The association of frontal plane alignment to MRI-defined worsening of patellofemoral osteoarthritis: the MOST study.

OBJECTIVE: To determine the sex-specific relation of frontal plane alignment (FPA) to magnetic resonance imaging (MRI)-defined features of patellofemoral osteoarthritis, and also to tibiofemoral osteoarthritis and knee pain. METHOD: The Multicenter Osteoarthritis Study is cohort study comprised of individuals with or at risk of knee osteoarthritis. We determined the sex-specific dose-response relation of baseline FPA to MRI-defined patellofemoral and tibiofemoral structural worsening, and incident knee pain, over 7 years. RESULTS: In women only, greater varus alignment was associated with medial patellofemoral osteophytes (risk ratio [RR] 1.7 [95% CI 1.2, 2.6]) and valgus with lateral patellofemoral osteophytes (RR 1.9 [1.0, 3.6]). In men, greater varus increased risk for medial tibiofemoral cartilage worsening (RR 1.7 [1.1, 2.6]), and valgus for lateral tibiofemoral cartilage worsening (RR 1.8 [1.6, 2.2]). In women, findings were similar for tibiofemoral cartilage, but varus also increased risk for medial bone marrow lesions [BMLs] (RR 2.2 [1.6, 3.1]) and medial osteophytes (RR 1.8 [1.3, 2.5]), and valgus for lateral BMLs (RR 3.3 [2.2, 4.5]) and osteophytes (RR 2.0 [1.2, 3.2]). Varus increased risk of incident pain in men (RR 1.7 [1.4, 2.2]) and women (RR 1.3 [1.0, 1.6]), valgus did so in men only (RR 1.5 [1.1, 1.9]). CONCLUSION: FPA was associated with patellofemoral osteophyte worsening in women, though overall was more strongly associated with tibiofemoral than patellofemoral osteoarthritis feature worsening. FPA in women was more consistently associated with structural worsening, yet men had higher associations with incident pain.

Probiotic or synbiotic alters the gut microbiota and metabolism in a randomised controlled trial of weight management in overweight adults.

The gut microbiota contributes to host energy metabolism, and altered gut microbiota has been associated with obesity-related metabolic disorders. We previously reported that a probiotic alone or together with a prebiotic controls body fat mass in healthy overweight or obese individuals in a randomised, double-blind, placebo controlled clinical study (ClinicalTrials.gov NCT01978691). We now aimed to investigate whether changes in the gut microbiota may be associated with the observed clinical benefits. Faecal and plasma samples were obtained from a protocol compliant subset (n=134) of participants from a larger clinical study where participants were randomised (1:1:1:1) into four groups: (1) placebo, 12 g/d microcrystalline cellulose; (2) Litesse® Ultra™ polydextrose (LU), 12 g/day; (3) Bifidobacterium animalis subsp. lactis 420™ (B420), 1010 cfu/d in 12 g microcrystalline cellulose; (4) LU+B420, 1010 cfu/d of B420 in 12 g/d LU for 6 months of intervention. The faecal microbiota composition and metabolites were assessed as exploratory outcomes at baseline, 2, 4, 6 months, and +1 month post-intervention and correlated to obesity-related clinical outcomes. Lactobacillus and Akkermansia were more abundant with B420 at the end of the intervention. LU+B420 increased Akkermansia, Christensenellaceae and Methanobrevibacter, while Paraprevotella was reduced. Christensenellaceae was consistently increased in the LU and LU+B420 groups across the intervention time points, and correlated negatively to waist-hip ratio and energy intake at baseline, and waist-area body fat mass after 6 months treatment with LU+B420. Functional metagenome predictions indicated alterations in pathways related to cellular processes and metabolism. Plasma bile acids glycocholic acid, glycoursodeoxycholic acid, and taurohyodeoxycholic acid and tauroursodeoxycholic acid were reduced in LU+B420 compared to Placebo. Consumption of B420 and its combination with LU resulted in alterations of the gut microbiota and its metabolism, and may support improved gut barrier function and obesity-related markers.

Non-nucleoside inhibitors of HIV-1 reverse transcriptase: molecular modeling and X-ray structure investigations.

The structural features of a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors (3) are presented. Comparison of the structural and electronic properties with those of TIBO (1) and Nevirapine (2) yields a common three-dimensional model. This model permits the improvement of the lead compound 3 by chemical modification (5,6). Additionally, two new types of inhibitors (4, 7) with similar biological activity can be derived from this model. The structure of the new compounds, including their absolute configuration, are determined by X-ray crystallography.

Phenotypic expression of malignancy in hybrid and cybrid mouse cells.

This study has been directed toward the effect of cytoplasmic transfer on the expression of marker properties in hybrid cell systems. Conventional hybrids between two nucleated cells were constructed between tumorigenic and nontumorigenic cells. Cytoplasmic hybrids, or cybrids, were constructed between enucleated chloramphenicol resistant (CAP R) donor cells (cytoplasts) and nucleated recipient cells. Clear-cut evidence for the cytoplasmic transmission of CAP resistance was obtained. Although cytoplasmic transfer had no effect on tumorigenicity or growth in soft agar, preliminary evidence was found that saturation density of the recipient cells could be altered by cytoplasmic addition in cybrids.

Elimination of mitochondrial elements and improved viability in hybrid cells.

Experiments were carried out to determine whether the mitochondria-specific dye rhodamine-6G (R6G) can affect transmission of cytoplasmic determinants in mammalian cells. When one parental cell type was treated with R6G prior to fusion with an untreated partner, the subsequent hybridization frequencies in both intra- and interspecific crosses were not adversely affected, even though R6G was extremely toxic to the parental cells. In addition, cells lethally treated with R6G could be rescued by fusion with cytoplasm alone from untreated cells. When chloramphenicol (CAP) resistant cells were used as the R6G-treated parent, the expression of CAP resistance in hybrids and cybrids was greatly reduced. Thus R6G can be used to control the input of cytoplasmic determinants into fused cells. In the interspecific (Chinese hamster x mouse) crosses, it was also seen that the majority of hybrids which had not been R6G pretreated grew poorly or degenerated after a short time. In contrast, nearly all hybrids in crosses where the hamster parent was R6G pretreated grew vigorously. The concomitant elimination of inviability and loss of mitochondrial determinants in R6G-pretreated hybrids suggests that interactions involving mitochondrial gene products or components can influence growth characteristics in interspecific somatic cell hybrids.

Differential sensitivity of metaphase to diamide and ouabain in HeLa cells.

We have examined the effects of diamide, an oxidizer of glutathione, on the progress of HeLa cells through the cell cycle. At concentrations which do not significantly alter generation time, anaphase or cytokinesis, diamide causes a two-fold increase in the duration of metaphase. At 3 X 10(-8) M, ouabain also prolongs metaphase without effect on anaphase or cytokinesis, though with a different time course. The data suggest that the metaphase stage of mitosis is particularly sensitive to alterations in both sulfhydryl groups and Na+ levels but that the effects of diamide are probably not primarily due to the oxidation of sulfhydryl groups of the Na+/K+-ATPase.

The alteration of mitotic events by ionophore A23187 and carbonyl cyanide n-chlorophenylhydrazone.

A large quantity of published work indicates that calcium ions may be involved in the regulation of mitotic events and recent reports suggest that the onset of chromosome movement is dependent upon a transient increase in free cytosolic calcium ions. In this paper we examine the effects of two agents known to perturb intracellular calcium pools on mitosis in HeLa cells. These were the calcium-selective ionophore A23187 and carbonyl cyanide n-chlorophenylhydrazone (CCCP), which is a protonophoric inhibitor of oxidative phosphorylation. Owing to a stimulation of glycolysis, the latter agent does not decrease intracellular ATP in HeLa but does cause mitochondria to release calcium ions. Our data show that, at low concentrations, both agents prolong metaphase but differ in their effects on anaphase and cytokinesis. Studies with chlorotetracycline, a commonly used probe for membrane-associated calcium, verify that these agents do affect calcium pools under the conditions of our experiments. The data presented are consistent with the idea that increased cytosolic calcium levels can directly or indirectly affect mitotic events but, contrary to other suggestions, cause a prolongation of metaphase, i.e. they delay the onset of chromosome movement.

Duration of ductal shunting in healthy preterm infants: an echocardiographic color flow Doppler study.

The purpose of this investigation was to assess the duration of ductal shunting after birth in healthy preterm infants (30 to 37 weeks gestational age) without evidence of respiratory distress. Thirty-six infants were evaluated in the first 12 hours of life by means of two-dimensional echocardiography and color flow Doppler techniques, and then once daily until no ductal flow was detected (defined as functional closure). Preterm infants were subdivided into two groups by gestational age: group 1 = 30 to 33 weeks (n = 12); group 2 = 34 to 37 weeks (n = 24). Sixteen full-term infants (38 to 41 weeks) were similarly evaluated as control subjects (Group 3). One infant from each group had a closed ductus at the time of the first study (performed at a mean of 7.7 +/- 3.2 hours). Subsequent studies for the entire group were performed at a mean of 31.3 +/- 5.4 hours (day 2), 55.0 +/- 4.5 hours (day 3), and 80.3 +/- 6.1 hours (day 4). For the three groups, the rates of ductal closure ranged from 50.0% to 58.3% on day 2 and 81.3% to 87.5% on day 3. For the entire group, all but one infant had demonstrated closure of the ductus arteriosus by day 4. Within the range of gestational ages studied, we conclude that prematurity, in the absence of respiratory distress syndrome, does not prolong the initial duration of physiologic ductal shunting.

Low incidence of rimantadine resistance in field isolates of influenza A viruses.

The spread of drug-resistant influenza viruses type A to close contacts in families, schools, and nursing homes has been well documented. To investigate whether drug-resistant influenza viruses circulate in the general population, 2017 isolates collected in 43 countries and territories during a 4-year period were tested for drug susceptibility in a bioassay. Drug resistance was confirmed by detection of specific mutations on the M2 gene that have been shown to confer resistance to amantadine or rimantadine. Sixteen viruses (0.8%) were found to be drug-resistant. Only 2 of these resistant viruses were isolated from individuals who received amantadine or rimantadine treatment at the time the specimens were collected. For 12 individuals use of amantadine or rimantadine could be excluded, and from the remaining 2 patients information about medication was unavailable. These results indicate that the circulation of drug-resistant influenza viruses is a rare event, but surveillance for drug resistance should be continued.