Interactions between clock gene mutation, circadian phenotype and tumor growth in mice

The relation between circadian physiology (rest-activity and body temperature) and the growth of a grafted tumor (Glasgow osteosarcoma-GOS) was investigated in the mice with mutation of clock gene (ClockDelta19(-)) or gene controlled by the clock (Vpac(-/-)). Circadian rhythms in temperature and activity were stable, with an approximately 24-h period in all the mice synchronized by the alternation of 12 h of light and 12 h of darkness (LD 12:12). Following exposure to constant darkness (DD), both rhythms persisted in ClockDelta19(-), yet with a lengthening of the period by 4.5 h compared to wild type. In DD, the amplitude increased by 45.9% for the temperature rhythm (p<0.001) and by 17.4% for the activity one (p=0.08) as compared to LD 12:12 in ClockDelta19(-). The improvement of circadian coordination and/or the lengthening of the circadian period observed in ClockDelta19(-) kept in DD was associated with a moderate slowing down of tumor growth. Although the exposure to DD ablated the activity and temperature rhythms in Vpac(-/-), no modification in tumor growth was observed as compared to wide type or Vpac(-/-) in LD 12:12. Major alternations of circadian physiology can result from interactions between photoperiodic environment and mutation of clock gene or gene controlled by the clock. In these conditions, we have shown that the alternation of the circadian phenotype does not seem to constitute an essential determinant of the growth of a grafted tumor.     

The ABCA subfamily—gene and protein structures, functions and associated hereditary diseases

To date, 12 members of the human ABCA subfamily are identified. They share a high degree of sequence conservation and have been mostly related with lipid trafficking in a wide range of body locations. Mutations in some of these genes have been described to cause severe hereditary diseases related with lipid transport, such as fatal surfactant deficiency or harlequin ichthyosis. In addition, most of them are hypothesized to participate in the subcellular sequestration of drugs, thereby being responsible for the resistance of several carcinoma cell lines against drug treatment. The objective of this review is to summarize the literature for this subfamily of ABC transporter proteins, excluding ABCA1 and ABCA4, which will be discussed in other chapters of this issue.     

Combination therapy vs. monotherapy for Gram-negative bloodstream infection: matching by predicted prognosis

The utility of empirical combination antimicrobial therapy for Gram-negative bloodstream infection (BSI) remains unclear. This retrospective, quasi-experimental matched cohort study examined the impact of empirical combination therapy on mortality in patients with Gram-negative BSI. Hospitalized adults with Gram-negative BSI from 1 January 2010 to 31 December 2013 at Palmetto Health Hospitals in Columbia, SC, USA were identified. Patients receiving combination therapy or beta-lactam monotherapy were matched 1:1 based on age, sex and Bloodstream Infection Mortality Risk Score (BSIMRS). Multivariate Cox proportional hazards regression with propensity score adjustment was used to examine overall 28–day mortality and within predefined BSIMRS categories (<5 and ≥5). A total of 380 patients receiving combination therapy or monotherapy for Gram-negative BSI were included in the study. Median age was 66 years and 204 (54%) were female. Overall, 28-day mortality in patients who received combination therapy and monotherapy was 13% and 15%, respectively (P?=?0.51). After stratification by BSIMRS, mortality in both combination therapy and monotherapy groups was 1.1% in patients with BSIMRS <5 (P?=?0.98) and 27% and 32%, respectively, in patients with BSIMRS ≥5 (P?=?0.47). After adjusting for propensity to receive combination therapy, risk of mortality was not significantly different for combination therapy compared to monotherapy (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.51–1.60). This finding persisted for both subgroups of BSIMRS <5 (HR 0.96, 95% CI 0.04–24.28) and BSIMRS ≥5 (HR 0.83, 95% CI 0.46–1.48). There is no survival benefit from empirical combination therapy over monotherapy in patients with Gram-negative BSI, regardless of predicted prognosis at initial presentation.     

Implementation of the redesigned Community Health Fund in the Dodoma region of Tanzania: A qualitative study of views from rural communities

The need to understand how an intervention is received by the beneficiary community is well recognised and particularly neglected in the micro–health insurance (MHI) domain. This study explored the views and reactions of the beneficiary community of the redesigned Community Health Fund (CHF) implemented in the Dodoma region of Tanzania. We collected data from focus group discussions with 24 groups of villagers (CHF members and nonmembers) and in‐depth interviews with 12 key informants (enrolment officers and health care workers). The transcribed material was analysed thematically. We found that participants highly appreciate the scheme, but to be resolved are the challenges posed by the implementation strategies adopted. The responses of the community were nested within a complex pathway relating to their interaction with the implementation strategies and their ongoing reflections regarding the benefits of the scheme. Community reactions ranged from accepting to rejecting the scheme, demanding the right to receive benefit packages once enrolled, and dropping out of the scheme when it failed to meet their expectations. Reported drivers of the responses included intensity of CHF communication activities, management of enrolment procedures, delivery of benefit packages, critical features of the scheme, and contextual factors (health system and socio‐political context). This study highlights that scheme design and implementation strategies that address people's needs, voices, and values can improve uptake of MHI interventions. The study adds to the knowledge base on implementing MHI initiatives and could promote interests in assessing the response to interventions within the MHI domain and beyond.     

Treatment of a clinically relevant plant-pathogenic fungus with an agricultural azole causes cross-resistance to medical azoles and potentiates caspofungin efficacy

Azoles are extensively applied in agriculture and medicine, and a relationship between the development of azole resistance in agriculture and the development of azole resistance in clinical practice may exist. The maize pathogen Colletotrichum graminicola, causing cutaneous mycosis and keratitis, has been used to investigate the acquisition of resistance to an agricultural azole and the resulting cross-resistance to various medical antifungal agents. Azole-adapted strains were less sensitive to all azoles tested but showed increased sensitivity to caspofungin, amphotericin B, and nystatin. Viability staining and infection assays with excised human skin confirmed these data.     

Regional and Systemic Haemodynamic Effects of Some Vasopressins: Structural Features of the Hormone which Prolong Activity

Abstract. Cardiac output and regional blood flows to myocardium, gut, uterus and kidney were determined in anaesthetised female rats by a single injection of ⁸⁶RbCl. The haemodynamic responses were measured at various time intervals up to 2 h after single I. V. injections of lysine-vasopressin and the following of its analogues: a) with extended peptide chains at the N-terminal (including “hormonogens”) N^a-glycyl-glycyl-glycyl-lysine-vasopressin, N^a-glycyl-glycyl-glycyl-arginine-vasopressin and N^a-D-valyl-lysine-vasopressin, b) “carba” modifications desamino-carba⁶-arginine-vasopressin, desamino-carba⁶-D-arginine⁸-vasopressin, desamino-carba⁶-ornithine⁸-vasopressin, desamino-dicarba-arginine-vasopressin and c) other steric alterations - desamino-D-arginine⁸-vasopressin and desamino-N-methylarginine⁸-vasopressin. Sub-pressor doses of lysine-vasopressin were followed by marked reductions in gut and uterus blood flows which reached a peak at 10 min. and had completely receded by 60 min. The presence of steric alterations in the C-terminal tripeptide of the molecule- D-arginine or N-methylarginine in sequence position 8- practically completely eliminated vascular activity. The same was true for N^a-D-valyl-lysine-vasopressin. None of the latter three analogues showed any inhibitor properties to the action of lysine-vasopressin. The two hormonogens (triglycyl N-terminal extensions) had to be given in doses 10 times greater to obtain a vasoconstrictor effect in gut and uterus equivalent in amplitude to that of lysine-vasopressin, but this effect was still present to the same degree 2 h later with the hormonogen of lysine-vasopressin, and was only starting to return to baseline values at the same time with the arginine-vasopressin hormonogen. The vascular potency of both mono-carba L-analogues was higher than that of lysine-vasopressin, and the effect was as prolonged as with the hormonogens. The dicarba analogue also showed a prolonged action, but with much reduced potency. No significant changes in renal or myocardial blood flows were observed at all. Molecular features of vasopressin smooth muscle activity were discussed, and a receptor model was proposed. It was suggested that the -S-S-, -SCH2 and -CH₂CH₂-bridges in the above analogues are not directly bound in the peptide-receptor complex and constitute the limiting factor determining complex duration, or persistence of the active peptide in the “receptor compartment”. These results provide an experimental basis for possible clinical application of triglycyl-vasopressin and carba-vasopressin in bleeding from both gut and uterus and for induction of menstruation.     

Apoptotic,inflammatory, and fibrogenic effects of two different types of multi-walled carbon nanotubes in mouse lung

There is increasing concern about the toxicity of inhaled multi-walled carbon nanotubes (MWCNTs). Pulmonary macrophages represent the primary cell type involved in the clearance of inhaled particulate materials, and induction of apoptosis in these cells has been considered to contribute to the development of lung fibrosis. We have investigated the apoptotic, inflammogenic, and fibrogenic potential of two types of MWCNTs, characterised by a contrasting average tube length and entanglement/agglomeration. Both nanotube types triggered H₂O₂ formation by RAW 264.7 macrophages, but in vitro toxicity was exclusively seen with the longer MWCNT. Both types of nanotubes caused granuloma in the mouse lungs. However, the long MWCNT induced a more pronounced pro-fibrotic (mRNA expression of matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1) and inflammatory (serum level of monocyte chemotactic protein-1) response. Masson trichrome staining also revealed epithelial cell hyperplasia for this type of MWCNT. Enhanced apoptosis was detected by cleaved caspase 3 immunohistochemistry in lungs of mice treated with the long and rigid MWCNT and, to a lesser extent, with the shorter, highly agglomerated MWCNT. However, staining was merely localised to granulomatous foci, and neither of the MWCNTs induced apoptosis in vitro, evaluated by caspase 3/7 activity in RAW 264.7 cells. In addition, our study reveals that the inflammatory and pro-fibrotic effects of MWCNTs in the mouse lung can vary considerably depending on their composition. The in vitro analysis of macrophage apoptosis appears to be a poor predictor of their pulmonary hazard.     

Racial Differences in Discharge Location After a Traumatic Brain Injury Among Older Adults

ObjectiveTo determine if there were racial differences in discharge location among older adults treated for traumatic brain injury (TBI) at a level 1 trauma center.DesignRetrospective cohort study.SettingR Adams Cowley Shock Trauma Center.ParticipantsBlack and white adults aged ≥65 years treated for TBI between 1998 and 2012 and discharged to home without services or inpatient rehabilitation (N=2902).Main Outcome MeasuresWe assessed the association between race and discharge location via logistic regression. Covariates included age, sex, Abbreviated Injury Scale-Head score, insurance type, Glasgow Coma Scale score, and comorbidities.ResultsThere were 2487 (86%) whites and 415 blacks (14%) in the sample. A total of 1513 (52%) were discharged to inpatient rehabilitation and 1389 (48%) were discharged home without services. In adjusted logistic regression, blacks were more likely to be discharged to inpatient rehabilitation than to home without services compared to whites (odds ratio 1.34, 95% confidence interval, 1.06-1.70).ConclusionsIn this group of Medicare-eligible older adults, blacks were more likely to be discharged to inpatient rehabilitation compared to whites.     

Bichat guidelines for the clinical management of anthrax and bioterrorism-related anthrax

The spore-forming Bacillus anthracis must be considered as one of the most serious potential biological weapons. The recent cases of anthrax caused by a deliberate release reported in 2001 in the United States point to the necessity of early recognition of this disease. Infection in humans most often involves the skin, and more rarely the lungs and the gastrointestinal tract. Inhalational anthrax is of particular interest for possible deliberate release: it is a life-threatening disease and early diagnosis and treatment can significantly decrease the mortality rate. Treatment consists of massive doses of antibiotics and supportive care. Isolation is not necessary. Antibiotics such as ciprofloxacin are recommended for post-exposure prophylaxis during 60 days.