THOC5, a member of the mRNA export complex, contributes to processing of a subset of wingless/integrated (Wnt) target mRNAs and integrity of the gut epithelial barrier.
THO (Suppressors of the transcriptional defects of hpr1 delta by overexpression) complex 5 (THOC5), an mRNA export protein, is involved in the expression of only 1% of all genes. Using an interferon inducible knockout mouse system, we have previously shown that THOC5 is an essential element in the maintenance of hematopoietic stem cells and cytokine-mediated hematopoiesis in adult mice. Here we interrogate THOC5 function in cell differentiation beyond the hematopoietic system and study pathological changes caused by THOC5 deficiency. To examine whether THOC5 plays a role in general differentiation processes, we generated tamoxifen inducible THOC5 knockout mice. We show here that the depletion of THOC5 impaired not only hematopoietic differentiation, but also differentiation and self renewal of the gut epithelium. Depletion of the THOC5 gene did not cause pathological alterations in liver or kidney. We further show that THOC5 is indispensable for processing of mRNAs induced by Wnt (wingless/integrated) signaling which play key roles in epithelial cell differentiation/proliferation. A subset of Wnt target mRNAs, SRY-box containing gene 9 (Sox9), and achaete-scute complex homolog 2 (Ascl2), but not Fibronectin 1 (Fn1), were down-regulated in THOC5 knockout intestinal cells. The down-regulated Wnt target mRNAs were able to bind to THOC5. Furthermore, pathological alterations in the gastrointestinal tract induced translocation of intestinal bacteria and caused sepsis in mice. The bacteria translocation may cause Toll-like receptor activation. We identified one of the Toll-like receptor inducible genes, prostaglandin-endoperoxidase synthase 2 (Ptgs2 or COX2) transcript as THOC5 target mRNA. THOC5 is indispensable for processing of only a subset of mRNAs, but plays a key role in processing of mRNAs inducible by Wnt signals. Furthermore, THOC5 is dispensable for general mRNA export in terminally differentiated organs, indicating that multiple mRNA export pathways exist. These data imply that THOC5 may be a useful tool for studying intestinal stem cells, for modifying the differentiation processes and for cancer therapy.


Sesquiterpenoids from myrrh inhibit androgen receptor expression and function in human prostate cancer cells.
To examine whether two naturally occurring sesquiterpenoids (ST1 and ST2) with anti-proliferative activity in prostate cancer cells inhibit androgen receptor (AR) signaling. Human prostate cancer cell lines LNCaP and PC3 were used. The expression of AR, AR translocation into the nucleus, and expression levels of AR coactivators ARA70 and steroid receptor coactivator-1 (SRC-1) in LNCaP cells were examined using real-time PCR and Western blot. Changes in prostate-specific antigen (PSA) protein levels, PSA promoter activity, and androgen response element (ARE)-mediated reporter gene activity were examined using enzyme-linked immunoabsorbent assay (ELISA) and transient transfection assays. Co-immunoprecipitation was performed to analyze the interaction between AR and the AR coactivators in ST1- and ST2-treated cells. In LNCaP cells, ST1 and ST2 (40 μmol/L) led to a significant decrease in the expression of AR as well as a reduction of AR translocation into the nucleus, but had no effect on AR protein translation. ST1 and ST2 treatment also resulted in a significant decrease in the level of PSA protein secreted into the medium and was able to suppress PSA promoter-dependent and ARE-dependent luciferase activity. Furthermore, decreased expression of ARA70 and SRC-1 was observed when LNCaP cells were exposed to ST1 and ST2, which interfered with their ability to interact with AR. The observations suggest that suppression of AR transactivation by ST1 and ST2 may be mediated, in part, by inhibiting AR nuclear translocation and/or interfering with the interaction between AR and its coactivators ARA70 and SRC-1. Therefore, sesquiterpenoids could be developed as novel therapeutic agents for treating prostate cancer.


Idiopathic arterial calcification of infancy in newborn siblings with unusual light and electron microscopic manifestations.
We report two cases of idiopathic arterial calcification of infancy (IACI) occurring in newborn siblings. Unusual gross and light microscopic findings included calcification of multiple nonarterial tissues, renal infarction, and macroscopic aortic involvement. One case manifested an extensive acute panarteritis suggesting that IACI may be the result of an inflammatory or infectious process. Ultrastructural examination confirmed that the mineral deposits were hydroxyapatite and also indicated that they contained iron. Calcified tissue components included smooth-muscle cells, fibroblasts, and collagen fibers, as well as elastic fibers. No matrix vesicles or mitochondrial calcifications that may serve as nucleation sites for crystalline calcium phosphate were identified. Thus, the mechanism of calcification in IACI may be unique, and may relate to altered iron metabolism.


[Vasculitis and malignant diseases].
Approximately 1 - 7% of all patients with cutaneous vasculitis have an associated malignant disease. In such cases, vasculitis most often accompanies myelo- and lymphoproliferative diseases. Histologically, leukocytoclastic or panarteritis nodosa-like vasculitis are the most frequently observed types, and in most instances manifest clinically as palpable purpura. Malignancy should be suspected if the clinical picture does not fit into any well defined category of connective tissue disease, and when drugs and infection are excluded as causes of the vasculitis. The author discusses possible mechanisms of paramalignant vasculitis.


Evidence for a link between TNFRSF11A and risk of breast cancer.
Intracellular signaling mediated by the receptor activator of nuclear factor-κB [Rank, encoded by the tumor necrosis factor receptor superfamily, member 11a (Tnfrsf11a) gene] is fundamental for mammary gland development in mice, regulating the expansion of stem and progenitor cell compartments. Conversely, Rank overexpression in mice promotes abnormal proliferation and impairs differentiation, leading to an increased incidence of tumorigenesis. Here, we show that a common genetic variant near the 5'-end of TNFRSF11A, rs7226991, is associated with breast cancer risk in the general population and among carriers of mutations in the breast cancer 2, early onset (BRCA2) gene. Akin to the results of the Cancer and Genetics Markers of Susceptibility initiative, combined analysis of rs7226991 in two Spanish case-control studies (1,365 controls and 1,323 cases in total) revealed a significant association with risk: odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.78-0.98, P (trend) = 0.025. Subsequent examination of BRCA1 (n = 1,017) and BRCA2 (n = 885) mutation carriers revealed a consistent association in the latter group: weighted hazard ratio ((w)HR) = 0.70; 95% CI 0.55-0.88; and P (trend) = 0.003; compared to BRCA1 mutation carriers, (w)HR = 0.91; 95% CI 0.76-1.10; and P (trend) = 0.33. The results of this study need to be replicated in other populations and with larger numbers of BRCA1/2 mutation carriers.


Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control.
This retrospective study was conducted to review the results of treatment and to identify prognostic factors for local and regional control in a population of 378 patients with nasopharyngeal carcinomas treated in a single institution by radiation therapy alone. All patients were treated at The University of Texas M. D. Anderson Cancer Center between 1954 and 1992 following a consistent treatment philosophy but with evolving technique. There were 286 males and 92 females with a median age of 52 years (range: 16-86 years). The majority of the patients were Caucasian (282 patients, 75%). Thirty-two patients (8%) had one or more cranial nerve deficits. Three-fourths of the patients presented with AJCC Stage IV disease (T4, N0-3, 118 patients; T1-3, N2-3 164 patients). Histologically, 193 tumors (51%) were squamous cell carcinomas, 154 (41%) lymphoepitheliomas, and 31 (8%) unclassified carcinomas. Average total dose varied with T-stage and ranged from 60.2 to 72.0 Gy. Median follow-up time was 10 years. For the entire population the 5-, 10-, and 20-year actuarial survival rates were 48, 34, and 18%, respectively, with 184 patients (49%) dying of nasopharyngeal cancer. Actuarial control rates at 5, 10, and 20 years were 71, 66, and 66% for the primary site and 84, 83, and 83% for the neck. A total of 100 patients (26%) had local failures and 51 patients (13%) had regional failures with a median time to recurrence of 8.2 months and 13 months, respectively. Advanced T-stage, squamous histology, and presence of cranial nerve deficits were poor prognostic factors for local control in both univariate and multivariate analyses. N-stage and tumor histology were significant factors for neck control. Treatment year, total dose within the ranges used, and duration of treatment did not have any significant effect on local or regional control. The actuarial incidence of Grade 3-5 late complications was 16, 19, and 29% at 5, 10, and 20 years, respectively. Twelve patients (3%) died of treatment-related complications; all but one fatal complication occurred before 1971 and the other in 1976. This study shows very good long-term local and regional control rates for nasopharyngeal carcinomas after definitive radiotherapy and establishes a benchmark for newer treatment strategies. Improvements in treatment technique over the years have dramatically reduced the frequency of severe late complications. Patients with advanced stage tumors and differentiated squamous histology have a relatively poor prognosis when treated with conventional radiotherapy and are candidates for dose escalation or combined modality studies.


[Toroidal globular state of circular DNA].
The influence of torsional elasticity of the double helix on compactization and structure of circular DNA in a compact form is studied in the case when the compact (globular) particle has a torus shape. For closed circular DNA the topological invariant, linking number of two strains, yields strict connection between conformation of double helix, considered as a unifilar homopolymer, and elastic energy of torsional twisting. The contribution of torsional elasticity to free energy of the toruslike globule is calculated. This contribution is shown to be proportional to the square of superturn's density. Torsional elasticity decreases the equilibrium radius of the toruslike globule formed by circular DNA in comparison with the case of linear DNA. Closure of linear DNA into a ring widens the stability range of the relatively short DNA compact form and tightens it for long DNA.


Measuring fatigue in polio survivors: content comparison and reliability of the Fatigue Severity Scale and the Checklist Individual Strength.
To compare the content of the Fatigue Severity Scale and the subscale "subjective experience of fatigue" of the Checklist Individual Strength, and (ii) to assess the reliability of both questionnaires in polio survivors. Repeated-measures at a 3-week interval. Consecutive series of 61 polio survivors. Concepts contained in the questionnaire items were linked to the International Classification of Functioning, Disability and Health (ICF), using standardized linking rules. Reliability analyses included tests of internal consistency, test-retest reliability and measurement error. Questionnaires differed in the extent to which they measured other than fatigue-related aspects of functioning (represented ICF components: "Body functions": 50% and 80%, "Activities and Participation": 30% and 0%, for the Fatigue Severity Scale and Checklist Individual Strength, respectively). Internal consistency and test-retest reliability were considered acceptable, while measurement error was large (Cronbach's α: 0.90 and 0.93, intraclass correlation coefficient: 0.80 and 0.85, smallest detectable change: 28.7% and 29.4% for the Fatigue Severity Scale and Checklist Individual Strength, respectively). Considering the acceptable clinimetric properties, we conclude that both the Fatigue Severity Scale and the Checklist Individual Strength can be applied in research on post-poliomyelitis syndrome when measuring fatigue. However, because the 2 questionnaires differ in content they cannot be used interchangeably.


Utility of the 6-minute walk test following lung transplantation.
The 6-minute walk test (6-MWT) has replaced standard cardiopulmonary exercises for the evaluation of lung disease. However, data on the utility and characteristics of the 6-MWT following lung transplant are lacking. This study aimed to determine if 6-MWT distance has a normal distribution at 6 months post-transplant and if lower 6-MWT distance was predictive of all-cause mortality. We performed a retrospective chart review of 6-MWT data on all patients who were lung transplant recipients at Ochsner Medical Center between 2000 and 2005. Forty-nine lung transplant recipients completed a 6-MWT at 6 months following transplant. Of these 49 patients, 34 had completed both the 6-month and 12-month 6-MWT, and data from these were used to evaluate change in distance walked over time. The mean age was 46 ± 16 years, 57% were female, and 69% received a bilateral lung transplant. Normal distribution by Kolmogorov-Smirnov was demonstrated for 6-MWT distance at 6 months (P = 0.873). Mean distance walked improved from 348 ± 15 m to 478 ±14 m at 12 months (P = 0.0001). The 6-MWT distance at 6 months was not a predictor of survival (OR = 1.002). Distance for the 6-MWT followed a normal distribution following lung transplant, and distances walked continued to improve for a year following transplant. Although 6-MWT distances are not a predictor of survival, other components of the test may strengthen the predictive value for morbidity and mortality post-transplant.


Mantle cell lymphoma with gastrointestinal involvement and the role of endoscopic examinations.
Studies on gastrointestinal (GI) tract involvement in mantle cell lymphoma (MCL) are lacking. We investigated the clinical characteristics and prognosis of MCL with GI tract involvement. We retrospectively analyzed 64 patients diagnosed with MCL from January 2009 to April 2017. At the time of MCL diagnosis, patients who were identified to have GI involvement by endoscopic or radiologic examination were assigned to the GI-MCL group. The other patients were assigned to the non GI-MCL group. The GI-MCL group included 28 patients (43.8%). The most common endoscopic finding of MCL was lymphomatous polyposis (20/28, 71.4%). The GI-MCL group had higher stage and International Prognostic Index status (P = 0.012 and P = 0.003, respectively). Among the total 51 GI lesions in the GI-MCL group, 31.4% (16/51) were detected only by endoscopic examinations and were not detected on CT or PET-CT. The cumulative incidence of recurrence was higher in the GI-MCL group compared with the non GI-MCL group but the difference was not statistically significant (P = 0.082). Stage (HR 1.994, 95% CI 1.007-3.948) and auto PBSCT (HR 0.133, 95% CI 0.041-0.437) were identified as independent predictive factors for recurrence. Recurrences at GI tract were identified in 59.1% (13/22) and 11.1% (2/18) of the GI-MCL and non GI-MCL group, respectively. Among 15 GI tract recurrences, five recurrences were detected only with endoscopic examinations. Endoscopy can reveal the GI involvement of MCL that is not visualized by radiological imaging. Endoscopic examinations are recommended during staging workup and the follow-up period of MCL patients.


Factors of trainability and predictability associated with military physical fitness test success.
Cuddy, JS, Slivka, DR, Hailes, WS, and Ruby, BC. Factors of trainability and predictability associated with military physical fitness test success. J Strength Cond Res 25(12): 3486-3494, 2011-The purpose of this study was to determine the trainability of college-aged men using varied training programs and to assess factors associated with successfully passing a Special Operations Forces (SOF) physical fitness test (PFT). One hundred thirty-five male subjects were stratified into 3 training groups (run focused, calisthenic focused, or combined run and calisthenic) and were trained 3 times·per week for 12 weeks. Body composition and accelerometer activity patterns were measured pretraining and posttraining. The PFT performance (pull-ups, sit-ups, push-ups, and 1.5-mile run time) was measured weekly throughout the study period. The subjects exhibited reduced body fat (18.4 ± 7.7 to 16.9 ± 7.3), increased fat-free mass (66.1 ± 8.2 to 67.4 ± 7.9), reduced fat mass (15.8 ± 9.2 to 14.6 ± 8.9) from pretraining to posttraining, respectively (p < 0.05). All groups improved in each component of PFT performance with training (p < 0.05). There was a significant 20 ± 35% increase in 6-day average daily activity for the run-focused training group from pretraining and posttraining. The key indicators of a candidate's potential to successfully reach SOF PFT standards (in 12 weeks) were determined to be as follows: enter the pipeline being able to run 2.4 km in ≤10:41 minutes, have a body fat percentage of ≤12.9%, and participate in a minimum of 30 min·d of vigorous physical activity. Training an individual's relative run or calisthenic deficiency did not prove to be a better training approach compared with a program that emphasizes training both running and calisthenic activities.


Associations of the serum vitamin D with mortality in postmenopausal women.
Current evidence on the association of serum vitamin D with mortality in postmenopausal women is limited and inconsistent. Therefore, the purpose of this study was to examine the relationship between serum vitamin D and mortality in postmenopausal women. In this study, we used data from the NHANES (2001-2018) and conducted a multivariate Cox regression model to examine associations between serum vitamin D and all-cause mortality, cardiovascular mortality (CVD), and cancer mortality. In a median follow-up period of 8.3 years, 1905 deaths of all causes were reported, 601 were due to CVD, and 385 deaths were due to cancer. After multivariable adjustment, higher serum vitamin D levels were significantly associated with a reduced risk of death. Compared to participants with lower vitamin D levels (<25 nmol/L), those with higher vitamin D levels (≥75.0 nmol/L) had a lower risk of all-cause mortality (hazard ratio 0.60, 95 % confidence interval 0.49 to 0.74), a lower risk of cardiovascular mortality (0.51, 0.35 to 0.74), and a lower risk of cancer mortality (0.43, 0.28 to 0.67). Moreover, we observed an L-shaped dose-response relationship of serum vitamin D levels with all-cause mortality, and cancer mortality, with this inflexion point being 55.9 nmol/L, and 51.2 nmol/L, respectively. Higher concentrations of serum vitamin D substantially correlated with a reduction in mortality risk from all-cause, CVD, and cancer in postmenopausal women. These results imply that upholding adequate vitamin D levels may help prevent premature death in postmenopausal women.


Laboratory-Based Correlative Soft X-ray and Fluorescence Microscopy in an Integrated Setup.
Correlative microscopy is a powerful technique that combines the advantages of multiple imaging modalities to achieve a comprehensive understanding of investigated samples. For example, fluorescence microscopy provides unique functional contrast by imaging only specifically labeled components, especially in biological samples. However, the achievable structural information on the sample in its full complexity is limited. Here, the intrinsic label-free carbon contrast of water window soft X-ray microscopy can complement fluorescence images in a correlative approach ultimately combining nanoscale structural resolution with functional contrast. However, soft X-ray microscopes are complex and elaborate, and are usually installed on large-scale synchrotron radiation sources due to the demanding photon flux requirements. Yet, with modern high-power lasers it has become possible to generate sufficient photon flux from laser-produced plasmas, thus enabling laboratory-based setups. Here, we present a compact table-top soft X-ray microscope with an integrated epifluorescence modality for "in situ" correlative imaging. Samples remain in place when switching between modalities, ensuring identical measurement conditions and avoiding sample alteration or destruction. We demonstrate our new method by multimodal images of several exemplary samples ranging from nanoparticles to various multicolor labeled cell types. A structural resolution of down to 50 nm was reached.


Validity of minimal clinically important difference values for the multiple sclerosis walking scale-12?
Minimal clinically important difference (MCID) values of 4 and 6 points have been proposed for interpreting meaningful change in Multiple Sclerosis Walking Scale-12 (MSWS-12) scores. This study examined the validity of those MCID values based on capturing corresponding changes in other walking outcomes in persons with multiple sclerosis (MS). On 2 occasions separated by 6 months, 82 persons with MS completed the MSWS-12, timed 25-ft walk (T25FW), 6-min walk (6MW), and gait analysis, and then wore an accelerometer over a 7-day period. We generated change scores for the MSWS-12 and formed groups of stable, worsened, and improved perceived walking based on both 4- and 6-point changes. The groups were compared for corresponding changes in other walking measures over time using mixed-model ANOVAs. The mixed-model ANOVAs did not identify statistically significant group-by-time interactions on the T25FW (p = 0.98 and p = 0.67), the 6MW (p = 0.89 and p = 0.72), gait (p = 0.54 and p = 0.21), or accelerometry (p = 0.40 and p = 0.68) for MCID values of 4- or 6-point changes in MSWS-12 scores. We did not confirm that MCID values of 4 and 6 points for the MSWS-12 correspond with changes in performance, gait, and free-living assessments of walking in MS.


Functional status and health-related quality of life of elderly osteoarthritic patients treated with celecoxib.
This study evaluates the impact of celecoxib on functional status, health-related quality of life (HRQOL), and safety of elderly patients (> or =70 years) with osteoarthritis (OA) of the knee and/or hip. Data were pooled from three prospective, randomized, multicenter, double-blind, parallel group trials, each having a 12-week treatment period. Multicenter studies were conducted in the United States and Canada. Data for patients diagnosed with active OA of the knee and/or hip in a flare state who were 70 years of age and older were included in the comparison of therapeutic doses of celecoxib or naproxen versus placebo (N = 768). Elderly patients from each of the three trials who were randomly assigned to groups treated with a placebo. 200 mg/day of celecoxib, 400 mg/ day of celecoxib, or 1000 mg/day of naproxen were included in this analysis. The Western Ontario and McMaster Universities Osteoarthritis Index was used to measure functional status. The Short Form-36 was used as a general measure of HRQOL. Safety was assessed according to the incidence and type of adverse reactions as reported by the patients and the rate of withdrawal due to adverse events. At the end of the treatment period, patients in the celecoxib groups had significant improvement in both functional status and HRQOL in comparison with the placebo group. The effects of total daily doses of 200 mg of celecoxib, 400 mg of celecoxib, and 1000 mg of naproxen on functioning and HRQOL were not found to be significantly different from each other. The incidence of serious adverse events and withdrawal from the studies due to adverse events were similar in the celecoxib groups as they were in the placebo group. Overall, the naproxen group reported a significantly higher incidence of gastrointestinal adverse events than did the placebo and the 200-mg-daily celecoxib groups. This study showed that celecoxib and naproxen significantly improved functional status and HRQOL in elderly patients compared with those treated with a placebo. Celecoxib-treated patients were also found to experience safety and tolerability similar to that of the placebo-treated patients.


Microtubule organization of unstimulated and stimulated adherent human neutrophils in Chediak-Higashi syndrome.
The numbers and length of centriole-associated microtubules of two patients with Chediak-Higashi syndrome (CHS) were examined. Detergent-extracted whole-mount preparations of adherent cells were studied by stereo high-voltage electron microscopy. Under conditions of random migration, neutrophils from both patients had a microtubule organization similar to that of the control; microtubule numbers (28 +/- 3) and length (7.0 +/- 2.8 micron) were within normal range. When cells were treated with phorbol myristate acetate (PMA), differences in the response of the two patients were noted. Neutrophils from patient No. 2 and the control showed a significant rise in numbers (38 +/- 5) and length (9.5 +/- 3.6 micron) of microtubules. In contrast, neutrophils from patient No. 1 were unresponsive to PMA treatment. Because vitamin C is used therapeutically in CHS patients and has been shown to correct microtubule-related cell function, neutrophils were exposed to ascorbic acid. A significant increase in microtubule numbers (35 +/- 6) was observed in cells from the control and patient No. 2 after ascorbate treatment; neutrophils from patient No. 1 showed no increase in microtubule numbers. While ascorbic acid did not affect microtubule length in the control cells, it caused a significant increase in microtubule length in neutrophils from both patients. Results suggest that adherent CHS neutrophils contain centriole-associated microtubules which are normal in number and length. However, differences between patients are observed regarding neutrophil responsiveness to stimuli which induce microtubule polymerization.


Balancing authority, deference and trust across the public-private divide in health care: tuberculosis health visitors in western Maharashtra, India.
While concepts such as 'partnership' are central to the terminology of private-public mix (PPM), little attention has been paid to how social relations are negotiated among the diverse actors responsible for implementing these inter-sectoral arrangements. India's Revised National Tuberculosis Control Programme (RNTCP) has used intermediary agents to facilitate the involvement of private providers in the expansion of Directly Observed Therapy, Short-Course (DOTS). We examine the roles of tuberculosis health visitors (TB HVs) in mediating working relationships among private providers, programme staff and patients that underpin a PPM-DOTS launched by the RNTCP in western Maharashtra. In addition to observations and informal interactions with the programme and participating health providers, researchers conducted in-depth interviews with senior programme officers and eight TB HVs. Framed by a political discourse of clinical governance, working relationships within the PPM are structured by the pluralistic context, social and professional hierarchies and paternalism of health care in India. TB HVs are at the nexus of these relationships, yet remain undervalued partly because accountability is measured through technical rather than social outcomes of the 'partnership'. Close attention to the dynamics of power relations in working practices within the health system can improve accountability and sustainability of partnerships.


Assimilatory sulfur metabolism in marine microorganisms: characteristics and regulation of sulfate transport in Pseudomonas halodurans and Alteromonas luteo-violaceus.
Sulfate transport capacity was not regulated by cysteine, methionine, or glutathione in Pseudomonas halodurans, but growth on sulfate or thiosulfate suppressed transport. Subsequent sulfur starvation of cultures grown on all sulfur sources except glutathione stimulated uptake. Only methionine failed to regulate sulfate transport in Alteromonas luteo-violaceus, and sulfur starvation of all cultures enhanced transport capacity. During sulfur starvation of sulfate-grown cultures of both bacteria, the increase in transport capacity was mirrored by a decrease in the low-molecular-weight organic sulfur pool. Little metabolism of endogenous inorganic sulfate occurred. Cysteine was probably the major regulatory compound in A. luteo-violaceus, but an intermediate in sulfate reduction, between sulfate and cysteine, controlled sulfate transport in P. halodurans. Kinetic characteristics of sulfate transport in the marine bacteria were similar to those of previously reported nonmarine systems in spite of significant regulatory differences. Sulfate and thiosulfate uptake in P. halodurans responded identically to inhibitors, were coordinately regulated by growth on various sulfur compounds and sulfur starvation, and were mutually competitive inhibitors of transport, suggesting that they were transported by the same mechanism. The affinity of P. halodurans for thiosulfate was much greater than for sulfate.


Assay strategies for the discovery and validation of therapeutics targeting Brugia pahangi Hsp90.
The chemotherapy of lymphatic filariasis relies upon drugs such as diethylcarbamazine and ivermectin that largely target the microfilarial stages of the parasite, necessitating continued treatment over the long reproductive life span of the adult worm. The identification of compounds that target adult worms has been a long-term goal of WHO. Here we describe a fluorescence polarization assay for the identification of compounds that target Hsp90 in adult filarial worms. The assay was originally developed to identify inhibitors of Hsp90 in tumor cells, and relies upon the ability of small molecules to inhibit the binding of fluorescently labelled geldanamycin to Hsp90. We demonstrate that the assay works well with soluble extracts of Brugia, while extracts of the free-living nematode C. elegans fail to bind the probe, in agreement with data from other experiments. The assay was validated using known inhibitors of Hsp90 that compete with geldanamycin for binding to Hsp90, including members of the synthetic purine-scaffold series of compounds. The efficacy of some of these compounds against adult worms was confirmed in vitro. Moreover, the assay is sufficiently sensitive to differentiate between binding of purine-scaffold compounds to human and Brugia Hsp90. The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target.


Interval breast cancers in New South Wales, Australia, and comparisons with trials and other mammographic screening programmes.
To present information on 1st year interval breast cancer from the New South Wales mammographic screening programme and to compare with published results from trials and services. New South Wales data were derived from a population based biennial mammographic screening programme, which achieved statewide coverage in 1995. Women aged 50-69 years screened during 1995-7 were included. Bilateral two view mammography with reading by two radiologists is used for biennial screening examinations. Interval cancers were detected by the screening programme and by linkage with the statewide cancer registry. In situ carcinoma was excluded. Incidence of interval cancer was estimated as a proportion of the expected underlying incidence of breast cancer. Comparative data were derived from the published literature and meta-analyses were performed. Although randomised trials of screening have a proportional incidence by meta-analysis of 19% (95% confidence interval (95% CI) 12% to 25%), service studies yield a proportional incidence by meta-analysis of 27% (95% CI 25% to 30%), and more than half report proportional incidences greater than 25%. In the New South Wales mammographic screening programme the proportional incidence of interval breast cancer was 33% (95% CI 29% to 38%) for ages 50-59 years, 28% (95% CI 24% to 32%) for ages 60-69 years, and 31% (95% CI 28% to 34%) for ages 50-69 years combined. Proportional incidence in the New South Wales programme for ages 50-69 years was not significantly different from the rate for service studies by meta-analysis. Effectiveness of mammographic screening for reducing mortality from breast cancer needs to be examined relative to rates of interval cancer from actual service situations as trials may concentrate resources and expertise in ways which may be less replicable in routine delivery of the service.


Effects and feasibility of an Integrative Medicine program for geriatric patients-a cluster-randomized pilot study.
Older adults often use complementary medicine; however, very few interventional studies have focused on them. The aim of this study was to evaluate the feasibility and to obtain preliminary data on effectiveness of an Integrative Medicine (IM) program compared to usual medical care. The study consisted of older adults living in shared apartment communities including caregiving. The shared apartments were cluster-randomized to the IM program or Usual Care (UC). IM consisted of additional lifestyle modification (exercise and diet), external naturopathic applications, homeopathic treatment, and modification of conventional drug therapy for 12 months. The UC group received conventional care alone. The following outcomes were used: Nurses Observation Scale for Geriatric Patients (NOSGER); Assessment of Motor and Process Skills; Barthel Index; Qualidem; Profile of Wellbeing; and Mini-mental State Examination. Exploratory effect sizes (Cohen's d, means adjusted for differences of baseline values) were calculated to analyze group differences. A total of eight shared apartment communities were included; four were allocated to IM (29 patients, median seven patients; [mean ± standard deviation] 82.7 ± 8.6 years) and four to UC (29 patients, median eight patients; 76.0 ± 12.8 years of age). After 12 months, effect sizes ≥0.3 were observed for activities of daily living on the NOSGER-Activities of Daily Living subscale (0.53), Barthel Index (0.30), Qualidem total sum score (0.39), Profile of Wellbeing (0.36), NOSGER-Impaired Social Behavior (0.47), and NOSGER-Depressed Mood subscales (0.40). Smaller or no effects were observed for all other outcomes. The intervention itself was found to be feasible, but elaborate and time consuming. This exploratory pilot study showed that for a full-scale trial, the outcomes of Activities of Daily Living and Quality of Life seem to be the most promising. The results have to be interpreted with care; larger confirmatory trials are necessary to validate the effects.


Withaferin A Induces Oxidative Stress-Mediated Apoptosis and DNA Damage in Oral Cancer Cells.
Withaferin A (WFA) is one of the most active steroidal lactones with reactive oxygen species (ROS) modulating effects against several types of cancer. ROS regulation involves selective killing. However, the anticancer and selective killing effects of WFA against oral cancer cells remain unclear. We evaluated whether the killing ability of WFA is selective, and we explored its mechanism against oral cancer cells. An MTS tetrazolium cell proliferation assay confirmed that WFA selectively killed two oral cancer cells (Ca9-22 and CAL 27) rather than normal oral cells (HGF-1). WFA also induced apoptosis of Ca9-22 cells, which was measured by flow cytometry for subG1 percentage, annexin V expression, and pan-caspase activity, as well as western blotting for caspases 1, 8, and 9 activations. Flow cytometry analysis shows that WFA-treated Ca9-22 oral cancer cells induced G2/M cell cycle arrest, ROS production, mitochondrial membrane depolarization, and phosphorylated histone H2A.X (γH2AX)-based DNA damage. Moreover, pretreating Ca9-22 cells with N-acetylcysteine (NAC) rescued WFA-induced selective killing, apoptosis, G2/M arrest, oxidative stress, and DNA damage. We conclude that WFA induced oxidative stress-mediated selective killing of oral cancer cells.


How to assess intra- and inter-observer agreement with quantitative PET using variance component analysis: a proposal for standardisation.
Quantitative measurement procedures need to be accurate and precise to justify their clinical use. Precision reflects deviation of groups of measurement from another, often expressed as proportions of agreement, standard errors of measurement, coefficients of variation, or the Bland-Altman plot. We suggest variance component analysis (VCA) to estimate the influence of errors due to single elements of a PET scan (scanner, time point, observer, etc.) to express the composite uncertainty of repeated measurements and obtain relevant repeatability coefficients (RCs) which have a unique relation to Bland-Altman plots. Here, we present this approach for assessment of intra- and inter-observer variation with PET/CT exemplified with data from two clinical studies. In study 1, 30 patients were scanned pre-operatively for the assessment of ovarian cancer, and their scans were assessed twice by the same observer to study intra-observer agreement. In study 2, 14 patients with glioma were scanned up to five times. Resulting 49 scans were assessed by three observers to examine inter-observer agreement. Outcome variables were SUVmax in study 1 and cerebral total hemispheric glycolysis (THG) in study 2. In study 1, we found a RC of 2.46 equalling half the width of the Bland-Altman limits of agreement. In study 2, the RC for identical conditions (same scanner, patient, time point, and observer) was 2392; allowing for different scanners increased the RC to 2543. Inter-observer differences were negligible compared to differences owing to other factors; between observer 1 and 2: -10 (95 % CI: -352 to 332) and between observer 1 vs 3: 28 (95 % CI: -313 to 370). VCA is an appealing approach for weighing different sources of variation against each other, summarised as RCs. The involved linear mixed effects models require carefully considered sample sizes to account for the challenge of sufficiently accurately estimating variance components.


[Obesity, migration and adolescence].
Weight management interventions during adolescence are challenging. Migration adds complexity to this problem, making migrant families more vulnerable. Teenagers confront families to new values transmitted by the host society: opulence, junk food, video games. Obesity should not be seen as a single issue of calories-excess, but must be considered as being part of a larger problem, which takes into account the context of the familial and societal life of the migrants. The caregivers must have an overall view of the situation to provide appropriate approaches to weight management.


General practitioners and women with urinary incontinence.
Urinary incontinence is a common problem for adult women. It results in a large financial and psychosocial cost. Much urinary incontinence goes unreported. Women with urinary incontinence can be successfully assessed and treated in general practice but studies have shown that many GPs manage the condition inadequately. This study aims to examine GPs' awareness of urinary incontinence in women and their management of, and attitudes to, female urinary incontinence. A qualitative study was conducted with 21 GPs responding to semi-structured interviews. Thematic analysis was carried out on these interviews, with recurrent views and experiences being identified and grouped. The interviews of 11 male and nine female GPs were suitable for analysis. GPs were aware of the prevalence and under-reporting of urinary incontinence in women. Many were unhappy with their own management of the condition and with the management options available to them. Male GPs in particular were reluctant to carry out gynaecological examinations, and few GPs expressed enthusiasm for teaching pelvic floor exercises or bladder drills. Medications were frequently used but generally considered ineffective or intolerable. The services of both public health nurses and practice nurses were under-used, largely because of lack of training in this area. Although incontinence nurses were employed in the area, many GPs did not know of their availability and, of those who did, few referred to them more than infrequently. This study demonstrates that many GPs avoid dealing with the problem of urinary incontinence in women and that they find it to be a difficult, chronic problem to treat. Specialist options seem not to be useful in general practice. The findings need to be explored in other GP settings.


[Biological properties of Trichinella spp. isolated from the Central Region of the Russian Federation].
The biological properties of Trichinella isolated from the muscles of a common fox inhabiting in the Central Region of the Russian Federation have been studied. The paper presents the results of passaging this isolate of Trichinella on laboratory rats and mice, shows morphometric variability in relation to the change of Trichinella habitat. Evidence is provided that the shape and size of Trichinella capsules depend on the strain of the parasite and the species of an animal host the muscles of which contain these tissue helminths. The morphological data, biological properties, and high negative temperature resistance of the Trichinella that are present in the muscles of a fox shot in the Ryazan Region allow the above isolate to be classified as Trichinella nativa.


HPV-mediated transformation of the anogenital tract.
Infection with high-risk human papillomavirus (HR-HPV) has been associated with intraepithelial neoplasia and carcinomas at various sites of the anogenital tract, including the cervix, vulva, vagina, penis and anus. Although HR-HPV is a necessary cause for cervical cancer, the majority of anal cancers and a subset of cancers at other genital sites, additional (epi)genetic events are required for malignant transformation. HPV-mediated transformation of human epithelial cells has been recognized as a multi-step process resulting from deregulated transcription of the viral oncogenes E6 and E7 in the proliferating cells. Interference of E6 and E7 with cell cycle regulators induces genetic instability, which drives the continuous selection of oncogenic alterations providing cells with a malignant phenotype. Early genetic events during cervical carcinogenesis associated with immortalization, include deletions at chromosomes 3p, 6 and 10p, whereas amongst others gain of chromosome 3q, loss of chromosome 11 and epigenetic alterations such as inactivation of the TSLC1 tumor suppressor gene represent later events associated with tumor invasion.


Coma-corrected rapid single-particle cryo-EM data collection on the CRYO ARM 300.
Single-particle cryogenic electron microscopy has recently become a major method for determining the structures of proteins and protein complexes. This has markedly increased the demand for throughput of high-resolution electron microscopes, which are required to produce high-resolution images at high rates. An increase in data-collection throughput can be achieved by using large beam-image shifts combined with off-axis coma correction, enabling the acquisition of multiple images from a large area of the EM grid without moving the microscope stage. Here, the optical properties of the JEOL CRYO ARM 300 electron microscope equipped with a K3 camera were characterized under off-axis illumination conditions. It is shown that efficient coma correction can be achieved for beam-image shifts with an amplitude of at least 10 µm, enabling a routine throughput for data collection of between 6000 and 9000 images per day. Use of the benchmark for the rapid data-collection procedure (with beam-image shifts of up to 7 µm) on apoferritin resulted in a reconstruction at a resolution of 1.7 Å. This demonstrates that the rapid automated acquisition of high-resolution micrographs is possible using a CRYO ARM 300.


An open and reconfigurable wireless sensor network for pervasive health monitoring.
Sensor networks constitute the backbone for the construction of personalized monitoring systems. Up to now, several sensor networks have been proposed for diverse pervasive healthcare applications, which are however characterized by a significant lack of open architectures, resulting in closed, non-interoperable and difficult to extend solutions. In this context, we propose an open and reconfigurable wireless sensor network (WSN) for pervasive health monitoring, with particular emphasis in its easy extension with additional sensors and functionality by incorporating embedded intelligence mechanisms. We consider a generic WSN architecture comprised of diverse sensor nodes (with communication and processing capabilities) and a mobile base unit (MBU) operating as the gateway between the sensors and the medical personnel, formulating this way a body area network (BAN). The primary focus of this work is on the intra-BAN data communication issues, adopting SensorML as the data representation mean, including the encoding of the monitoring patterns and the functionality of the sensor network. In our prototype implementation two sensor nodes are emulated; one for heart rate monitoring and the other for blood glucose observations, while the MBU corresponds to a personal digital assistant (PDA) device. Java 2 Micro Edition (J2ME) is used to implement both the sensor nodes and the MBU components. Intra-BAN wireless communication relies on the Blue-tooth protocol. Via an adaptive user interface in the MBU, health professionals may specify the monitoring parameters of the WSN and define the monitoring patterns of interest in terms of rules. This work constitutes an essential step towards the construction of open, extensible, inter-operable and intelligent WSNs for pervasive health monitoring.


Prevalence of Drug Fever Among Cases of Nosocomial Fever: A Systematic Review and Meta-analysis.
Objective Drug fever is defined as a fever that temporally coincides with the start of a culprit drug and disappears after discontinuation of the drug. It is a common cause of nosocomial fever, which refers to a fever that develops beyond the first 48 h after hospital admission. However, the exact prevalence of drug fever among cases of nosocomial fever is unclear, as is the variation in prevalence depending on the clinical setting and most common causative drugs. Methods PubMed MEDLINE, Dialog EMBASE, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials. gov were systematically searched. Studies that reported the prevalence of drug fever in patients with nosocomial fever were included. Two of the four reviewers conducted independent assessments of the inclusion, data extraction, and quality. Pooled adjusted odds ratios were generated using a random-effects model and presented with 95% confidence intervals (CIs). Results Fifteen meta-analysis from 15 studies were included. Ten studies did not report the definition of drug fever or excluded febrile patients who were admitted to the hospital within 24-48 h. The pooled prevalence of drug fever among cases of nosocomial fever was 3.0% (95% CI, 0.6%-6.8%), which was largely consistent across the settings, except for at Oriental Medicine Hospital. Only four studies reported the causative agents, and antibiotics were the most frequently reported. Conclusions The prevalence of drug fever is low in patients with nosocomial fever. Clinicians should recognize that drug fever is a diagnosis of exclusion, even in cases of nosocomial fever.


Are adolescents chronically sleep-deprived? An investigation of sleep habits of adolescents in the Southwest of Germany.
Adolescent sleep receives increasing attention. Several studies have shown that adolescents generally do not sleep enough. This survey assessed adolescents' sleep patterns, and results were compared with sleep logs. A total of 818 students aged 12-18 attending three different school types were asked to complete a questionnaire, adapted from the 'School Sleep Habits Survey', and filled in a sleep protocol over 2 weeks. Information on sleep patterns and demographic data were obtained additionally. A total of 601 students completed the questionnaire (i.e. 73.5% return rate), 55.1% female and 44.9% male. Average sleep duration during the week amounted to 8.04+/-0.89 h and 9.51+/-1.65 h on weekends. Sleep duration times on school days decreased from an average 8.64+/-0.83 h for the age category 12-13 years to 7.83+/-0.72 h for students above 16 years. 91.6% of all students slept less than 9.2 h per night during the week. Data from the 153 returned sleep logs showed even lower sleep times (7.75+/-0.82 h for school nights). The main hypothesis that students sleep on average considerably less than the recommended 9 h during weekdays was confirmed. Bedtimes changed throughout the week with the latest on Friday and Saturday nights and the least sleep around midweek. There were no significant group differences regarding school type and environment (rural vs. urban). Interestingly, the majority reported only little daytime sleepiness and no impaired performance. Results regarding the consequences of chronic sleep deprivation in the literature are inconclusive. The impact on physiological parameters, especially metabolic functions, requires further investigations.


Vision for the 12 LABOURS Digital Twin Platform.
Clinical translation of personalised computational physiology workflows and digital twins can revolutionise healthcare by providing a better understanding of an individual's physiological processes and any changes that could lead to serious health consequences. However, the lack of common infrastructure for developing these workflows and digital twins has hampered the realisation of this vision. The Auckland Bioengineering Institute's 12 LABOURS project aims to address these challenges by developing a Digital Twin Platform to enable researchers to develop and personalise computational physiology models to an individual's health data in clinical workflows. This will allow clinical trials to be more efficiently conducted to demonstrate the efficacy of these personalised clinical workflows. We present a demonstration of the platform's capabilities using publicly available data and an existing automated computational physiology workflow developed to assist clinicians with diagnosing and treating breast cancer. We also demonstrate how the platform facilitates the discovery and exploration of data and the presentation of workflow results as part of clinical reports through a web portal. Future developments will involve integrating the platform with health systems and remote-monitoring devices such as wearables and implantables to support home-based healthcare. Integrating outputs from multiple workflows that are applied to the same individual's health data will also enable the generation of their personalised digital twin.Clinical Relevance- The proposed 12 LABOURS Digital Twin Platform will enable researchers to 1) more efficiently conduct clinical trials to assess the efficacy of their computational physiology workflows and support the clinical translation of their research; 2) reuse primary and derived data from these workflows to generate novel workflows; and 3) generate personalised digital twins by integrating the outputs of different computational physiology workflows.


COQ10 PROVIDES CARDIOPROTECTION AGAINST THE TOXIC EFFECTS OF TRASTUZUMAB AND DOXORUBICIN IN RAT MODEL.
The study was aimed at investigating the effect of coenzyme Q10 (CoQ10) on reducing the cardiotoxic effects of trastuzumab (TRZ) and doxorubicin (DOX) in a rat model. The experiment duration was 20 days and involved sixteen healthy albino rats, subdivided into four groups: the negative control group, in which rats received a daily dose of a placebo vehicle; the positive control group, receiving a daily placebo vehicle and a single dose of a combination of TRZ+DOX; the third group, pretreated with CoQ10 (10 mg/kg orally daily for 10 days), followed by 10 days of placebo vehicle and a single dose of a combination of TRZ+DOX at day 10; and finally, the fourth group pretreated with 10 days of placebo vehicle then followed by CoQ10 (10 mg/kg orally daily for 10 days) and a single dose of a combination of TRZ+DOX at day 10. Histological analysis of cardiac tissues was conducted, and the serum levels of cardiac troponin and redox markers were evaluated. The results showed that there were several histopathological changes like necrosis, edema, inflammation, and others in Group 2, which did not receive CoQ10, with high serum levels of cTnI. However, a high degree of improvement was achieved in Groups 3 and 4 in which rats were administered CoQ10 either before or after TRZ and DOX administration. The improvement was expressed by the disappearance of histopathological changes and a significant decrease in the serum level of cardiac troponin compared with Group 2. The findings of the study suggest that the administration of CoQ10 could be beneficial in minimizing the cardiac side effects caused by TRZ and DOX. This study provides a basis for further research and development of CoQ10 as a potential cardioprotective agent against the cardiac side effects of chemotherapy.


Serotonin reuptake inhibitors for the treatment of premenstrual dysphoria.
Premenstrual dysphoria (PMD) is a severe form of premenstrual syndrome, afflicting approximately 5% of all women of fertile age. The cardinal symptoms are irritability and anger. In addition, sadness, tension and carbohydrate craving are common complaints. The symptoms surface regularly between ovulation and menstruation, and disappear completely within a few days after the onset of the bleeding; in patients with remaining symptoms during the follicular phase, alternative diagnoses should be considered. In a large number of recent trials, serotonin reuptake inhibitors (clomipramine, citalopram, fluoxetine, paroxetine, sertraline) have been shown to reduce the symptoms of PMD much more effectively than placebo; in contrast, non-serotonergic antidepressants (maprotiline, bupropion) appear to be ineffective. Interestingly, the onset of action of clomipramine and selective serotonin reuptake inhibitors (SSRIs) is much shorter when used for PMD than when used for depression, panic disorder, or obsessive-compulsive disorder. Consequently, patients with PMD can restrict the medication to the luteal phase of the cycle. In a recent placebo-controlled trial, intermittent administration of the SSRI citalopram was shown to reduce the symptoms of PMD significantly better than placebo, but also better than continuous administration of the drug. A reasonable interpretation of the latter, unexpected finding is that continuous medication may be associated with a certain development of tolerance than can be avoided by intermittent drug administration. The observation that the symptoms of PMD may be effectively reduced by SSRIs is of considerable clinical importance since previously no effective treatment for this common condition - apart from those disrupting ovarian cyclicity - has been available. It is also of theoretical importance because it constitutes one of the first pharmacological observations supporting the concept that serotonin may dampen irritability and anger in humans.


Low-dose recombinant human bone morphogenetic protein-2 to enhance the osteogenic potential of the Schneiderian membrane in the early healing phase: in vitro and in vivo studies.
The objectives of this study were to confirm the osteogenic potential of the Schneiderian membrane and to elucidate the early healing pattern of low-dose recombinant human bone morphogenetic protein-2 (rhBMP-2)-coated biphasic calcium phosphate (BCP). The osteogenic potential of the Schneiderian membrane and enhancement by rhBMP-2 were evaluated by in vitro analysis. RhBMP-2-coated BCP (experimental group) and BCP soaked with saline (control group) were applied to the maxillary sinus in rabbits. After 2 weeks, micro-computed tomographic and histometric analyses were performed. Enhanced osteogenic potential was found when cells from the Schneiderian membrane were treated with rhBMP-2. Micro-computed tomographic analysis showed that the total augmented volume was significantly larger in the experimental group. Different healing patterns were observed in 3 regions, although the area of new bone did not differ significantly. Although more newly formed bone appeared, particularly along the Schneiderian membrane in the experimental group, the difference was not statistically significant. RhBMP-2 enhanced the osteogenic potential of the Schneiderian membrane in vitro. However, low-dose rhBMP-2-coated BCP failed to exert a statistically significant effect in vivo, although it appeared to be effective in sinus augmentation specifically for the volumetric increase in the early phase.


[Misoprostol and oxytocin in induction of labour in women with prolonged pregnancy--safety and effectiveness comparison].
16 women with prolonged pregnancy and indications to induction of labour were involved into prospective analysis. Sixty of them were given 50 micrograms of Mizoprostol straight into posterior vaginal fornix (only once). In 56 women the labour was induced by intravenous administration of 5 IU Oxytocin. Effectiveness and safety of both preparations used in labour induction were compared. Non-significant higher effectiveness and significant faster induction of uterine contractions by Oxytocin was found. Mizoprostol administration significantly shortens duration of the first labour period. Eventually, time from the medicine administration until the labour in both groups was comparative.


V2-Net: An Attention-guided Volumetric Regression Network for Tooth Landmark Localization on CT Images with Metal Artifacts.
For virtual surgical planning in orthognathic surgery, marking tooth landmarks on CT images is an important procedure. However, the manual localization procedure of tooth landmarks is time-consuming, labor-intensive, and requires expert knowledge. Also, direct and automatic tooth landmark localization on CT images is difficult because of the lower resolution and metal artifacts of dental images. The purpose of this study was to propose an attention-guided volumetric regression network (V2-Net) for accurate tooth landmark localization on CT images with metal artifacts and lower resolution. V2-Net has an attention-guided network architecture using a coarse-to-fine-attention mechanism that guided the 3D probability distribution of tooth landmark locations within anatomical structures from the coarse V-Net to the fine V-Net for more focus on tooth landmarks. In addition, we combined attention-guided learning and a 3D attention module with optimal Pseudo Huber loss to improve the localization accuracy. Our results show that the proposed method achieves state-of-the-art accuracy of 0.85 ± 0.40 mm in terms of mean radial error, outperforming previous studies. In ablation studies, we observed that the proposed attention-guided learning and a 3D attention module improved the accuracy of tooth landmark localization in CT images of lower resolution and metal artifacts. Furthermore, our method achieved 97.92% in terms of the success detection rate within the clinically accepted accuracy range of 2.0 mm.


Accelerometer derived physical activity patterns in 27.890 middle-aged adults: The SCAPIS cohort study.
The present study aims to describe accelerometer-assessed physical activity (PA) patterns and fulfillment of PA recommendations in a large sample of middle-aged men and women, and to study differences between subgroups of socio-demographic, socio-economic, and lifestyle-related variables. A total of 27 890 (92.5% of total participants, 52% women, aged 50-64 years) middle-aged men and women with at least four days of valid hip-worn accelerometer data (Actigraph GT3X+, wGT3X+ and wGT3X-BT) from the Swedish CArdioPulmonary bioImage Study, SCAPIS, were included. In total, 54.5% of daily wear time was spent sedentary, 39.1% in low, 5.4% in moderate, and only 0.1% in vigorous PA. Male sex, higher education, low financial strain, born in Sweden, and sedentary/light working situation were related to higher sedentary time, but also higher levels of vigorous PA. High BMI and having multiple chronic diseases associated strongly with higher sedentary time and less time in all three PA intensities. All-year physically active commuters had an overall more active PA pattern. The proportion fulfilling current PA recommendations varied substantially (1.4% to 92.2%) depending on data handling procedures and definition used. Twenty-eight percent was defined as having an "at-risk" behavior, which included both high sedentary time and low vigorous PA. In this large population-based sample, a majority of time was spent sedentary and only a fraction in vigorous PA, with clinically important variations between subgroups. This study provides important reference material and emphasizes the importance of a comprehensive assessment of all aspects of the individual PA pattern in future research and clinical practice.


Quantifying Importance of Major Risk Factors for Coronary Heart Disease.
To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the associations of key modifiable CHD risk factors-specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking-with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age. Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non-high-density lipoprotein cholesterol (non-HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed. Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non-HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non-HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to <130 mm Hg or lowering low-density lipoprotein cholesterol by 30% would be expected to lower a baseline 10-year CHD risk of 10.7% to 7.0 and 8.0, respectively (absolute risk reductions: 3.7% and 2.7%, respectively). Prognostic performance decreases with age (C indices for age groups 45-54, 55-64, 65-74, 75-84 are 0.75, 0.72, 0.66, and 0.62, respectively), whereas absolute risk reductions increase (SBP: 1.1%, 2.3%, 5.4%, 10.3%, respectively; non-HDL-C: 1.1%, 2.0%, 3.7%, 5.9%, respectively). Although individual modifiable CHD risk factors contribute only modestly to prognostic performance, our models indicate that eliminating or controlling these individual factors would lead to substantial reductions in total population CHD events. Metrics used to judge importance of risk factors should be tailored to the research objectives.


Proton Dynamics in Palladium-Silver: An Inelastic Neutron Scattering Investigation.
Proton dynamics in Pd77Ag23 membranes is investigated by means of various neutron spectroscopic techniques, namely Quasi Elastic Neutron Scattering, Incoherent Inelastic Neutron Scattering, Neutron Transmission, and Deep Inelastic Neutron Scattering. Measurements carried out at the ISIS spallation neutron source using OSIRIS, MARI and VESUVIO spectrometers were performed at pressures of 1, 2, and 4 bar, and temperatures in the 330-673 K range. The energy interval spanned by the different instruments provides information on the proton dynamics in a time scale ranging from about 102 to 10-4 ps. The main finding is that the macroscopic diffusion process is determined by microscopic jump diffusion. In addition, the vibrational density of states of the H atoms in the metal lattice has been determined for a number of H concentrations and temperatures. These measurements follow a series of neutron diffraction experiments performed on the same sample and thus provide a complementary information for a thorough description of structural and dynamical properties of H-loaded Pd-Ag membranes.


On the mechanism of the hofmeister effect.
Vibrational sum frequency spectroscopy was used to probe fatty amine monolayers spread on various electrolyte solutions. The spectra revealed ion specific changes in both monolayer ordering and water structure with the former following the Hofmeister series. Separate measurements of the surface potential as a function of ion tracked closely to changes in alkyl chain structure, but less closely to changes in water structure. The disruption of the monolayer ordering could be ascribed to the relative ability of the ions to penetrate past the hydrophilic surface of the monolayer's headgroups and into the more hydrophobic portion of the thin film. The corresponding trends observed in the surface water structure showed significant deviations from the Hofmeister series, leading to the conclusion that the changes in surface water structure, often credited with being the origin of Hofmeister effects, are probably not of primary importance. On the other hand, dispersion forces almost certainly play a large role in the order of the Hofmeister series.


Toll-like receptors: a growing family of immune receptors that are differentially expressed and regulated by different leukocytes.
Toll is a Drosophila gene essential for ontogenesis and antimicrobial resistance. Several hortologues of Toll have been identified and cloned in vertebrates, namely Toll-like receptors (TLR). Human TLR are a growing family of molecules involved in innate immunity. TLR are structurally characterized by a cytoplasmic Toll/interleukin-1R (TIR) domain and by extracellular leucine-rich repeats. TLR characterized so far activate the MyD88/IRAK signaling cascade, which bifurcates and leads to NF-kappaB and c-Jun/ATF2/TCF activation. Genetic, gene transfer, and dominant-negative approaches have involved TLR family members (TLR2 and TLR4) in lipopolysaccharide recognition and signaling. Accumulating evidence suggests that some TLR molecules are also involved in signaling receptor complexes that recognize components of gram-positive bacteria and mycobacteria. However, the definitive role of other TLR is still lacking. A systematic approach has been used to determine whether different human leukocyte populations selectively or specifically expressed TLR mRNA. Based on expression pattern, TLR can be classified as ubiquitous (TLR1), restricted (TLR2, TLR4, and TLR5), and specific (TLR3). Expression and regulation of distinct though overlapping ligand recognition patterns may underlie the existence of a numerous, seemingly redundant, TLR family. Alternately, the expression of a TLR in a single cell type may indicate a specific role for this molecule in a restricted setting.


Temporal and spatial control over soluble protein signaling for musculoskeletal tissue engineering.
Orthopedic tissue engineering strategies have developed rapidly in response to large and growing clinical needs. However, current clinical methods for replacement of natural tissue function have significant limitations, and pragmatic challenges have hindered clinical use of emerging tissue engineering approaches. In addition, current methods are not yet capable of achieving complex spatial and temporal regulation of soluble signaling (e.g. growth factor signaling), which may be required for complex, functional tissue regeneration. We have begun to develop a series of new medical devices, which are designed to temporally and spatially regulate growth factor and cytokine signaling during tissue regeneration. The initial goal of these studies is to regulate the behavior of multipotent stem cells, and to promote formation of clinically relevant tissue interfaces (e.g. bone-tendon interfaces). The ultimate goal is to further understand and recapitulate the complex processes that lead to functional musculoskeletal development and regeneration.


Mental disorders and the risk of adult violent and psychological victimisation: a prospective, population-based study.
Psychiatric patients are at increased risk to become victim of violence. It remains unknown whether subjects of the general population with mental disorders are at risk of victimisation as well. In addition, it remains unclear whether the risk of victimisation differs across specific disorders. This study aimed to determine whether a broad range of mood, anxiety and substance use disorders at baseline predict adult violent (physical and/or sexual) and psychological victimisation at 3-year follow-up, also after adjustment for childhood trauma. Furthermore, this study aimed to examine whether specific types of childhood trauma predict violent and psychological victimisation at follow-up, after adjustment for mental disorder. Finally, this study aimed to examine whether the co-occurrence of childhood trauma and any baseline mental disorder leads to an incrementally increased risk of future victimisation. Data were derived from the first two waves of the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2): a psychiatric epidemiological cohort study among a nationally representative adult population. Mental disorders were assessed using the Composite International Diagnostic Interview version 3.0. Longitudinal associations between 12 mental disorders at baseline and violent and psychological victimisation at 3-year follow-up (n = 5303) were studied using logistic regression analyses, with adjustment for sociodemographic characteristics and childhood trauma. Furthermore, the moderating effect of childhood trauma on these associations was examined. Associations with victimisation varied considerably across specific mental disorders. Only alcohol dependence predicted both violent and psychological victimisation after adjustment for sociodemographic characteristics and childhood trauma. Depression, panic disorder, social phobia, generalised anxiety disorder and alcohol dependence predicted subsequent psychological victimisation in the fully adjusted models. All types of childhood trauma independently predicted violent and psychological victimisation after adjustment for any mental disorder. The presence of any childhood trauma moderated the association between any anxiety disorder and psychological victimisation, whereas no interaction between mental disorder and childhood trauma on violent victimisation existed. The current study shows that members of the general population with mental disorders are at increased risk of future victimisation. However, the associations with violent and psychological victimisation vary considerably across specific disorders. Clinicians should be aware of the increased risk of violent and psychological victimisation in individuals with these mental disorders - especially those with alcohol dependence - and individuals with a history of childhood trauma. Violence prevention programmes should be developed for people at risk. These programmes should not only address violent victimisation, but also psychological victimisation.


Worker and perceived team climate factors influence the use of restraint and seclusion in youth residential treatment centers: Results from a mixed-method longitudinal study.
Restraint and seclusion (R&S) are controversial methods of intervention aimed at protecting children from immediate harm in residential treatment centers (RTC). Previous studies have mainly focused on situational factors and youth characteristics to predict its use. This study sought to evaluate the role other potential predictors could play in the decision to use R&S, namely characteristics of residential workers and their perceived team climate. For two months, a total of 132 residential workers from different RTC in the greater Montreal area completed weekly diaries of standardized questionnaires. Using an explanatory sequential design (i.e., mixed methods), this study aimed at exploring the role of residential workers' characteristics (e.g., exposure to client aggression, stress and fatigue) and aspects of their perceived team climate (e.g., order and organization, communication and openness) as predictors of R&S use. Survey results were later also presented to four focus groups for discussion. Results indicated that exposure to verbal violence from youths was associated with the increased use of R&S. Meanwhile, perceived communication and openness were associated with lower rates of R&S use. Participants shared that repeated exposure to verbal violence diminished their level of tolerance while teamwork provided them with the emotional space needed to focus on the needs of youths and find alternatives to R&S. This study sheds light on the complex role of human emotions in the decision to use of R&S. Specifically, intense momentary emotions during crisis interventions had a greater influence on the use R&S than chronic states, such as fatigue.


Characterizations of and interactions between bile ductule cells and hepatocytes in early stages of rat hepatocarcinogenesis induced by ethionine.
Numerous hepatic cell lineage pathways have been proposed for the development of hepatocarcinogensis induced by chemical carcinogens in rats. The roles of bile ductule cells and hepatocytes in the development of carcinogenesis were investigated using light and electron microscopic procedures to detect differences in morphology and in the phenotypic expression of antigens that are associated with each cell type. In early stages of hepatocarcinogenesis (4-10 weeks after initiation of feeding of a choline-deficient ethionine containing diet), both bile ductulelike (BDL) cells and hepatocytes were seen in mitosis. At the light microscope level, BDL cells showed intense cytoplasmic pyronin (RNA) staining and were positive for the antigens defined by monoclonal antibody 270.38 (bile ductule cells and "oval" cell marker) and glutathione-S-transferase (Yp isoform), whereas hepatocytes were positive for the antigens defined by monoclonal antibodies 270.26 and 258.26 (liver parenchymal cell markers), catalase activity (peroxisome marker) and adenosine triphospatase activity (bile canalicular marker). The authors frequently encountered BDL cells and hepatocytes in close proximity. Ultrastructural examination showed extensive plasma membrane appositions between a subset of BDL cells and hepatocytes. Desmosome structures, tight junctions, microvilli interdigitations and ATPase-positive bile canalicularlike structures were present along the contiguous plasma membrane domains of BDL cells and hepatocytes. Many of the BDL cells attached to hepatocytes were also attached to other BDL cells that had retained a basal lamina. In many cases, BDL cells connected to both hepatocytes and other BDL cells were no longer completely surrounded by basal lamina and had acquired a dual polarity as a consequence of their sharing apical and lateral membrane domains with both BDL cells and hepatocytes. BDL cells showed increased numbers of microperoxisomes (catalase positive organelles) and numerous free ribosomes. Hepatocytes showed a prominent development of the smooth endoplasmic reticulum, a feature prominent in hepatocytes within hyperplastic nodules. Since BDL cells and hepatocytes proliferate and BDL cells and hepatocytes develop intercellular junction sites, the authors propose that both cell types in early stages of carcinogenesis have the capacity to enter the cell lineage pathway leading to the development of hepatocarcinoma. Furthermore, the finding that BDL cells and hepatocytes form multiple attachment sites at the level of the plasma membrane, suggests the possibility that at some stage convergence of separate hepatic cell pathways may occur.


Apatite-type crystal deposition in arthritic cartilage.
Osteoarthritis or 'Joint Failure' is a multi-factorial disease with a final common pathway of cartilage degeneration and bone eburnation. The association of arthritic disease and joint degeneration with the deposition of sodium urate crystals in gout and calcium pyrophosphate crystals in pseudogout (chondrocalcinosis) is clinically well established. Electron microscopy coupled with electron probe analysis has revealed the presence of various other calcium phosphate crystals in joint tissues and fluids. We have found three new morphological types of apatite crystals in human articular cartilage which are too small to be detected by X-rays of human joints or even by light microscopy of joint tissues. Two morphologically distinct types of apatite crystals in articular cartilage are associated with extracellular matrix vesicles formed from the cell processes of chondrocytes. 'Cuboid' crystals, which are found in the pericellular regions near the surface zone of articular cartilage, appear to be a variant of apatite and may even be 'Whitlockite' because there are traces of magnesium present. There are increased numbers of these microscopic 'cuboid' crystals (Type II) and Mineral Nodules (Type I) in arthritic cartilage and this is coupled with increased numbers of matrix vesicles and alkaline phosphatase activity. Clusters of fine needle-shaped apatite crystals (Type III) found on the surface of articular cartilage are not associated with matrix vesicles. Thus some forms of osteoarthritis are closely associated with apatite type crystal deposition and may imply abnormal mineral formation in articular cartilage as a pathogenic mechanism.


Drosophila TRPN(=NOMPC) channel localizes to the distal end of mechanosensory cilia.
A TRPN channel protein is essential for sensory transduction in insect mechanosensory neurons and in vertebrate hair cells. The Drosophila TRPN homolog, NOMPC, is required to generate mechanoreceptor potentials and currents in tactile bristles. NOMPC is also required, together with a TRPV channel, for transduction by chordotonal neurons of the fly's antennal ear, but the TRPN or TRPV channels have distinct roles in transduction and in regulating active antennal mechanics. The evidence suggests that NOMPC is a primary mechanotransducer channel, but its subcellular location-key for understanding its exact role in transduction-has not yet been established. Here, by immunostaining, we locate NOMPC at the tips of mechanosensory cilia in both external and chordotonal sensory neurons, as predicted for a mechanotransducer channel. In chordotonal neurons, the TRPN and TRPV channels are respectively segregated into distal and proximal ciliary zones. This zonal separation is demarcated by and requires the ciliary dilation, an intraciliary assembly of intraflagellar transport (IFT) proteins. Our results provide a strong evidence for NOMPC as a primary transduction channel in Drosophila mechansensory organs. The data also reveals a structural basis for the model of auditory chordotonal transduction in which the TRPN and TRPV channels play sequential roles in generating and amplifying the receptor potential, but have opposing roles in regulating active ciliary motility.


LRP5 gene polymorphisms predict bone mass and incident fractures in elderly Australian women.
Postmenopausal osteoporosis and bone mass are influenced by multiple factors including genetic variation. The importance of LDL receptor-related protein 5 (LRP5) for the regulation of bone mass has recently been established, where loss of function mutations is followed by severe osteoporosis and gain of function is related to increased bone mass. The aim of this study was to evaluate the role of polymorphisms in the LRP5 gene in regulating bone mass and influencing prospective fracture frequency in a well-described, large cohort of normal, ambulatory Australian women. A total of 1301 women were genotyped for seven different single nucleotide polymorphisms (SNPs) within the LRP5 gene of which five were potentially informative. The effects of these gene polymorphisms on calcaneal quantitative ultrasound measurements (QUS), osteodensitometry of the hip and bone-related biochemistry was examined. One SNP located in exon 15 was found to be associated with fracture rate and bone mineral density. Homozygosity for the less frequent allele of c.3357 A > G was associated with significant reduction in bone mass at most femoral sites. The subjects with the GG genotype, compared to the AA/AG genotypes showed a significant reduction in BUA and total hip, femoral neck and trochanter BMD (1.5% P = 0.032; 2.7% P = 0.047; 3.6% P = 0.008; 3.1% P = 0.050, respectively). In the 5-year follow-up period, 227 subjects experienced a total of 290 radiologically confirmed fractures. The incident fracture rate was significantly increased in subjects homozygous for the GG polymorphism (RR of fracture = 1.61, 95% CI [1.06-2.45], P = 0.027). After adjusting for total hip BMD, the fracture rate was still increased (RR = 1.67 [1.02-2.78], P = 0.045), indicating factors other than bone mass are of importance for bone strength. In conclusion, genetic variation in LRP5 seems to be of importance for regulation of bone mass and osteoporotic fractures.


Multiple sclerosis: patients' information sources and needs on disease symptoms and management.
To investigate the current information sources of patients with multiple sclerosis (MS) in the early stages of their disease and to identify patients' preferred source of information. The relative amounts of information from the different sources were also compared. Participants at a newly diagnosed information session organized by the Multiple Sclerosis Society of South Australia were invited to complete a questionnaire. Participants were asked to rate on a visual analog scale how much information they had received about MS and optic neuritis from different information sources and how much information they would like to receive from each of the sources. A close to ideal amount of information is being provided by the MS society and MS specialist nurses. There is a clear deficit between what information patients are currently receiving and the amount of information they actually want from various sources. Patients wish to receive significantly more information from treating general practitioners, eye specialists, neurologists, and education sessions. Patients have identified less than adequate information received on optic neuritis from all sources. This study noted a clear information deficit regarding MS from all sources. This information deficit is more pronounced in relation to optic neuritis and needs to be addressed in the future. More patient information and counselling needs to be provided to MS patients even at early stages of their disease, especially in relation to management of disease relapse.


Functional heterogeneity of resident fibroblasts in the kidney.
Chronic kidney disease (CKD) is a global public health problem, affecting over 10% of the world's population and more than half of the population aged over 70 years, imposing major costs on healthcare systems. Although the primary causes of CKD include various diseases such as diabetes, glomerulonephritis, and acute kidney injury (AKI), the progression of CKD is mediated by a common pathological pathway, which is mainly characterized by fibrosis and chronic inflammation. In this process, resident fibroblasts in the kidney play crucial roles. Accumulating evidence highlights the existence of functional heterogeneity and plasticity of fibroblasts and their diverse roles in kidney disease progression and resolution. In addition to renal fibrosis, renal anemia and peritubular capillary loss, two major complications of progressive CKD, are also caused by dysfunction of resident fibroblasts. Furthermore, age-dependent alterations in fibroblast behavior also contribute to age-dependent unique pathological conditions. In this article, we describe the current understanding regarding the behaviors of fibroblasts in the kidney in health, disease, and aging.


Protocol for AREST: Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation-A Randomized Controlled Trial of Early Anticoagulation After Acute Ischemic Stroke in Atrial Fibrillation.
Background: Optimal timing to initiate anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF) is currently unknown. Compared to other stroke etiologies, AF typically provokes larger infarct volumes and greater concern of hemorrhagic transformation, so seminal randomized trials waited weeks to months to begin anticoagulation after initial stroke. Subsequent data are limited and non-randomized. Guidelines suggest anticoagulation initiation windows between 3 and 14 days post-stroke, with Class IIa recommendations, and level of evidence B in the USA and C in Europe. Aims: This open-label, parallel-group, multi-center, randomized controlled trial AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) is designed to evaluate the safety and efficacy of early anticoagulation, based on stroke size, secondary prevention of ischemic stroke, and risks of subsequent hemorrhagic transformation. Methods: Subjects are randomly assigned in a 1:1 ratio to receive early apixaban at day 0-3 for transient ischemic attack (TIA), 3-5 for small-sized AIS (<1.5 cm), and 7-9 for medium-sized AIS (1.5 cm or greater but less than a full cortical territory), or warfarin at 1 week post-TIA or 2 weeks post-stroke. Large AISs are excluded. Study Outcomes: Primary: recurrent ischemic stroke, TIA, and fatal stroke; secondary: intracranial hemorrhage (ICH); hemorrhagic transformation (HT) of ischemic stroke; cerebral microbleeds (CMBs); neurologic disability [e.g., modified Rankin Scores (mRS), National Institutes of Health Stroke Scale (NIHSS), Stroke Specific Quality of Life scale (SS-QOL)]; and cardiac biomarkers [e.g., AF burden, transthoracic echo (TTE)/transesophageal echo (TEE) abnormalities]. Sample Size Estimates: Enrollment goal was 120 for 80% power (two-sided type I error rate of 0.05) to detect an absolute risk reduction of 16.5% postulated to occur with apixaban in the primary composite outcome of fatal stroke/recurrent ischemic stroke/TIA within 180 days. Enrollment was suspended at 91 subjects in 2019 after a focused guideline update recommended direct oral anticoagulants (DOACs) over warfarin in AF, excepting valvular disease (Class I, level of evidence A). Discussion: AREST will offer randomized controlled trial data about timeliness and safety of anticoagulation in AIS patients with AF. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02283294.


Demyelinating myelin oligodendrocyte glycoprotein-specific autoantibody response is focused on one dominant conformational epitope region in rodents.
Conformational epitopes of myelin oligodendrocyte glycoprotein (MOG) provide a major target for demyelinating autoantibodies in experimental autoimmune encephalomyelitis and recent studies indicate that a similar situation may exist in multiple sclerosis. We recently solved the crystal structure of the extracellular domain of MOG (MOG(ex)) in complex with a Fab derived from the demyelinating mAb 8-18C5 and identified the conformational 8-18C5 epitope on MOG that is dominated by the surface exposed FG loop of MOG. To determine the importance of this epitope with regard to the polyclonal Ab response to MOG(ex) we investigated the effects of mutating His(103) and Ser(104), the two central amino acids of the FG loop, on Ab binding. Mutation of these two residues reduced binding of a panel of eight demyelinating conformation-dependent mAbs to <20% compared with binding to wild-type MOG(ex), whereas substitution of amino acids that do not contribute to the 8-18C5 epitope had only a minor effect on Ab binding. The same restriction was observed for the polyclonal MOG-specific Ab response of MOG DNA-vaccinated BALB/c and SJL/J mice. Our data demonstrate that the pathogenic anti-MOG Ab response primarily targets one immunodominant region centered at the FG loop of MOG. Comparison of the structure of MOG(ex) with the structures of related IgV-like domains yields a possible explanation for the focused Ab response.


Thioredoxin-interacting protein: a novel target for neuroprotection in experimental thromboembolic stroke in mice.
Redox imbalance in the brain significantly contributes to ischemic stroke pathogenesis, but antioxidant therapies have failed in clinical trials. Activation of endogenous defense mechanisms may provide better protection against stroke-induced oxidative injury. TXNIP (thioredoxin-interacting protein) is an endogenous inhibitor of thioredoxin (TRX), a key antioxidant system. We hypothesize that TXNIP inhibition attenuates redox imbalance and inflammation and provides protection against a clinically relevant model of embolic stroke. Male TXNIP-knockout (TKO), wild-type (WT), and WT mice treated with a pharmacological inhibitor of TXNIP, resveratrol (RES; 5 mg/kg body weight), were subjected to embolic middle cerebral artery occlusion (eMCAO). Behavior outcomes were monitored using neurological deficits score and grip strength meter at 24 h after eMCAO. Expression of oxidative, inflammatory, and apoptotic markers was analyzed by Western blot, immunohistochemistry, and slot blot at 24 h post-eMCAO. Our result showed that ischemic injury increases TXNIP in WT mice and that RES inhibits TXNIP expression and protects the brain against ischemic damage. TKO and RES-treated mice exhibited a 39.26 and 41.11 % decrease in infarct size and improved neurological score and grip strength compared to WT mice after eMCAO. Furthermore, the levels of TRX, nitrotyrosine, NOD-like receptor protein (NLRP3), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and activations of caspase-1, caspase-3, and poly-ADP-ribose polymerase (PARP) were significantly (P < 0.05) attenuated in TKO and RES-treated mice. The present study suggests that TXNIP is contributing to acute ischemic stroke through redox imbalance and inflammasome activation and inhibition of TXNIP may provide a new target for therapeutic interventions. This study also affirms the importance of the antioxidant effect of RES on the TRX/TXNIP system.


[Thrombosis of the mesenteric vessels as a complication of food toxicoinfection].
The authors have observed 189 patients with thromboses of the mesenteric vessels. In 85.7% of the cases thrombosis developed in the mesenteric major vessels (mainly in the upper mesenteric artery), in 14.3% in the microcirculation system as a complication of food poisoning. Differential-diagnostic signs for both groups and clinical illustrations are presented. The importance of efficient rehydration therapy in food poisoning for the correction of rheological and homeostatic disorders in the microcirculation system is emphasized.


Experimental Traumatic Brain Injury Induces Bone Loss in Rats.
Few studies have investigated the influence of traumatic brain injury (TBI) on bone homeostasis; however, pathophysiological mechanisms involved in TBI have potential to be detrimental to bone. The current study assessed the effect of experimental TBI in rats on the quantity and quality of two different weight-bearing bones, the femur and humerus. Rats were randomly assigned into either sham or lateral fluid percussion injury (FPI) groups. Open-field testing to assess locomotion was conducted at 1, 4, and 12 weeks post-injury, with the rats killed at 1 and 12 weeks post-injury. Bones were analyzed using peripheral quantitative computed tomography (pQCT), histomorphometric analysis, and three-point bending. pQCT analysis revealed that at 1 and 12 weeks post-injury, the distal metaphyseal region of femora from FPI rats had reduced cortical content (10% decrease at 1 week, 8% decrease at 12 weeks; p < 0.01) and cortical thickness (10% decrease at 1 week, 11% decrease at 12 weeks p < 0.001). There was also a 23% reduction in trabecular bone volume ratio at 1 week post-injury and a 27% reduction at 12 weeks post-injury in FPI rats compared to sham (p < 0.001). There were no differences in bone quantity and mechanical properties of the femoral midshaft between sham and TBI animals. There were no differences in locomotor outcomes, which suggested that post-TBI changes in bone were not attributed to immobility. Taken together, these findings indicate that this rat model of TBI was detrimental to bone and suggests a link between TBI and altered bone remodeling.


Ultrasound anatomy of the normal stifle in the sheep.
Though the ovine stifle is commonly used as a model in research, there is no description of its anatomy at ultrasonography (US). The objective of this study was to provide reference US images of the ovine stifle that are relevant in musculoskeletal research. Four pairs of hindlimbs were scanned, whilst four other pairs were frozen and cut in different planes to compare gross anatomy to US scans. In another pair, the synovial compartments of the stifle were injected and scanned. This study demonstrated that US could be used to assess the ovine stifle. Several structures of clinical interest could be identified with cranial, lateral and medial approaches, such as (a) the tendons of m. quadriceps femoris, m. gluteobiceps, m. popliteus, (b) the common tendon of m. peroneus tertius-extensor longus digitorum-extensor digiti III proprius, (c) the patellar ligament, (d) the medial and lateral collateral ligaments, (e) the cranial horn and middle segment of medial and lateral meniscus, and (f) the synovial recesses. However, the caudal approach was not successful to identify caudal anatomical structures of the joint, due to the muscular mass, that is the caudal aspects of the articular surfaces of the femoral and tibial condyles, the caudal horns of the menisci and the supracondylar synovial recesses. In addition, US remained challenging to assess the internal structures such as cruciate ligaments and articular surfaces. The feasibility of US needs to be tested in vivo.


What Do We Know about Inequalities in NAFLD Distribution and Outcomes? A Scoping Review.
With prevalence high and rising given the close relationship with obesity and diabetes mellitus, non-alcoholic fatty liver disease (NAFLD) is progressively becoming the most common chronic liver condition worldwide. However, little is known about the health inequalities in NAFLD distribution and outcomes. This review aims to analyze health inequalities in NAFLD distribution globally and to assess the health disparities in NAFLD-related outcomes. We conducted a scoping review of global health inequalities in NAFLD distribution and outcomes according to gender/sex, ethnicity/race, and socioeconomic position from PubMed's inception to May 2021. Ultimately, 20 articles were included in the review, most (75%) of them carried out in the United States. Males were found to have a higher NAFLD prevalence (three articles), while available evidence suggests that women have an overall higher burden of advanced liver disease and complications (four articles), whereas they are less likely to be liver-transplanted once cirrhosis develops (one article). In the US, the Hispanic population had the highest NAFLD prevalence and poorer outcomes (seven articles), whereas Whites had fewer complications than other ethnicities (two articles). Patients with low socioeconomic status had higher NAFLD prevalence (four articles) and a higher likelihood of progression and complications (five articles). In conclusion, globally there is a lack of studies analyzing NAFLD prevalence and outcomes according to various axes of inequality through joint intersectional appraisals, and most studies included in our review were based on the US population. Available evidence suggests that NAFLD distribution and outcomes show large inequalities by social group. Further research on this issue is warranted.


Illumination-tolerant face verification of low-bit-rate JPEG2000 wavelet images with advanced correlation filters for handheld devices.
Face recognition on mobile devices, such as personal digital assistants and cell phones, is a big challenge owing to the limited computational resources available to run verifications on the devices themselves. One approach is to transmit the captured face images by use of the cell-phone connection and to run the verification on a remote station. However, owing to limitations in communication bandwidth, it may be necessary to transmit a compressed version of the image. We propose using the image compression standard JPEG2000, which is a wavelet-based compression engine used to compress the face images to low bit rates suitable for transmission over low-bandwidth communication channels. At the receiver end, the face images are reconstructed with a JPEG2000 decoder and are fed into the verification engine. We explore how advanced correlation filters, such as the minimum average correlation energy filter [Appl. Opt. 26, 3633 (1987)] and its variants, perform by using face images captured under different illumination conditions and encoded with different bit rates under the JPEG2000 wavelet-encoding standard. We evaluate the performance of these filters by using illumination variations from the Carnegie Mellon University's Pose, Illumination, and Expression (PIE) face database. We also demonstrate the tolerance of these filters to noisy versions of images with illumination variations.