The debate regarding maintenance treatment with antipsychotic drugs in schizophrenia.
Several large meta-analyses of maintenance trials have confirmed that patients who suffer from chronic schizophrenia, randomized to placebo, are likely to experience earlier symptomatic worsening than patients randomized to a dopamine (DA)-blocking drug. These findings led expert groups to issue treatment guidelines, which recommend treatment with DA-blocking drugs for periods ranging from several years to indefinitely. The recommendations were accepted by the majority of, but not all, the experts, some of whom proposed a targeted or intermittent therapy approach by which DA-blocking drugs are discontinued upon symptomatic remission, to be renewed in case of symptom re-emergence. The debate between continued and targeted treatment approaches arises from disagreements regarding scientific and ethical questions. Scientifically, the discussion focuses on the quality and interpretation of the supporting or detracting evidence regarding each treatment option. For example, what is the percentage of individuals who can maintain stability off drugs? What is the rate of individuals who exacerbate despite maintenance treatment? What is the percentage of individuals who experience drug-related adverse effects? How can we interpret results of open-label, nonrandomized targeted trials? Regarding ethical questions, the debating sides disagree on how to weigh the impact of the decreased risk for exacerbation versus the certainty of adverse effects on the patients quality of life, and how to reach a patient-therapist shared decision within the constraints of mental illness.


Blockade of colchicine-induced inhibition of vasopressin-stimulated osmotic water flow: failure to influence microtubule formation.
Colchicine inhibits vasopressin-induced osmotic water flow across isolated toad urinary bladder. Concomitantly, colchicine has been shown to reduce the relative cytoplasmic volume fraction of microtubules in the apical granular cells of this epithelium that have been shown previously to mediate the hydroosmotic effect of vasopressin. Therefore, an intact cytoskeleton has been postulated to be a requirement for a full response to vasopressin. Since it has been demonstrated recently that cyclooxygenase inhibitors (meclofenamic acid) abrogate the inhibition by colchicine of vasopressin-stimulated water flow, we tested by stereological criteria the hypothesis that colchicine in the presence of meclofenamic acid does not prevent the polymerization of tubulin. Our results show that the relative cytoplasmic volume fraction of microtubules was reduced 75% by colchicine in the presence or absence of meclofenamic acid. An alternative explanation of the inhibitory action of colchicine is its ability in the toad urinary bladder to enhance the endogenous synthesis of and sensitivity to prostaglandin E, a potent negative modulator of vasopressin-stimulated water flow. An intact microtubular component of the cytoskeleton does not appear to be required for a maximal response to a physiological dose of vasopressin.


Identification of in vivo-induced bacterial proteins during human infection with Salmonella enterica serotype Paratyphi A.
Salmonella enterica serotype Paratyphi A is a human-restricted pathogen and the cause of paratyphoid A fever. Using a high-throughput immunoscreening technique, in vivo-induced antigen technology (IVIAT), we identified 20 immunogenic bacterial proteins expressed in humans who were bacteremic with S. Paratyphi A but not those expressed in S. Paratyphi A grown under standard laboratory conditions. The majority of these proteins have known or potential roles in the pathogenesis of S. enterica. These include proteins implicated in cell adhesion, fimbrial structure, adaptation to atypical conditions, oxidoreductase activity, proteolysis, antimicrobial resistance, and ion transport. Of particular interest among these in vivo-expressed proteins were S. Paratyphi A (SPA)2397, SPA2612, and SPA1604. SPA2397 and SPA2612 are prophage related, and SPA1604 is in Salmonella pathogenicity island 11 (SPI-11). Using real-time quantitative PCR (RT-qPCR), we confirmed increased levels of mRNA expressed by genes identified by IVIAT in a comparison of mRNA levels in organisms in the blood of bacteremic patients to those in in vitro cultures. Comparing convalescent- to acute-phase samples, we also detected a significant increase in the reaction of convalescent-phase antibodies with two proteins identified by IVIAT: SPA2397 and SPA0489. SPA2397 is a phage-related lysozyme, Gp19, and SPA0489 encodes a protein containing NlpC/P60 and cysteine, histidine-dependent amidohydrolase/peptidase (CHAP) domains. In a previous study utilizing a different approach, we found that transcripts for 11 and 7 of the genes identified by IVIAT were detectable in organisms in the blood of humans in Bangladesh who were bacteremic with S. Paratyphi A and Salmonella enterica serovar Typhi, respectively. S. Paratyphi A antigens identified by IVIAT warrant further evaluation for their contributions to pathogenesis and might have diagnostic, therapeutic, or preventive relevance.


Functional magnetic resonance imaging of cerebellar activation during the learning of a visuomotor dissociation task.
We have used functional magnetic resonance imaging (fMRI) to study the changes in cerebellar activation that occur during the acquisition of motor skill in human subjects presented with a new task. The standard paradigm consisted of a center-out movement in which subjects used a joystick to superimposed a cursor onto viusual targets. Two variations of this paradigm were introduced: (1) a learning paradigm, where the relationship between movement of the joystick and cursor was reversed, requiring the learning of a visuomotor transformation to optimize performance and (2) a random paradigm, where the joystick/cursor relationship was changed randomly for each trial. Activation in the cerebellum was highest during the random paradigm and during the early stages of the learning paradigm. In the early stages of learning and during the random paradigm performance was poor with a decrease in the number of completed movements, and an increase in the time and length of movements. With repeated practice at the learning paradigm performance improbed and reached the same level of proficiency as in the standard task. Commensurate with the improbement in performance was a decrease in cerebellar activation, that is, activation in the cerebellum changed in a parallel, but inverse relationship with performance. Linear regression analysis demonstarated that the inverse correlation between cerebellar activation and motor performance was significant. Repeated practice at the random paradigm did not produce improvements in performance and cerebellar activity remained high. The data support the hypothesis that the cerebellum is strongly activated when motor performance is inaccurate, consistent with a role for the cerebellum in the detection of, and correction for visuomotor errors.


Cricopharyngeal dysphagia and gastro-oesophageal reflux.
Nasal regurgitation of milk and choking after feeding were observed in a 1,450 g newborn boy. A nasogastric tube was inserted and several episodes of aspiration pneumonia occurred after every interruption of gavage. Weight gain was very slow. At the age of 7 months, cineradiographic studies depicted cricopharyngeal spasm and passage of the barium into the nasopharynx and larynx. Pharyngo-oesophageal manometry showed incoordination, high cricopharyngeal pressure and incomplete relaxation of the muscle. Extended lower oesophageal pH-metering revealed severe gastro-oesophageal reflux. After cricopharyngeal myotomy and fundoplication the patient recovered, x-ray findings improved, and so did manometry except for a persistent incoordination. Functional studies are mandatory for diagnosis of this complex clinical pattern. The need for ruling out gastrooesophageal reflux before myotomy in order to prevent subsequent severe aspiration, is pointed out.


Point-of-Care Knowledge-Based Resource Needs of Clinicians: A Survey from a Large Academic Medical Center.
To better understand the literature searching preferences of clinical providers we conducted an institution-wide survey assessing the most preferred knowledge searching techniques. A survey regarding literature searching preferences was sent to 1862 unique clinical providers throughout Mayo Clinic. The survey consisted of 25 items asking respondents to select which clinical scenarios most often prompt literature searches as well as identify their most preferred knowledge resources. A total of 450 completed surveys were returned and analyzed (24% response rate). 48% of respondents perform literature searches for more than half of their patient interactions with 91% of all searches occurring either before or within 3 hours of the patient interaction. When a search is performed 57% of respondents prefer synthesized information sources as compared to only 13% who prefer original research. 82% of knowledge searches are performed on a workstation or office computer while just 10% occur on a mobile device or at home. Providers in our survey demonstrate a need to answer clinical questions on a regular basis, especially in the diagnosis and therapy domains. Responses suggest that most of these searches occur using synthesized knowledge sources in the patient care setting within a very short time from the patient interaction.


Initial Effects of Differently Treated Biogas Residues from Municipal and Industrial Wastes on Spring Barley Yield Formation.
Soil application of biogas residues (BGRs) is important for closing nutrient cycles. This study examined the efficiency and impact on yields and yield formation of solid-liquid separated residues from biodegradable municipal and industrial wastes (bio-waste) in comparison to complete BGRs, nitrification inhibitor, agricultural BGRs, mineral fertilizer and unfertilized plots as control. The experiment was set up as a randomized block design on silt loam Cambisol. Biogas residues from four biogas plants were evaluated. Plants per m², ears per plant, grains per ear and thousand grain weight (TGW) were measured at harvest. Fertilization with BGRs resulted in similar biomass yields compared with mineral fertilizer. Mineral fertilizer (71 dt/ha) and plots fertilized with liquid fraction (59-62 dt/ha) indicated a trend to higher yields than solid fraction or complete BGR due to its high ammonia content. Liquid fractions and fraction with nitrification inhibitor induced fewer plants per m² than corresponding solid and complete variants due to a potential phytotoxicity of high NH4-N concentration during germination. However, barley on plots fertilized with liquid fraction compensated the disadvantages at the beginning during the vegetation period and induced higher grain yields than solid fraction. This was attributable to a higher number of ears per plant and grains per ear. In conclusion, BGRs from biodegradable municipal and industrial wastes can be used for soil fertilization and replace considerable amounts of mineral fertilizer. Our study showed that direct application of the liquid fraction of BGR is the most suitable strategy to achieve highest grain yields. Nevertheless potential phytotoxicity of the high NH4-N concentration in the liquid fraction should be considered.


Virtual environments as a tool for improving sequence ability of deaf and hard of hearing children.
The study examined the efficacy of an early intervention program to improve children's sequential time perception through virtual versus pictorial training in arranging episodes of temporal scripts. The researchers examined 65 deaf and hard of hearing children ages 4-7 years who were divided into two groups: (a) virtual environments technological intervention and (b) pictorial nontechnological intervention. Participants completed pretest and posttest measures. Both groups demonstrated significant improvement in sequential time achievement following intervention. However, the improvement was much more significant in the technological group.


Tissue-specific and hormonally regulated expression of a rat alpha 2u globulin gene in transgenic mice.
To investigate the tissue-specific and hormonal regulation of the rat alpha 2u globulin gene family, we introduced one cloned member of the gene family into the mouse germ line and studied its expression in the resulting transgenic mice. Alpha 2u globulingene 207 was microinjected on a 7-kilobase DNA fragment, and four transgenic lines were analyzed. The transgene was expressed at very high levels, specifically in the liver and the preputial gland of adult male mice. The expression in male liver was first detected at puberty, and no expression was detected in female transgenic mice. This pattern of expression is similar to the expression of endogenous alpha 2u globulin genes in the rat but differs from the expression of the homologous mouse major urinary protein (MUP) gene family in that MUPs are synthesized in female liver and not in the male preputial gland. We conclude that these differences between rat alpha 2u globulin and mouse MUP gene expression are due to evolutionary differences in cis-acting regulatory elements. The expression of the alpha 2u globulin transgene in the liver was abolished by castration and fully restored after testosterone replacement. The expression could also be induced in the livers of female mice by treatment with either testosterone or dexamethasone, following ovariectomy and adrenalectomy. Therefore, the cis-acting elements responsible for regulation by these two hormones, as well as those responsible for tissue-specific expression, are closely linked to the alpha 2u globulin gene.


The Effect of Posterior Tibial Slope on the Risk of Revision Surgery After Anterior Cruciate Ligament Reconstruction.
A significant proportion of patients undergoing anterior cruciate ligament (ACL) reconstruction (ACLR) later experience graft failure. Some studies suggest an association between a steep posterior tibial slope (PTS) and graft failure. To examine the PTS in a large cohort of patients about to undergo ACLR and to determine whether a steep PTS is associated with later revision surgery. Case-control study; Level of evidence, 3. A retrospective review of a cohort undergoing isolated ACLR between 2002 and 2012 (with 8-19 years of follow-up) was conducted. Preoperative sagittal radiographs of knees in full extension were used for measurements of the PTS. There were 2 independent examiners who performed repeated measurements to assess the reliability of the method. Statistical analyses were performed to compare the PTS in the groups with and without later revision surgery. A total of 728 patients, with a mean age of 28 years at the time of surgery, were included. Overall, 10% (n = 76) underwent revision surgery during the observation period. The group of injured knees had a significantly steeper PTS compared with the group of uninjured knees (9.5° vs 8.7°, respectively; P < .05). The mean PTS in the no revision group was 9.5° compared with 9.3° in the revision group (not significant). Dichotomized testing of revision rates related to PTS cutoff values of ≥10°, ≥12°, ≥14°, ≥16°, and ≥18° showed no association of PTS steepness (not significant) to graft failure. Patients with revision were younger than the ones without (mean age, 24 ± 8 vs 29 ± 10 years, respectively) and had a shorter time from injury to ACLR (mean, 14 ± 27 vs 24 ± 44 months, respectively) as well as a smaller graft size (8.2 vs 8.4 mm, respectively; P = .040). The current study did not find any association between a steep PTS measured on lateral knee radiographs and revision ACL surgery. However, a steeper PTS was seen in the group of injured knees compared with the group of uninjured (contralateral) knees. Independent of the PTS, younger patients, those with a shorter time from injury to surgery, and those with a smaller graft size were found to undergo revision surgery more often.


Household Water and Food Insecurity Are Positively Associated with Poor Mental and Physical Health among Adults Living with HIV in Western Kenya.
Household food insecurity (FI) and water insecurity (WI) are prevalent public health issues that can co-occur. Few studies have concurrently assessed their associations with health outcomes, particularly among people living with HIV. We aimed to investigate the associations between FI and WI and how they relate to physical and mental health. Food-insecure adult smallholder farmers living with HIV in western Kenya were recruited to participate in a cluster-randomized controlled trial of a multisectoral agricultural and asset loan intervention. We used baseline data on experiences of FI (using the Household Food Insecurity Access Scale, range: 0-27) and WI (using a modified scale developed for this region, range: 0-51) in the prior month (n = 716). Outcomes included probable depression (using the Hopkins Symptom Checklist), fatigue and diarrhea in the prior month, and overall mental and physical health (using the Medical Outcomes Study HIV Health Survey, range: 0-100). We first assessed Pearson correlations between FI, WI, and sociodemographic characteristics. We then developed 3 regressions for each health outcome (control variables and FI; control variables and WI; control variables, FI, and WI) and compared model fit indexes. Correlations between household FI, WI, and wealth were low, meaning they measure distinct constructs. FI and WI were associated with numerous physical and mental health outcomes; accounting for both resource insecurities typically provided the best model fit. For instance, when controlling for FI, each 10-point higher WI score was associated with a 6.42-point lower physical health score (P < 0.001) and 2.92 times greater odds of probable depression (P < 0.001). Assessing both FI and WI is important for correctly estimating their relation with health outcomes. Interventions that address food- and water-related issues among persons living with HIV concurrently will likely be more effective at improving health than those addressing a single resource insecurity. This trial was registered at clinicaltrials.gov as NCT02815579.


[Diffuse T-cell lymphoma of the cervix uteri: an unusual localization of an infrequent tumor].
Non-Hodgkin lymphomas are frequent tumors. However, extraglandulary forms are very unusual, and the location in the uterine cervix is also extraordinary. A case of an elderly woman with symptoms not related with the tumor, in whom the diagnosis was made from the incidental finding of a distended obstructive bladder is presented. Pelvic mass is one of the forms of presentation of primary malignant lymphomas of the uterine cervix. Diagnosis was made in this case by transvaginal biopsy under general anesthesia. Biopsy showed a diffuse T-cell lymphoma, a very rare finding considering that most of published cases are B-cell type. The importance of distinguishing malignant lymphoma from undifferentiated carcinoma or sarcoma is emphasized since cervical malignant lymphoma can be successfully treated with irradiation.


Estimation of gender bias in clinical trials.
The perception is that the clinical trials enterprise has been biased in favour of males by devoting a disproportionate effort to males and to the diseases and conditions afflicting them - a perception reinforced by a few high profile male-only heart trials undertaken in the 1970s and 1980s. The perception was sufficient to cause the U.S.A. Congress to enact legislation to require that a clinical trial 'is designed and carried out in a manner sufficient to provide for a valid analysis of whether the variables being studied in the trial affect women ...differently than other subjects in the trial'. Observed effort differentials are based on counts of single-gender trials indexed in MEDLINE and published in U.S. journals. Differentials are compared to those expected using male-female differentials in mortality and years of potential life loss due to mortality before age 65 to estimate effort bias. The ratios of female-only to male-only published trials were 0.53, 0.89 and 0.95 for the decades of 1966-1975, 1976-1985 and 1986-1995, respectively. The expected ratios, if single-gender trials were done in proportion to female-male mortality differentials, would be 0.57, 0.56 and 0.57, respectively. The differences in observed versus expected female to male ratios correspond to a slight excess of male-only trials in the decade of 1966-1975 and to sizeable excesses in female-only trials in the decades of 1976-1985 and 1986-1995. The results do not support the perception that women have been understudied relative to males in clinical trials. Most differentials favour females, whether based on mortality or years of potential life loss due to mortality before age 65 years.


Carotenoids in human skin.
The interaction of free radicals with antioxidants is a topic of increasing interest in the development of prevention strategies against skin ageing. Carotenoids can serve as marker substances for the complete antioxidative network of human skin. Recently, it has become possible to measure the carotenoids non-invasively and online using resonance Raman spectroscopy. This method has been used in various studies to investigate the interaction of carotenoid antioxidants and free radicals in human skin. In this review, the results of the selected studies are summarized and compared. It could be demonstrated that the carotenoid concentration of the skin reflects the lifestyle of individuals. A high level of carotenoids can be achieved with a healthy diet rich, for instance, in fruit and vegetables. Stress factors such as illness, UV and IR radiation of the sun, and smoking and alcohol consumption reduce the concentration of the carotenoids in the skin. It could be demonstrated that premature skin ageing was less in people with a high level of antioxidants in their tissue. Consequently, the furrows and wrinkles were not so deep and dense as in the skin of individuals with a low antioxidant level. The measurements are highly suited for the development of anti-ageing strategies and can be efficiently used in the medical diagnostics and therapy control.


Heart rate variability changes during high frequency yoga breathing and breath awareness.
Pre and post comparison after one minute of high frequency yoga breathing (HFYB) suggested that the HFYB modifies the autonomic status by increasing sympathetic modulation, but its effect during the practice was not assessed. Thirty-eight male volunteers with group average age ± S.D., 23.3 ± 4.4 years were each assessed on two separate days in two sessions, (i) HFYB and (ii) breath awareness. Each session was for 35 minutes, with 3 periods, i.e., pre (5 minutes), during HFYB or breath awareness (15 minutes) and post (5 minutes). There was a significant decrease in NN50, pNN50 and the mean RR interval during and after HFYB and after breath awareness, compared to the respective 'pre' values (p < 0.05) (repeated measures ANOVA followed by post-hoc analysis). The LF power increased and HF power decreased during and after breath awareness and LF/HF ratio increased after breath awareness (p < 0.05). The results suggest that there was reduced parasympathetic modulation during and after HFYB and increased sympathetic modulation with reduced parasympathetic modulation during and after breath awareness.


Interplay between the NADP-linked thioredoxin and glutathione systems in Arabidopsis auxin signaling.
Intracellular redox status is a critical parameter determining plant development in response to biotic and abiotic stress. Thioredoxin (TRX) and glutathione are key regulators of redox homeostasis, and the TRX and glutathione pathways are essential for postembryonic meristematic activities. Here, we show by associating TRX reductases (ntra ntrb) and glutathione biosynthesis (cad2) mutations that these two thiol reduction pathways interfere with developmental processes through modulation of auxin signaling. The triple ntra ntrb cad2 mutant develops normally at the rosette stage, undergoes the floral transition, but produces almost naked stems, reminiscent of the phenotype of several mutants affected in auxin transport or biosynthesis. In addition, the ntra ntrb cad2 mutant shows a loss of apical dominance, vasculature defects, and reduced secondary root production, several phenotypes tightly regulated by auxin. We further show that auxin transport capacities and auxin levels are perturbed in the mutant, suggesting that the NTR-glutathione pathways alter both auxin transport and metabolism. Analysis of ntr and glutathione biosynthesis mutants suggests that glutathione homeostasis plays a major role in auxin transport as both NTR and glutathione pathways are involved in auxin homeostasis.


NF-kappa B: a family of inducible and differentially expressed enhancer-binding proteins in human T cells.
A sensitive DNA-protein crosslinking approach has been used to characterize four inducible T-cell proteins (50 kDa, 55 kDa, 75 kDa, and 85 kDa) that specifically bind to kappa B enhancer elements. Partial proteolytic mapping revealed a distinct cleavage pattern for three of these proteins. These polypeptides are sequestered as inactive precursors in the cytosol of unstimulated T cells but can be converted into active forms in vivo by phorbol ester stimulation or in vitro by detergent treatment. The induction of these proteins by phorbol ester results in a strikingly biphasic pattern of nuclear expression with the 55-kDa and 75-kDa species appearing within minutes, whereas the 50-kDa and 85-kDa species appear only several hours after cellular stimulation. These data suggest that NF-kappa B-binding activity may not correspond to a single polypeptide but rather a family of at least four inducible and differentially regulated DNA-binding proteins that are expressed with distinct kinetics in human T lymphocytes.


ICTV Virus Taxonomy Profile: Tristromaviridae.
Tristromaviridae is a family of viruses with linear, double-stranded DNA genomes of 16-18 kbp. The flexible, filamentous virions (400±20 nm×30±3 nm) consist of an envelope and an inner core constructed from two structural units: a rod-shaped helical nucleocapsid and a nucleocapsid-encompassing matrix protein layer. Tristromaviruses are lytic and infect hyperthermophilic archaea of the order Thermoproteales. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the Tristromaviridae, which is available at www.ictv.global/report/tristromaviridae.


Fluid phase biopsy for detection and characterization of circulating endothelial cells in myocardial infarction.
Elevated levels of circulating endothelial cells (CECs) occur in response to various pathological conditions including myocardial infarction (MI). Here, we adapted a fluid phase biopsy technology platform that successfully detects circulating tumor cells in the blood of cancer patients (HD-CTC assay), to create a high-definition circulating endothelial cell (HD-CEC) assay for the detection and characterization of CECs. Peripheral blood samples were collected from 79 MI patients, 25 healthy controls and six patients undergoing vascular surgery (VS). CECs were defined by positive staining for DAPI, CD146 and von Willebrand Factor and negative staining for CD45. In addition, CECs exhibited distinct morphological features that enable differentiation from surrounding white blood cells. CECs were found both as individual cells and as aggregates. CEC numbers were higher in MI patients compared with healthy controls. VS patients had lower CEC counts when compared with MI patients but were not different from healthy controls. Both HD-CEC and CellSearch® assays could discriminate MI patients from healthy controls with comparable accuracy but the HD-CEC assay exhibited higher specificity while maintaining high sensitivity. Our HD-CEC assay may be used as a robust diagnostic biomarker in MI patients.


Worm-like soft nanostructures in nonionic systems: principles, properties and application as templates.
The principles, occurrence, structure and properties of worm-like micellar solutions in nonionic surfactant systems is reviewed, with focus in certain experimental methods used to characterize such soft nanostructured systems. Formulation plays a critical role in the design of worm-like micellar systems and derived viscoelastic networks. Micellar growth in one dimension, and hence formation of worm-like aggregates, is favoured by an increase in the average surfactant molecular packing parameter. Such an increase can be induced by addition of cosurfactant or amphiphilic oil that tends to penetrate in the surfactant palisade layer and reduce the specific surface area. On the other hand, long and bulky oils prone to be solubilized in the micellar core, cause a rod-sphere transition and therefore a decrease in viscosity. Salts have a small effect on the behaviour of nonionic worm-like micelles, contrary to what is found for ionic surfactant systems. The effect of raising temperature on worm-like micellar solutions is the result of a balance between the dehydration of the surfactant head groups, which favors elongation, the kinetics of micellar disruption and the formation of structures with nearly zero curvature. Therefore, a viscosity maximum as a function of temperature is found in many systems. Reverse worm-like micelles with a hydrophilic core can also be formed in organic solvents, even in the absence of ionic components or water. Worm-like micelles are useful as templates for the formation of ordered mesoporous oxides. The interaction of micelles with silica species results in the formation of silica-surfactant complexes that later precipitate as hexagonal phase via a cooperative mechanism.


The Contribution of Physical Education to Physical Activity Within a Comprehensive School Health Promotion Program.
Purpose: Little is known about the role of physical education (PE) in a school health promotion model, particularly where wellness is placed at the forefront. The purpose of this study was to understand how PE contributes to the overall amount of moderate to vigorous physical activity (MVPA) that children receive in a school recognized for health promotion. Methods: As part of an in-depth case study, participants in grades 4-8 (N = 105) wore ActiGraph wGT3X+ accelerometers over 7 days to assess activity levels. Data were scored using ActiLife software. Using SPSS statistics software, students were grouped into low, moderate, and high activity through calculating tertile splits of average daily MVPA. Two 2 × 2 ANCOVA (sex x activity level) tests were conducted to determine the ratio of MVPA in PE to school and daily MVPA, controlling for age. Results: Participants accrued 8 min MVPA on average during PE with differences among low (6.4 ± 2.5), moderate (8.3 ± 3.7), and highly active participants (10.1 ± 4.0). ANCOVA analyses revealed non-significant interactions between sex and activity level explaining variance in contribution of PE to school MVPA (F(2, 99) = .235, p = .791, partial ŋ2 = .005) and daily MVPA (F(2, 99) = .299, p = .742, partial ŋ2 = .006), but significant main effects between high and low activity for daily MVPA were observed F(2, 99) = 5.118 p = .008, partial ŋ2 = .094. Conclusions: PE remains a priority in supporting children's PA, particularly for those least active. Despite relatively low levels of MVPA, findings provide rationale for policy change supporting more frequent PE in schools.


Identification of a chromosomal determinant of alpha-toxin production in Staphylococcus aureus.
Production of alpha-toxin (the Hla+ phenotype, controlled by the Hla gene and scored as alpha-hemolytic activity) is a property of some isolates of Staphylococcus aureus NCTC 8325 and not of others. Genetic transformation between strains differing in the Hla phenotype revealed that the hla+ gene resides in the following sequence: purB110-bla+-hla+-ilv-129-pig-131; previously, the enterotoxin A (entA) gene of strain S-6 was shown to map very close to hla+. The hla+ mutations occurring naturally in strain Ps6 and after various mutagenic treatments in strains 8325 and 233 also mapped between bla+ and ilv-129. Among the isolates of strain 8325, the Hla+ phenotype was always associated with fibrinolytic activity, whereas Hla- isolates were non-fibrinolytic. This relationship was also observed among transformants selected for their Hla+ or Hla- phenotypes. The failure of Hla- strains and mutants to revert to hla+ at detectable frequencies, the instability of the Hla+ phenotype, and the previously observed pattern of recombination of the hla+ and entA+ determinants lend support to the view that hla+ may reside on a transposon; according to this view, Hla- mutants have lost the hla+-bearing transposon. It remains unclear whether hla+ is the structural gene for alpha-toxin.


[Thrombolytic therapy of pulmonary artery embolism in early pregnancy with recombinant tissue-type plasminogen activator].
We report on successful thrombolytic treatment of massive pulmonary embolism in a patient in early pregnancy with recombinant tissue-type plasminogen activator (rt-PA). Therapy was started with 20 mg rt-PA intravenously over 20 minutes, followed by two further infusions of 20 mg rt-PA within the next 8 hours. Clinical symptoms and haemodynamic parameters improved 24 hours after initiation of therapy. No bleeding complications were observed and the foetus was not affected. Further thromboembolic episodes could be prevented by anticoagulation with low molecular weight heparin up to full term normal delivery.


Herbal medicine, Hachimi-jio-gan, and its component cinnamomi cortex activate the peroxisome proliferator-activated receptor alpha in renal cells.
Hachimi-jio-gan is widely used to improve several disorders associated with diabetes, but its mechanism remains poorly understood. In an attempt to clarify the mechanism of Hachimi-jio-gan, we investigated the effects of this herbal medicine and its components in transfection studies of CV1 cells, especially nuclear receptor-mediated actions. One half (0.5) mg/ml of Hachimi-jio-gan activated peroxisome proliferator-activated receptor (PPARalpha), mediating the activation by 3.1-fold on DR1 response elements; however, it did not affect PPARgamma, thyroid hormone receptor, androgen receptor, estrogen receptor or RXR. In addition, this activation was observed in a dose-dependent manner. Next, to determine which components of Hachimi-jio-gan activate PPARalpha-mediated transcription, 8 of its components (rehmanniae radix, orni fructus, dioscoreae rhizoma, alismatis rhizoma, hoelen, moutan cortex, cinnamomi cortex, aconiti) were tested. Only cinnamomi cortex (1.0 mg/ml) increased PPARalpha-mediated transcription by 4.1-fold, and this activation was specific for PPAR alpha, and not for other nuclear receptors. Moreover, this PPARalpha-related activation by cinnamomi cortex is specifically observed in renal cells. Taken together, these findings indicate that Hachimi-jio-gan and cinnamomi cortex may have a pharmacological effect through the target site for PPARalpha.


Adolescents in The Netherlands underestimate risk for sexually transmitted infections and deny the need for sexually transmitted infection testing.
Worldwide, adolescents are at risk for sexually transmitted infections (STI). In The Netherlands, test rates among young heterosexual people are low and knowledge on the behavioral determinants of testing is scarce. In this study, we investigated STI testing in more detail with two independent samples of 16-25 year old vocational school students (n = 756/n = 1302). The aim of this study was to examine risk perceptions in relation to STI testing among lower educated adolescents in order to inform the development of an intervention promoting STI testing. We compared multiple measures of risk perception, fear of testing, self-efficacy for testing, and risk knowledge between groups of adolescents engaging and not engaging in risk behavior. The results show that at least half of the participating students with sexual experience underestimated their susceptibility for STI and showed an optimistic bias. Students with sexual experience also considered STI very severe but lacked self-efficacy for testing. This combination can yield a defensive reaction to the threat of STI that, in turn, results in the underestimation of personal risks. However, self-efficacy did not mediate the relationship between intention to test and perceived relative risk. In conclusion, our findings show underestimation of personal risks by vocational school students, a high perceived severity of STI and low self-efficacy for testing. A low level of knowledge regarding sexual risks and symptoms of STI might have contributed to low risk perceptions. Self-efficacy did not change the relation of intention-to-test to perceived risk.


Trace fossils from the athabasca oil sands, alberta, Canada.
A diverse and well-preserved ichnofossil suite has been identified from surface exposures of the middle and upper parts of the Lower Cretaceous McMurray Formation. The suite, consisting of representatives of at least ten ichnogenera, is one of the few clues to the original biotic component of the deposit. The distribution and abundance of these biogenic structures present strong evidence that the deep channel complex in which the sediments were deposited was closely associated with a nearby marine shoreline.


Induction of early light-inducible protein gene expression in Pisum sativum after exposure to low levels of UV-B irradiation and other environmental stresses.
Plants are constantly subjected to environmental changes and have developed various defence mechanisms to facilitate their continued existence. Pisum sativum plants were exposed to low levels of UV-B radiation and ELIP (early light-inducible proteins) mRNA, with a probable protective function, was rapidly and strongly induced during this type of stress. To our knowledge, this is the only photosynthetic gene that is up-regulated following exposure to UV-B, and this result has to be compared with studies predominantly reporting down-regulation by UV-B of genes encoding proteins localised in the plastid. The expression pattern of ELIP mRNA in pea was also investigated during salt, wounding and ozone stress. The transcript levels of ELIP were induced after the salt and wounding treatments but not during ozone fumigation.


Simple and rapid nicotine analysis using a disposable silica nanochannel-assisted electrochemiluminescence sensor.
Nicotine analysis is essential to medicine, toxicology and the tobacco industry. However, no simple, portable and disposable method was developed to meet their demands. Here, we report a simple, rapid and disposable silica nanochannel (SAN)-based electrochemiluminescence (ECL) sensor for nicotine analysis by simply assembling a SAN electrode with a paper cover. The sensing principle of the disposable sensor is based on the size exclusion effect and charge selectivity, which obviously prolong the sensor service time. We find that the sensor exhibits good specificity to nicotine, and most of the complex matrices are unlikely to impact the detection. The performance of the disposable sensor in cigarettes, e-cigarettes, nicotine gums, and lozenges is fully validated, showing satisfactory linearity, sensitivity (a limit of detection of 27.82 nM), and accuracy (a recovery between 96.00% and 106.51%). The disposable sensor can be potentially applied for on-site nicotine analysis.


Acute lesion of the intrafusal muscle of muscle spindles: ultrastructural and electrophysiological consequences.
Experiments were performed to functionally separate the neural and muscular elements in muscle spindles. Cat muscle spindles were dissected free in vitro and were transected on both sides of the sensory nerve endings. This resulted in an acute lesion of the intrafusal muscle fibers but spared the sensory endings. Within 45 min, the intrafusal muscle fibers degenerated to the condition in which there were no myofilaments left in the sensory zone and the muscle fiber membrane had begun to disintegrate. During this degeneration period, and afterward, the sensory nerve fibers continued to fire action potentials. However, the postlesion discharge was usually more irregular than normal, and the mean rate of firing was often dramatically increased. In addition, multiplex frequencies of firing were often observed; that is, the interspike intervals were clustered around 2 or more modal values. Computer modeling of 2 action potential initiators competing for access to the same output line suggests that the multiplexing results from at least one of the competitors having a fraction of its spikes aborted. Overall, the results indicate that the nerve endings have an intrinsic capability to function as sensory receptors in the absence of a muscle substrate.


Hepatocyte nuclear factor 4α regulates megalin expression in proximal tubular cells.
Hepatocyte nuclear factor 4α (HNF4α) is a member of the nuclear receptor superfamily and upregulates expression of many genes in the liver, pancreas, small intestine, and colon. HNF4α is also highly expressed in proximal tubular epithelial cells (PTECs) in kidney. PTECs reabsorb various substances through transporters, ion channels, and receptors, but the target genes for HNF4α in PTECs have not been investigated in detail. In the present study, we aimed to identify novel HNF4α target genes that are highly expressed in PTECs. Expression of many solute carrier transporter genes was upregulated by HNF4α in human PTEC-derived HK-2 cells. Notably, expression of megalin (LRP2), an endocytic receptor of various molecules involved in development and progression of chronic kidney disease (CKD), was strongly induced by HNF4α, and the transactivation potential of the megalin promoter was dependent on HNF4α expression. Moreover, HNF4α was found to directly bind to an HNF4α binding site near the transcription start site in the megalin gene. These results indicate that HNF4α plays an important role in maintaining reabsorption and metabolism in PTECs by positive regulation of several solute carrier transporter and megalin genes at the transcriptional level.


Evaluation of the animal welfare during religious slaughtering.
Plasma cortisol and its metabolites are physiological indicators for stress assessment and slaughtering method may affect their levels, playing an important role in the correct acidification of meat. The aim of the study was to determine and compare plasma cortisol values in animals slaughtered using traditional procedures, which include stunning (using captive bolt pistol), with those in animals slaughtered using Halal method, which does not involve stunning. The study was carried out on a total of 60 Charolais male beef cattle of eight months of age, bred in free paddock outdoors. The animals were divided into two experimental groups, each consisting of 30 individuals, on the basis of the slaughtering method, i.e. traditional or Halal, to verify the whole production chain and to ensure that the product conformed to Muslim rules. Plasma cortisol levels (detected by Elisa test) were evaluated at two different times of animal productive life: on the farm, one week before slaughter (T0) and during bleeding (T1). The 30 calves slaughtered after stunning showed plasma cortisol values of 4.06±1.94 and 43.72±12.09 nmol/L, respectively on the farm and during exsanguination. Conversely, the average values found in the 30 calves subjected to ritual slaughter were 3.26±1.01 and 88.81±41.02 nmol/L. The study demonstrated that throughout the animal's productive life (from pasture to slaughter) the greatest variation between slaughter with and without stunning was observed during bleeding.


Life-review therapy with computer supplements for depression in the elderly: a randomized controlled trial.
Life-review therapy has been recognized as an effective therapeutic approach for depression in older adults. Additionally, the use of new media is becoming increasingly common in psychological interventions. The aim of this study was to investigate a life-review therapy in a face-to-face setting with additional computer use. This study explored whether a six-week life-review therapy with computer supplements from the e-mental health Butler system constitutes an effective approach to treat depression in older adults aged 65 and over. A total of 36 participants with elevated levels of depressive symptoms were randomized to a treatment group or a waiting-list control group and completed the post-assessment. Fourteen individuals in the intervention group completed the follow-up assessment. Analyses revealed significant changes from pre- to post-treatment or follow-up for depression, well-being, self-esteem, and obsessive reminiscence, but not for integrative reminiscence and life satisfaction. Depressive symptoms decreased significantly over time until the three-month follow-up in the intervention group compared to the control group (pre to post: d = 1.13; pre to follow-up: d = 1.27; and group × time effect pre to post: d = 0.72). Furthermore, the therapy led to an increase in well-being and a decrease in obsessive reminiscence among the participants in the intervention group from pre-treatment to follow-up (well-being: d = 0.70; obsessive reminiscence: d = 0.93). Analyses further revealed a significant but small group × time effect regarding self-esteem (d = 0.19). By and large, the results indicate that the life-review therapy in this combined setting could be recommended for depressive older adults.


Epigenetic Targets for Oligonucleotide Therapies of Pulmonary Arterial Hypertension.
Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.


Arthrogryposis and multicystic encephalopathy after acute fetal distress in the end stage of gestation.
The natural history of the rare association "multicystic encephalopathy-arthrogryposis" was traced in a fetus carefully followed after artificial insemination. The fetus exhibited normal viability and brain morphology up to the 32nd week. At 36 weeks, active movements diminished and at 37 weeks, hydramnios and signs of fetal distress led to cesarean section. The infant presented with severe arthrogryposis of the limbs and spine, but not with the other elements of a long-lasting akinesia. US showed multicystic encephalopathy. Both the clinical and the neuropathological findings established that multicystic encephalopathy was neither the cause nor the sequential consequence of the fetal akinesia, but the result of a recent diffuse, acute malacic process that also involved the anterior horn cells. Acute fetal distress, responsible for major ischemic damage to CNS but compatible with fetal survival, remains an obscure condition which allows for the development of severe arthrogryposis in a few weeks.


Design, Synthesis, and Characterization of Bis(7-(N-(2-morpholinoethyl)sulfamoyl)benzo[c][1,2,5]oxadiazol-5-yl)sulfane for Nonprotein Thiol Imaging in Lysosomes in Live Cells.
Thiols are critical to cellular structures and functions. Disturbance of cellular thiols has been found to affect cell functions and cause various diseases. Intracellularly, thiols were found unevenly distributed in subcellular organelles. Probes capable of detecting subcellular thiol density in live cells are valuable tools in determining thiols' roles at the subcellular level. The subcellular organelle lysosome is the place where unwanted macromolecules are removed through degradation by hydrolytic enzymes. The degradation also serves as a regulation of a variety of cellular functions such as autophagy, endocytosis, and phagocytosis to maintain cellular homeostasis. Thiols are found to be involved in the lysosomal degradation process. A probe that can detect lysosomal thiols in live cells will be a valuable tool in unveiling the roles of thiols in lysosomes. We would like to report bis(7-(N-(2-morpholinoethyl)sulfamoyl)benzo[c][1,2,5]-oxadiazol-5-yl)sulfane (BISMORX) as a thiol specific fluorogenic agent for live cell nonprotein thiol (NPSH) imaging in lysosomes through fluorescence microscopy. BISMORX itself shows no fluorescence and reacts readily with a NPSH to form a fluorescent thiol adduct with excitation and emission wavelengths of 380 and 540 nm, respectively. BISMORX does not react with compounds containing nucleophilic functional groups other than thiols such as -OH, -NH2, and -COOH. No reaction was observed either when BISMORX was mixed with protein thiols. BISMORX was able to image, quantify, and detect the change of NPSH in lysosomes in live cells. A colocalization experiment with LysoTracker Red DND-99 confirmed that the thiols imaged by BISMORX were indeed lysosomal thiols.


Coronary-coronary bypass using the internal thoracic artery: a sparing procedure of the arterial conduit.
The internal thoracic artery (ITA) is well known to be the best conduit for coronary artery bypass grafting. However, the bilateral use of ITAs remains limited because in situ right ITAs (RITAs) do not possess an adequate length to be directed to the posterolateral myocardium. We thus considered using free ITAs for conduits between the two segments of the same coronary artery. From March 1997 to May 1999, 17 patients underwent coronary-coronary bypass grafting (C-CBG) using free ITAs. Early operative results were analyzed. C-CBG was indicated when the right ITA had an inadequate length or when a distal part of the ITA was left unused. No patient died after C-CBG and none have experienced angina since C-CBG (mean follow-up period 27.3 +/- 19.8 months). Postoperative angiography was performed in all subjects at discharge. Only one coronary-coronary bypass graft was occluded, the other grafts were patent, and there were no stenotic changes. Bilateral ITAs were used in 75% of the patients undergoing CABG during the period of this study. C-CBG can expand the use of bilateral ITAs and can provide an alternative method for revascularization of the posterolateral myocardium.


Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis.
Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4+ T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.


Perceptions of work stress causes and effective interventions in employees working in public, private and non-governmental organisations: a qualitative study.
Aims and method To identify causes of stress at work as well as individual, organisational and personal interventions used by employees to manage stress in public, private and non-governmental organizations (NGOs). Qualitative interviews were conducted with 51 employees from a range of organisations. Results Participants reported adverse working conditions and management practices as common causes of work stress. Stress-inducing management practices included unrealistic demands, lack of support, unfair treatment, low decision latitude, lack of appreciation, effort-reward imbalance, conflicting roles, lack of transparency and poor communication. Organisational interventions were perceived as effective if they improved management styles, and included physical exercise, taking breaks and ensuring adequate time for planning work tasks. Personal interventions used outside of work were important to prevent and remedy stress. Clinical implications Interventions should improve management practices as well as promoting personal interventions outside of the work setting.


Characterization of the cryptic AV3 promoter of ageratum yellow vein virus in prokaryotic and eukaryotic systems.
A cryptic prokaryotic promoter, designated AV3 promoter, has been previously identified in certain begomovirus genus, including ageratum yellow vein virus isolate NT (AYVV-NT). In this study, we demonstrated that the core nucleotides in the putative -10 and -35 boxes are necessary but not sufficient for promoter activity in Escherichia coli, and showed that AYVV-NT AV3 promoter could specifically interact with single-stranded DNA-binding protein and sigma 70 of E. coli involved in transcription. Several AYVV-NT-encoded proteins were found to increase the activity of AV3 promoter. The transcription start sites downstream to AV3 promoter were mapped to nucleotide positions 803 or 805 in E. coli, and 856 in Nicotiana benthamiana. The eukaryotic activity of AV3 promoter and the translatability of a short downstream open reading frame were further confirmed by using a green fluorescent protein reporter construct in yeast (Saccharomyces cerevisiae) cells. These results suggested that AV3 promoter might be a remnant of evolution that retained cryptic activity at present.


Automatically created concept graphs using descriptive keywords in the medical domain.
Besides keyword search, navigational search is an important means to find relevant information in digital object collections. Such navigation is often supported by categorization systems or thesauri, which provide a hierarchical view on a particular domain and allow for browsing digital collections. Existing categorization systems, however, require large and expensive efforts for the manual creation and maintenance. Our Semantic GrowBag algorithm fully automatically creates concept graphs, i.e. directed graphs similar to categorization systems but without strong subsumption semantics. This article sketches our algorithm and evaluates it for the medical domain. Our Semantic GrowBag algorithm uses descriptive keywords and exploits higher-order co-occurrences between them to create concept graphs (so-called GrowBag graphs) from annotated object collections. In this study, we have automatically created more than 2000 GrowBag graphs based on the Medline data set to show the applicability of our algorithm in the medical domain. For the evaluation, we first compared our algorithm to a baseline algorithm that does not take higher-order co-occurrences into account, and then compared the resulting GrowBag graphs systematically against the manually crafted MeSH thesaurus. Our experiments revealed that the Semantic GrowBag approach essentially increases the number of relevant relationships in comparison to a baseline approach by about 50%. Furthermore, the identified relations usually correspond to and hardly ever contradict to relationships as stated by MeSH. The Semantic GrowBag algorithm allows creating concept graphs fully automatically. While it does not systematically exploit specifics of a domain (such as the fundamental separation between 'drugs' and 'therapy' in MeSH), the resulting GrowBag graphs are nevertheless well-suited to support navigation in digital object collections. Moreover, they can also be used to help maintaining existing categorization systems based on the actual usage of categories.


Organ preservation in anal and rectal cancers.
For the past 10 to 15 years, radiation therapy and chemotherapy have played an increasingly important role in the treatment of various gastrointestinal malignancies, most prominently in anal and rectal cancer. Critical issues in the care of patients with anal and rectal cancer include not only local control and survival but organ preservation as well. For patients with carcinoma of the anal canal, external-beam irradiation with 5-fluorouracil and chemotherapy with mitomycin C have replaced surgery as primary therapy. Current studies are optimizing this therapy. In contrast, the management of distal rectal cancer is in evolution. Although the abdominoperineal resection has been long regarded as the definitive treatment of distal rectal cancer, it is associated with substantial morbidity (loss of anorectal function with a permanent colostomy and a high incidence of sexual and genitourinary dysfunction). As an alternative, treatment programs utilizing sphincter-preserving procedures with radiation therapy and chemotherapy are under active investigation. In selected patients, these strategies appear promising, and there have been reports of satisfactory local control and survival, as well as preservation of sphincter integrity.


Risk factor analysis of coexisting endometrial carcinoma in patients with endometrial hyperplasia: a retrospective observational study of Taiwanese Gynecologic Oncology Group.
To evaluate the clinical outcome and parameters related to coexisting endometrial carcinoma in women with tissue-diagnosed endometrial hyperplasia. Between January 1991 and December 2009, three hundred and eighty-six patients with the presumptive diagnosis of endometrial hyperplasia were retrieved. Among these, one hundred and twenty-five patients were identified as having coexisting endometrial carcinoma in hysterectomy specimens. The three hundred and eighty-six patients were divided into two groups: the hyperplasia-benign group (261 cases) and the hyperplasia-malignant group (125 cases). Several clinical parameters including age, menopausal status, history of abnormal uterine bleeding, obstetrical history, medical history of diabetes and hypertension, BMI, and preoperative pathologic results were investigated. Age ≥53 (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.26 to 4.57), menopausal status (OR, 2.07; 95% CI, 1.14 to 3.76), diabetes history (OR, 7.33; 95% CI, 2.79 to 19.26), abnormal uterine bleeding (OR, 3.99; 95% CI, 1.22 to 13.02), atypical endometrial hyperplasia (OR, 7.38; 95% CI, 4.03 to 13.49), and body mass index ≥27 (OR, 3.24; 95% CI, 1.76 to 5.97) were independent risk factors for prediction of endometrial hyperplasia coexisting with endometrial carcinoma. The diagnostic efficacy of atypical endometrial hyperplasia to predict the endometrial hyperplasia coexisting with endometrial carcinoma was better than or similar to those of other independent factors and combinations of these factors. Coexisting malignancy should be considered when examining endometrial hyperplasia patients with the related risk factors, especially atypical endometrial hyperplasia.


Medical costs of osteoporosis in the elderly Medicare population.
Prior national cost estimates of osteoporosis and fractures in the USA have been based on diverse sets of provider data or selected commercial insurance claims. Based on a random population-based sample of older adults, the US medical cost of osteoporosis and fractures is estimated at $22 billion in 2008. National cost estimates of osteoporosis and fractures in the USA have been based on diverse sets of provider data or selected commercial insurance claims. We sought to characterize prevalence and costs for osteoporosis using a random population-based sample of older adults. A cross-sectional estimate of medical cost was made with 2002 data from the Medicare Current Beneficiary Survey (MCBS). MCBS combines health interviews with claims information from all payers to profile a random sample of 12,700 Medicare recipients. Three cohorts aged 65 or over were defined: (1) patients experiencing a fracture-related claim in 2002; (2) patients with a diagnosis, medication, or self-report for osteoporosis or past hip fracture; and (3) non-case controls. The total cost of patient claims was compared to that of controls using multiple regression. Of 30.2 million elderly Medicare recipients in 2002, 1.6 million (5%) were treated for a fracture that year, and an additional 7.2 million (24%) have osteoporosis without a fracture. The estimated mean impact of fractures on annual medical cost was $8,600 (95% confidence interval, $6,400 to $10,800), implying a US cost of $14 billion ($10 to $17 billion). Half of the non-fracture osteoporosis patients received drug treatment, averaging $500 per treated patient, or $2 billion nationwide. The annual cost of osteoporosis and fractures in the US elderly was estimated at $16 billion, using a national 2002 population-based sample. This amount corroborates previous estimates based on substantially different methodologies. Projected to 2008, the national cost of osteoporosis and fractures was $22 billion.


Phenylalanyl-tRNA synthetase from baker's yeast. Salt dependence of steady-state kinetics indicates two molecular forms of the enzyme.
Steady-state kinetic data of aminoacylation of tRNAPhe by phenylalanyl-tRNA synthetase depend on salt concentration. At 5 mM KCl and 20 mM MgSO4 a non-linear curve is found in the double-reciprocal plot for ATP and phenylalanine, while at 200 mM KCl and 50 mM MgSO4 a linear curve is observed. KCl and MgSO4 dependence of the reaction also show biphasic curves with intersection points of the two extrapolated linear parts at 50 mM and 10 mM, respectively. A biphasic curve is also found if the concentration of CTP is varied at constant low ATP concentration. Extrapolations of the linear parts of the curves for ATP as well as for CTP at 5 mM KCl and 20 mM MgSO4 intersected the 1/[NTP] axis at 1.2 +/- 0.1 mM. Hence the existence of a non-linear curve for ATP as well as phenylalanine does not necessarily indicate two non-equivalent binding sites for these substrates. A more likely explanation is the existence of two different molecular forms of phenylalanyl-tRNA synthetase which are interconvertible by salt. This explanation is substantiated by the observation that proteolytic digestion of phenylalanyl-tRNA synthetase is more easily achieved at low than at medium ionic strength. In addition mischarging of tRNAIle with phenylalanine by phenylalanyl-tRNA synthetase occurs at a moderate rate at 5 mM KCl and 20 mM MgSO4 whereas it is largely depressed by addition of either 5 mM CTP or 150 mM KCl.


Functional Comorbidity Index and health-related quality of life in patients with obstructive sleep apnea.
The role of comorbidities in determining health-related quality of life (HRQL) in obstructive sleep apnea (OSA) pa-tients has not been thoroughly investigated. Commonly used comorbidity tools, such as Charlson Comorbidity Index (CCI), have been designed with mortality as the outcome variable. A new tool, the Functional Comorbidity Index (FCI), has been especially developed to assess the effect of comorbidities on the "physical functioning" subscale of the Medical Outcomes Short Form-36 Health Survey (SF-36). 1) To determine the role of FCI in the prediction of the effect of comorbidities on HRQL in OSA. 2) To determine whether FCI and CCI are equally robust in predicting the effect of comorbidities on HRQL in OSA. Two hundred and fifty-five OSA patients were enrolled. Patients completed the SF-36 and the Medical Outcomes Study Sleep Scale (MOS-SS) forms, while their comorbidity status was assessed by FCI and CCI. The SF-36 physical (PCS-36) and mental component summary (MCS-36) scores were also calculated. PCS-36 was predicted by FCI (p < 0.001), male gender (p = 0.001), BMI (p = 0.002) and the "awakening with "breathlessness/headache" MOS-SS subscale (p = 0.011) (R2 = 0.348). Among these predictors, FCI exerted the most important quantitative effect. MCS-36 was predicted only by the "sleep disturbance" (p = 0.005) and the "awakening with breathlessness/headache" MOS-SS subscales (p < 0.001) (R2 = 0.221). In patients with OSA, FCI is an independent predictor of the physical aspect of their HRQL. FCI is more robust than CCI in assessing the effect of comorbidities on HRQL in OSA.


Burn wound coverings - a review.
Few injuries are more traumatic to the victim than a burn. To assist in preventing further damage beyond the burn site, a range of burn wound coverings has emerged over the years. These wound coverings, both natural and synthetic are discussed in connection with their historical significance and their effects on promoting the healing process. Particular reference is made to the choice of material for synthetic wound coverings.


Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses.
To assess associations between baseline values of four different circulating markers of inflammation and future risk of coronary heart disease, potential triggers of systemic inflammation (such as persistent infection), and other markers of inflammation. Nested case-control comparisons in a prospective, population based cohort. General practices in 18 towns in Britain. 506 men who died from coronary heart disease or had a non-fatal myocardial infarction and 1025 men who remained free of such disease until 1996 selected from 5661 men aged 40-59 years who provided blood samples in 1978-1980. Plasma concentrations of C reactive protein, serum amyloid A protein, and serum albumin and leucocyte count. Information on fatal and non-fatal coronary heart disease was obtained from medical records and death certificates. Compared with men in the bottom third of baseline measurements of C reactive protein, men in the top third had an odds ratio for coronary heart disease of 2.13 (95% confidence interval 1.38 to 3.28) after age, town, smoking, vascular risk factors, and indicators of socioeconomic status were adjusted for. Similar adjusted odds ratios were 1.65 (1.07 to 2.55) for serum amyloid A protein; 1.12 (0.71 to 1.77) for leucocyte count; and 0.67 (0.43 to 1.04) for albumin. No strong associations were observed of these factors with Helicobacter pylori seropositivity, Chlamydia pneumoniae IgG titres, or plasma total homocysteine concentrations. Baseline values of the acute phase reactants were significantly associated with one another (P<0.0001), although the association between low serum albumin concentration and leucocyte count was weaker (P=0.08). In the context of results from other relevant studies these findings suggest that some inflammatory processes, unrelated to the chronic infections studied here, are likely to be involved in coronary heart disease.


MRI Radiomic Analysis of IMRT-Induced Bladder Wall Changes in Prostate Cancer Patients: A Relationship with Radiation Dose and Toxicity.
The main purpose of this study was to assess the structural changes in the bladder wall of prostate cancer patients treated with intensity-modulated radiation therapy using magnetic resonance imaging texture features analysis and to correlate image texture changes with radiation dose and urinary toxicity. Ethical clearance was granted to enroll 33 patients into this study who were treated with intensity-modulated radiation therapy for prostate cancer. All patients underwent two magnetic resonance imagings before and after radiation therapy (RT). A total of 274 radiomic features were extracted from MR-T2W-weighted images. Wilcoxon singed rank-test was performed to assess significance of the change in mean radiomic features post-RT relative to pre-RT values. The relationship between radiation dose and feature changes was assessed and depicted. Cystitis was recorded as urinary toxicity. Area under receiver operating characteristic curve of a logistic regression-based classifier was used to find correlation between radiomic features with significant changes and radiation toxicity. Thirty-three bladder walls were analyzed, with 11 patients developing grade ≥2 urinary toxicity. We showed that radiomic features may predict radiation toxicity and features including S5.0SumVarnc, S2.2SumVarnc, S1.0AngScMom, S0.4SumAverg, and S5. _5InvDfMom with area under receiver operating characteristic curve 0.75, 0.69, 0.65, 0.63, and 0.62 had highest correlation with toxicity, respectively. The results showed that most of the radiomic features were changed with radiation dose. Feature changes have a good correlation with radiation dose and radiation-induced urinary toxicity. These radiomic features can be identified as being potentially important imaging biomarkers and also assessing mechanisms of radiation-induced bladder injuries.


Incorporating occupational medicine methodology into military fitness for duty and readiness issues.
The need for the U.S. Air Force (USAF) to know its personnel's fitness for duty and readiness status is one of the most significant criteria for determining their ability to complete the missions assigned to them. This is especially critical in the current milieu of increasing deployments. However, the USAF has a very limited program to meet this need. Occupation Medicine has had extensive experience in determining job requirements, assessing individuals, and monitoring performance over time. Further integrating Occupational Medicine methodology and the current state of scientific knowledge on physical performance is advocated to improve the USAF's ability to have a fit and ready force able to meet its burgeoning mission. This paper reviews the literature with the following recommendations: a) assess the physical fitness of the force given future demands due to readiness taskings and if necessary mandate individual and unit exercise and provide time for these activities; b) eliminate the weight management and cycle ergometry programs; c) establish physical fitness standards appropriate for each job as well as for initial entry into the USAF, these standards should incorporate ongoing testing, evaluation, and training; d) body fat should be treated only as a medical condition and not as an image standard; and e) establish case management teams to optimize the identification, treatment, return to duty and medical boarding of personnel with injuries or subpar performance.


Cortisol, cytokines, and hippocampal volume interactions in the elderly.
Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.


Studies on thymus function. II. Cooperative effect of newborn and embryonic hemopoietic liver cells with thymus function.
Significant immunological restoration of 45-day old, neonatally thymectomized C3Hf mice was obtained by the cooperation of syngeneic newborn or embryonic hemopoietic liver cells with thymic function. Thymic function or cells alone are almost ineffective or restore approximately 10% of the animals. Newborn liver cells are effective in association with thymus grafts or humoral thymic function (thymoma grafts and thymus or thymomas in diffusion chambers). Embryonic liver cells are ineffective, even in large numbers, when associated with humoral thymic function. On the other hand, embryonic liver cells are effective in the cooperative effect only in association with viable thymus grafts, preferably syngeneic, whether the grafts were placed subcutaneously, intraperitoneally, or under the kidney capsule. Dispersed viable thymic cells are ineffective in association with embryonic liver cells. Cells capable of cooperating with humoral thymic function start to appear to embryonic liver by day 19-21 of gestation and are detectable until day 5-6 postbirth. Embryonic hemopoietic liver cells from 12 to 18 days of gestation contain cells capable of cooperation only with viable free thymus grafts and not with humoral thymic function. A prethymic cell population of partially differentiated cells of hemopoietic origin, insensitive to humoral activity of the thymus but requiring thymic stroma and traffic through the thymus is postulated to explain our results. This population of prethymic cells can become postthymic through this process and eventually develop into competent cells. Postthymic cells are characterized by their sensitivity to humoral activity of the thymus and by their wide distribution in the lymphohemopoietic tissues of newborn and young adult mice.


A Network Analysis of Clinical Variables in Chronic Pain: A Study from the Swedish Quality Registry for Pain Rehabilitation (SQRP).
Efforts to identify specific variables that impact most on outcomes from interdisciplinary pain rehabilitation are challenged by the complexity of chronic pain. Methods to manage this complexity are needed. The purpose of the study was to determine the network structure entailed in a set of self-reported variables, examine change, and look at potential predictors of outcome, from a network perspective. In this study we apply network analysis to a large sample of people seeking interdisciplinary pain treatment (N = 2,241). Variables analyzed include pain intensity, pain interference, extent of pain, depression, anxiety, insomnia, and psychological variables from cognitive behavioral models of chronic pain. We found that Acceptance, Pain Interference, and Depression were key, "central," variables in the pretreatment network. Interestingly, there were few changes in the overall network configuration following treatment, specifically with respect to which variables appear most central relative to each other. On the other hand, Catastrophizing, Depression, Anxiety, and Pain Interference each became less central over time. Changes in Life Control, Acceptance, and Anxiety were most strongly related to changes in the remainder of the network as a whole. Finally, no network differences were found between treatment responders and non-responders. This study highlights potential future targets for pain treatment. Further application of a network approach to interdisciplinary pain rehabilitation data is recommended. Going forward, it may be better to next do this in a more comprehensive theoretically guided fashion, and ideographically, to detect unique individual differences in potential treatment processes.


Cancer as a dynamical phase transition.
This paper discusses the properties of cancer cells from a new perspective based on an analogy with phase transitions in physical systems. Similarities in terms of instabilities and attractor states are outlined and differences discussed. While physical phase transitions typically occur at or near thermodynamic equilibrium, a normal-to-cancer (NTC) transition is a dynamical non-equilibrium phenomenon, which depends on both metabolic energy supply and local physiological conditions. A number of implications for preventative and therapeutic strategies are outlined.


Factors Influencing Use of Hormone Therapy for Ductal Carcinoma In Situ: A National Cancer Database Study.
Adjuvant hormonal therapy (HT) reduces breast cancer recurrence risk in estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS). We assessed national practice patterns and influence of surgery and pathology on HT use in DCIS. Data on DCIS patients diagnosed from 2004 to 2014 were extracted from the National Cancer Database, and patients were classified according to ER status and whether HT was received. Factors associated with HT use were assessed using Chi square tests for univariate analysis and logistic regression for multivariate analysis. Overall, 207,738 patients were evaluable as follows: ER+ (69.3%), ER- (13.7%), and ER unknown (17.0%). Among ER+ DCIS patients, 46.5% received HT, and HT use increased over time (42.3% in 2004 to 50.6% in 2014; p < 0.001). In contrast, 7.8% of ER- DCIS patients received HT, decreasing from 10.7% in 2004 to 5.9% in 2014 (p < 0.001). HT use varied by surgery type (BCS, 53.9%; unilateral mastectomy, 31.5%; and bilateral mastectomy, 8.1%; p < 0.001) and use was higher in BCS patients receiving adjuvant radiation than those not receiving radiation (62.7 vs. 29.1%; p < 0.001). Males treated with BCS were less likely to receive HT than females (43.2 vs. 54.0%; p < 0.001). In the BCS subset, higher use of HT was associated with more recent calendar year, age between 40 and 80 years, female sex, positive progesterone receptor status, and radiation use. Adjuvant HT use in ER+ DCIS has increased over time, with the highest rates in patients treated with BCS and radiation. While inappropriate HT use was observed in ER- and bilateral mastectomy patients, the frequency of use in these categories decreased over time.


Unique Structural Features of Influenza Virus H15 Hemagglutinin.
Influenza A H15 viruses are members of a subgroup (H7-H10-H15) of group 2 hemagglutinin (HA) subtypes that include H7N9 and H10N8 viruses that were isolated from humans during 2013. The isolation of avian H15 viruses is, however, quite rare and, until recently, geographically restricted to wild shorebirds and waterfowl in Australia. The HAs of H15 viruses contain an insertion in the 150-loop (loop beginning at position 150) of the receptor-binding site common to this subgroup and a unique insertion in the 260-loop compared to any other subtype. Here, we show that the H15 HA has a high preference for avian receptor analogs by glycan array analyses. The H15 HA crystal structure reveals that it is structurally closest to H7N9 HA, but the head domain of the H15 trimer is wider than all other HAs due to a tilt and opening of the HA1 subunits of the head domain. The extended 150-loop of the H15 HA retains the conserved conformation as in H7 and H10 HAs. Furthermore, the elongated 260-loop increases the exposed HA surface and can contribute to antigenic variation in H15 HAs. Since avian-origin H15 HA viruses have been shown to cause enhanced disease in mammalian models, further characterization and immune surveillance of H15 viruses are warranted.IMPORTANCE In the last 2 decades, an apparent increase has been reported for cases of human infection by emerging avian influenza A virus subtypes, including H7N9 and H10N8 viruses isolated during 2013. H15 is the other member of the subgroup of influenza A virus group 2 hemagglutinins (HAs) that also include H7 and H10. H15 viruses have been restricted to Australia, but recent isolation of H15 viruses in western Siberia suggests that they could be spread more globally via the avian flyways that converge and emanate from this region. Here we report on characterization of the three-dimensional structure and receptor specificity of the H15 hemagglutinin, revealing distinct features and specificities that can aid in global surveillance of such viruses for potential spread and emerging threat to the human population.


Deployment of a fully-automated green fluorescent protein imaging system in a high arctic autonomous greenhouse.
Higher plants are an integral part of strategies for sustained human presence in space. Space-based greenhouses have the potential to provide closed-loop recycling of oxygen, water and food. Plant monitoring systems with the capacity to remotely observe the condition of crops in real-time within these systems would permit operators to take immediate action to ensure optimum system yield and reliability. One such plant health monitoring technique involves the use of reporter genes driving fluorescent proteins as biological sensors of plant stress. In 2006 an initial prototype green fluorescent protein imager system was deployed at the Arthur Clarke Mars Greenhouse located in the Canadian High Arctic. This prototype demonstrated the advantageous of this biosensor technology and underscored the challenges in collecting and managing telemetric data from exigent environments. We present here the design and deployment of a second prototype imaging system deployed within and connected to the infrastructure of the Arthur Clarke Mars Greenhouse. This is the first imager to run autonomously for one year in the un-crewed greenhouse with command and control conducted through the greenhouse satellite control system. Images were saved locally in high resolution and sent telemetrically in low resolution. Imager hardware is described, including the custom designed LED growth light and fluorescent excitation light boards, filters, data acquisition and control system, and basic sensing and environmental control. Several critical lessons learned related to the hardware of small plant growth payloads are also elaborated.


[Childhood obesity risk index (IROBIC) for small administrative areas in Chile].
Introduction: although the prevalence of childhood obesity (CO) is high globally, there are no composite indices to estimate territorial aspects associated with its risk Objective: to develop an obesity risk index (IROBIC) for small administrative units, called "comunas" in Chile Methods: we used 2019 data from public sources on children under 10 years living in "comunas" of the two largest regions. IROBIC includes 16 indicators standardized for each "comuna" and grouped together into four domains, determined by principal component analysis (health, socio-economic, built-in and educational environments). IROBIC was calculated as a weighted geometric mean. Differences in obesity risk between the 10 and 5 "comunas" with the highest and lowest IROBIC and of each domain, were calculated with the disparity ratio. Results: in spite of the poorest "comunas" having the highest IROBIC, when its value and that for each domain were considered, we observed that the effect of inequality could be mitigated. The 10 and 5 "comunas" with the highest IROBIC have a 2.41 and 4.05 higher risk of CO compared to those with the lowest values Conclusions: IROBIC is a useful tool for monitoring the risk of CO and its factors from a territorial perspective.


[Adrenomelanic deposits (after long term use of levoepinephrine) (author's transl)].
A patient treated for open angle glaucoma during six years with levoepinephrine with conjuctival melanin deposits is presented. The histopathologic study shows that the deposits are in cystic cavities, presenting characteristic tinetorial qualities. The biomicroscopic aspect for an accurate diagnosis is emphasized.


Matrix metalloproteinase-9, -10, and -12, MDM2 and p53 expression in mouse liver during dimethylnitrosamine-induced oxidative stress and genomic injury.
Treatment during early tumor development has greater success because tissue growth remains largely confined to its original locus. At later stages, malignant cells migrate from their original location, invade surrounding normal areas, and can disseminate widely throughout the body. Remodeling of the extracellular matrix (ECM) serves as a key facilitator of this dissemination. Proteolytic enzymes including plasmin and matrix metalloproteinases (MMPs) play an integral role in degrading the surrounding ECM proteins and clearing a path for tumor cell migration. Specific MMPs are highly expressed late during malignant tumor invasion. It is not understood whether early changes in MMPs influence apoptotic and necrotic cell death, processes known to govern the early stages of carcinogenesis. Similarly, the interaction between MDM2 and p53 is tightly controlled by a complex array of post-translational modifications, which in turn dictates the stability and activity of both p53 and MDM2. The present studies examine the hypothesis that model hepatotoxin dimethylnitrosamine (DMN), which is also a model carcinogen, will induce the MMP family of proteins after administration in hepatotoxic doses. Doses of 25, 50, and 100 mg/kg DMN were administered i.p. to male C3H mice. Changes in parameters associated with apoptotic and necrotic cell death, DNA damage, cell proliferation, and extracellular proteinases were examined in liver at 24 h. Serum ALT activity, oxidative stress [malondialdehyde], and caspase-activated DNAse mediated DNA laddering increased in a dose-dependent manner, as did the level of MDM2 protein. MMP-9, -10 and -12 (gelatinase-B, stromelysin-2, macrophage elastase), and p53 protein levels increased following 25 mg/kg DMN, but were successively decreased after higher DMN doses. The results of this study demonstrate changes in MDM2 and MMPs during DMN-induced acute liver injury and provide a plausible linkage between DMN-induced oxidative stress-mediated genomic injury and its likely involvement in setting the stage for initiating subsequent metastatic disease at later circumstances.


Trivalent mRNA Vaccine against SARS-CoV-2 and Variants with Effective Immunization.
mRNA vaccines encoding a single spike protein effectively prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the emergence of SARS-CoV-2 variants leads to a wide range of immune evasion. Herein, a unique trivalent mRNA vaccine based on ancestral SARS-CoV-2, Delta, and Omicron variant spike receptor-binding domain (RBD) mRNAs was developed to tackle the immune evasion of the variants. First, three RBD mRNAs of SARS-CoV-2, Delta, and Omicron were coencapsulated into lipid nanoparticles (LNPs) by using microfluidic technology. After that, the physicochemical properties and time-dependent storage stability of the trivalent mRNA vaccine nanoformulation were tested by using dynamic light scattering (DLS). In vitro, the trivalent mRNA vaccine exhibited better lysosomal escape ability, transfection efficiency, and biocompatibility than did the commercial transfection reagent Lipo3000. In addition, Western blot analyses confirmed that the three RBD proteins can be detected in cells transfected with the trivalent mRNA vaccine. Furthermore, ex vivo imaging analysis indicated that the livers of BALB/c mice had the strongest protein expression levels after intramuscular (IM) injection. Using a prime-boost strategy, this trivalent vaccine elicited robust humoral and T-cell immune responses in both the high-dose and low-dose groups and showed no toxicity in BALB/c mice. Three specific IgG antibodies in the high-dose group against SARS-CoV-2, Delta, and Omicron variants approached ∼1/1,833,333, ∼1/1,866,667, and ∼1/925,000, respectively. Taken together, two doses of inoculation with the trivalent mRNA vaccine may provide broad and effective immunization responses against SARS-CoV-2 and variants.


"As Black as Ink": A Case of Alkaptonuria-Associated Myelopathy and a Review of the Literature.
Case report and literature review. To characterize the rare presentation of myelopathy occurring secondary to alkaptonuria and to evaluate the available evidence regarding its treatment. Alkaptonuria is an autosomal recessive genetic condition with an estimated incidence of 1 in 250,000 to 1 in 1,000,000 people. Mutation of the enzyme homogentisate 1,2-dioxygenase leads to the production of high levels of homogentisic acid, with subsequent deposition in ligaments, cartilage, and menisci. Involvement of the spine is termed "ochronotic spondyloarthropathy," of which myelopathy is an uncommon presentation. We present the case of a 57-year-old man with alkaptonuria-associated myelopathy, who underwent surgical decompression. Ten additional cases were identified in the literature by a systematic search of PubMed and Google Scholar. In a patient presenting with myelopathy, alkaptonuria may be suspected because of medical history, family history, symptoms (including darkened urine, pigmented ear cartilage, and sclera), or radiographic changes, such as multilevel disc collapse, progressive wafer-like disc calcification, extensive osteophyte formation, and spinal deformity. The diagnosis can be confirmed by urine homogentisic acid testing. Of the 11 patients presented here or identified in the literature, 2 were treated nonoperatively, 8 were treated with decompressive spinal surgery, and treatment of the myelopathy was not discussed for 1 patient. In all cases in which outcomes were reported, substantial improvement in the patient's condition was seen. Alkaptonuria is a rare cause of myelopathy, but one that clinicians should understand. Although no disease-modifying treatment currently exists for alkaptonuria, the use of symptomatic treatments and, particularly, surgical decompression is recommended to address myelopathy if it develops. 4.


Pancreatic islet cell tumors.
Tumors arising from the pancreatic islet cells represent a heterogeneous group of lesions. Some tumors present with well-characterized syndromes, while others appear to be nonfunctioning. Eighty-four patients with pancreatic islet cell tumors operated on at the Cleveland Clinic during a 35-year period were reviewed. The tumor types include 21 nonfunctioning tumors, 41 insulinomas, 16 gastrinomas, two vasoactive intestinal polypeptide (VIP)-omas, two carcinoids, and two probable cases of pancreatic parathyrinoma. Eleven patients had multiple endocrine neoplasia type I syndrome. Preoperative localization was possible in 63% of patients in whom it was attempted. Complete mobilization of the head and distal pancreas with bimanual palpation of the entire gland is critical for intraoperative tumor localization. Distal pancreatectomy is favored for tumors in the body and tail. In the head of the pancreas, small, benign lesions require enucleation, and large or malignant lesions necessitate a Whipple procedure. The operative morbidity rate was 24%, and the mortality rate was 3.6%. The 10-year survival rate was 54.7% for nonfunctioning lesions, 68.4% for gastrinomas, and 92.4% for insulinomas. At this time surgery represents the only way to cure these lesions.


Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development.
The ErbB2 tyrosine kinase functions as coreceptor for the neuregulin receptors ErbB3 and ErbB4 and can participate in signaling of EGF receptor (ErbB1), interleukin receptor gp130, and G-protein coupled receptors. ErbB2(-/-) mice die at midgestation because of heart malformation. Here, we report a genetic rescue of their heart development by myocardial expression of erbB2 cDNA that allows survival of the mutants to birth. In rescued erbB2 mutants, Schwann cells are lacking. Motoneurons form and can project to muscle, but nerves are poorly fasciculated and disorganized. Neuromuscular junctions form, as reflected in clustering of AChR and postsynaptic expression of the genes encoding the alpha-AChR, AChE, epsilon-AChR, and the RI subunit of the cAMP protein kinase. However, a severe loss of motoneurons on cervical and lumbar, but not on thoracic levels occurs. Our results define the roles of Schwann cells during motoneuron and synapse development, and reveal different survival requirements for distinct motoneuron populations.


[A patient with lessened sensitivity to acenocoumarol during a period of enteral feeding].
A 69-year-old man was operated on for a subdural haematoma which had developed during the use of acenocoumarol. Directly after the operation the patient was started on enteral feeding. The acenocoumarol was restarted at a later stage. The dose of acenocoumarol needed for an appropriate level of blood-dilution was twice as high during the period of enteral feeding than it had been preoperatively. After the transition from enteral feeding to oral feeding it was possible to lower the dose of acenocoumarol. The need for a higher dose was probably due to enhanced binding of the proteins in the enteral feeding. The patient was admitted to a nursing home. The combination of acenocoumarol and enteral feeding occurs frequently in patients being rehabilitated. It is important to monitor the blood-dilution when starting and stopping enteral feeding.


Outcomes research as a tool for defining the role of respiratory care practitioners in the intensive care unit setting.
The impact of respiratory care practitioners on the outcomes of critically ill patients has not been examined in a systematic manner. This is in contrast to clinical investigations which have demonstrated the beneficial influence of specially trained critical care physicians and nurses on patient outcomes in the ICU setting. Outcomes research represents a method for the formal evaluation of various healthcare provider staffing patterns within the ICU. Specific patient outcomes including hospital mortality, respiratory complications, lengths of stay, and medical care costs can be used to determine the optimal ICU staffing strategy for respiratory care practitioners. Until recently, we have lacked good outcomes data for assessing the role of respiratory care practitioners in the ICU. Several barriers have contributed to this deficiency of data including a lack of funding, absence of a national research initiative aimed at this specific issue, and the paucity of clinical investigators in this area of study. Good outcomes research requires appropriate levels of funding, adequately trained and experienced clinical investigators from various disciplines (e.g., statistics, epidemiology, general medical sciences), and the support of both local and national organizations with an interest in respiratory care services and their impact on patient outcomes. To accomplish these research goals, an organized and dedicated approach must be developed based upon strong research proposals. This will allow advances to be made in the area of outcomes research as it relates to the role of respiratory care practitioners in the ICU. Similarly, the methods of outcomes research can be employed to better define the benefits and limitations of other ICU practices.


MUC5B is the major mucin in the gel phase of sputum in chronic obstructive pulmonary disease.
Overproduction of mucus is a contributory factor in the progression of chronic obstructive pulmonary disease (COPD). The polymeric mucins are major macromolecules in the secretion. Therefore, we hypothesized that the polymeric mucin composition or properties may be different in the sputum from individuals with COPD and smokers without airflow obstruction. To determine the major polymeric mucins in COPD sputum and whether these are different in the sputum from individuals with COPD compared with that from smokers without airflow obstruction. The polymeric mucin composition of sputum from patients with COPD and smokers without airflow obstruction was analyzed by Western blotting analysis. The tissue localization of the mucins was determined by immunohistochemistry, and their size distribution was analyzed by rate-zonal centrifugation. MUC5AC and MUC5B were the major mucins. MUC5AC was the predominant mucin in the smoker group, whereas MUC5B was more abundant from the patients with COPD, with a significant difference in the ratio of MUC5B to MUC5AC (P = 0.004); this ratio was correlated with FEV(1) in the COPD group (r = 0.63; P = 0.01). The lower-charged glycosylated form of MUC5B was more predominant in COPD (P = 0.012). No significant associations were observed with respect to sex, age, or pack-year history. In both groups, MUC5AC was produced by surface epithelial cells and MUC5B by submucosal gland cells. Finally, there was a shift toward smaller mucins in the COPD group. Our data indicate that there are differences in mucin amounts and properties between smokers with and without COPD. Further studies are needed to examine how this may impact disease progression.