifts. While acknowledging its limitations, this research sets the stage for future investigations to gain a more nuanced understanding of adaptive behaviors amidst changing societal dynamics. Ultimately, these efforts aim to develop more comprehensive and relevant assessment tools for adaptive behavior in today's rapidly evolving world.

A Case Series on Spotted Fever and Typhus Fever Seropositivity at National Center for Disease Control and Epidemiological Perspective.

Background: The rickettsioses, except for typhus fever and scrub typhus (ST), were not really recognized as distinct clinical entities until the early 20th century. Only when specific rickettsial serologic testing was introduced in the 1940s could the precise etiologies of various rickettsial diseases (RDs) be determined with certainty. Although ST is a well- recognized zoonotic disease entity, but non-scrub typhus rickettsial infection like spotted fever group and typhus group are not well studied in India and are still underestimated. Methods: We report cases who had shown seropositivity of spotted fever and typhus fever RD in IgM and IgG ELISA whose samples were referred from various hospitals of Delhi/National Capital Region in which clinicians had strong suspicion of rickettsiosis other than ST or Weil-Felix test found positive for any of the OX2, 19, and K antigens. Results: We reported 18 cases of SFG and TGRD with mostly cases presented with fever followed by hepato-intestinal symptoms. Conclusion: The vast variability and nonspecific presentation of rickettsiosis in spotted and typhus fever at times have often made it difficult to diagnose clinically. Prompt antibiotic therapy shortens the course of the disease, lowers the risk of complications, and in turn, reduces morbidity and mortality owing to RDs. There is a distinct need for physicians and health care workers at all levels of care in India to be aware of the clinical features, available diagnostic tests and their interpretation, and the therapy for these infections.

Correction: Reddy et al. Rlip Reduction Induces Oxidative Stress and Mitochondrial Dysfunction in Mutant Tau-Expressed Immortalized Hippocampal Neurons: Mechanistic Insights. Cells 2023, 12, 1646.

The authors wish to make the following changes to their paper [...].

Brief intervention to enhance cessation of smokeless tobacco use in newly diagnosed patients with head and neck cancers: A randomized controlled trial in patient-relative dyads.

Introduction: Tobacco use is a major causative factor for head and neck cancers (HNC). Continued use of tobacco even after cancer diagnosis is common and is associated with all-cause and cancer-specific mortality, cancer recurrence and poor treatment response. Evidence suggests that behavioral interventions, help achieve greater smoking cessation rates in HNC patients. However, intervention studies focussed on HNC patients using smokeless tobacco, which is more common than smoking in India, are sparse. Materials and Methods: We conducted a parallel arm randomized controlled trial (RCT) on dyads of patients with recently diagnosed HNC and a close relative. The experimental arm received a brief tobacco cessation intervention (BTCI) and the control arm received treatment as usual (TAU); 27 and 25 dyads in each arm completed the trial. Results: Overall for the dyads using SLT, the relative risk of continuing to use SLT was 3.23 times higher (odds ratio = 7.01) if BTCI was not undertaken at one-month follow-up and 4.43 times higher (odds ratio = 8.65) at 3-months follow-up. For patients only, the relative risk of continuing to use SLT at one-month and 3-months follow-ups was 4.99 and 12.04 times higher, respectively, if BTCI was not undertaken. For relatives only, the corresponding relative risk values were 2.14 and 2.2. Conclusion: We conclude that BTCI delivered to patient-relative dyads, compared to TAU, is effective in enhancing the discontinuation rates of the use of SLT in newly diagnosed patients with HNC. This form of intervention is significantly effective for discontinuing SLT use in the relatives too.

Leveraging cryoablation and checkpoint inhibitors for high-risk triple negative breast cancer.

Breast cancer is the second most common cancer among women in the United States in which the standard of care treatment is surgery with adjunctive therapy. Cryoablation, which destroys the tumor using extremely cold temperatures while preserving the potential tumor antigens, is a promising alternative to surgical resection. It is less invasive, cosmetically appeasing, cost-effective, and capable of contributing to the abscopal effect - the immune response targeting potential distant metastasis. However, to maximize the immunologic benefit of cryoablation in biologically high-risk breast cancers, combination with therapies that enhance immune activation, such as immune checkpoint inhibitors (ICIs) may be necessary. This mini review describes the fundamentals of cryoablation and treatment with ICIs, as well as discuss the caveats in both strategies and current clinical trials aimed to improve this approach to benefit patients.

Rlip Reduction Induces Oxidative Stress and Mitochondrial Dysfunction in Mutant Tau-Expressed Immortalized Hippocampal Neurons: Mechanistic Insights.

RalBP1 (Rlip) is a stress-activated protein that is believed to play a large role in aging and neurodegenerative diseases such as Alzheimer's disease (AD) and other tauopathies. The purpose of our study was to understand the role of Rlip in mutant Tau-expressed immortalized hippocampal HT22 cells. In the current study, we used mutant Tau (mTau)-expressed HT22 neurons and HT22 cells transfected with Rlip-cDNA and/or silenced RNA, and studied the cell survival, mitochondrial respiration, mitochondrial function, immunoblotting, and immunofluorescence analysis of synaptic and mitophagy proteins and the colocalization of Rlip and mTau proteins. We found Rlip protein levels were reduced in mTau-HT22 cells, Rlip silenced HT22 cells, and mTau + Rlip RNA silenced HT22 cells; on the other hand, increased Rlip levels were observed in Rlip cDNA transfected HT22 cells. We found cell survival was decreased in mTau-HT22 cells and RNA-silenced HT22 cells. However, cell survival was increased in Rlip-overexpressed mTau-HT22 cells. A significantly reduced oxygen consumption rate (OCR) was found in mTau-HT22 cells and in RNA-silenced Rlip-HT22 cells, with an even greater reduction in mTau-HT22 + Rlip RNA-silenced HT22 cells. A significantly increased OCR was found in Rlip-overexpressed HT22 cells and in all groups of cells that overexpress Rlip cDNA. Mitochondrial function was defective in mTau-HT22 cells, RNA silenced Rlip in HT22 cells, and was further defective in mTau-HT22 + Rlip RNA-silenced HT22 cells; however, it was rescued in Rlip overexpressed in all groups of HT22 cells. Synaptic and mitophagy proteins were decreased in mTau-HT22 cells, and further reductions were found in RNA-silenced mTau-HT22 cells. However, these were increased in mTau + Rlip-overexpressed HT22 cells. An increased number of mitochondria and decreased mitochondrial length were found in mTau-HT22 cells. These were rescued in Rlip-overexpressed mTau-HT22 cells. These observations strongly suggest that Rlip deficiency causes oxidative stress/mitochondrial dysfunction and Rlip overexpression reverses these defects. Overall, our findings revealed that Rlip is a promising new target for aging, AD, and other tauopathies/neurological diseases.

Rlip overexpression reduces oxidative stress and mitochondrial dysfunction in Alzheimer's disease: Mechanistic insights.

Alzheimer's disease (AD) is a neurodegenerative disease that affects a large proportion of the aging population. RalBP1 (Rlip) is a stress-activated protein that plays a crucial role in oxidative stress and mitochondrial dysfunction in aging and neurodegenerative diseases but its precise role in the progression of AD is unclear. The purpose of our study is to understand the role of Rlip in the progression and pathogenesis of AD in mutant APP/amyloid beta (Aß)-expressed mouse primary hippocampal (HT22) hippocampal neurons. In the current study, we used HT22 neurons that express mAPP, transfected with Rlip-cDNA and/or RNA silenced, and studied cell survival, mitochondrial respiration, mitochondrial function, immunoblotting & immunofluorescence analysis of synaptic and mitophagy protein's and colocalization of Rlip and mutant APP/Aß proteins and mitochondrial length and number. We also assessed Rlip levels in autopsy brains from AD patients and control subjects. We found cell survival was decreased in mAPP-HT22 cells and RNA-silenced HT22 cells. However, cell survival was increased in Rlip-overexpressed mAPP-HT22 cells. Oxygen consumption rate (OCR) was decreased in mAPP-HT22 cells and RNA-silenced Rlip-HT22 cells. OCR was increased in Rlip-overexpressed in mAPP-HT22 cells. Mitochondrial function was defective in mAPP-HT22 cells and RNA silenced Rlip in HT22 cells, however, it was rescued in Rlip overexpressed mAPP-HT22 cells. Synaptic and mitophagy proteins were decreased in mAPP-HT22 cells, further reducing RNA-silenced Rlip-HT22 cells. However, these were increased in mAPP+Rlip-HT22 cells. Colocalization analysis revealed Rlip is colocalized with mAPP/Aß. An increased number of mitochondria and decreased mitochondrial length were found in mAPP-HT22 cells. These were rescued in Rlip overexpressed mAPP-HT22 cells. Reduced Rlip levels were found in autopsy brains from AD patients. These observations strongly suggest that Rlip deficiency causes oxidative stress/mitochondrial dysfunction and Rlip overexpression reduced these defects.

Effects of proton and oxygen ion irradiation on cardiovascular function and structure in a rabbit model.

PURPOSE: Astronauts on missions beyond low Earth orbit will be exposed to galactic cosmic radiation, and there is concern about potential adverse cardiovascular effects. Most of the research to identify cardiovascular risk of space radiation has been performed in rodent models. To aid in the translation of research results to humans, the current study identified long-term effects of high-energy charged particle irradiation on cardiovascular function and structure in a larger non-rodent animal model. MATERIALS AND METHODS: At the age of 12 months, male New Zealand white rabbits were exposed to whole-body protons (250 MeV) or oxygen ions (16O, 600 MeV/n) at a dose of 0 or 0.5 Gy and were followed for 12 months after irradiation. Ultrasonography was used to measure in vivo cardiac function and blood flow parameters at 10- and 12-months post-irradiation. At 12 months after irradiation, blood cell counts and blood chemistry values were assessed, and cardiac tissue and aorta were collected for histological as well as molecular and biochemical analyses. Plasma was used for metabolomic analysis and to quantify common markers of cardiac injury. RESULTS: A small but significant decrease in the percentage of circulating lymphocytes and an increase in neutrophil percentage was seen 12 months after 0.5 Gy protons, while 16O exposure resulted in an increase in monocyte percentage. Markers of cardiac injury, cardiac troponin I (cTnI) and N-Terminal pro-B-type Natriuretic Peptide were modestly increased in the proton group, and cTnI was also increased after 16O. On the other hand, metabolomics on plasma at 12 months revealed no changes. Both types of irradiation demonstrated alterations in cardiac mitochondrial morphology and an increase in left ventricular protein levels of inflammatory cell marker CD68. However, changes in cardiac function were only mild. CONCLUSION: Low dose charged particle irradiation caused mild long-term changes in inflammatory markers, cardiac function, and structure in the rabbit heart, in line with previous studies in mouse and rat models.

Serological evidence of rickettsial infections in Delhi.

BACKGROUND & OBJECTIVES: Rickettsial infections remain under-diagnosed due to lack of diagnostic facilities in developing world. Here we present our experience at National Centre for Disease Control, Delhi, about a serosurvey done in Delhi for rickettsial disease with easy to perform low cost, low expertise Weil Felix test. METHODS: On the basis of cut-off titre obtained in healthy population, Weil Felix test results were interpreted along with clinical data. Entomological investigation was also carried out in select areas of Delhi. Rodents were trapped from houses and gardens and vector mites were collected. RESULTS: When serum samples were collected during initial 5 yr period from patients with fever of unknown origin, seropositivity was 8.2 per cent whereas when rickettsial infection was kept as one of the differential diagnosis by clinicians seropositivity increased to 33.3 per cent. Rickettsial infections detected were scrub typhus (48.2%) followed by spotted fever group (27.5%) and typhus group (6.8%) during 2005-2009. In preliminary entomological survey vector mite Leptotombidium deliense was found on rodents. INTERPRETATION & CONCLUSIONS: Our findings showed that results of Weil Felix test should not be disregarded, rather clinically compatible cases should be treated to save lives.