Multicenter Observational Study of the Use of Nebulized Hypertonic Saline to Treat Children Hospitalized for Bronchiolitis From 2008 to 2014.
Among children hospitalized for bronchiolitis, we examined temporal trends in the use of hypertonic saline (HTS) and the characteristics associated with receiving this treatment. We conducted a secondary analysis of data from 2 large, multicenter prospective cohort studies that included young children hospitalized with bronchiolitis during 5 winter seasons (2008-2014). Our outcome was receipt of HTS any time during the preadmission visit or hospitalization. For comparison with the observed trends in HTS use, we conducted a PubMed literature review of studies evaluating HTS use for bronchiolitis. We classified publications according to their assessment of HTS efficacy (positive, negative, or neutral). Among 2709 hospitalized children, 241 (8.9%) received HTS. There was marked variability in HTS use by site (0%-91%), with use more common among children admitted to the ICU than those treated on the ward (31% vs 15%). Over the study period, administration of HTS increased from 2% during the 2008-2009 season to 27% during the 2011-2012 season, but then it decreased to 11% during the 2013-2014 season. Before 2010, the number of PubMed HTS publications ranged from 0 to 3 articles per year, with all classified as either positive or neutral. The number of positive publications increased in 2010 (n = 5), whereas negative publications peaked in 2014 (n = 4). Use of HTS in children hospitalized with bronchiolitis increased during the 2008 to 2012 winter seasons and then declined. These findings paralleled trends in the HTS literature, with positive articles encouraging HTS use in early years followed by a growing number of neutral and negative articles after 2012.


Lung recruitment during mechanical positive pressure ventilation in the PICU: what can be learned from the literature?
A literature review was conducted to assess the evidence for recruitment manoeuvres used in conventional mechanical positive pressure ventilation. A total of 61 studies on recruitment manoeuvres were identified: 13 experimental, 31 ICU, 6 PICU and 12 anaesthesia studies. Recruitment appears to be a continuous process during inspiration and expiration and is determined by peak inspiratory pressure (PIP) and positive end expiratory pressure (PEEP). Single or repeated recruitment manoeuvres may result in a statistically significant increase in oxygenation; however, this is short lasting and clinically irrelevant, especially in late ARDS and pneumonia. Temporary PIP elevation may be effective but only after PEEP loss (for example disconnection and tracheal suctioning). Continuous PEEP elevation and prone positioning can increase P(a)O2 significantly. Adverse haemodynamic or barotrauma effects are reported in various studies. No data exist on the effect of recruitment manoeuvres on mortality, morbidity, length of stay or duration of mechanical ventilation. Although recruitment manoeuvres can improve oxygenation, they can potentially increase lung injury, which eventually determines outcome. Based on the presently available literature, prone position and sufficient PEEP as part of a lung protective ventilation strategy seem to be the safest and most effective recruitment manoeuvres. As paediatric physiology is essentially different from adult, paediatric studies are needed to determine the role of recruitment manoeuvres in the PICU.


The role of plasmapheresis in severe acute disseminated encephalomyelitis with clinical findings of transverse myelitis.
Acute disseminated encephalomyelitis is a rare acute demyelinating disease of the central nervous system (CNS). The pathogenesis remains unclear but is suspected to be autoimmune. High doses of methylprednisolone (HDMP) are currently considered standard of treatment. Plasmapheresis (PE) is typically given in steroid refractory cases. There is currently limited evidence supporting its use in ADEM. We report a 16-year-old girl with ADEM who improved rapidly after initiating PE. The patient presented with acute onset of multifocal CNS symptoms, including encephalopathy, requiring intensive care unit management. Despite HDMP administration, her clinical condition continued to deteriorate. PE was therefore initiated on the same day as HDMP. Her clinical condition improved significantly following the first session. She was extubated and discharged from the intensive care unit the following day. HDMP combined with PE may be an effective first-line treatment in patients with fulminant ADEM.


Factors associated with mortality among persistently viraemic triple-antiretroviral-class-experienced patients receiving antiretroviral therapy in the HIV Outpatient Study (HOPS).
Identifying factors associated with mortality for HIV-infected patients with persistent viraemia despite antiretroviral (ARV) therapy may inform diagnostic and treatment strategies. We analysed data from viraemic triple-ARV-class-experienced HIV Outpatient Study patients seen during 1 January 1999 to 31 December 2012 who, despite treatment that included ARVs from three major drug classes [nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors and protease inhibitors (PIs)], had plasma HIV RNA levels [viral load (VL)] >1000 copies/mL ['triple ARV class failure' (TCF)]. The baseline was defined as the date of meeting the TCF criteria during 1999-2008. We identified factors associated with mortality using Cox regression. Of 597 patients who met the TCF criteria (median follow-up after baseline 4.9 years), 115 (19.3%) died. Baseline factors associated with mortality were age per 10 years [hazard ratio (HR) 1.61, 95% CI 1.28-2.02], risk of HIV from use of injection drugs (HR 1.81, 95% CI 1.10-2.98), CD4+ T cell count <200 cells/mm(3) (HR 3.68, 95% CI 2.41-5.62), VL ≥5.0 log10 copies/mL (HR 2.91, 95% CI 1.88-4.49) and receiving a first combination ARV therapy regimen that was PI-based (HR 2.44, 95% CI 1.47-4.06); receiving a novel ARV agent during follow-up (HR 0.45, 95% CI 0.22-0.93) was protective. Genotypic resistance testing results were available for 274 (45.9%) of the TCF patients, of whom 47 (17.2%) died. In this group, factors associated with death were increasing age (HR 1.94, 95% CI 1.36-2.78, per 10 year increment), risk of HIV from use of injection drugs (HR 2.71, 95% CI 1.37-5.39), baseline VL ≥5.0 log10 copies/mL (HR 5.35, 95% CI 2.82-10.1) and receiving PI-based first combination ARV therapy regimen (HR 3.20, 95% CI 1.25-8.17). No HIV mutations or combinations of mutations were significantly associated with survival. Factors significantly associated with mortality risk among TCF patients who received ongoing ARV therapy included traditional clinical predictors but not the presence, type or number of HIV genetic mutations. The use of novel ARV drugs by these ARV therapy-experienced patients was associated with an improved survival.


Association of Hospital Performance Based on 30-Day Risk-Standardized Mortality Rate With Long-term Survival After Heart Failure Hospitalization: An Analysis of the Get With The Guidelines-Heart Failure Registry.
Among patients hospitalized with heart failure (HF), the long-term clinical implications of hospitalization at hospitals based on 30-day risk-standardized mortality rates (RSMRs) is not known. To evaluate the association of hospital-specific 30-day RSMR with long-term survival among patients hospitalized with HF in the American Heart Association Get With The Guidelines-HF registry. The longitudinal observational study included 106 304 patients with HF who were admitted to 317 centers participating in the Get With The Guidelines-HF registry from January 1, 2005, to December 31, 2013, and had Medicare-linked follow-up data. Hospital-specific 30-day RSMR was calculated using a hierarchical logistic regression model. In the model, 30-day mortality rate was a binary outcome, patient baseline characteristics were included as covariates, and the hospitals were treated as random effects. The association of 30-day RSMR-based hospital groups (low to high 30-day RSMR: quartile 1 [Q1] to Q4) with long-term (1-year, 3-year, and 5-year) mortality was assessed using adjusted Cox models. Data analysis took place from June 29, 2017, to February 19, 2018. Thirty-day RSMR for participating hospitals. One-year, 3-year, and 5-year mortality rates. Of the 106 304 patients included in the analysis, 57 552 (54.1%) were women and 84 595 (79.6%) were white, and the median (interquartile range) age was 81 (74-87) years. The 30-day RSMR ranged from 8.6% (Q1) to 10.7% (Q4). Hospitals in the low 30-day RSMR group had greater availability of advanced HF therapies, cardiac surgery, and percutaneous coronary interventions. In the primary landmarked analyses among 30-day survivors, there was a graded inverse association between 30-day RSMR and long-term mortality (Q1 vs Q4: 5-year mortality, 73.7% vs 76.8%). In adjusted analysis, patients admitted to hospitals in the high 30-day RSMR group had 14% (95% CI, 10-18) higher relative hazards of 5-year mortality compared with those admitted to hospitals in the low 30-day RSMR group. Similar findings were observed in analyses of survival from admission, with 22% (95% CI, 18-26) higher relative hazards of 5-year mortality for patients admitted to Q4 vs Q1 hospitals. Lower hospital-level 30-day RSMR is associated with greater 1-year, 3-year, and 5-year survival for patients with HF. These differences in 30-day survival continued to accrue beyond 30 days and persisted long term, suggesting that 30-day RSMR may be a useful HF performance metric to incentivize quality care and improve long-term outcomes.


Effect of type of enrichment and duration of incubation on salmonella recovery from meat-and-bone meal.
Twenty-five meat-and-bone meal samples were enriched with either selenite-cystine or tetrathionate and incubated for 1 and 2 days. Seven were previously found to be positive; of the other 18, 16 were positive for salmonella. The number of somatic serogroups per sample ranged from 1 to 11 with a mean of 3.8. Significantly more (P < 0.01) group C(1) salmonellae were isolated using tetrathionate than selenite, whereas significantly more of groups G, 35, and Difco poly-valent D were isolated from selenite than tetrathionate. Seventy-six percent of the presumptive colonies from Brilliant Green agar showed a positive lysine decarboxylase reaction, and there were no differences between media or times of incubation. Ninety-four per cent of the lysine decarboxylase-positive cultures showed a positive somatic antiserum response; again there were no differences between times or enrichments although there were significantly more total positive serogroups at 2 days than at 1 day from tetrathionate but not from selenite. There were indications that certain serogroups preferred either one or the other enrichment. There were no differences in total positive samples with the two enrichments although neither alone was sufficient to identify all positives. Several lactose-positive salmonellae were recovered.


Predictability of Interruptions During Medication Administration With Related Behavioral Management Strategies.
The aim of this qualitative study was to examine the nature of interruptions during medication administration. Focus groups were conducted with medical/surgical nurses (n = 15), critical care nurses (n = 13), and nurse managers/educators/specialists (n = 6). Most interruptions (78%) were predictable. Nurse-adopted strategies included blocking, engaging, mediating, multitasking, and preventing. Educational content was developed that relates behavioral strategies to respond to predictable and unpredictable interruptions.


Treatment of papermaking tobacco sheet wastewater by electrocoagulation combined with electrochemical oxidation.
Attempts were made in this study to examine the efficiency of electrocoagulation (EC) using aluminum (Al) anode and stainless steel net cathode combined with electrochemical oxidation with a β-PbO₂anode or a mixed metal oxide (MMO) anode for treatment of papermaking tobacco sheet wastewater, which has the characteristics of high content of suspended solids (SS), intensive color, and low biodegradability. The wastewater was first subjected to the EC process under 40 mA/cm² of current density, 2.5 g/L of NaCl, and maintaining the original pH of wastewater. After 6 minutes of EC process, the effluent was further treated by electrochemical oxidation. The results revealed that the removal of SS during the EC process was very beneficial to mass transfer of organics during electrochemical oxidation. After the combined process, 83.9% and 82.8% of chemical oxygen demand (COD) removal could be achieved on the β-PbO₂and MMO anodes, respectively. The main components of the final effluent were biodegradable organic acids, such as acetic acid, propionic acid, butyric acid, valeric acid, and hexahyl carbonic acid; the 5-day biochemical oxygen demand/chemical oxygen demand (BOD₅/COD) ratio increased from 0.06 to 0.85 (Al + β-PbO₂) or 0.80 (Al + MMO). Therefore, this integrated process is a promising alternative for pretreatment of papermaking tobacco sheet wastewater prior to biological treatment.


cis-4-[18F]fluoro-L-proline Molecular Imaging Experimental Liver Fibrosis.
Introduction: Early-stage liver fibrosis is potentially reversible, but difficult to diagnose. Clinical management would be enhanced by the development of a non-invasive imaging technique able to identify hepatic injury early, before end-stage fibrosis ensues. The analog of the amino acid proline, cis-4-[18F]fluoro-L-proline ([18F]fluoro-proline), which targets collagenogenesis in hepatic stellate cells (HSC), was used to detect fibrosis. Methods: Acute steatohepatitis was induced in experimental animals by liquid ethanol diet for 8 weeks, intra-gastric binge feedings every 10th day along with lipopolysaccharide (LPS) injection. The control animals received control diet for 8 weeks and an equivalent volume of saline on the same schedule as the acute steatohepatitis model. First, in vitro cellular experiments were carried out to assess [3H]proline uptake by HSC, hepatocytes and Kupffer cells derived from rats with acute steatohepatitis (n = 14) and controls (n = 14). Next, ex vivo liver experiments were done to investigate unlabeled proline-mediated collagen synthesis and its associated proline transporter expression in acute steatohepatitis (n = 5) and controls (n = 5). Last, in vivo dynamic and static [18F]fluoro-proline micro-PET/CT imaging was performed in animal models of acute steatohepatitis (n = 7) and control (n = 7) mice. Results: [3H]proline uptake was 5-fold higher in the HSCs of steatohepatitis rats than controls after incubation of up to 60 min. There was an excellent correlation between [3H]proline uptake and liver collagen expression (r-value > 0.90, p < 0.05). Subsequent liver tissue studies demonstrated 2-3-fold higher proline transporter expression in acute steatohepatitis animals than in controls, and proline-related collagen synthesis was blocked by this transporter inhibitor. In vivo micro-PET/CT studies with [18F]fluoro-proline showed 2-3-fold higher uptake in the livers of acute steatohepatitis mice than in controls. There was an excellent correlation between [18F]fluoro-proline uptake and liver collagen expression in the livers of acute steatohepatitis mice (r-value = 0.97, p < 0.001). Conclusion: [18F]fluoro-proline localizes in the liver and correlates with collagenogenesis in acute steatohepatitis with a signal intensity that is sufficiently high to allow imaging with micro-PET/CT. Thus, [18F]fluoro-proline could serve as a PET imaging biomarker for detecting early-stage liver fibrosis.


Accumulation of suspended barite at mesopelagic depths and export production in the southern ocean.
The relation between the accumulation of barite (BaSO(4)) microcrystals in suspended matter from the mesopelagic depth region (100 to 600 meters) and the type of production in the euphotic layer (new versus recycled) was studied for different Southern Ocean environments. Considerable subsurface barite accumulated in waters characterized by maintained new production and limited grazing pressure during the growth season. On the other hand, little if any barite accumulated in areas where relatively large amounts of photosynthetically fixed carbon were transferred to the microheterotrophic community and where recycled production became predominant.


Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.
Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K(IR)6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on beta-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.


[Potentially fatal orbital disorder].
Fulminant processes of the orbit can cause considerable diagnostic difficulties with regards to the clinical, radiological and microbiological appearance. Rhino-orbito-cerebral mucormycosis is a rare but, when untreated, fatal orbital disease capable of destructive infiltration of soft tissue and bone. It occurs preferably in the ill adjusted diabetic or in the course of an immunodeficiency. The following case report describes a leukaemia patient developing a severe rhino-orbito-cerebral mucormycosis which was initially not recognised. Since untreated mucormycosis is fatal, an aggressive surgical approach with excision of the whole necrotic area is necessary even if the diagnosis cannot be confirmed with certainty.


Visual cues and gait improvement in Parkinson's disease: which piece of information is really important?
Visual exproprioception refers to information of the body relative to the environment and may be the critical piece of sensory information that explains why gait improvements can be achieved with visual step cues in people with Parkinson's disease (PD). The primary aim of current study was to investigate the role of visual exproprioception in the positive effect of visual cues on gait in patients with PD. Nineteen individuals with PD and 15 healthy subjects participated in this study. Four conditions of self-paced gait were tested: normal walking, without exproprioception (exproprioceptive information of lower limbs removed), visual step length cues, and visual step length cues but without exproprioception. Gaze behavior, gait parameters and the accuracy and precision of foot placement on the visual cues were recorded. Individuals with PD improved step length in both cued conditions. Both groups fixated close to 46% on visual cues necessary to accomplish the next step (ongoing step), while 54% of fixations were focused on visual cues one or more steps ahead. Also, both groups increased absolute error and error variability of the foot placement around the visual cues without vision of their feet. These results suggest that exproprioceptive information is not critical to achieve step length and overall gait benefits with visual cues in PD, but is critical for the accuracy and precision of foot placement on targets. People with PD and healthy individuals use visual information from visual cues in both on-line and feedforward fashions. In conclusion, patients with PD likely focus attention on the discrete goal of each foot hitting a visual cue placed on the floor and then use the exteroceptive information (i.e. position of next foot placement location) to plan each step individually at a cortical level.


Evaluation of ghrelin level and appetite regulation in patients with acute exacerbations of chronic obstructive pulmonary disease.
Appetite reduction is a major cause of cachexia in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). This study tested the correlation of appetite and circulating levels of acylated ghrelin in patients with AECOPD. Thirty-six patients with AECOPD and 23 healthy adults were enrolled in this study. Circulating total ghrelin, acylated ghrelin, and obestatin levels, Simplified Nutritional Appetite Questionnaire (SNAQ) score, and caloric intake were compared in patients and healthy controls. Additionally, the above parameters were compared between admission and discharge in the patients with AECOPD. Compared with healthy controls, SNAQ scores and caloric intake were significantly lower in patients with AECOPD, but there were no significant differences in total ghrelin, acyl ghrelin, or obestatin levels. In patients with AECOPD, the total ghrelin level was significantly higher at admission than on discharge, the SNAQ score and caloric intake were significantly increased at discharge when compared with admission, and there was no significant difference in acylated ghrelin level between admission and discharge. We demonstrated lower appetite scores and caloric intake in patients with AECOPD, but could not confirm that these effects were caused by insufficient levels of the orexigenic peptide, acyl ghrelin. Further studies are needed to confirm our findings and to determine the mechanism regulating appetite in patients with AECOPD.


Progression of experimental infantile hydrocephalus and effects of ventriculoperitoneal shunts: an analysis correlating magnetic resonance imaging with gross morphology.
Although previous ultrasonographic studies did monitor ventricular enlargement successfully in experimentally-induced models of feline hydrocephalus, the resolution of neuroanatomic detail was relatively poor after placement of a ventriculoperitoneal (VP) shunt because the skull had ossified over the coronal sutures. Therefore, the present study employed magnetic resonance imaging to follow the progression of ventriculomegaly more accurately, as well as to evaluate the compensatory effects of VP shunting. Hydrocephalus was induced in kittens between 7 and 10 days old by injection of kaolin into the cisterna magna. Age-matched controls received similar injections of saline. At 9 to 14 days after the kaolin injection, the hydrocephalic animals received VP shunts. Anesthetized kittens were scanned at various intervals before and after shunt placement and were killed for morphological correlation. The features observed on the magnetic resonance imaging scans were consistent with the gross morphological changes that accompanied ventricular enlargement. The lateral ventricle began to enlarge as early as 1 day after the kaolin injection, and within 3 days, both the occipital and temporal horns, along with the 4th ventricle, showed signs of moderate dilatation. By 5 days, a bilateral communication had been established through the septum pellucidum. Continued expansion of the ventricular system occurred from 6 to 20 days after injection, to the point where the cerebral cortex was reduced to less than 25% of its original thickness. The internal capsule was stretched and edematous, the caudate nucleus was compressed ventrolaterally, and the cerebellar hemispheres were eroded and/or compressed. Animals in which shunts were successfully placed demonstrated a dramatic improvement in behavior, and a reduction of about 50% in the size of the lateral ventricles within 2 days. In some cases, the lateral ventricles became slit-like within 1 week. When they were killed, about half of the animals that received shunts exhibited mild to moderate ventriculomegaly. These results indicate that magnetic resonance imaging is an excellent method for visualizing the morphological changes associated with this animal model, that these alterations occur soon after the onset of hydrocephalus, and that VP shunting can successfully reduce ventriculomegaly.


Dried Plum Consumption Improves Total Cholesterol and Antioxidant Capacity and Reduces Inflammation in Healthy Postmenopausal Women.
Dried plums contain bioactive components that have demonstrated antioxidant and anti-inflammatory effects. The objective of this study was to determine if dried plum consumption reduces the risk factors for cardiovascular disease (CVD) in postmenopausal women, specifically examining lipid profiles, oxidative stress, antioxidant capacity, and inflammation in a dose-dependent manner. We conducted a 6-month, parallel-design controlled clinical trial, where 48 postmenopausal women were randomly assigned to consume 0, 50, or 100 g of dried plum each day. After 6 months of intervention, total cholesterol (TC) in the 100 g/day treatment group (P = .002) and high-density lipoprotein cholesterol in the 50 g/day treatment group (P = .005) improved significantly compared to baseline. Inflammatory biomarkers interleukin-6 (P = .044) and tumor necrosis factor-α (P = .040) were significantly lower after 6 months within the 50 g/day dried plum group compared to baseline. Moreover, total antioxidant capacity increased significantly within the 50 g/day group (P = .046), and superoxide dismutase activity increased significantly within both 50 and 100 g/day groups (P = .044 and P = .027, respectively) after 6 months compared to baseline. In addition, plasma activities of alanine transaminase (P = .046), lactate dehydrogenase (P = .039), and creatine kinase (P = .030) were significantly lower after 6 months in the 50 g/day dried plum group. These findings suggest that daily consumption of 50-100 g dried plum improves CVD risk factors in postmenopausal women as exhibited by lower TC, oxidative stress, and inflammatory markers with no clear dose dependence.


Effects of urban wastewater on hyporheic habitat and invertebrates in Mediterranean streams.
Wastewater discharges into fluvial ecosystems represent a significant and continuous source of fine particles and nutrients that can severely modify stream community composition and functionality. Depending on both wastewater and stream features (e.g., nutrient removal treatments and stream dilution capacity), the ecological effects can be more or less severe. To determine how hyporheic habitat and hyporheos are affected, we analysed eight Mediterranean streams both upstream and downstream of a wastewater effluent. The results demonstrated that environmental factors associated with clogging, such as the quantity of fine particulate and organic matter in sediment, were magnified downstream of the wastewater inputs. Likewise, dissolved nutrients also increased but depended to a greater extent on the presence of a wastewater treatment plant and on the nitrogen and phosphorus removal treatments. The hyporheic invertebrates were more affected by clogging than by eutrophication. Both richness and diversity parameters were negatively correlated with clogging features but were not correlated with eutrophication. The most affected taxa were Macrocrustaceans, Hydrachnidia and several insect species, which decreased or were not detected downstream of the effluents. On the contrary, other taxa such as Naididae (Oligochaeta), Orthocladiinae (Chironomidae) and Potamopyrgus antipodarum (Gastropoda) benefited from the wastewater inputs.


Risk of iatrogenic damage to the sciatic nerve in dairy cattle.
Sciatic nerve damage in cattle could lead to pain, paralysis and lameness, creating welfare and productivity issues. Damage following intramuscular injection is highlighted in some clinical texts although there is no indication of prevalence. This cross-sectional study investigated the anatomical size and position of the sciatic nerve in four dairy cattle type cadavers. To evaluate the risk of iatrogenic damage, 54 participants placed needles in the dorsal gluteal region of two cadavers each, as per their routine intramuscular injection method. The distance from needle tip to the sciatic nerve was estimated for each. Sixty-nine per cent of injections were placed within 5 cm of the sciatic nerve. Direct nerve puncture occurred in the cadaver in poorest body condition. A short questionnaire revealed that 70 per cent of the participants regularly used the dorsal gluteal region for intramuscular injection and 50 per cent commonly used a volume of ≥20 mL at a single site. It is concluded that the sciatic nerve is at considerable risk of iatrogenic damage. The neck should be promoted as the optimum site for intramuscular injection and improved guidelines are required if the gluteal region is to remain in common use. A lateral site, between the tuber coxae and tuber ischium, is recommended.


Primary health-care responses to methamphetamine use in Australian Indigenous communities.
Crystal methamphetamine (commonly known as 'ice') use is currently a deeply concerning problem for some Australian Indigenous peoples and can cause serious harms to individual, families and communities. This paper is intended to support best practice responses by primary health-care staff working with Australian Indigenous people who use methamphetamine. It draws on a systematic search of relevant databases to identify literature from January 1999 to February 2014, providing an overview of prevalence, treatment, education and harm reduction, and community responses. The prevalence of methamphetamine use is higher in Indigenous than non-Indigenous communities, particularly in urban and regional settings. No evidence was identified that specifically related to effective treatment and treatment outcomes for Indigenous Australians experiencing methamphetamine dependence or problematic use. While studies involving methamphetamine users in the mainstream population suggest that psychological and residential treatments show short-term promise, longer-term outcomes are less clear. Community-driven interventions involving Indigenous populations in Australia and internationally appear to have a high level of community acceptability; however, outcomes in terms of methamphetamine use are rarely evaluated. Improved national data on prevalence of methamphetamine use among Indigenous people and levels of treatment access would support service planning. We argue for the importance of a strength-based approach to addressing methamphetamine use, to counteract the stigma and despair that frequently accompanies it.


Voltage-dependent gating of single sodium channels from mammalian neuroblastoma cells.
Single sodium channel currents have been studied in cell-attached patches from the mouse neuroblastoma cell line N1E115. Distributions of open duration, latency until first opening, and the average probability of a channel being open after a voltage step, p(t), were analyzed and compared to predicted distributions from various kinetic models for voltage-dependent gating. It was found that, over most of the voltage range under which channel gating occurs, the slow steps in gating are opening transitions and that inactivation of open channels is significantly faster than the decline in p(t) (tau h). This view of gating is confirmed by comparison of the kinetics of ensemble averages of single-channel currents obtained from step- and tail-current records at the same voltage. The probability of a channel reopening after having closed was calculated by comparing p(t) with the convolution of the first-latency probability density and the conditional probability of remaining open t milliseconds after opening. This reopening probability is small but slightly voltage dependent over the voltage range where the mean open duration remains constant and tau h changes considerably. The voltage dependence of open channel inactivation and deactivation were calculated from the probability of reopening and the mean open duration. The equivalent gating charge for the inactivation rate is a few tenths of an electronic charge, whereas the equivalent charge for the closing rate is 2.5-3.5 electronic charges.


Understanding successful development of complex health and healthcare interventions and its drivers from the perspective of developers and wider stakeholders: an international qualitative interview study.
Identify how individuals involved in developing complex health and healthcare interventions (developers), and wider stakeholders in the endeavour, such as funders, define successful intervention development and what factors influence how interventions are developed. In-depth interviews with developers and wider stakeholders to explore their views and experiences of developing complex health and healthcare interventions. Interviews conducted with individuals in the UK, Europe and North America. Twenty-one individuals were interviewed: 15 developers and 6 wider stakeholders. Seventeen participants were UK based. Most participants defined successful intervention development as a process that resulted in effective interventions that were relevant, acceptable and could be implemented in real-world contexts. Accounts also indicated that participants aimed to develop interventions that end users wanted, and to undertake a development process that was methodologically rigorous and provided research evidence for journal publications and future grant applications. Participants' ambitions to develop interventions that had real-world impact drove them to consider the intervention's feasibility and long-term sustainability early in the development process. However, this process was also driven by other factors: the realities of resource-limited health contexts; prespecified research funder priorities; a reluctance to deviate from grant application protocols to incorporate evidence and knowledge acquired during the development process; limited funding to develop interventions and the need for future randomised controlled trials (RCTs) to prove effectiveness. Participants expressed concern that these drivers discouraged long-term thinking and the development of innovative interventions, and prioritised evaluation over development and future implementation. Tensions exist between developers' goal of developing interventions that improve health in the real world, current funding structures, the limited resources within healthcare contexts, and the dominance of the RCT for evaluation of these interventions. There is a need to review funding processes and expectations of gold standard evaluation.


Phytoremediation of polycyclic aromatic hydrocarbons in soil: part I. Dissipation of target contaminants.
Phytoremediation has been demonstrated to be a viable cleanup alternative for soils contaminated with petroleum products. This study evaluated the application of phytoremediation to soil from a manufactured gas plant (MGP) site with high concentrations of recalcitrant, polycyclic aromatic hydrocarbons (PAHs). Two greenhouse studies investigated the potential dissipation and plant translocation of PAHs by fescue (Festuca arundinacea) and switchgrass (Panicum virgatum) in the first experiment and zucchini (Curcubita pepo Raven) in the second. The MGP soil was highly hydrophobic and initially inhibited plant growth. Two unplanted controls were established with and without fertilization. In the first experiment, concentrations of PAHs decreased significantly in all treatments after 12 mo. Plant biomass and microbial numbers were statistically equivalent among plant species. PAH concentrations in plant biomass were negligible for fescue and switchgrass. In the second experiment, zucchini enhanced the dissipation of several PAHs after 90 d of treatment when compared to the unvegetated soil. Plant tissue concentrations of PAHs were not elevated in the zucchini roots and shoots, and PAHs were not detectable in the fruit.


Isolation and characterization of the two major apoproteins in human lipoprotein [a].
Human Lp[a] was isolated in preparative amounts from two donors; the native lipoprotein and its constituent apoproteins, apo[a] and apoB, were characterized extensively. Based on differences in apparent molecular weight, four different isoforms of apo[a], a1-a4, were observed between the two donors. The number and relative distribution of these isoforms varied between donors but were constant for each donor. Each apo[a] isoform was shown to be derived from a discrete apo[a]-B100 disulfide-linked complex present before reduction. Complete delipidation of Lp[a] was followed by solubilization, reduction, and carboxamidomethylation of the constituent apoproteins. These apoproteins were then separated by immunoaffinity chromatography using anti-apo[a]- or anti-apoB-Sepharose; their purity and structural integrity were demonstrated by Western blot analysis. ApoB isolated by this procedure was essentially identical to apoB from autologous LDL with respect to molecular weight, secondary structure, amino acid composition, and sialic acid content. However, apo[a] differed from apoB in that it exhibited: a much less alpha-helical, less beta, but much more disordered structure; a lower proportion of aspartate, isoleucine, leucine, phenylalanine, and lysine, but a higher proportion of proline, glycine, and threonine; and a much higher content of sialic acid. These results indicate that apo[a] is not a superglycosylated form of apoB but is distinctly different in its composition and structure.


Cooperation for direct fitness benefits.
Studies of the evolution of helping have traditionally used the explanatory frameworks of reciprocity and altruism towards relatives, but recently there has been an increasing interest in other kinds of explanations. We review the success or otherwise of work investigating alternative processes and mechanisms, most of which fall under the heading of cooperation for direct benefits. We evaluate to what extent concepts such as by-product benefits, pseudo-reciprocity, sanctions and partner choice, markets and the build-up of cross-species spatial trait correlations have contributed to the study of the evolution of cooperation. We conclude that these alternative ideas are successful and show potential to further increase our understanding of cooperation. We also bring up the origin and role of common interest in the evolution of cooperation, including the appearance of organisms. We note that there are still unresolved questions about the main processes contributing to the evolution of common interest. Commenting on the broader significance of the recent developments, we argue that they represent a justified balancing of the importance given to different major hypotheses for the evolution of cooperation. This balancing is beneficial because it widens considerably the range of phenomena addressed and, crucially, encourages empirical testing of important theoretical alternatives.


Correlation of inflammatory and proangiogenic cytokines from undiluted vitreous samples with spectral domain OCT scans, in untreated branch retinal vein occlusion.
To assess the levels of inflammatory and angiogenic cytokines in undiluted vitreous from treatment-naïve patients with macular edema secondary to nonischemic branch retinal vein occlusion (BRVO), with flow cytometric bead array (CBA) and to correlate the results with subjective and multiple spectral-domain optical coherence tomography (SD-OCT) parameters. A total of 43 eyes from 43 patients (mean age 69.7 years, 23 male) were divided into groups of new, "fresh" (n = 28; mean duration after onset 4.1 months) and older BRVO (n = 15; 11.6 months). Because of macular edema, these patients underwent an intravitreal therapy combining a single-site 23 g core vitrectomy with bevacizumab and dexamethasone. Undiluted vitreous was then analyzed for interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor isoform A (VEGF-A) levels with CBA and correlated with visual acuity (VA), clinical parameters of BRVO (type and perfusion status), and morphologic parameters, such as central macular thickness, central retinal thickness, thickness of the neurosensory retina, thickness of the serous retinal detachment, and the disruption of the ellipsoid line (photoreceptor inner and outer segments) and the external limiting membrane, as measured with SD-OCT. Twenty-eight undiluted vitreous samples from patients with idiopathic, nonuveitis vitreous floaters served as the controls. The mean IL-6 was 23.2 pg/mL (standard deviation, ±48.8), MCP-1 was 602.6 (±490.3), and VEGF-A was 161.8 (±314.3), and this was higher than in the control group, which had a mean IL-6 of 6.2 ± 3.4 pg/mL (P = 0.17), MCP-1 of 253.2 ± 73.5 (P < 0.0000001), and VEGF-A of 7.0 ± 4.9 (P < 0.003). In all BRVO samples, IL-6 correlated positively with MCP-1 and VEGF-A (correlation coefficient r = 0.79 and r = 0.46, respectively). VEGF-A was the only cytokine to correlate significantly with SD-OCT parameters (thickness of the neurosensory retina r = 0.31; disruption of the ellipsoid line r = 0.33). In the older BRVO group, there was a positive correlation between cytokines (IL-6 with MCP-1, r = 0.77; Il-6 with VEGF-A, r = 0.68; MCP-1 and VEGF-A, r = 0.68), whereas only IL-6 correlated with MCP-1 in the fresh group (r = 0.8). The inflammatory markers and VEGF-A were elevated in the vitreous fluid of patients with BRVO, and these correlated with one another. VEGF-A was more often correlated with the morphologic changes assessed by SD-OCT, whereas the inflammatory markers had no significant influence on SD-OCT changes.


NPAS4 suppresses propofol-induced neurotoxicity by inhibiting autophagy in hippocampal neuronal cells.
Propofol, a general intravenous anesthetic, has been demonstrated to cause a profound neuroapoptosis in the developing brain followed by long-term neurocognitive impairment. Our study aimed to examine the neuroprotective effect of neuronal PAS domain protein 4 (NPAS4), an activity-dependent neuron-specific transcription factor, on propofol-induced neurotoxicity in hippocampal neuronal HT22 cells. The differentially expressed genes in HT22 cells after treatment with propofol were screened from Gene Expression Omnibus dataset GSE106799. NPAS4 expression in HT22 cells treated with different doses of propofol was investigated by qRT-PCR and Western blot analysis. Cell viability, lactate dehydrogenase (LDH) release, caspase-3 activity, and apoptosis were evaluated by MTT, a LDH-Cytotoxicity Assay Kit, a Caspase-3 Colorimetric Assay Kit, and TUNEL assay, respectively. The protein levels of LC3-I, LC3-II, Beclin 1, p62 and NPAS4 were detected using Western blot analysis. Propofol treatment concentration-dependently decreased NPAS4 expression in HT22 cells. Propofol treatment inhibited cell viability, increased LDH release and caspase-3 activity, and induced apoptosis and autophagy in HT22 cells. NPAS4 overexpression suppressed propofol-induced cell injury and autophagy in HT22 cells. Mechanistically, autophagy agonist rapamycin attenuated the neuroprotective effect of NPAS4 in propofol-treated HT22 cells. In conclusion, NAPS4 overexpression protected hippocampal neuronal HT22 cells against propofol-induced neurotoxicity by reducing autophagy.


Enhanced interstitial fluid drainage in the hippocampus of spontaneously hypertensive rats.
Hypertension is associated with cognitive decline and various forms of dementia, including Alzheimer's disease. In animal models of hypertension, many of Alzheimer's disease characteristics are recapitulated, including brain atrophy, cognitive decline, amyloid β accumulation and blood brain barrier dysfunction. Removal of amyloid β and other waste products depends in part on clearance via the brain interstitial fluid (ISF). Here we studied the impact of hypertension on ISF drainage, using spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). At 8 months, high (500 kD) and low (3 kD) fluorescent molecular weight tracers released passively into the hippocampus showed a drastically enhanced spreading in SHR. Tracer spreading was inhomogeneous, with accumulation at ISF-CSF borders, around arteries, and towards the stratum lacunosum moleculare. These locations stained positively for the astrocyte marker GFAP, and aquaporin 4. Despite enhanced dispersion, clearance of tracers was not affected in SHR. In conclusion, these data indicate enhanced bulk flow of ISF in the hippocampus of hypertensive rats. ISF drains along astrocytes towards the cerebrospinal fluid compartment, which leads to sieving of high molecular weight solutes. Sieving may lead to a local increase in the concentration of waste products and potentially promotes the aggregation of amyloid β.


Length-weight relationship and condition factor of giant tiger shrimp, Penaeus monodon (Fabricius, 1798) from four breeding families.
Length-weight relationships and condition factors of giant tiger shrimp Penaeus monodon (Fabricius, 1798) from four breeding families (family S: South China seas family, family A: African family, family SA: ♂ South China seas family × ♀ Africa family, family AS: ♂ Africa family × ♀ South China seas family) were evaluated in this study. Length-weight relationships can be expressed as W = 0.0239BL(2.789) (R (2) = 0.8977) in family S, W = 0.0206BL(2.9107) (R (2) = 0.9107) in family A, W = 0.0211BL(2.831) (R (2) = 0.8869) in family SA, and W = 0.0249BL(2.781) (R (2) = 0.9159) in family AS. The growth of P. monodon from four breeding families follows a negative allometric trend. Fulton's body condition factor (K) was not significantly different in males, while in females, the highest K (3.07) was observed in family AS, and the lowest K was found in family A (1.88). Results from the present study indicate that the cross group family AS (♂ Africa family × ♀ South China seas family) has obvious heterosis in females. This may suggest that the direction of further breeding of P. monodon, should be conducted by using Africa family as male parent, and South China seas family as female parent. Results from the present study will provide valuable information on selective breeding in P. monodon. Methodology used in the present study can also be applied in other similar species.


Environmental awareness among physicians: what are environmental health and environmental medicine?
Increased awareness of environmental health issues by the biomedical community and the general public places higher demands on all health and medical practitioners to understand the key terms and concepts related to environmental health and medicine. We all exist in 3 different environments (home, workplace, and community), each of which has its own array of hazards and means of exposure. Environmental medicine is a discipline that addresses preventive measures and provides assessment, diagnosis, and treatment of persons who experience adverse health effects of environmental exposures. In addition to basic clinical skills, environmental medicine uses specialized tools including biostatistics and epidemiologic studies, the science of toxicology and risk assessment, the discipline of industrial hygiene, and administrative and public policy skills. Examples of environmental issues that are faced by society today include asbestos exposure in public buildings as well as pesticide and other agricultural chemical residues present in various environmental media.


The effect of diazepam on pentagastrin-stimulated and nocturnal (sleeping) gastric secretion in man.
Intravenous diazepam will not significantly suppress gastric secretion within the first hour after "maximal" stimulation with pentagastrin. In the second and third hours, however, gastric secretion is significantly diminished. Further suppression after pentagastrin and diazepam is possible in each of the three post-stimulation hours by the simultaneous administration of atropine. Diazepam does not suppress the seven-hour basal nocturnal gastric secretion during sleep. This suggests that diazepam acts during wakefulness by inhibition of secretory stimuli arising centrally, thus providing a rationale for use of this drug in patients with peptic ulcer in whom stress may be a factor in the pathogenesis.


[Invasive fungal infections in liver transplant recipients: analysis of 21 cases].
Invasive fungal infections (IFI) are one of the most important causes of mortality in liver transplant (LT) recipients. The aim of this study was to describe the characteristics of IFI in the LT program of our institution with an special emphasis in the differences between Candida infections (CI) and that caused by other fungi (NCI). Retrospective analysis of the hospital charts of 21 patients who underwent a LT from February 1987 to December 1995. The diagnosis of IFI required the histological evidence of tissue invasion or a positive culture in a tissue sample or in an usually sterile fluid. Esophageal candidiasis was not considered as IFI. Antifungal prophylaxis was performed either with nystatin or fluconazole. Twenty-one of 356 patients (6%) developed a total of 23 episodes of IFI. Pathogens were Candida spp. (n = 10), Aspergillus (n = 8), Zygomicetes (n = 4) and Cryptococcus (n = 1). Fifty-seven percent of the episodes of IFI (80% of those caused by Candida and 38% of those produced by other fungi; p < 0.05) developed in the first 3 months after transplantation and only 5 episodes appeared after the sixth month. The diagnosis of IFI was done at autopsy in 6 patients (29%). Overall, NCI (13 episodes) predominated over CI (10 episodes), being the later the cause of the 54% of the episodes in the first 178 recipients but only the 30% in the last 178 patients (p = 0.09). No differences were found in the distribution of the risk factors amongst those patients with CI or NCI. Seventeen of the 21 patients (71%) died and 15 of these deaths (72%) were attributable to fungi; 15 patients who died either did not receive amphotericin (n = 6) or received a cumulative dose lower than 500 mg. Six patients received a cumulative dose of more than 1.5 g (mean, 3.2 g) and four of them were cured. Mortality in the nonfungal infection group was 26% (p < 0.001). IFI was a rare but severe complication in our LT recipients. The relative frequency of CI was progressively decreasing during the study period, being NCI the predominant infections. Amphotericin therapy was effective only when a high cumulative dose could be administered.


Analysis of gene expression in mutiple sclerosis lesions using cDNA microarrays.
In multiple sclerosis (MS) patients, a coordinated attack of the immune system against the primary constituents of oligodendrocytes and/or the myelin sheath of oligodendrocytes results in the formation of lesions in the brain and spinal cord. Thus far, however, a limited number of genes that potentially contribute to lesion pathology have been identified. Using cDNA microarray technology, we have performed experiments on MS tissue monitoring the expression pattern of over 5,000 genes and compared the gene expression profile of normal white matter with that found in acute lesions from the brain of a single MS patient. Sixty-two differentially expressed genes were identified, including the Duffy chemokine receptor, interferon regulatory factor-2, and tumor necrosis factor alpha receptor-2 among others. Thus, cDNA microarray technology represents a powerful new tool for the identification of genes not previously associated with the MS disease process.


Amphiphilic branched polymers as antimicrobial agents.
Cationic amphiphilic polymers were prepared from PEI and functional ethylene carbonates bearing cationic, hydrophobic or amphiphilic groups. The polymers are designed to exhibit antimicrobial properties. In a one-step addition, different functional ethylene carbonates were added to react with the primary amine groups of PEI. The water soluble polymers were studied regarding their ability to form soluble aggregates. Their hydrodynamic radii, their inhibition potential against proliferation of E. coli and their hemolytic potential were determined. A structure-property relationship was established by analyzing the antimicrobial activity as a function of the ratio of alkyl to cationic groups, length of the alkyl chains, and molecular weight of the PEI.


Clinical application of a microfluidic chip for immunocapture and quantification of circulating exosomes to assist breast cancer diagnosis and molecular classification.
Increasing attention has been attracted by exosomes in blood-based diagnosis because cancer cells release more exosomes in serum than normal cells and these exosomes overexpress a certain number of cancer-related biomarkers. However, capture and biomarker analysis of exosomes for clinical application are technically challenging. In this study, we developed a microfluidic chip for immunocapture and quantification of circulating exosomes from small sample volume and applied this device in clinical study. Circulating EpCAM-positive exosomes were measured in 6 cases breast cancer patients and 3 healthy controls to assist diagnosis. A significant increase in the EpCAM-positive exosome level in these patients was detected, compared to healthy controls. Furthermore, we quantified circulating HER2-positive exosomes in 19 cases of breast cancer patients for molecular classification. We demonstrated that the exosomal HER2 expression levels were almost consistent with that in tumor tissues assessed by immunohistochemical staining. The microfluidic chip might provide a new platform to assist breast cancer diagnosis and molecular classification.


Metabolism of boldione in humans by mass spectrometric techniques: detection of pseudoendogenous metabolites.
Boldione is an anabolic androgenic steroid (AAS) related to boldenone, androstenedione, and testosterone bearing two double bonds in C1 and C4 positions. Boldione is rapidly transformed to the well-known AAS boldenone, being both compounds included in the list of prohibited substances and methods published yearly by the World Anti-Doping Agency (WADA). After the administration of boldione to a male volunteer, the already described urinary metabolites of boldenone produced after reduction in C4, oxydoreduction in C3 and C17, and hydroxylation have been detected. In addition, minor new metabolites have been detected and their structure postulated after mass spectrometric analyses. Finally, the reduction of the double bound in C1 produces metabolites identical to the endogenously produced ones. A method based on gas chromatography coupled to isotope ratio mass spectrometry (GC/C/IRMS) after a urine sample purification by high performance liquid chromatography (HPLC) permitted to confirm the main synthetic like boldione/boldenone metabolite (17β-hydroxy-5β-androst-1-en-3-one) and boldenone at trace levels (< 5 ng/mL) and then to establish its synthetic or endogenous origin, and to determine the exogenous origin of metabolites with the same chemical structure of the endogenous ones. The detection of pseudoendogenous androgens of synthetic origin partially overlapped boldenone and its main metabolite detection, being an additional proof of synthetic steroids misuse. By the use of IRMS, the correct evaluation of the modifications of the steroid profile after the administration of synthetic AAS that could be converted into endogenous like ones is possible.


Nitrogenase of Klebsiella pneumoniae. Kinetics of the dissociation of oxidized iron protein from molybdenum-iron protein: identification of the rate-limiting step for substrate reduction.
Stopped-flow spectrophotometry and e.p.r. spectroscopy were used to study the kinetics of reduction by dithionite of the oxidized Fe protein of nitrogenase from Klebsiella pneumoniae (Kp2ox.) in the presence of MgADP at 23 degrees C at pH 7.4. The active reductant, SO2.-, produced by the predissociation of S2O4(2-) in equilibrium 2SO2.-, reacts with Kp2ox. (MgADP)2, with k4 = 3.0 X 10(6) +/- 0.4 X 10(6) M-1 X s-1. The inhibition of this reaction by the Mo-Fe protein (Kp1) has enabled the rate of dissociation of Kp2ox. (MgADP)2 from Kp1+ (the Kp2-binding site on Kp1) to be measured (k-3 = 6.4 +/- 0.8 s-1). Comparison with the steady-state rate of substrate reduction shows that the dissociation (k-3) of the complex Kp2ox. (MgADP)2-Kp1+, which is formed after MgATP-induced electron transfer from Kp2 to Kp1+, is the rate-limiting step in the catalytic cycle for substrate reduction.


Waist-to-height ratio, waist circumference and BMI as indicators of percentage fat mass and cardiometabolic risk factors in children aged 3-7 years.
To assess whether waist-to-height-ratio (WHtR) is a better estimate of body fat percentage (BF%) and a better indicator of cardiometabolic risk factors than BMI or waist circumference (WC) in young children. WHtR, WC and BMI were measured by trained staff according to standardized procedures. (2)H2O and (2)H2(18)O isotope dilution were used to assess BF% in 61 children (3-7 years) from the general population, and bioelectrical impedance (Horlick equation) was used to assess BF% in 75 overweight/obese children (3-5 years). Cardiometabolic risk factors, including diastolic and systolic blood pressure, HOMA2-IR, leptin, adiponectin, triglycerides, total cholesterol, HDL- and LDL-cholesterol, TNFα and IL-6 were determined in the overweight/obese children. In the children from the general population, after adjustments for age and gender, BMI had the highest explained variance for BF% compared to WC and WHtR (R(2) = 0.32, 0.31 and 0.23, respectively). In the overweight/obese children, BMI and WC had a higher explained variance for BF% compared to WHtR (R(2) = 0.68, 0.70 and 0.50, respectively). In the overweight/obese children, WHtR, WC and BMI were all significantly positively correlated with systolic blood pressure (r = 0.23, 0.30, 0.36, respectively), HOMA2-IR (r = 0.53, 0.62, 0.63, respectively), leptin (r = 0.70, 0.77, 0.78, respectively) and triglycerides (r = 0.33, 0.36, 0.24, respectively), but not consistently with other parameters. In young children, WHtR is not superior to WC or BMI in estimating BF%, nor is WHtR better correlated with cardiometabolic risk factors than WC or BMI in overweight/obese children. These data do not support the use of WHtR in young children.


Early lysosome defects precede neurodegeneration with amyloid-β and tau aggregation in NHE6-null rat brain.
Loss-of-function mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome in males. Christianson syndrome involves endosome dysfunction leading to early cerebellar degeneration, as well as later-onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in post-mortem studies. In addition, there is reported evidence of modulation of amyloid-β levels in experimental models wherein NHE6 expression was targeted. We have recently shown that loss of NHE6 causes defects in endosome maturation and trafficking underlying lysosome deficiency in primary mouse neurons in vitro. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously-expressed amyloid-β and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously-expressed (non-transgenic) tau or amyloid-β. Therefore, to study neurodegeneration in Christianson syndrome and the possibility of amyloid-β and tau pathology, we generated an NHE6-null rat model of Christianson syndrome using CRISPR-Cas9 genome-editing. Here, we present the sequence of pathogenic events in neurodegenerating NHE6-null male rat brains across the lifespan. NHE6-null rats demonstrated an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observed biochemical and in situ evidence of both amyloid-β and tau aggregation in the aged NHE6-null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observed tau deposition in both neurons and glia, as has been reported in Christianson syndrome post-mortem studies previously. In summary, this experimental model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously-expressed amyloid-β and tau. This NHE6-null rat will serve as a new robust model for Christianson syndrome. Furthermore, these studies provide evidence for linkages between endolysosome dysfunction and neurodegeneration involving protein aggregations, including amyloid-β and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer's disease and related dementias.


Do avian species survive better on islands?
Island species are often predictably different from their mainland counterparts. Milder climates and reduced predation risk on islands have been involved to explain shifts in body size and a suite of life-history traits such as clutch size and offspring growth rate. Despite the key role of adult survival on risk taking and reproduction, the prediction that living on islands increases adult survival has yet to be tested systematically. I gathered data on adult annual apparent survival from the island and mainland year-round resident species of birds from around the world. With this large dataset (697 species), I found that species of birds living on islands showed higher apparent survival than their mainland counterparts in the two Hemispheres and at all latitudes, controlling for several known predictors of adult survival, including body size, clutch size and breeding system. These results shed light on the ecological factors that influence survival on islands and extend the life-history island syndrome to adult survival.


Pathways controlling trigeminal and auditory nerve-evoked abducens eyeblink reflexes in pond turtles.
An in vitro brain stem preparation from turtles exhibits a neural correlate of eyeblink classical conditioning during pairing of auditory (CS) and trigeminal (US) nerve stimulation while recording from the abducens nerve. The premotor neuronal circuits controlling abducens nerve-mediated eyeblinks in turtles have not been previously described, which is a necessary step for understanding cellular mechanisms of conditioning in this preparation. The purpose of the present study was to neuroanatomically define the premotor pathways that underlie the trigeminal and auditory nerve-evoked abducens eyeblink responses. The results show that the principal sensory trigeminal nucleus forms a disynaptic pathway from both the trigeminal and auditory nerves to the principal and accessory abducens motor nuclei. Additionally, the principal abducens nucleus receives vestibular inputs, whereas the accessory nucleus receives input from the cochlear nucleus. The late R2-like component of abducens nerve responses is mediated by the spinal trigeminal nucleus in the medulla. Both the principal sensory trigeminal nucleus and the abducens motor nuclei receive CS-US convergence and therefore both, or either, might be considered potential sites of synapse modification during in vitro abducens conditioning. Further data are required to determine the role of the principal sensory trigeminal nucleus in in vitro conditioning.


Yeast recombination: the association between double-strand gap repair and crossing-over.
In previous experiments, we have used yeast transformation to study the recombinogenic repair of double-strand breaks and gaps. A plasmid containing a double-strand gap within sequences homologous to the yeast genome integrates efficiently by crossing-over. During the process of integration, the double-strand gap is repaired, using chromosomal information as a template. This repair reaction results in the transfer of genetic information from one DNA duplex to another and is therefore a pathway for gene conversion. Because meiotic gene conversion is associated with a high frequency (up to 50%) of crossing-over, we wished to determine the degree of association of double-strand gap repair with crossing-over. Only the class of repair events resulting in crossovers (plasmid integration) were detected in our earlier experiments with nonreplicating plasmids. In this paper, we describe the outcome of double-strand gap repair in plasmids that are capable of autonomous replication and therefore allow recovery of both crossover and noncrossover products. After the correct repair of a double-strand gap, we recover approximately equal numbers of integrated and nonintegrated plasmids. Thus, gene conversion by double-strand gap repair can occur either with or without crossing-over, and it is similar in this respect to meiotic gene conversion. Circularization of linear plasmid DNA by ligation is also observed, suggesting that yeast has an additional repair pathway for double-strand breaks that is independent of recombination. Gap repair on replicating plasmids permits rapid cloning of chromosomal alleles.


Calcinosis cutis in a patient with eosinophilia-myalgia syndrome: case report.
Eosinophilia-myalgia syndrome (EMS) often is a disabling disorder caused by the consumption of contaminated L-tryptophan. Affected patients present with an array of symptoms, including cutaneous manifestations, peripheral eosinophilia, myalgias, and long-term neurocognitive disability. This article is the first reported case of a patient with EMS who developed calcinosis cutis. While many long-term sequelae of EMS are reported in the literature, there are no reports of the development of dystrophic calcification in these patients. The calcinosis cutis in this patient with EMS may represent a new manifestation of EMS that has not been documented to date. If more patients with EMS develop calcinosis cutis, it will present a therapeutic challenge to the physicians managing these patients.


Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer.
As a core chromatin-regulatory scaffolding protein, WDR5 mediates numerous protein-protein interactions (PPIs) with other partner oncoproteins. However, small-molecule inhibitors that block these PPIs exert limited cell-killing effects. Here, we report structure-activity relationship studies in pancreatic ductal adenocarcinoma (PDAC) cells that led to the discovery of several WDR5 proteolysis-targeting chimer (PROTAC) degraders, including 11 (MS132), a highly potent and selective von Hippel-Lindau (VHL)-recruiting WDR5 degrader, which displayed positive binding cooperativity between WDR5 and VHL, effectively inhibited proliferation in PDAC cells, and was bioavailable in mice and 25, a cereblon (CRBN)-recruiting WDR5 degrader, which selectively degraded WDR5 over the CRBN neo-substrate IKZF1. Furthermore, by conducting site-directed mutagenesis studies, we determined that WDR5 K296, but not K32, was involved in the PROTAC-induced WDR5 degradation. Collectively, these studies resulted in a highly effective WDR5 degrader, which could be a potential therapeutic for pancreatic cancer and several potentially useful tool compounds.


Serum CA 19-9 levels as a diagnostic marker in cystic fibrosis patients with borderline sweat tests.
Patients with normal or borderline sweat tests present a diagnostic challenge. In spite of the availability of genetic analysis and measurement of nasal potential difference, there is still uncertainty in diagnosing cystic fibrosis in some patients. CA 19-9 is a tumor-associated antigen whose levels were previously found to be elevated in some cystic fibrosis patients. We investigated whether serum CA 19-9 levels can contribute to establishing the diagnosis of cystic fibrosis in patients with a borderline sweat test, and evaluated the influence of different clinical variables on CA 19-9 levels. Serum CA 19-9 levels were measured in 82 cystic fibrosis patients grouped according to their genotype and in 38 healthy individuals. Group A included 50 patients who carried two mutations previously found to be associated with a pathological sweat test and pancreatic insufficiency (DeltaF508, W1282X, G542X, N1303K, and S549R). Group B included 13 compound heterozygote cystic fibrosis patients who carried one mutation known to cause mild disease with a borderline or normal sweat test and pancreatic sufficiency (3849+10kb C-->T, 5T). Group C included 38 normal controls. Nineteen cystic fibrosis patients carried at least one unidentified mutation. An association between CA 19-9 levels and age, pulmonary function, pancreatic status, sweat chloride, previous pancreatitis, serum lipase, meconium ileus, distal intestinal obstruction, liver disease, and diabetes was investigated. The distribution of CA 19-9 levels was significantly different between the three groups ( p<0.01); high CA 19-9 levels were found in 60% (30/50) of group Apatients and in 46.6% (6/13) of group B patients, but in only 5.2% (2/38) of the controls. CA 19-9 levels were inversely related to forced expiratory volume in 1 s, while no association was found with the other clinical parameters examined. Our findings suggest that the serum CA 19-9 in cystic fibrosis patients originates in the respiratory system, and has a useful ancillary role, particularly when diagnostic uncertainty exists. Hence, the diagnosis of cystic fibrosis should be considered in patients with borderline sweat tests and high CA 19-9 levels, but normal levels do not exclude cystic fibrosis.


Current management and emerging treatment strategies for multiple myeloma.
Multiple myeloma is a malignant plasma cell neoplasm that is incurable despite significant progress in treatment over the past several decades. The incorporation of novel agents and combinations into the MM treatment paradigm has resulted in improved survival and tolerability, as well as deeper responses including achieving a minimal residual disease negative state. The addition of new treatment options and combinations has added complexity in treatment selection for myeloma patients. The current strategy for newly diagnosed myeloma involves induction, consolidation, and maintenance therapy. However, nearly all myeloma patients will develop refractory disease. This highlights the need for more effective therapies targeting the myeloma cells and their microenvironment. In this article, we summarize current management of transplant eligible and ineligible newly diagnosed patients in both the upfront and relapsed refractory setting, highlighting risk adapted strategies. We also summarize emerging therapies, such as immune and targeted approaches, as well as drugs with novel mechanisms of action. Emerging strategies offer individualized treatment options and may ultimately offer the possibility of a cure for myeloma patients.


Interferon-gamma enhances the expression of the major histocompatibility class I antigens on mouse pancreatic beta cells.
Cell surface antigens of the major histocompatibility complex (MHC) play a crucial role in the initiation of immune reactions. To investigate whether the expression of MHC antigens on pancreatic islet cells could be altered, we have cultured mouse islets in the presence of interferon-gamma (IFN-gamma) and subsequently examined the levels of MHC antigen by indirect immunofluorescence using monoclonal antibodies. IFN-gamma induced a 10-fold increase in H-2K antigen expression on islet cells, the percentage of cells with detectable H-2K expression increasing from 24% to 98%. The effects of IFN-gamma on H-2D and la antigen expression were less marked, with only a twofold increase in mean fluorescence levels, the percentage of cells with detectable levels of expression increasing from 10% to 48% and 5% to 16%, respectively. Using double-indirect immunofluorescence, it was demonstrated that IFN-gamma enhanced expression of H-2K and H-2D antigens on beta-cells. However la-positive beta-cells were undetectable in the presence or absence of IFN-gamma. The ability of IFN-gamma to induce increased expression of H-2 antigens on beta-cells may represent a mechanism for targeting immune (cytotoxic) reactions to beta-cells, e.g., in autoimmune insulitis or allograft rejection.


The extracellular matrix of the dental pulp and dentin.
The dental pulp is a loose connective tissue, characterized by its specific anatomical location. Its extracellular components are obvious subjects for study, since such components are largely responsible for the physiological properties of the tissue. Several clinically important processes occur extracellularly, e.g., defense mechanisms such as inflammatory reactions and formation of calcified tissue. The dental mesenchyme has a crucial role during early tooth morphogenesis. The dental pulp, or rather the dental papilla, seems to have only an indirect role during dentinogenesis. This review discusses proteoglycans and glycosaminoglycans, fibronectin and other non-collagenous proteins, and the different types of collagen that have been studied in pulp connective tissue. With regard to its biochemical constituents, the pulp is similar to other loose connective tissues. Collagen type I is the major fibrous component, but collagen type III also constitutes a large portion. Fibronectin is present, as is a high content of proteoglycan. In the proteoglycans, all normally occurring connective tissue glycosaminoglycans can be demonstrated. The composition of the pulpal extracellular matrix during tooth development is quite different from that of the mature tooth. Thus, it is important not to draw any too-far-reaching conclusions about the situation in human pulp from results obtained by studying pulp from animal teeth with ongoing dentinogenesis. In spite of their common ancestry, pulp and dentin differ considerably in extracellular matrix composition. Proteoglycans and collagen type I are present in dentin. No type III collagen or fibronectin can be found in the dentin, although it is present in the dental pulp.(ABSTRACT TRUNCATED AT 250 WORDS)


Intravitreal injection of forskolin, homotaurine, and L-carnosine affords neuroprotection to retinal ganglion cells following retinal ischemic injury.
Retinal ganglion cell (RGC) death is the final event leading to visual impairment in glaucoma; therefore, identification of neuroprotective strategies able to slow down or prevent the process is one of the main challenges for glaucoma research. The purpose of this study was to evaluate the neuroprotective potential of RGC death induced by the in vivo transient increase in intraocular pressure (IOP) of a combined treatment with forskolin, homotaurine, and L-carnosine. Forskolin (7beta-acetoxy-8, 13-epoxy-1a, 6β, 9a-trihydroxy-labd-14-en-11-one) is an activator of adenylate cyclase that decreases IOP by reducing aqueous humor production and functions as a neuroprotector due to its neurotrophin-stimulating activity. Homotaurine is a natural aminosulfonate compound endowed with neuromodulatory effects, while the dipeptide L-carnosine is known for its antioxidant properties. Retinal ischemia was induced in the right eye of adult male Wistar rats by acutely increasing the IOP. Forskolin, homotaurine, and L-carnosine were intravitreally injected and RGC survival evaluated following retrograde labeling with FluoroGold. Total and phosphorylated Akt and glycogen synthase kinase-3β (GSK-3β) protein levels, as well as calpain activity, were analyzed with western blot. Protein kinase A (PKA) was inhibited by intravitreal injection of H89. A synergic neuroprotective effect on RGC survival was observed following the combined treatment with forskolin, homotaurine, and L-carnosine compared to forskolin alone. The observed neuroprotection was associated with reduced calpain activity, upregulation of phosphoinositide 3-kinase (PI3K)/Akt pathway, and inhibition of GSK-3β but was independent from PKA activation and distinct from the hypotensive effects of forskolin. A multidrug/multitarget approach, by interfering with several pathways involved in RGC degeneration, may be promising to achieve glaucoma neuroprotection.


Reversible switching of quantum cascade laser-modes using a pH-responsive polymeric cladding as transducer.
We present a novel approach for the reversible switching of the emission wavelength of a quantum cascade laser (QCL) using a halochromic cladding. An air-waveguide laser ridge is coated with a thin layer of polyacrylic acid. This cladding introduces losses corresponding to the absorption spectrum of the polymer. By changing the state of the polymer, the absorption spectrum and losses change, inducing a shift of 7 cm(-1) in the emission wavelength. This change is induced by exposure to acidic or alkaline vapors under ambient conditions and is fully reversible. Such lasers can be used as multi-color light source and as sensor for atmospheric pH.


Perinatal and neonatal use of sedation and analgesia.
Optimal obstetric and neonatal care requires the provision of adequate analgesia for painful procedures. However, anesthetic and analgesic agents have the potential to adversely impact the developing fetal/neonatal brain. In this setting, clinicians must assess the risks and benefits of pharmacologic anesthesia and analgesia for specific indications in this population. General anesthesia is required for non-obstetric surgery and cesarean section in the absence of neuraxial anesthesia for the health of the mother and fetus. Although experimental data raise concerns, human data are reassuring and future research may focus on neuroprotective adjuncts in the setting of repeated or prolonged anesthetic exposures. Opioid analgesia is standard of care for preterm infants undergoing major procedures including invasive surgery and endotracheal intubation. The use of opioids for agitation resulting from mechanical ventilation is controversial, but prevalent. Randomized and retrospective studies detect short-term toxicity with inconclusive long-term impact, suggesting the need to explore alternative therapies.


Comprehensive identification of mutations induced by heavy-ion beam irradiation in Arabidopsis thaliana.
Heavy-ion beams are widely used for mutation breeding and molecular biology. Although the mutagenic effects of heavy-ion beam irradiation have been characterized by sequence analysis of some restricted chromosomal regions or loci, there have been no evaluations at the whole-genome level or of the detailed genomic rearrangements in the mutant genomes. In this study, using array comparative genomic hybridization (array-CGH) and resequencing, we comprehensively characterized the mutations in Arabidopsis thaliana genomes irradiated with Ar or Fe ions. We subsequently used this information to investigate the mutagenic effects of the heavy-ion beams. Array-CGH demonstrated that the average number of deleted areas per genome were 1.9 and 3.7 following Ar-ion and Fe-ion irradiation, respectively, with deletion sizes ranging from 149 to 602,180 bp; 81% of the deletions were accompanied by genomic rearrangements. To provide a further detailed analysis, the genomes of the mutants induced by Ar-ion beam irradiation were resequenced, and total mutations, including base substitutions, duplications, in/dels, inversions, and translocations, were detected using three algorithms. All three resequenced mutants had genomic rearrangements. Of the 22 DNA fragments that contributed to the rearrangements, 19 fragments were responsible for the intrachromosomal rearrangements, and multiple rearrangements were formed in the localized regions of the chromosomes. The interchromosomal rearrangements were detected in the multiply rearranged regions. These results indicate that the heavy-ion beams led to clustered DNA damage in the chromosome, and that they have great potential to induce complicated intrachromosomal rearrangements. Heavy-ion beams will prove useful as unique mutagens for plant breeding and the establishment of mutant lines.


Optical probes for the detection of protons, and alkali and alkaline earth metal cations.
Luminescent sensors and switches continue to play a key role in shaping our understanding of key biochemical processes, assist in the diagnosis of disease and contribute to the design of new drugs and therapies. Similarly, their contribution to the environment cannot be understated as they offer a portable means to undertake field testing for hazardous chemicals and pollutants such as heavy metals. From a physiological perspective, the Group I and II metal ions are among the most important in the periodic table with blood plasma levels of H(+), Na(+) and Ca(2+) being indicators of several possible disease states. In this review, we examine the progress that has been made in the development of luminescent probes for Group I and Group II ions as well as protons. The potential applications of these probes and the mechanism involved in controlling their luminescent response upon analyte binding will also be discussed.


The regulator of G protein signaling RGS4 selectively enhances alpha 2A-adreoreceptor stimulation of the GTPase activity of Go1alpha and Gi2alpha.
Agonist-stimulated high affinity GTPase activity of fusion proteins between the alpha(2A)-adrenoreceptor and the alpha subunits of forms of the G proteins G(i1), G(i2), G(i3), and G(o1), modified to render them insensitive to the action of pertussis toxin, was measured following transient expression in COS-7 cells. Addition of a recombinant regulator of G protein signaling protein, RGS4, did not significantly affect basal GTPase activity nor agonist stimulation of the fusion proteins containing Galpha(i1) and Galpha(i3) but markedly enhanced agonist-stimulation of the proteins containing Galpha(i2) and Galpha(o1.) The effect of RGS4 on the alpha(2A)-adrenoreceptor-Galpha(o1) fusion protein was concentration-dependent with EC(50) of 30 +/- 3 nm and the potency of the receptor agonist UK14304 was reduced 3-fold by 100 nm RGS4. Equivalent reconstitution with Asn(88)-Ser RGS4 failed to enhance agonist function on the alpha(2A)-adrenoreceptor-Galpha(o1) or alpha(2A)-adrenoreceptor-Galpha(i2) fusion proteins. Enzyme kinetic analysis of the GTPase activity of the alpha(2A)-adrenoreceptor-Galpha(o1) and alpha(2A)-adrenoreceptor-Galpha(i2) fusion proteins demonstrated that RGS4 both substantially increased GTPase V(max) and significantly increased K(m) of the fusion proteins for GTP. The increase in K(m) for GTP was dependent upon RGS4 amount and is consistent with previously proposed mechanisms of RGS function. Agonist-stimulated GTPase turnover number in the presence of 100 nm RGS4 was substantially higher for alpha(2A)-adrenoreceptor-Galpha(o1) than for alpha(2A)-adrenoreceptor-Galpha(i2). These studies demonstrate that although RGS4 has been described as a generic stimulator of the GTPase activity of G(i)-family G proteins, selectivity of this interaction and quantitative variation in its function can be monitored in the presence of receptor activation of the G proteins.


Protein kinase enzymes in the human vagina-relation to key mediators of the cyclic AMP and cyclic GMP pathways.
Aside from phosphodiesterase (PDE) isoenzymes, protein kinases (cAK=cyclic AMP-binding protein kinase, cGK=cyclic GMP-binding protein kinase) have also been identified as important receptors for cyclic nucleotides. A significance of protein kinases in the control of the function of the male and female reproductive tract has been suggested; however, up until today, only a few approaches have addressed these enzymes in female genital tissues. The present study aimed to investigate by means of biochemical and immunohistochemical methods the expression of cAK and cGK. The distribution of cAK(I) and cGK(I) in relation to the vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and PDE type 4 (PDE4) was also evaluated. Cytosolic supernatants prepared from specimens of vaginal wall smooth muscle or epithelium were subjected to anion exchange chromatography and the activities of cAK and cGK(I) measured. To evaluate the distribution of cAK(I) and cGK(I) in relation to VIP, CGRP and PDE4, immunohistochemistry was conducted in sections of the human vaginal wall (full-wall specimens). Activities representing cGK(I) and cAK(I) were resolved from the chromatography column. Staining specific for cAK(Iα) was identified in both vascular and non-vascular vaginal smooth musculature, immunoreactivity for cGK(Iβ) was observed in the smooth muscle and endothelium of small arteries interspersing the sections. cAK(Iα)-positive vessels were found innervated by slender varicose nerve fibers presenting the expression of VIP and CGRP. These arteries also expressed PDE4. Localization of cAK and cGK in close relation to key mediators of the cyclic AMP (PDE4, VIP) and cyclic GMP (CGRP) pathways indicate that both signaling systems may synergistically work together in human vaginal tissue.


Nondestructive mass selection of small van der waals clusters.
Clusters of atoms or molecules have been extensively studied by a variety of spectroscopies because of their unusual properties. Experiments with van der Waals clusters of defined sizes are not easily possible because nozzle beam expansions used in their production yield broad size distributions. Moreover, being weakly bound they readily fragment in the commonly used electron impact-ionization mass spectrometer detectors. Here it is shown that light fragile clusters of He, H(2), and D(2) can be selected and identified nondestructively by diffraction from a transmission grating. The method is universally applicable also to heavier species and well suited for spectroscopic studies.


Epidemiology of Tibial Fractures in Professional American Football Athletes From 2013 to 2019.
Lower extremity injuries occur with high frequency in National Football League (NFL) athletes and cause high burden to players and teams. Tibial fractures are among the most severe lower extremity injuries sustained in athletes and are associated with prolonged time loss from sport. To determine the number of tibial fractures in NFL athletes from the 2013 to 2019 NFL seasons and describe athlete demographics, fracture characteristics, and details of injury onset. Case series; Level of evidence, 4. A retrospective review of the NFL injury database was performed to identify all NFL athletes sustaining tibial fractures over the 2013 to 2019 NFL seasons. Athlete characteristics, injury characteristics, days missed, and treatment (operative vs nonoperative) were examined. Descriptive statistics were used to calculate means, standard deviations, ranges, and percentages. A total of 64 tibial fractures were identified in 60 athletes, resulting in a median loss of 74 days. Defensive secondary athletes had the highest number of injuries (n = 10; 16%), followed by running backs (n = 9; 14%), while 61% of these injuries occurred during NFL regular-season games, primarily between weeks 13 and 17. The most commonly reported activity during injury was athletes being tackled, with a direct impact to the tibia being the most common mechanism of injury. Lateral tibial plateau fractures were the most frequently reported, while distal tibial fractures resulted in the greatest number of days lost. The median time lost for injuries requiring surgery was 232 days compared with 56 days for injuries treated using conservative management. The highest proportion of tibial fractures were injuries to defensive secondary athletes and athletes being tackled while sustaining a direct impact to the leg, primarily to the lateral tibial plateau. Tibial fracture injuries were commonly sustained during NFL regular-season games, primarily during the final 4 weeks of the NFL regular season. Further investigations examining performance and career longevity in athletes sustaining tibial fractures are warranted to help improve the health and safety of NFL athletes.


[Use of the proton magnetic relaxation technic in the study of experimental burns].
Experiments with the use of proton magnetic relaxation have shown the presence of marked biophysical changes in the organs during deep skin burns with an area of 6% of the body surface. The method is highly responsive to the changes in tissue hydratation and is characterized by good reproducibility of the results. The technical simplicity of the method (5-10 minutes per sample) permits using proton magnetic relaxation on a large scale. The data obtained allow a conclusion that the method under consideration should be recommended for studying the status of water in experimental burns and in clinical trials.


Calix[4]arenes with two different chemical modifications at the bridges.
Hexabromocalix[4]arene derivatives (3a and 3b) possessing pairs of dibromomethylene and bromomethylene groups located at distal or proximal positions of the calix scaffold were prepared via photochemical bromination of tetramethoxycalix[4]arene. The dibromomethylene groups undergo hydrolysis to afford calix[4]arenes possessing pairs of carbonyl groups and bromomethylene groups located at distal or proximal bridges (4a and 4b, respectively). The bromomethylene groups of 4 undergo reactions with nucleophiles under S(N)1 conditions to afford a wide array of derivatives possessing two different chemical modifications at the bridges.


Determinants of cervical cancer screening utilization among HIV-positive women, in public general hospitals of Central Zone, Tigray, Ethiopia, 2020: Case-control study.
Cervical cancer is the second leading cause of cancer-related morbidity and mortality in Ethiopia. Evidence showes that, despite the magnitude and severity of cervical cancer, utilization of cervical cancer screening in the study area among HIV-positive women is low. This study aimed to assess the determinants of cervical cancer screening utilizationamong HIV-positive women in general public hospitals in the central zone of Tigray, Ethiopia. This study was a facility-based unmatched case-control study conductedamong HIV-infected womenin public general hospitals in the central zone of Tigray. Cases were HIV infected women not screened for cervical cancer, and controls were HIV infected women screened for cervical cancer. A total of 800participants (400 cases and 400 controls) wereselected using systematic random sampling with a 1:1 case-to-control ratio.Data collection was done using a pre-tested interviewer-administered questionnaire and a medical record review.The determinants of cervical cancer screeningutilization were identified through binary logistic regression. Significant determinants of cervical cancer screening utilization among HIV-infected women in the central zone of Tigray werebeing in the age group of 18-30 [AOR = 0.46, 95% CI = 0.22, 0.98], living in rural areas [AOR = 0.47, 95% CI = 0.26, 0.87], no formal education [AOR = 0.25, 95% CI = 0.14, 0.45] and primary education [AOR = 0.28, 95% CI = 0.16,0.49], not working outside the home [AOR = 0.21, 95% CI = 0.10, 0.44], poor knowledge about cervical cancer [AOR = 0.29, 95% CI = 0.19, 0.44], and about cervical cancer screening [AOR = 0.44, 95% CI = 0.28, 0.70], and unfavorable attitudes toward cervical cancer screening [AOR = 0.52, 95% CI = 0.34, 0.79]. Being in the age group of 18-30, living in rural areas, lacking formal education or havingonly primary level education, not working outside of the home, having poor knowledge of cervical cancer and screening,and having unfavourable attitudestowards cervical cancer screeningare significant determinat factors in cervical cancer screening utilization among HIV-infected women in the central zone of Tigray, Ethiopia. Considering such factors during the design of policies and programs could enhance the utilization of cervical cancer screening in the region.


Accelerometer-measured sedentary behaviour and physical activity of inpatients with severe mental illness.
Sedentary behaviour and lack of physical activity threatens health. Research concerning these behaviours of inpatients with severe mental illness is limited but urgently needed to reveal prevalence and magnitude. In total, 184 inpatients (men n =108, women n =76, mean age 57,4, 20% first generation antipsychotics, 40% second generation antipsychotics, 43% antidepressants, mean years hospitalisation 13 years), with severe mental illness of a Dutch psychiatric hospital wore an accelerometer for five days to objectively measure total activity counts per hour and percentages in sedentary behaviour, light intensity physical activity and moderate to vigorous physical activity. Accelerometer data were compared with data of 54 healthy ward employees. Patients showed significantly less activity counts per hour compared to employees (p=0.02), although the differences were small (d=0.32). Patients were sedentary during 84% of the wear time (50min/h), spend 10% in light intensity physical activity and 6% in moderate to vigorous physical activity. Age was the only significant predictor, predicting less total activity counts/h in higher ages. Decreasing sedentary behaviour and improving physical activity in this population should be a high priority in clinical practice.


Collagen Fibril Orientation in Tissue Specimens From Atherosclerotic Plaque Explored Using Small Angle X-Ray Scattering.
Atherosclerotic plaques can gradually develop in certain arteries. Disruption of fibrous tissue in plaques can result in plaque rupture and thromboembolism, leading to heart attacks and strokes. Collagen fibrils are important tissue building blocks and tissue strength depends on how fibrils are oriented. Fibril orientation in plaque tissue may potentially influence vulnerability to disruption. While X-ray scattering has previously been used to characterize fibril orientations in soft tissues and bones, it has never been used for characterization of human atherosclerotic plaque tissue. This study served to explore fibril orientation in specimens from human plaques using small angle X-ray scattering (SAXS). Plaque tissue was extracted from human femoral and carotid arteries, and each tissue specimen contained a region of calcified material. Three-dimensional (3D) collagen fibril orientation was determined along scan lines that started away from and then extended toward a given calcification. Fibrils were found to be oriented mainly in the circumferential direction of the plaque tissue at the majority of locations away from calcifications. However, in a number of cases, the dominant fibril direction differed near a calcification, changing from circumferential to longitudinal or thickness (radial) directions. Further study is needed to elucidate how these fibril orientations may influence plaque tissue stress-strain behavior and vulnerability to rupture.


[The assessment of the effectiveness of fenspiride (erespal) for the combined treatment of the patients presenting with exudative otitis media].
The objective of the present work was to estimate the effectiveness and safety of combined anti-inflammatory therapy of exudative otitis media with the use of fenspiride (erespal). The study included 75 patients of whom 35 (group 1) were given standard therapy supplemented by erespal (80 mg thrice daily); the remaining patients receiving standard therapy alone formed group 2 (control). The patients treated with erespal reported the subjective improvement of hearing and reduced congestion on days 7 - 8. Similar changes in group 2 occurred on day 10. It is concluded that the use of erespal for the combined treatment of the patients presenting with exudative otitis media reduces the duration of hospital stay, accelerates recovery, and promotes rapid normalization of hearing.


Prevention of common mental disorders: what can we learn from those who have gone before and where do we go next?
Prevention strategies have made a major contribution to the considerable successes in reductions in cardiovascular disease and cancer mortality seen in recent decades. However, in the field of psychiatry, similar population-level initiatives in the prevention of common mental disorders, depression and anxiety, are noticeably lacking. This paper aims to provide a brief overview of the existing literature on the topic of the prevention of common mental disorders and a commentary regarding the way forward for prevention research and implementation. This commentary considers what we currently know, what we might learn from the successes and failures of those working in prevention of other high prevalence health conditions, and where we might go from here. Taking cognisance of previous preventive models, this commentary additionally explores new opportunities for preventive approaches to the common mental disorders. The consensus from a large body of evidence supports the contention that interventions to prevent mental disorders across the lifespan can be both effective and cost-effective. However, funding for research in the area of prevention of common mental disorders is considerably lower than that for research in the areas of treatment, epidemiology and neurobiology. Thus, there is a clear imperative to direct funding towards prevention research to redress this imbalance. Future prevention interventions need to be methodologically rigorous, scalable to the population level and include economic evaluation. Evidence-based knowledge translation strategies should be developed to ensure that all stakeholders recognise preventing mental disorders as an imperative, with appropriate resources directed to this objective. There has been a recent expansion of research into potentially modifiable risk factors for depression, and it is now timely to make a concerted effort to advance the field of prevention of common mental disorders.