Divergent effects of the antiretroviral drugs, dolutegravir, tenofovir alafenamide, and tenofovir disoproxil fumarate, on human adipocyte function.

Combined antiretroviral therapy (cART) has been associated with increased body weight accompanied by metabolic alterations in people living with human immunodeficiency virus (PLWH). To gain insight into the combined effects of cART components on adipocyte dysfunction, we assessed whether and how treatment of human adipocytes with dolutegravir (DTG) and the nucleotide-analog reverse-transcriptase inhibitors (NRTIs), tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF), alone and in combination, altered biological processes related to adipose tissue dysfunction. DTG, TAF, and TDF were applied to human Simpson-Golabi-Behmel syndrome (SGBS) adipose cells during differentiation (day 10) and ensuing differentiation (day 14). Expression of selected marker genes was determined by qPCR, the release of adipokines and inflammatory cytokines to the culture media was assessed, and cell respiration was measured. Adipogenesis was not altered by the combined treatment of human adipocytes. However, DTG at the highest dose repressed adipogenesis marker genes expression, and TAF and TDF appeared to mitigate this effect. DTG repressed the expression of adiponectin and the release of adiponectin and leptin in differentiating adipocytes, and these effects were mantained in combination with TAF and TDF. DTG plus TAF or TDF on human adipocytes enhanced inflammation and stress and increased the release of proinflammatory cytokines to the culture media. Together, our results show that combined therapy with these drugs can alter inflammation, cellular stress, and fibrosis in human adipocytes. These findings may improve our understanding and management of the effects of cART on body adiposity and metabolic dysregulation in PLWH.

Autophagy is Involved in Cardiac Remodeling in Response to Environmental Temperature Change.

Objectives: To study the reversibility of cold-induced cardiac hypertrophy and the role of autophagy in this process. Background: Chronic exposure to cold is known to cause cardiac hypertrophy independent of blood pressure elevation. The reversibility of this process and the molecular mechanisms involved are unknown. Methods: Studies were performed in two-month-old mice exposed to cold (4°C) for 24 h or 10 days. After exposure, the animals were returned to room temperature (21°C) for 24 h or 1 week. Results: We found that chronic cold exposure significantly increased the heart weight/tibia length (HW/TL) ratio, the mean area of cardiomyocytes, and the expression of hypertrophy markers, but significantly decreased the expression of genes involved in fatty acid oxidation. Echocardiographic measurements confirmed hypertrophy development after chronic cold exposure. One week of deacclimation for cold-exposed mice fully reverted the morphological, functional, and gene expression indicators of cardiac hypertrophy. Experiments involving injection of leupeptin at 1 h before sacrifice (to block autophagic flux) indicated that cardiac autophagy was repressed under cold exposure and re-activated during the first 24 h after mice were returned to room temperature. Pharmacological blockage of autophagy for 1 week using chloroquine in mice subjected to deacclimation from cold significantly inhibited the reversion of cardiac hypertrophy. Conclusion: Our data indicate that mice exposed to cold develop a marked cardiac hypertrophy that is reversed after 1 week of deacclimation. We propose that autophagy is a major mechanism underlying the heart remodeling seen in response to cold exposure and its posterior reversion after deacclimation.

Streptococcal vertebral osteomyelitis: multiple faces of the same disease.

The role of Streptococcus species as an aetiological microorganism of vertebral osteomyelitis (VO) is considered to be of little relevance. We aimed to describe a large number of cases of streptococcal vertebral osteomyelitis (SVO), to analyze the clinical features associated with different Streptococcus species, and to compare them with a cohort of patients with VO caused by Staphylococcus aureus. An incidence study and a retrospective, multicenter, observational clinical study of cases of SVO (1991-2011) were performed. Statistical comparison of SVO by different species and between them and staphylococcal VO was carried out. Over the whole period there was an increasing incidence in the number of VOs and SVOs per year (p <0.05). Among 58 cases of SVO, those caused by non-viridans streptococcus (Streptococcus pneumoniae, Streptococcus agalactiae and Streptococcus pyogenes; n = 26) mimicked VO by S. aureus, and presented with more fever, neurological symptoms and paravertebral abscesses in comparison with those caused by the viridans group (remaining species). In contrast, the latter have a sub-acute clinical picture and were associated with the presence of endocarditis (p <0.05). Among non-viridans SVOs, concomitant infection was specifically related to S. pneumoniae (p <0.05). In conclusion, SVO presents a wide range of clinical patterns. The relationship between VO and diagnosis of endocarditis was established with SVO caused by the viridans group. Whereas non-viridans SVO mimics acute characteristics of VO caused by S. aureus, cases of viridans SVO are significantly more likely to have a sub-acute clinical presentation. The increased incidence of SVO during the last decades could support a new epidemiological scenario.

Timing of antibiotic administration and outcomes of hospitalized patients with community-acquired and healthcare-associated pneumonia.

The effects of antibiotic timing on outcomes of patients with community-acquired pneumonia (CAP) are controversial. Moreover, no information is available regarding this issue in healthcare-associated pneumonia (HCAP). We aimed to determine the impact of antibiotic timing on 30-day mortality of patients with CAP and HCAP. Non-immunocompromised adults admitted to hospital through the emergency department (ED) with community-onset pneumonia were prospectively observed from 2001 to 2009. Patients who received prior antibiotics were excluded. Of 1593 patients with pneumonia who were analyzed, 1274 had CAP and 319 HCAP. The mean time from patient arrival at the ED until antibiotic administration was 5.8 h (standard deviation (SD) 3.5) in CAP and 6.1 h (SD 3.8) in HCAP (p 0.30). Mortality was higher in patients with HCAP (5.5% vs. 13.5%; p <0.001). After adjusting for confounding factors in a logistic regression analysis, the antibiotic administration ≤4 h was not associated with decreased 30-day mortality in patients with CAP (odds ratio (OR) 1.12, 95% confidence interval (CI) 0.57-2.21) and in patients with HCAP (OR 0.59, 95% CI 0.19-1.83). Similarly, antibiotic administration ≤8 h was not associated with decreased 30-day mortality in CAP (OR 1.58, 95% CI 0.64-3.88) and HCAP patients (OR 0.59, 95% CI 0.19-1.83). In conclusion, antibiotic administration within 4 or 8 h of arrival at the ED did not improve 30-day survival in hospitalized adults for CAP or HCAP.

Low incidence of multidrug-resistant organisms in patients with healthcare-associated pneumonia requiring hospitalization.

Healthcare-associated pneumonia (HCAP) includes a broad spectrum of patients who acquire pneumonia through outpatient contact with the health system. Although limited prospective data exist, it has been suggested that all patients with HCAP should receive empirical therapy with a multidrug regimen directed against drug-resistant organisms. We aimed to determine the differences in aetiology and outcomes between HCAP groups and a community-acquired pneumonia (CAP) group, and to assess the presence of antibiotic-resistant bacteria. All consecutive non-immunocompromised adults hospitalized with pneumonia were prospectively included from 2001 to 2009. Patients who had had recent contact with the health system through nursing homes, home healthcare programmes, haemodialysis clinics or prior hospitalization were considered to have HCAP. A total of 2245 patients with pneumonia were hospitalized through the emergency room, of whom 577 (25.7%) had HCAP. Significant differences in causative pathogens were found between groups. Antibiotic-resistant organisms, including methicillin-resistant Staphylococcus aureus, resistant strains of Pseudomonas aeruginosa, and extended-spectrum ß-lactamase-producing Enterobacteriaceae, were scarce in all groups. In contrast, aspiration pneumonia was particularly frequent. No differences were found regarding inappropriate initial empirical antibiotic therapy between groups. Overall mortality was higher in patients who attended a hospital or haemodialysis clinic or received intravenous chemotherapy in the 30 days before pneumonia, and among patients who resided in a nursing home or long-term-care facility. In conclusion, most HCAP patients could be treated in the same way as patients with CAP, after carefully ruling out the presence of aspiration pneumonia.

Genetics of human body size and shape: body proportions and indices.

BACKGROUND: The study of the genetic component in morphological variables such as body height and weight, head and chest circumference, etc. has a rather long history. However, only a few studies investigated body proportions and configuration. AIM: The major aim of the present study was to evaluate the extent of the possible genetic effects on the inter-individual variation of a number of body configuration indices amenable to clear functional interpretation. SUBJECTS AND METHODS: Two ethnically different pedigree samples were used in the study: (1) Turkmenians (805 individuals) from Central Asia, and (2) Chuvasha (732 individuals) from the Volga riverside, Russian Federation. To achieve the aim of the present study we proposed three new indices, which were subjected to a statistical-genetic analysis using modified version of "FISHER" software. The proposed indices were: (1) an integral index of torso volume (IND#1), an index reflecting a predisposition of body proportions to maintain a balance in a vertical position (IND#2), and an index of skeletal extremities volume (IND#3). Additionally, the first two principal factors (PF1 and PF2) obtained on 19 measurements of body length and breadth were subjected to genetic analysis. Variance decomposition analysis that simultaneously assess the contribution of gender, age, additive genetic effects and effects of environment shared by the nuclear family members, was applied to fit variation of the above three indices, and PF1 and PF2. RESULTS: The raw familial correlation of all study traits and in both samples showed: (1) all marital correlations did not differ significantly from zero; (2) parent-offspring and sibling correlations were all positive and statistically significant. The parameter estimates obtained in variance analyses showed that from 40% to 75% of inter-individual variation of the studied traits (adjusted for age and sex) were attributable to genetic effects. For PF1 and PF2 in both samples, and for IND#2 (in Chuvasha pedigrees), significant common sib environmental effects were also detectable. CONCLUSION: Genetic factors substantially influence inter-individual differences in body shape and configuration in two studied samples. However, further studies are needed to clarify the extent of pleiotropy and epigenetic effects on various facets of the human physique.

Assessment of mucosal inflammation and blood flow in response to four weeks' intervention with probiotics in patients operated with a J-configurated ileal-pouch-anal-anastomosis (IPAA).

BACKGROUND: Pouchitis is a common and troublesome condition in patients operated on with ileal-pouch-anal-anastomosis (IPAA). A disturbed mucosal perfusion in the pouch has been suggested as a possible cause. Laser Doppler flowmetry (LDF) has been used successfully to measure gastric and colonic mucosal perfusion in humans. In a previous study, we demonstrated a reduced mucosal perfusion in the distal part of the pouch, during probiotic intervention, examined by LDF measurement. The aim of the present study was to confirm our previous results in a much larger material, and to compare the results of LDF measurements and inflammatory activity in ulcerative colitis (UC) patients with those in familial adenomatous polyposis (FAP) patients. METHODS: Five hundred millilitres of a fermented milk product (Cultura), containing live lactobacilli (La-5) and bifidobacteria (Bb-12), was given daily for 4 weeks to 41 UC and 10 patients with FAP, operated on with IPAA. Mucosal perfusion was measured with LDF and the degree of inflammation was examined at predefined levels of the distal bowel by histology and faecal calprotectin measurements both before and after intervention. We also evaluated the applicability of a Pouchitis Disease Activity Index (PDAI). RESULTS: The LDF measurements were reproducible in the pelvic pouch at each of the predefined levels, but did not change during intervention. Mucosal perfusion was significantly reduced in the distal compared to the proximal part of the pouch in the UC group (P < 0.05). The perfusion levels were higher in the FAP patients compared to the UC patientsat all predefined levels (P < 0.05). Calprotectin levels and histological score did not change significantlyafter intervention in any of the groups. The calprotectin level was significantly lower in the FAP compared to the UC group both before and after intervention. The PDAI decreased in both groups from alevel considered diagnostic for pouchitis to a level considered as not active pouchitis. The decreasewas significant for the UC patients. CONCLUSIONS: The results did not demonstrate an effect of probiotics on histology, although a significant effect on the PDAI was achieved, which concurs with the previously reported effect on symptoms and endoscopic score. The significantly reduced blood flow in the UC group compared to the FAP group, operated on with the same procedure, and the significantly increased calprotectin levels in the UC group, are original findings. Both findings may be related to an increased risk for pouchitis among UC patients. The lack of effect of intervention on mucosal perfusion does not exclude a role for reduced circulation as a cause of pouchitis based on the reduced LDF measurements in the distal part of the pouch.