Regulation of the adaptor molecule LAT2, an in vivo target gene of AML1/ETO (RUNX1/RUNX1T1), during myeloid differentiation.
The leukaemia-specific fusion oncoprotein RUNX1/RUNX1T1 (AML1/ETO), resulting from the chromosomal translocation (8;21) in acute myeloid leukaemia (AML), imposes a striking genotype-phenotype relationship upon this distinct subtype of AML, which is mediated by multiple, co-ordinate downstream effects induced by this chimeric transcription factor. We previously identified the LAT2 gene, encoding the adaptor molecule LAT2 (NTAL, LAB), which is phosphorylated by KIT and has a role in mast cell and B-cell activation, as a target of the repressor activity of RUNX1/RUNX1T1. These results were confirmed and extended by demonstrating downregulation of the LAT2 protein in response to conditional RUNX1/RUNX1T1 expression, and its absence in primary AML with the t(8;21). In contrast, in a cohort of 43 AML patients, higher levels of LAT2 were associated with myelomonocytic features. Differentiation of HL-60 and NB4 cells towards granulocytes by all trans-retinoic acid (ATRA) resulted in downregulation of LAT2; conversely, it was upregulated during phorbol ester-induced monocytic differentiation of HL-60 cells. Forced expression of LAT2 in Kasumi-1 cells resulted in a striking block of ATRA- and phorbol ester-induced differentiation, implicating disturbances of the graded expression of this adaptor molecule in the maturation block of myeloid leukaemia cells.


Effect of Radiofrequency Neurolysis on the Symptoms of Chronic Rhinitis: A Randomized Controlled Trial.
To determine the safety and efficacy of temperature-controlled radiofrequency (RF) neurolysis of the posterior nasal nerve (PNN) area for the treatment of chronic rhinitis. A multicenter, prospective, single-blinded, randomized controlled trial, in which the control arm underwent a sham procedure. Sixteen otolaryngology centers. Patients with 24-hour reflective Total Nasal Symptom Score (rTNSS) ≥6, including moderate to severe rhinorrhea and mild to severe congestion, were randomized 2:1 to active treatment of the posterior nasal nerve area with a temperature-controlled RF device or a sham procedure, with no RF energy delivery. The stylus was applied bilaterally to nonoverlapping areas of the posterior middle meatus and posterior inferior turbinate in each nostril in the region of the PNN. The primary endpoint was responder rate at 3 months, where a response was defined as ≥30% improvement (decrease) in rTNSS from baseline. Patients had a mean baseline rTNSS of 8.3 (95% CI, 7.9-8.7) and 8.2 (95% CI, 7.6-8.8) (P = .797) in the active treatment (n = 77) and sham control (n = 39) arms, respectively. At 3 months, responder rate was significantly higher in the active treatment arm: 67.5% (95% CI, 55.9%-77.8%) vs 41.0% (95% CI, 25.6%-57.9%) (P = .009). The active treatment arm had a significantly greater decrease in rTNSS (mean, -3.6 [95% CI, -4.2 to -3.0] vs -2.2 [95% CI, -3.2 to -1.3]) (P = .013). Three adverse events related to the device/procedure were reported, and all resolved. This randomized controlled trial showed temperature-controlled neurolysis of the PNN area is free from significant adverse events and superior to a sham procedure in decreasing the symptom burden of chronic rhinitis.


Adverse Cell Culture Conditions Mimicking the Tumor Microenvironment Upregulate ABCG2 to Mediate Multidrug Resistance and a More Malignant Phenotype.
ABCG2 is an efflux transporter commonly found to overexpress in multidrug resistant (MDR) cancer cells. It is also believed to be a survival factor for cancer stem cells to drive tumor growth. Tumor microenvironment represents an attractive new drug target because it allows complex interaction between a tumor and its surrounding normal cells, molecules, and blood vessels, which all participate in tumor progression. Hypoxia, glucose deprivation and acidosis are the hallmarks of tumor microenvironment. This study investigated the upregulation of ABCG2 by these adverse growth conditions within the tumor microenvironment. Reporter gene assay revealed that a region within the ABCG2 promoter close to the reported HIF-1α response element is responsible for ABCG2 upregulation. Increased ABCG2 efflux activity was observed under the same conditions, subsequently leading to reduced response to ABCG2 substrate anticancer drug. Importantly, glucose deprivation and hypoxia were also found to enhance the resistance level of ABCG2-overexpressing resistant cells with pre-existing genetic and epigenetic MDR mechanisms. Hypoxia was further demonstrated to cause a more malignant anchorage-independent growth phenotype in the resistant cells, which can be abolished by knocking down ABCG2. A better understanding of ABCG2 regulation by the tumor microenvironment may help design novel strategies to improve treatment outcome.


Transbilayer phosphatidylethanolamine movements in the yeast plasma membrane. Evidence for a protein-mediated, energy-dependent mechanism.
Aminophospholipid movements in the plasma membrane of higher eukaryotic cells seem to be regulated by an ATP-dependent, protein-mediated process. To examine whether similar mechanisms exist in yeast cells, we have analysed phosphatidylethanolamine (PtdEtn) distributions in Saccharomyces cerevisiae (A184D) cells under a variety of conditions, with trinitrobenzenesulfonic acid and fluorescamine as the external membrane probes. The levels of external PtdEtn in the intact cells were reduced to about 50% by pretreatment of the cells with inhibitors of mitochondrial ATP synthesis, ATPase inhibitors or protein-sulfhydryl-group-modifying reagents, or by depletion of the cells of ATP by metabolic starvation. The levels of external PtdEtn could be restored to normal by repletion of the energy-depleted cells with ATP. Furthermore, treatment of the energy-depleted cells with sulfhydryl-modifying reagents did not cause further reduction in the external PtdEtn levels but decreased the accessibility of PtdEtn to fluorescamine after restoration of the cellular ATP levels to normal in these cells. These results demonstrate an involvement of an ATP-dependent, protein-mediated process(es) in the regulation of the PtdEtn distribution across the plasma-membrane bilayer of yeast cells. The results are discussed with regard to possible models that can generate and maintain the transbilayer phospholipid asymmetry in the yeast plasma membrane.


Remediation of theory of mind in children with autism spectrum disorders: Effectiveness and transferability of training effects to behavioral symptoms.
Children with autism spectrum disorders (ASD) struggle with impaired theory of mind. We aimed to evaluate the effect of remediation of theory of mind on theory of mind, face perception, and behavioral symptoms in children with ASD. Thirty children with ASD were randomly assigned to two equal groups of theory of mind training and active control group. Attentive remediation of theory of mind (ARTOM) and story-telling sessions were used for intervention in the groups. Theory of mind and facial emotion recognition tests as well as Gilliam autism rating scale (GARS) were used for assessment in three baseline, post-intervention, and follow-up sessions. Repeated measures ANOVAs were used for analysis. The results showed improvement in facial emotion recognition and theory of mind in intervention group. The behavioral symptoms, measured by GARS, were ameliorated in the intervention group. The training effects lasted until follow-up session. The results suggest remediation of basic components of theory of mind, without direct intervention on theory of mind, improves theory of mind skill. The results also suggest that the remediation of basic components of theory of mind improves social and communicational performance and ameliorates stereotypes symptoms in children with ASD.


Nifedipine-induced histological changes in the parotid glands of hypertensive rats.
Nifedipine is a widely used anti-anginal and anti-hypertensive agent. It is associated with significant gingival changes attributed more to collagen hyperplasia than to enhancement of protein synthesis. We investigated the influence of nifedipine on morphological changes in the parotid glands of rats in a model of hypertension. Twenty-eight male Wistar rats (8-10 weeks; 200±15 g) were divided into four groups (A-D). Hypertension was induced by surgical means in groups C and D. Animals in groups B and D were treated with nifedipine (0.85 mg/kg) via a gastroesophageal catheter the day after surgery (experimental day-1) for 2 weeks. A significant difference was observed between the control group and nifedipine group and between the control group and hypertension group with regard to the weight of the parotid gland and its surface area. Histological findings demonstrated changes in the parotid glands of hypertensive animals with mild vessel dilatation and infiltration of inflammatory cells. These histological findings seemed to be due more to changes in venous function than to alterations in gland architecture.


Erythroid differentiation and protoporphyrin IX down-regulate frataxin expression in Friend cells: characterization of frataxin expression compared to molecules involved in iron metabolism and hemoglobinization.
Friedreich ataxia (FA) is caused by decreased frataxin expression that results in mitochondrial iron (Fe) overload. However, the role of frataxin in mammalian Fe metabolism remains unclear. In this investigation we examined the function of frataxin in Fe metabolism by implementing a well-characterized model of erythroid differentiation, namely, Friend cells induced using dimethyl sulfoxide (DMSO). We have characterized the changes in frataxin expression compared to molecules that play key roles in Fe metabolism (the transferrin receptor [TfR] and the Fe transporter Nramp2) and hemoglobinization (beta-globin). DMSO induction of hemoglobinization results in a marked decrease in frataxin gene (Frda) expression and protein levels. To a lesser extent, Nramp2 messenger RNA (mRNA) levels were also decreased on erythroid differentiation, whereas TfR and beta-globin mRNA levels increased. Intracellular Fe depletion using desferrioxamine or pyridoxal isonicotinoyl hydrazone, which chelate cytoplasmic or cytoplasmic and mitochondrial Fe pools, respectively, have no effect on frataxin expression. Furthermore, cytoplasmic or mitochondrial Fe loading of induced Friend cells with ferric ammonium citrate, or the heme synthesis inhibitor, succinylacetone, respectively, also had no effect on frataxin expression. Although frataxin has been suggested by others to be a mitochondrial ferritin, the lack of effect of intracellular Fe levels on frataxin expression is not consistent with an Fe storage role. Significantly, protoporphyrin IX down-regulates frataxin protein levels, suggesting a regulatory role of frataxin in Fe or heme metabolism. Because decreased frataxin expression leads to mitochondrial Fe loading in FA, our data suggest that reduced frataxin expression during erythroid differentiation results in mitochondrial Fe sequestration for heme biosynthesis.


Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice.
In Duchenne muscular dystrophy (DMD), dystrophin mutation leads to progressive lethal skeletal muscle degeneration. For unknown reasons, dystrophin deficiency does not recapitulate DMD in mice (mdx), which have mild skeletal muscle defects and potent regenerative capacity. We postulated that human DMD progression is a consequence of loss of functional muscle stem cells (MuSC), and the mild mouse mdx phenotype results from greater MuSC reserve fueled by longer telomeres. We report that mdx mice lacking the RNA component of telomerase (mdx/mTR) have shortened telomeres in muscle cells and severe muscular dystrophy that progressively worsens with age. Muscle wasting severity parallels a decline in MuSC regenerative capacity and is ameliorated histologically by transplantation of wild-type MuSC. These data show that DMD progression results, in part, from a cell-autonomous failure of MuSC to maintain the damage-repair cycle initiated by dystrophin deficiency. The essential role of MuSC function has therapeutic implications for DMD.


Sexual behavior mutants revisited: molecular and cellular basis of Drosophila mating.
The study of Drosophila melanogaster by a combination of forward genetics with specific mutants, and reverse genetics, in which a given gene is expressed in an appropriate brain area to test its effect on behavior, provides a unique opportunity to explore the causal relationship between a particular gene, its function in the cell and the behavioral outcome at the organismic level. Enhanced male-to-male courtship has been shown to occur as a result of mutations in several different genes. For example, the Voila mutant exhibits intense GAL4 reporter expression in the tarsal gustatory sensilla, suggesting the importance of tapping by a male on the female abdomen with his forelegs. Feminization of parts of the antennal lobe and mushroom body by targeted expression of a female-determining gene transformer+ (tra+) drives the male to court other males. Mutations in the tra target gene fruitless (fru), which is expressed in the antennal lobe as well as the suboesophageal ganglion (the gustatory inputs are processed here), also induce homosexual courtship in males. These results suggest that sensory inputs mediated and/or processed by the tarsal receptors, suboesophageal ganglion, antennal lobe and mushroom body contribute to the regulation of male-female courtship. Mosaic analysis localized the neural center for male courtship behavior to the posterior dorsal brain, in which the sensory information processed by the aforementioned neural structures may be integrated. Another mosaic study mapped the neural center for female sexual behavior, as measured by her receptiveness to copulation, to the anterior dorsal brain. The issue as to how the mutations that reduce female sexual receptiveness, e.g. dissatisfaction (dsf), spinster (spin) and chaste (cht), affect the structure and/or function of this neural center deserves to be addressed urgently.


The Role of Brain Barriers in Maintaining Brain Vitamin Levels.
It is increasingly recognized that tissue-specific nutrient deficiencies can exist in the absence of whole-body deficiency and that these deficiencies may result from disease or disease-related physiological processes. Brain and central nervous system tissues require adequate nutrient levels to function. Many nutrients are concentrated in the cerebrospinal fluid relative to the serum in healthy individuals, and other nutrients resist depletion in the presence of whole-body nutrient depletion. The endothelial, epithelial, and arachnoid brain barriers work in concert to selectively transport, concentrate, and maintain levels of the specific nutrients required by the brain while also blocking the passage of blood-borne toxins and pathogens to brain and central nervous system tissues. These barriers preserve nutrient levels within the brain and actively concentrate nutrients within the cerebrospinal fluid and brain. The roles of physical and energetic barriers, including the blood-brain and blood-nerve barriers, in maintaining brain nutrient levels in health and disease are discussed.


Prevalence and clinical aspects of hearing loss among the South Korean adolescent: Data from a population-based study.
Slight/mild hearing loss is detrimental to communication and academic achievements. This study aimed to describe the prevalence of hearing loss, and to investigate the factors related to noise-induced hearing loss among South Korean adolescent. As a population-based retrospective study, 1845 South Korean adolescents aged from 12 to 19 years were analyzed using the data from Korea National Health and Nutrition Examination Survey V (KNHANES V, 2010-2012). The prevalence of hearing loss according to the side, severity, and frequency was calculated. For assessing the noise-induced hearing loss in adolescent, the prevalence of hearing loss only in high-frequency (onlyHFHL, defined as 1) thresholds at 0.5 and 1 kHz of ≤15 dB HL, and 2) maximal thresholds at 3, 4, or 6 kHz ≥ 15 dB HL higher than the highest threshold for 0.5 and 1 kHz) was analyzed. Moreover, the relevance of onlyHFHL in context of sociodemographic factors and noise exposure history was evaluated. The prevalence of unilateral and bilateral hearing loss based on the average of six frequencies (0.5, 1, 2, 3, 4, and 6 kHz) in South Korean adolescents were 8.56% and 1.03%, respectively, and most cases were hearing loss with slight/mild degree. The prevalence of unilateral and bilateral onlyHFHL were 32.74% and 5.53%, respectively. Factors found to be associated with onlyHFHL were sex (female) and household income (high). According to this population-based study, the prevalence of slight/mild hearing loss and onlyHFHL in the South Korean adolescents were considerably high. With knowledge of the factors related with onlyHFHL, paying more attention to slight/mild hearing loss will be helpful in preventing hearing loss in adolescents.


Small-molecule screening and profiling by using automated microscopy.
Automated fluorescence microscopy provides a powerful tool for analyzing the physiological state of single cells with high throughput and high information content. Here I discuss two types of experiments in which this technology was used to discover and characterize bioactive small molecules. In phenotypic-screening experiments, the goal is to find "hits" with specific effects on cells by screening large libraries of small molecules. An example is screening for small molecules that perturb mitosis by novel mechanisms. In cytological-profiling experiments, the goal is to characterize the bioactivity of a limited number of small molecules in considerable depth, and thus understand their mechanism and toxicities at the cellular level. I discuss an example in which 100 small molecules with known bioactivity were profiled by using multiple fluorescent probes, and clustered into mechanistic classes by automated statistical analysis.


Microevolution of a standard strain of Cryptococcus neoformans resulting in differences in virulence and other phenotypes.
Cryptococcus neoformans is a major fungal pathogen for patients with debilitated immune systems. However, no information is available on the stability of virulence or of phenotypes associated with virulence for C. neoformans laboratory strains. A serendipitous observation in our laboratory that one isolate of C. neoformans ATCC 24067 (strain 52D) became attenuated after continuous in vitro culture prompted us to perform a comparative study of nine strain 24067 isolates obtained from six different research laboratories. Each isolate was characterized by DNA typing, virulence for mice, proteinase production, extracellular protein synthesis, melanin synthesis, carbon assimilation pattern, antifungal drug susceptibility, colony morphology, growth rate, agglutination titers, phagocytosis by murine macrophages, capsule size, and capsular polysaccharide structure. All isolates had similar DNA typing patterns consistent with their assignment to the same strain, although minor chromosome size polymorphisms were observed in the electrophoretic karyotypes of two isolates. Several isolates had major differences in phenotypes that may be associated with virulence, including growth rate, capsule size, proteinase production, and melanization. These findings imply that C. neoformans is able to undergo rapid changes in vitro, probably as a result of adaptation to laboratory conditions, and suggest the need for careful attention to storage and maintenance conditions. In summary, our results indicate that C. neoformans (i) can become attenuated by in vitro culture and (ii) is capable of microevolution in vitro with the emergence of variants exhibiting new genotypic and phenotypic characteristics.


Ultraviolet Pretreatment of Titanium Dioxide and Tin-Doped Indium Oxide Surfaces as a Promoter of the Adsorption of Organic Molecules in Dry Deposition Processes: Light Patterning of Organic Nanowires.
In this article we present the preactivation of TiO2 and ITO by UV irradiation under ambient conditions as a tool to enhance the incorporation of organic molecules on these oxides by evaporation at low pressures. The deposition of π-stacked molecules on TiO2 and ITO at controlled substrate temperature and in the presence of Ar is thoroughly followed by SEM, UV-vis, XRD, RBS, and photoluminescence spectroscopy, and the effect is exploited for the patterning formation of small-molecule organic nanowires (ONWs). X-ray photoelectron spectroscopy (XPS) in situ experiments and molecular dynamics simulations add critical information to fully elucidate the mechanism behind the increase in the number of adsorption centers for the organic molecules. Finally, the formation of hybrid organic/inorganic semiconductors is also explored as a result of the controlled vacuum sublimation of organic molecules on the open thin film microstructure of mesoporous TiO2.


Rehabilitation characteristics and patient barriers to and facilitators of ACL reconstruction rehabilitation: A cross-sectional survey.
To investigate patient-reported rehabilitation characteristics and barriers to and facilitators of ACL reconstruction rehabilitation. Survey-based study. Online survey platform. Adults 1-20 years post ACL reconstruction (n = 304). 1) rehabilitation characteristics, 2) barriers to and facilitators of rehabilitation. Fear of re-injury (43.8%) was the highest rating barrier to rehabilitation adherence, while a good relationship with your rehabilitation provider was regarded as the most important factor (83.6%) in facilitating rehabilitation. Rehabilitation frequency reduced across the duration of rehabilitation from most commonly 1 x week (38.2%) in the first three months to once every month (26%) from 6 to 9 months. Almost all participants (95.7%) consulted a rehabilitation provider for the first six months. Only 43.4% of respondents returned to their previous level of sport. The exploratory analysis identified that low barriers to rehabilitation and a longer duration of supervised rehabilitation are associated with a faster return to sport, greater likelihood of return to previous level of sport and fewer reported ongoing problems with the knee. This cross-sectional survey provides insight into the patient's experience of rehabilitation practices and a patient's perspective on the key barriers to and facilitators of ACL rehabilitation adherence and participation.


Acute and Subacute Changes in Hip Strength and Range of Movement After Arthroscopy to Address Chondrolabral Pathology.
Hip pain is associated with reduced muscle strength, range of movement (ROM), and function. Hip arthroscopy is undertaken to address coexistent intra-articular pathologies with the aim of reducing pain and improving function. To evaluate changes in strength and ROM in a cohort with chondrolabral pathology before surgery to 3 and 6 months after hip arthroscopy. Case series; Level of evidence, 4. Sixty-seven individuals with hip pain who were scheduled for hip arthroscopy were matched with 67 healthy controls. Hip strength and ROM were collected preoperatively and at 3 and 6 months postoperatively. Repeated measures analysis of variance evaluated whether strength and ROM differed between limbs and among time points. Bonferroni post hoc tests determined differences in hip strength and ROM among testing times and between the hip pain group and matched controls. Hip extension, internal rotation (IR), external rotation (ER), and adduction (P < .040) strength were greater at 3 months after surgery; all directions, including flexion, abduction, and squeeze, were greater at 6 months (P < .015). Hip flexion ROM was greater at 3 months after surgery (P = .013). Flexion, IR, and ER ROM was greater at 6 months (P < .041). At 6 months, IR ROM (P = .003) and flexion, IR, and ER strength (P < .005) remained less than matched controls. With the exception of squeeze and flexion, all directions of hip strength and hip flexion ROM are significantly improved 3 months after arthroscopy to address chondrolabral pathology. By 6 months after arthroscopy, strength in all directions and flexion and rotation ROM are significantly improved in both limbs, but hip flexion, IR, and ER strength and IR ROM remain significantly less than that of healthy matched controls in both limbs.


The Academic Viewpoint on Patient Data Ownership in the Context of Big Data: Scoping Review.
The ownership of patient information in the context of big data is a relatively new problem, which is not yet fully recognized by the medical academic community. The problem is interdisciplinary, incorporating legal, ethical, medical, and aspects of information and communication technologies, requiring a sophisticated analysis. However, no previous scoping review has mapped existing studies on the subject. This study aims to map and assess published studies on patient data ownership in the context of big data as viewed by the academic community. A scoping review was conducted based on the 5-stage framework outlined by Arksey and O'Malley and further developed by Levac, Colquhoun, and O'Brien. The organization and reporting of results of the scoping review were conducted according to PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses and its extensions for Scoping Reviews). A systematic and comprehensive search of 4 scientific information databases, PubMed, ScienceDirect, Scopus, and Springer, was performed for studies published between January 2000 and October 2019. Two authors independently assessed the eligibility of the studies and the extracted data. The review included 32 eligible articles authored by academicians that correspond to 3 focus areas: problem (ownership), area (health care), and context (big data). Five major aspects were studied: the scientific area of publications, aspects and academicians' perception of ownership in the context of big data, proposed solutions, and practical applications for data ownership issues in the context of big data. The aspects in which publications consider ownership of medical data are not clearly distinguished but can be summarized as ethical, legal, political, and managerial. The ownership of patient data is perceived primarily as a challenge fundamental to conducting medical research, including data sales and sharing, and to a lesser degree as a means of control, problem, threat, and opportunity also in view of medical research. Although numerous solutions falling into 3 categories, technology, law, and policy, were proposed, only 3 real applications were discussed. The issue of ownership of patient information in the context of big data is poorly researched; it is not addressed consistently and in its integrity, and there is no consensus on policy decisions and the necessary legal regulations. Future research should investigate the issue of ownership as a core research question and not as a minor fragment among other topics. More research is needed to increase the body of knowledge regarding the development of adequate policies and relevant legal frameworks in compliance with ethical standards. The combined efforts of multidisciplinary academic teams are needed to overcome existing gaps in the perception of ownership, the aspects of ownership, and the possible solutions to patient data ownership issues in the reality of big data.


Chronic rhinosinusitis and nasal polyposis; indicia of heterogeneity.
Nasal polyposis (NP) is considered to be a subgroup of chronic rhinosinusitis (CRS). However differences in cellular and mediator profiles suggest that they could be distinct entities. To look for group differences in characteristics and symptom severity before and after surgery in patients suffering from CRS and bilateral NP that could clinically support the hypothesis that NP and CRS are different pathological processes and to compare the effect of functional endoscopic sinus surgery (FESS) in CRS patients and NP patients. Forty-five patients with CRS and 57 patients with bilateral NP were included in this prospective trial. We used t-tests for independent groups to compare preoperative symptoms as recorded on visual analogue scale (VAS). To evaluate if there were differences in symptom improvement between the groups we used analysis of covariance. Categorical variables were compared using exact tests. Mean age was 38 years for the CRS group and 47 years for the NP group, the difference was significant (p = 0.0001). NP patients underwent significantly more posterior ethmoidectomies than patients suffering from CRS (p = 0.001), and asthma was significantly more prevalent in NP than in CRS (p = 0.007). Comparing preoperative symptoms as recorded on VAS we found significant differences. While patients with NP suffered significantly more from nasal blockage and change in their sense of smell than CRS patients, patients with CRS presented with more facial pain and headache. There were no differences in symptom improvement, as both conditions responded similarly to FESS. Differences in symptom severity, nasal endoscopy, age of patients and prevalence of asthma indicate that NP and CRS are different entities. Nevertheless, both conditions respond similarly to FESS.


A flexible silicone patch for treatment of hemorrhoids after birth: a pilot study of HEMOCIN® Patch.
To test a non-pharmacological silicone patch for treatment of symptomatic hemorrhoids with focus on usability, safety, and self-reported short-term effect. Puerperal women in a Danish maternity ward were cluster randomized to treatment with the HEMOCIN® patch (intervention) or no systematic treatment (control group). On inclusion and after 2 weeks, they completed a questionnaire regarding history and hemorrhoid symptoms scored from 0 to 10. Women in the intervention group also reported on the usability of the patch and any side effects. We included 31 women in the intervention group and 33 in the control group. Twenty-eight (90.3%) women in the intervention group and 27 (81.8%) women in the control group responded to follow-up. Except from a difference in the severity of swelling at inclusion, there were no differences between the two groups for any symptoms, neither at inclusion, nor at follow-up, or in the change of symptoms during the two weeks (p > 0.05). Twenty-three women (85.2%) in the control group used medical treatment vs. one woman in the intervention group. The patch was used on an average of 9.3 days, 15.5 h/day and for 7.1 h before changing the patch. No severe side effects were reported. This pilot study finds that the HEMOCIN® patch is a safe and feasible treatment option for hemorrhoids. However, we did not detect any significant effect on hemorrhoid symptoms. The patch could be an option for people who seek non-pharmacological treatment for symptomatic hemorrhoids or need long-term treatment without steroid side effects.


Sequencing breakthroughs for genomic ecology and evolutionary biology.
Techniques involving whole-genome sequencing and whole-population sequencing (metagenomics) are beginning to revolutionize the study of ecology and evolution. This revolution is furthest advanced in the Bacteria and Archaea, and more sequence data are required for genomic ecology to be fully applied to the majority of eukaryotes. Recently developed next-generation sequencing technologies provide practical, massively parallel sequencing at lower cost and without the requirement for large, automated facilities, making genome and transcriptome sequencing and resequencing possible for more projects and more species. These sequencing methods include the 454 implementation of pyrosequencing, Solexa/Illumina reversible terminator technologies, polony sequencing and AB SOLiD. All of these methods use nanotechnology to generate hundreds of thousands of small sequence reads at one time. These technologies have the potential to bring the genomics revolution to whole populations, and to organisms such as endangered species or species of ecological and evolutionary interest. A future is now foreseeable where ecologists may resequence entire genomes from wild populations and perform population genetic studies at a genome, rather than gene, level. The new technologies for high throughput sequencing, their limitations and their applicability to evolutionary and environmental studies, are discussed in this review.


A rare case of watermelon stomach in woman with continuous ambulatory peritoneal dialysis and systemic lupus erythematosus.
We report a case of a 42-year-old woman with systemic lupus erythematosus and chronic kidney disease stage 5 undergoing continuous ambulatory peritoneal dialysis, presenting asthenia, dizziness, abdominal pain and small efforts dyspnea. After a complete physical and clinical examination, including laboratory tests, esophagogastroduodenal endoscopy and gastric lesions biopsy, she was diagnosed with gastric antral vascular ectasia. We are facing a rare case of antral vascular ectasia in a patient associating both chronic kidney disease and autoimmune disease.


Endoscopic treatment of biliary fistulas developing after liver resections.
Bile leaks are a major cause of mortality and morbidity after liver resections. We prospectively evaluated the safety and efficacy of endoscopic treatment of biliary fistulas developing after liver resections in 15 patients. Fistulas developed after extended right hepatectomy in 4, extended left hepatectomy in 8, and segmentectomy in 3 patients. Median time interval between surgery and endoscopic intervention was 10 days (range, 7 to 35 d). Endoscopic sphincterotomy followed by a nasobiliary drain insertion was the initial treatment. If the fistula persisted after 2 weeks, nasobiliary drain was replaced by a plastic stent. The effect of output (low in 10 and high in 5 patients) and the origin of fistula (stump in 10 and resection surface of the liver in 5 patients) on the time for closure were evaluated. Bile leakage ceased by only nasobiliary drainage catheter placement in 11 patients (73.3%). Plastic stents were inserted in 4 patients. There was a significant correlation between the output of bile leakage and the time needed for fistula closure. Endoscopic treatment methods are effective in patients with bile leaks due to liver resections.


Altitudinal patterns in breeding bird species richness and density in relation to climate, habitat heterogeneity, and migration influence in a temperate montane forest (South Korea).
Altitudinal patterns in the population ecology of mountain bird species are useful for predicting species occurrence and behavior. Numerous hypotheses about the complex interactions among environmental factors have been proposed; however, these still remain controversial. This study aimed to identify the altitudinal patterns in breeding bird species richness or density and to test the hypotheses that climate, habitat heterogeneity (horizontal and vertical), and heterospecific attraction in a temperate forest, South Korea. We conducted a field survey of 142 plots at altitudes between 200 and 1,400 m a.s.l in the breeding season. A total of 2,771 individuals from 53 breeding bird species were recorded. Altitudinal patterns of species richness and density showed a hump-shaped pattern, indicating that the highest richness and density could be observed at moderate altitudes. Models constructed with 13 combinations of six variables demonstrated that species richness was positively correlated with vertical and horizontal habitat heterogeneity. Density was positively correlated with vertical, but not horizontal habitat heterogeneity, and negatively correlated with migratory bird ratio. No significant relationships were found between spring temperature and species richness or density. Therefore, the observed patterns in species richness support the hypothesis that habitat heterogeneity, rather than climate, is the main driver of species richness. Also, neither habitat heterogeneity nor climate hypotheses fully explains the observed patterns in density. However, vertical habitat heterogeneity does likely help explain observed patterns in density. The heterospecific attraction hypothesis did not apply to the distribution of birds along the altitudinal gradient. Appropriate management of vertical habitat heterogeneity, such as vegetation cover, should be maintained for the conservation of bird diversity in this area.


A structured diet and exercise program promotes favorable changes in weight loss, body composition, and weight maintenance.
A number of diet and exercise programs purport to help promote and maintain weight loss. However, few studies have compared the efficacy of different methods. To determine whether adherence to a meal-replacement-based diet program (MRP) with encouragement to increase physical activity is as effective as following a more structured meal-plan-based diet and supervised exercise program (SDE) in sedentary obese women. Randomized comparative effectiveness trial. From July 2007 to October 2008, 90 obese and apparently healthy women completed a 10-week university-based weight loss trial while 77 women from this cohort also completed a 24-week weight maintenance phase. Participants were matched and randomized to participate in an MRP or SDE program. Weight loss, health, and fitness-related data were assessed at 0 and 10 weeks on all subjects as well as at 14, 22, and 34 weeks on participants who completed the weight maintenance phase. Data were analyzed by multivariate analysis of variance for repeated measures. During the 10-week weight loss phase, moderate and vigorous physical activity levels were significantly higher in the SDE group with no differences observed between groups in daily energy intake. The SDE group lost more weight (-3.1 ± 3.7 vs -1.6 ± 2.5 kg; P = 0.03); fat mass (-2.3 ± 3.5 vs -0.9 ± 1.6 kg; P = 0.02); centimeters from the hips (-4.6 ± 7 vs -0.2 ± 6 cm; P = 0.002) and waist (-2.9 ± 6 vs -0.6 ± 5 cm; P = 0.05); and, experienced a greater increase in peak aerobic capacity than participants in the MRP group. During the 24-week maintenance phase, participants in the SDE group maintained greater moderate and vigorous physical activity levels, weight loss, fat loss, and saw greater improvement in maximal aerobic capacity and strength. In sedentary and obese women, an SDE-based program appears to be more efficacious in promoting and maintaining weight loss and improvements in markers of health and fitness compared to an MRP type program with encouragement to increase physical activity.


Upregulation of proinflammatory cytokines in the fetal brain of the Gaucher mouse.
Gaucher disease is caused by a deficiency of glucocerebrosidase. Patients with Gaucher disease are divided into three major phenotypes: chronic nonneuronopathic, acute neuronopathic, and chronic neuronopathic, based on symptoms of the nervous system, the severity of symptoms, and the age of disease onset. The characteristics of patients with acute neuronopathic- and chronic neuronopathic-type Gaucher disease include oculomotor abnormalities, bulbar signs, limb rigidity, seizures and occasional choreoathetoid movements, and neuronal loss. However, the mechanisms leading to the neurodegeneration of this disorder remain unknown. To investigate brain dysfunction in Gaucher disease, we studied the possible role of inflammation in neurodegeneration during development of Gaucher disease in a mouse model. Elevated levels of the proinflammatory cytokines, IL-1alpha, IL-1beta, IL-6, and TNF-alpha, were detected in the fetal brains of Gaucher mice. Moreover, the levels of secreted nitric oxide and reactive oxygen species in the brains of Gaucher mice were higher than in wild-type mice. Thus, accumulated glucocerebroside or glucosylsphingosine, caused by glucocerebrosidase deficiency, may mediate brain inflammation in the Gaucher mouse via the elevation of proinflammatory cytokines, nitric oxide, and reactive oxygen species.


Analysis of the clonal relationship among clinical isolates of Salmonella enterica serovar Infantis by different typing methods.
Salmonella Infantis has been the second most common serovar in Argentina in the last two years, being isolated mostly from paediatric hospitalised patients. In order to determine the clonal relationship among Salmonella Infantis strains, we examined 15 isolates from paediatric patient faeces in Argentina (12 geographically related and 3 geographically non-related) by using antimicrobial susceptibility, plasmid profiling, repetitive extragenic palindromic (REP) PCR, enterobacterial repetitive intergenic consensus (ERIC) PCR, and low-frequency restriction analysis of chromosomal DNA by pulsed field gel electrophoresis (PFGE). Four Spanish strains were included as controls of clonal diversity in molecular techniques. Antibiotype and plasmid profile was not useful as epidemiological tools. PFGE and REP-PCR were able to discriminate between Argentinean and Spanish isolates of Salmonella Infantis allowing to detect genetically related strains in three different cities. This finding indicates that a possible spread of a clone of this serovar in the North-eastern Region of Argentina has taken place in 1998.


Lipidomic profiling of subchronic As4S4 exposure identifies inflammatory mediators as sensitive biomarkers in rats.
Arsenic sulfide compounds provide nearly all of the world's supply of arsenic. However, the risk of arsenic trisulfide exposure is still not fully investigated. Here, we systemically assessed the toxicology of As4S4 in rats by combining arsenic metabolite detection, routine testing and lipidomic profiling. It was revealed that the oral administration of As4S4 for two months increased the total arsenic content in the liver reaching a saturation level. Further analysis by anion exchange chromatography coupled with inductively coupled plasma mass spectrometry (ICP-MS) technology showed no trace of inorganic arsenic, but there was significant presence of dimethylarsinic acid (DMA), in the livers of rats. This arsenic metabolite was less toxic to rats and did not induce overt liver pathology and functional injury. In contrast, lipidomic profiling provided a comprehensive map of lipids and uncovered a more complex inflammatory response, exhibiting more sensitive change to arsenic exposure. We observed that metabolites of cyclooxygenase, including PGF2α, dhk PGF2α, 15k PGF2α, 8-iso-PGF2a, PGE2, dhk PGE2, PGD2, 15d-PGD2, and PGJ2, were significantly elevated. But mediators from lipoxygenase, cytochrome P450, docosahexaenoic acid, and eicosapentaenoic acid pathways were not markedly affected. In summary, we identified DMA as the predominant arsenic species in the livers of rats, and found cyclooxygenase-derived lipids as the inflammatory mediators before the development of overt liver injury for subchronic As4S4 exposure. These mediators could translate into potential metabolic biomarkers in early arsenic risk assessment and as targets for therapeutic intervention.


Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis.
Cisplatin is a widely used chemotherapeutic agent; however, nephrotoxicity and neuropathy are obstacles for drug efficacy. Little is known about the genes or genetic variants contributing to the risk of developing these toxicities or chemotherapeutic response. Thus, we have applied a cell-based model to identify and characterize previously unknown genes that may be involved in cellular susceptibility to cisplatin. Lymphoblastoid cell lines from 27 large Centre d'Etude du Polymorphisme Humain pedigrees were used to elucidate the genetic contribution to cisplatin-induced cytotoxicity. Phenotype was defined as cell growth inhibition following exposure of cell lines to increasing concentrations of cisplatin for 48 h. Significant heritability, ranging from 0.32 to 0.43 (P<10), was found for the cytotoxic effects of each concentration (1, 2.5, 5, 10, and 20 micromol/l) and IC50, the concentration required for 50% cell growth inhibition. Linkage analysis revealed 11 genomic regions on six chromosomes with logarithm of odds (LOD) scores above 1.5 for cytotoxic phenotypes. The highest LOD score was found on chromosome 4q21.3-q35.2 (LOD=2.65, P=2.4x10(-4)) for 5 micromol/l cisplatin. Quantitative transmission disequilibrium tests were performed using 191973 nonredundant single nucleotide polymorphisms (SNPs) located in the 1 LOD confidence interval of these 11 regions. Twenty SNPs, with 10 SNPs located in five genes, were significantly associated with cisplatin-induced cytotoxicity (P<or=1x10(-4)). Four of these 20 SNPs were found to explain over 10% of the variation in cisplatin-induced apoptosis. Our results suggest that genetic factors involved in cytotoxicity also contribute to cisplatin-induced apoptosis. These cell lines provide a paradigm to identify previously unknown pharmacogenetic variants associated with drug cytotoxicity.


Hospital setting for birth and use of medical procedures in low-risk women.
This study examined the use of selected medical procedures in low-risk women during childbirth. Data from the 1980 National Natality Survey merged with an American Hospital Association annual survey for the same year were used to assess the frequency with which low-risk women in the United States received certain childbirth procedures and to determine whether their use varied by the hospital setting for birth. Stratified analysis was used to assess the relation of hospital level for delivery with the use of electronic fetal monitoring, labor induction, and primary cesarean delivery in low-risk women, with control for potential confounding factors. As the level of available perinatal technology increased, the use of these procedures increased. Results of the study suggest that low-risk women may have received excess interventions and confirm the need for further examination of care procedures for this group.


Bismuth-Based Nanomaterials: Recent Advances in Tumor Targeting and Synergistic Cancer Therapy Techniques.
Despite all of the efforts in the field of cancer therapy, the heterogeneous properties of tumor cells induce an insufficient therapeutic outcome when treated with conventional monotherapies, necessitating a shift in cancer treatment from monotherapy to combination therapy for complete cancer treatment. Multifunctional bismuth (Bi)-based nanomaterials (NMs) with therapeutic functions hold great promise for the fields of cancer diagnosis and therapy based on their low toxicity, X-ray sensitive capabilities, high atomic number, near-infrared driven semiconductor properties, and low cost. Herein, a comprehensive review of recent advances in various medicinal aspects of Bi-based NMs is presented including: evaluation of in-tumor site accumulation, tumor targeting, and therapeutic performance, as well as the characteristics, benefits, and shortcomings of Bi-based NM-mediated major monotherapies. In addition, the cooperative enhancement mechanisms between two or more of these monotherapies are described in detail to address common challenges in cancer therapy, such as multidrug resistance, hypoxia, and metastasis. Finally, this review opens new insights into the design of multimodal synergistic therapies for potential future clinical applications of Bi-based NMs.


Environmental uncertainty and digital technologies corporate in shaping corporate green behavior and tax avoidance.
This study contributes to the field of sustainability by analyzing changes in firms following the adoption of new environmental protection laws to meet community sustainability needs. Focusing on the Chinese context, it examined the relationship between firms' environmental protection measures (i.e., corporate green behavior) and profitability (i.e., corporate tax avoidance). The moderating roles of environmental uncertainty and digital technology application in this relationship were also investigated. The findings offer insights into the complex dynamics linking firms' environmental initiatives to their business outcomes and financial decisions within the framework of a sustainable community. Ultimately, this study highlights the importance and implications of sustainable practices for both the environment and corporate financial performance. Firms' environmental behaviors are enablers of sustainable communities by deploying natural resources and creating a more resilient economy through active community participation in green production models.


[Escherichia coli's endocarditis in a prosthetic aortic valve - diagnostic and therapeutic particularities].
Escherichia coli endocarditis is a rare condition, even though bacteriemia by such agent is common. The infection, normally from a urinary origin, may, in fact, progress without major hemodynamic disturbance and minimal symptoms, regardless its ability of destruction of heart's valvular apparatus. We present a case report of a 68-year-old man, with a history of aortic valvular mechanic prosthesis, dyslipidemia and hypertension, admitted at the emergency room with refractory fever and urinary tract symptoms. On the hypothesis of endocarditis, he was submitted to transesofagic echocardiography that suggested a prosthetic vegetation, without hemodynamic dysfunction. E. coli was cultured from the blood soon after, and antibiotics adapted according to sensibility testing. Nevertheless, the patient deteriorated, both clinically and echocardiographically, with development of periprosthesis abscess, detachment of the prosthesis and extension of the infection to other valves, with hemodynamic dysfunction. The infection was only restrained with a surgical approach, which reflects the importance of this therapeutic weapon in these situations, including the correct timing.


Benzodithiophenes induce differentiation and apoptosis in human leukemia cells.
All-trans retinoic acid (ATRA) induces clinical remission in patients with t(15;17) acute promyelocytic leukemia (APL) carrying leukemogenic promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion protein by overcoming PML-RARalpha transcriptional repression and inducing myeloid differentiation. To identify more potent chemical differentiation inducers, a screening assay was developed utilizing an ATRA-insensitive NB4 cell line (NB4-c) in which differentiation could be measured after 48 hours when primed with ATRA followed by other potential inducers. Over 300 cytostatic agents selected from the National Cancer Institute library were screened using this established method. Three compounds, NSC656243, NSC625748, and NSC144168, were identified to amplify ATRA-induced differentiation with acceptable cytotoxicity in NB4-c cells. In the absence of ATRA, these compounds also induced HL-60 and murine erythroleukemia cells to undergo partial differentiation. NSC656243, a benzodithiophene compound, was selected for further studies to examine the underlying mechanism of action. The differentiation effect of NSC656243 was associated with enhanced ATRA-mediated up-regulation of cell cycle regulatory proteins p21waf1 and p27kip1, retinoblastoma dephosphorylation, expression of RIG-E and RIG-G, and myelomonocytic differentiation-specific down-regulation of the myeloperoxidase (MPO) gene. Moreover, at 2- to 3-fold higher concentrations than those used to synergize with ATRA, NSC656243 induced apoptosis in NB4-c cells by reactive oxygen species-mediated pathways. The dual effects of benzodithiophenes (i.e., differentiation and apoptosis induction) support further development of these compounds as therapeutic agents for leukemia.


Semi-Automatic Tracking of Laser Speckle Contrast Images of Microcirculation in Diabetic Foot Ulcers.
Foot ulcers are a severe complication of diabetes mellitus. Assessment of the vascular status of diabetic foot ulcers with Laser Speckle Contrast Imaging (LSCI) is a promising approach for diagnosis and prognosis. However, manual assessment during analysis of LSCI limits clinical applicability. Our aim was to develop and validate a fast and robust tracking algorithm for semi-automatic analysis of LSCI data. The feet of 33 participants with diabetic foot ulcers were recorded with LSCI, including at baseline, during the Post-Occlusive Reactive Hyperemia (PORH) test, and during the Buerger's test. Different regions of interest (ROIs) were used to measure microcirculation in different areas of the foot. A tracking algorithm was developed in MATLAB to reposition the ROIs in the LSCI scans. Manual- and algorithm-tracking of all recordings were compared by calculating the Intraclass Correlation Coefficient (ICC). The algorithm was faster in comparison with the manual approach (90 s vs. 15 min). Agreement between manual- and algorithm-tracking was good to excellent during baseline (ICC = 0.896-0.984; p < 0.001), the PORH test (ICC = 0.790-0.960; p < 0.001), and the Buerger's test (ICC = 0.851-0.978; p < 0.001), resulting in a tracking algorithm that delivers assessment of LSCI in diabetic foot ulcers with results comparable to a labor-intensive manual approach, but with a 10-fold workload reduction.


Elevated free IGF2 levels in localized, early-stage breast cancer in women.
Epidemiological studies imply an association between circulating IGF1 and breast cancer, whereas the role of IGF2, which also acts on the IGF1 receptor, is less settled. This study investigates the association between IGF2 and breast cancer in patients with localized disease. The participants were women with well-characterized, early stage, localized breast cancer (n=43) and matched healthy women (n=38), from whom fasting serum levels of IGF-related peptides were measured. In patients, mean free IGF2 was increased (+57%, P<0.001), in spite of reduced total IGF2 levels (-12%, P=0.003) when compared with controls. Similar changes were seen in free IGF1 (+28%, P=0.004) and total IGF1 (-16% P=NS). Pro-IGF2 and IGF-binding protein 1 (IGFBP1) were unchanged. IGFBP2 was reduced by 22% in the patients (P=0.004). The patients showed reduced IGFBP3 protease activity and accordingly increased levels of intact IGFBP3, whereas total IGFBP3 was unchanged. Women with localized, early-stage breast cancer show elevated circulating free IGF1 and IGF2, reduced total IGF2 and alterations in IGFBPs. The changes observed despite minimal cancer disease suggest a role for the circulating IGF system in the progression of breast cancer in women.


Phosphodiesterase 5A inhibition induces Na+/H+ exchanger blockade and protection against myocardial infarction.
Acute phosphodiesterase 5A inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1), detected by the almost null intracellular pH recovery from an acute acid load (ammonium prepulse) in isolated papillary muscles from Wistar rats. Inhibition of phosphoglycerate kinase-1 (KT5823) restored normal NHE-1 activity, suggesting a causal link between phosphoglycerate kinase-1 increase and NHE-1 inhibition. We then tested whether the beneficial effects of NHE-1 inhibitors against the deleterious postmyocardial infarction (MI) remodeling can be detected after sildenafil-mediated NHE-1 inhibition. MI was induced by left anterior descending coronary artery ligation in Wistar rats, which were randomized to placebo or sildenafil (100 mg kg(-1) day(-1)) for 6 weeks. Sildenafil significantly increased left ventricular phosphoglycerate kinase-1 activity in the post-MI group without affecting its expression. MI increased heart weight/body weight ratio, left ventricular myocyte cross-sectional area, interstitial fibrosis, and brain natriuretic peptide and NHE-1 expression. Sildenafil blunted these effects. Neither a significant change in infarct size nor a change in arterial or left ventricular systolic pressure was detected after sildenafil. MI decreased fractional shortening and the ratio of the maximum rate of rise of LVP divided by the pressure at the moment such maximum occurs, effects that were prevented by sildenafil. Intracellular pH recovery after an acid load was faster in papillary muscles from post-MI hearts (versus sham), whereas sildenafil significantly inhibited NHE-1 activity in both post-MI and sildenafil-treated sham groups. We conclude that increased phosphoglycerate kinase-1 activity after acute phosphodiesterase 5A inhibition blunts NHE-1 activity and protects the heart against post-MI remodeling and dysfunction.


Combined effect of alpha particles and cigarette smoke on human lung epithelial cells in vitro.
Purpose: The combined toxicity of alpha particles and cigarette smoke to the critical cells in the lungs was investigated to assess the risk of smoking workers who handle naturally occurring radioactive materials. Materials and methods: The toxicity of alpha particles and cigarette smoke extract (CSE) was evaluated in terms of DNA double-strand break (DSB) induction and clonogenic cell death of human lung epithelial cells in vitro. The cells were exposed to alpha particles at doses of up to 0.25 Gy for gamma-H2AX assay and from 1.25 Gy to 5 Gy for clonogenic assay. CSE exposure of the cells was facilitated in the culture medium at CSE concentrations ranging from 1% to 12%. Additional experiments were performed using mouse endothelial cells for comparison. Results: The increases in the levels of DNA DSBs were linearly dependent on radiation dose and CSE concentration. The CSE-treated cells also responded with a linearly increasing number of DNA DSBs to the radiation dose. Both human lung epithelial cells and mouse endothelial cells showed exponential decreases in clonogenic surviving fraction as the dose from alpha particle exposure increased. Both cells responded with the clonogenic surviving fractions decreasing in a linear proportion to the CSE concentration in the culture medium. Conclusion: In our experimental in vitro setup, CSE treatment and alpha particle exposure affected the cells in an additive manner either for DNA DSB production or for clonogenic cell death induction.


P4 medicine and pediatric occupational therapy.
Pediatric occupational therapy practitioners face a complex and ever-changing health care environment, creating many challenges and opportunities. P4 medicine is a systems approach to health care that emphasizes proactive wellness over reactive acute care disease management. The four Ps of P4 medicine stand for predictive, personalized, preventive, and participatory, concepts that align well with the practice of pediatric occupational therapy. P4 medicine offers a model for pediatric occupational therapy practitioners to demonstrate the value of occupational therapy services.


Do Pentraxins Bind to Fungi in Invasive Human Gastrointestinal Candidiasis?
Tissue from 13 autopsy cases with invasive gastrointestinal candidiasis was studied for the binding of the pentraxins, C-reactive protein (CRP), pentraxin 3 (PTX3), and serum amyloid P component (SAP) to fungal surfaces. Invasive candidal infection was demonstrated using a hematoxylin and eosin stain and a Gomori methenamine silver stain (GMS). Immunohistochemistry was performed with CRP and PTX3 monoclonal antibodies and did not demonstrate CRP or PTX3 bound to fungi (0 of 13 cases), although CRP was extensively deposited on human tissue. A polyclonal antibody to SAP showed that SAP was bound to fungi in 12 of 13 cases. Although all three pentraxins have been reported to bind to fungi or bacteria, only SAP was bound to filamentous and yeast forms of Candida in human tissue, as detected by immunohistochemistry. SAP was abundantly present on fungi and may have affected the host innate immune response to the invading fungi.


Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes.
There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation.


Birth weight influences cardiac structure, function, and disease risk: evidence of a causal association.
Low birth weight is a common pregnancy complication, which has been associated with higher risk of cardiometabolic disease in later life. Prior Mendelian randomization (MR) studies exploring this question do not distinguish the mechanistic contributions of variants that directly influence birth weight through the foetal genome (direct foetal effects), vs. variants influencing birth weight indirectly by causing an adverse intrauterine environment (indirect maternal effects). In this study, MR was used to assess whether birth weight, independent of intrauterine influences, is associated with cardiovascular disease risk and measures of adverse cardiac structure and function. Uncorrelated (r2 < .001), genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms were extracted from genome-wide association studies summary statistics for birth weight overall, and after isolating direct foetal effects only. Inverse-variance weighted MR was utilized for analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 16 measures of cardiac structure and function. Multiple comparisons were accounted for by Benjamini-Hochberg correction. Lower genetically-predicted birth weight, isolating direct foetal effects only, was associated with an increased risk of coronary artery disease (odds ratio 1.21, 95% confidence interval 1.06-1.37; P = .031), smaller chamber volumes, and lower stroke volume, but higher contractility. The results of this study support a causal role of low birth weight in cardiovascular disease, even after accounting for the influence of the intrauterine environment. This suggests that individuals with a low birth weight may benefit from early targeted cardiovascular disease prevention strategies, independent of whether this was linked to an adverse intrauterine environment during gestation.


The Impact of Pollutants and Deforestation on the Spread of Monkeypox: An Unintended Consequence of Progress.
Monkeypox (MPX) is a rare zoonotic illness, like smallpox, caused by the monkeypox virus, which is a member of the Orthopoxvirus genus of the Chordopoxvirinae subfamily that falls under the classification of the Poxviridae family. MPX is clinically characterized by a wide variety of symptoms and signs, including fever, sore throat, headache, myalgia, lymphadenopathy, and rashes. As the world is undergoing progressive industrialization over time, there is a corresponding increase in environmental pollutants and deforestation. Previous studies have found a correlation between exposure to environmental contaminants and the incidence of MPX. Additionally, it has been hypothesized that deforestation may also have played a role in the disease's resurgence or in its ability to spread. Habitat loss and ecological instability brought on by environmental contaminants and deforestation may increase human-infected animal interaction and hasten the spread. The likely connection should be known by health authorities and doctors, as well as government officials, to help fund further investigations and craft strategies to combat the risk of an increasing prevalence of MPX in the world, especially in densely populated underdeveloped regions of Asia and Africa, where containment of MPX poses greater challenges. In this article, we have provided an important real-world perspective and suggested future recommendations to halt the further spread of MPX to new places.


Effectiveness of a parent "buddy" program for mothers of very preterm infants in a neonatal intensive care unit.
Very preterm birth (< 30 weeks' gestation) is a stressful event for parents, and few support interventions for these parents have been evaluated. In this study, we evaluated the effectiveness of parent-to-parent peer support for mothers of very preterm infants in a neonatal intensive care unit (NICU). In this cohort study, 32 mothers were recruited for the intervention group from the Mount Sinai Hospital and 28 mothers were recruited for the control group from the Sunnybrook and Women's College Health Sciences Centre, both located in Toronto. The NICUs of these hospitals serve the same region and accept referrals on alternate days. Mothers in the intervention group were paired with trained mothers who had previously had a very preterm infant in the NICU and who provided principally telephone support. Participants in both groups received standard medical and social work services. Primary outcome data consisted of self-reported, standardized measures of parental stress, state anxiety and depression. Secondary measures included self-reported, standardized measures of perceived social support and trait anxiety. At 4 weeks after enrolment in the study, mothers in the intervention group reported less stress than those in the control group (mean score 1.54 v. 2.93, p < 0.001). At 16 weeks after enrolment, the intervention group reported less state anxiety (mean score 31.4 v. 38.6, p < 0.05), less depression (mean score 2.20 v. 4.88, p < 0.01) and greater perceived social support (mean score 6.49 v. 5.48, p < 0.01) than the control group. There was no difference between the groups in terms of trait anxiety. Of the 24 mothers who evaluated the program, 21 (87.5%) indicated that it was very helpful or helpful. Support from individual, trained peers was found to be effective in helping mothers deal with the stress of very preterm birth.


Differential effects of food availability on minimum and maximum rates of metabolism.
Metabolic rates reflect the energetic cost of living but exhibit remarkable variation among conspecifics, partly as a result of the constraints imposed by environmental conditions. Metabolic rates are sensitive to changes in temperature and oxygen availability, but effects of food availability, particularly on maximum metabolic rates, are not well understood. Here, we show in brown trout (Salmo trutta) that maximum metabolic rates are immutable but minimum metabolic rates increase as a positive function of food availability. As a result, aerobic scope (i.e. the capacity to elevate metabolism above baseline requirements) declines as food availability increases. These differential changes in metabolic rates likely have important consequences for how organisms partition available metabolic power to different functions under the constraints imposed by food availability.


Biosynthesis of ethylene. 4-methylmercapto-2-oxobutyric acid: an intermediate in the formation from methionine.
The enzyme responsible for the conversion of methionine into a precursor of ethylene in cauliflower florets is a transaminase. The formation of 4-methyl-mercapto-2-oxobutyric acid by this enzyme has been shown. The oxo acid stimulates the synthesis of ethylene when added to floret tissue, and tracer experiments have shown that (14)C is incorporated into ethylene from the labelled oxo acid. The evidence is consistent with the view that the oxo acid is an intermediate in the formation of ethylene from methionine.


Parkin-Independent Mitophagy Controls Chemotherapeutic Response in Cancer Cells.
Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance.


Lactobacilli carry cryptic genes encoding peptidase-related proteins: characterization of a prolidase gene (pepQ) and a related cryptic gene (orfZ) from Lactobacillus delbrueckii subsp. bulgaricus.
Two genes, pepQ and orfZ, encoding a prolidase and a prolidase-like protein, respectively, were cloned and characterized from Lactobacillus delbrueckii subsp. bulgaricus. The identity of the pepQ and orfZ genes with the Lactobacillus delbrueckii subsp. lactis prolidase gene (pepQ) was shown to be 98% and 60%, respectively. Both pepQ and orfZ were preceded by a putative promoter region. Northern analysis of pepQ mRNA revealed a 1.1 kb transcript indicating that pepQ forms a monocistronic transcriptional unit. Under the growth conditions used, no evidence was obtained that orfZ was expressed, either by mRNA size determination in Northern analysis or by primer extension analysis. With reverse transcription-PCR, however, the presence of monocistronic orfZ transcripts was established. The orfZ gene could also be overexpressed in E. coli using the vector pKK223-3. The size of the protein synthesized, 41 kDa, confirmed the molecular mass of OrfZ calculated according to DNA sequence analysis. In contrast to PepQ, which showed a substrate specificity characteristic of prolidase enzymes, no enzymic activity for the orfZ-encoded protein was found with the peptide substrates tested. These results indicate that orfZ is a cryptic gene, which is expressed at a very low level under the growth conditions used. It is noteworthy that homologues of the Lb. delbrueckii subsp. bulgaricus orfZ and pepQ genes appeared to be present in both Lb. delbrueckii subsp. lactis and Lactobacillus helveticus.


Glucocorticoids and depression.
Depression has been associated with impaired mineralocorticoid receptor function, restrained glucocorticoid receptor feedback at the level of the hypothalamic-pituitary-adrenal (HPA) axis, raised cortisol level and increased corticotropin-releasing factor activity, which may act in concert to induce the signs and symptoms of the disorder. Pre-clinical and clinical evidence suggests that both genetic and environmental factors contribute to the development of these HPA axis abnormalities in depressed patients. Support for this view derives from models using genetically modified animals and/or chronic stress exposure at different developmental stages, although all of the current approaches have to be viewed within their limitations to model the disease. However, both animal and human studies challenging the HPA system show at least some neuroendocrine and behavioural changes comparable to those seen in depression, suggesting that some of the depressive symptoms can be attributed to HPA axis hyperactivity. Moreover, normalization of the neuroendocrine function following chronic antidepressant drug treatment seems to be a prerequisite for stable remission of depressive psychopathology, i.e. that normalization of HPA function is critical for relief of the clinical symptomatology of this disorder.


Protein proximity networks and functional evaluation of the casein kinase 1 gamma family reveal unique roles for CK1γ3 in WNT signaling.
Aberrant activation or suppression of WNT/β-catenin signaling contributes to cancer initiation and progression, neurodegeneration, and bone disease. However, despite great need and more than 40 years of research, targeted therapies for the WNT pathway have yet to be fully realized. Kinases are considered exceptionally druggable and occupy key nodes within the WNT signaling network, but several pathway-relevant kinases remain understudied and "dark." Here, we studied the function of the casein kinase 1γ (CSNK1γ) subfamily of human kinases and their roles in WNT signaling. miniTurbo-based proximity biotinylation and mass spectrometry analysis of CSNK1γ1, CSNK1γ2, and CSNK1γ3 revealed numerous components of the β-catenin-dependent and β-catenin-independent WNT pathways. In gain-of-function experiments, we found that CSNK1γ3 but not CSNK1γ1 or CSNK1γ2 activated β-catenin-dependent WNT signaling, with minimal effect on other signaling pathways. We also show that within the family, CSNK1γ3 expression uniquely induced low-density lipoprotein receptor-related protein 6 phosphorylation, which mediates downstream WNT signaling transduction. Conversely, siRNA-mediated silencing of CSNK1γ3 alone had no impact on WNT signaling, though cosilencing of all three family members decreased WNT pathway activity. Finally, we characterized two moderately selective and potent small-molecule inhibitors of the CSNK1γ family. We show that these inhibitors and a CSNK1γ3 kinase-dead mutant suppressed but did not eliminate WNT-driven low-density lipoprotein receptor-related protein 6 phosphorylation and β-catenin stabilization. Our data suggest that while CSNK1γ3 expression uniquely drives pathway activity, potential functional redundancy within the family necessitates loss of all three family members to suppress the WNT signaling pathway.


MASTOS: Mammography Simulation Tool for design Optimization Studies.
Mammography is a high quality imaging technique for the detection of breast lesions, which requires dedicated equipment and optimum operation. The design parameters of a mammography unit have to be decided and evaluated before the construction of such a high cost of apparatus. The optimum operational parameters also must be defined well before the real breast examination. MASTOS is a software package, based on Monte Carlo methods, that is designed to be used as a simulation tool in mammography. The input consists of the parameters that have to be specified when using a mammography unit, and also the parameters specifying the shape and composition of the breast phantom. In addition, the input may specify parameters needed in the design of a new mammographic apparatus. The main output of the simulation is a mammographic image and calculations of various factors that describe the image quality. The Monte Carlo simulation code is PC-based and is driven by an outer shell of a graphical user interface. The entire software package is a simulation tool for mammography and can be applied in basic research and/or in training in the fields of medical physics and biomedical engineering as well as in the performance evaluation of new designs of mammography units and in the determination of optimum standards for the operational parameters of a mammography unit.


Proximity Spin-Orbit Torque on a Two-Dimensional Magnet within van der Waals Heterostructure: Current-Driven Antiferromagnet-to-Ferromagnet Reversible Nonequilibrium Phase Transition in Bilayer CrI3.
The recently discovered two-dimensional magnetic insulator CrI3 is an intriguing case for basic research and spintronic applications since it is a ferromagnet in the bulk but an antiferromagnet in bilayer form, with its magnetic ordering amenable to external manipulations. Using the first-principles quantum transport approach, we predict that injecting unpolarized charge current parallel to the interface of the bilayer-CrI3/monolayer-TaSe2 van der Waals (vdW) heterostructure will induce spin-orbit torque and thereby drive the dynamics of magnetization on the first monolayer of CrI3 in direct contact with TaSe2. By combining the calculated complex angular dependence of spin-orbit torque with the Landau-Lifshitz-Gilbert equation for classical dynamics of magnetization, we demonstrate that current pulses can switch the direction of magnetization on the first monolayer to become parallel to that of the second monolayer, thereby converting CrI3 from antiferromagnet to ferromagnet while not requiring any external magnetic field. We explain the mechanism of this reversible current-driven nonequilibrium phase transition by showing that first monolayer of CrI3 carries current due to evanescent wave functions injected by metallic transition metal dichalcogenide TaSe2, while concurrently acquiring strong spin-orbit coupling via such a proximity effect, whereas the second monolayer of CrI3 remains insulating. The transition can be detected by passing vertical read current through the vdW heterostructure, encapsulated by a bilayer of hexagonal boron nitride and sandwiched between graphite electrodes, where we find a tunneling magnetoresistance of ≃240%.


Acute hepatic failure due to Plasmodium falciparum liver injury.
Nine patients with acute liver failure due to Plasmodium falciparum liver injury admitted to the Rajgarhia Liver Unit of the All-India Institute of Medical Sciences during 1982-84 are presented. The liver was palpable in all the patients, and eight had splenomegaly. Investigations revealed mild to moderate abnormality in liver function tests. All were negative for the markers of acute infection due to hepatitis A and B viruses. Blood film examination showed P. falciparum alone in seven and along with P. vivax in the remaining two patients. Liver histology, which was identical in all eight patients where liver biopsy was done, showed centrizonal necrosis and hyperplastic Kupffer cells loaded with malarial pigment. All the patients recovered with specific anti-malarial and supportive treatment. Our observations suggest that malaria due to P. falciparum may present as jaundice and encephalopathy which stimulates acute hepatic failure due to fulminant hepatitis.


Comparative analysis of regional outcomes and adverse events after continuous-flow left ventricular assist device implantation: An IMACS analysis.
Regional outcomes after implantation of continuous-flow left ventricular assist devices (LVADs) have not been described. We examined differences in patient selection, survival, and adverse events across 3 geographic regions of the world: the Americas, Asia-Pacific, and Europe. Using data from The International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support registry, all adult patients implanted with a continuous-flow LVADs were included in this International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support analysis (n = 15,560), of whom, 9,988 (64%) received axial-flow devices and 5,572 (36%) received centrifugal-flow devices. There were significant interregional differences in the rate of implantation of patients aged >70 years (Americas: 14%, Asia-Pacific: 1%, Europe: 5%; p < 0.0001), morbidly obese (Americas: 5%, Asia-Pacific: 1%, Europe: 1%; p < 0.0001), male (Americas: 79%, Asia-Pacific: 77%, Europe: 85%; p < 0.0001), and implanted as destination therapy (Americas: 48%, Asia-Pacific: 4%, Europe: 22%; p < 0.0001). The rates of centrifugal pump usage varied by region (Americas: 30%, Asia-Pacific: 34%, Eu: 74%; p < 0.0001). Survival rates varied by region and the type of pump flow, with survival at 12 and 48 months (axial flow vs centrifugal flow) being 82% vs 82% and 52% vs 53 in Americas; 92% vs 86% and 83% vs 74% in Asia-Pacific; and 80% vs 75% and 69% vs 53% in Europe, respectively (regional survival p < 0.0001). There are marked global differences in LVAD recipient characteristics, device utilization, and post-operative care. These heterogeneities along with differences in patient management and transplantation rates may impact long-term survival. Regional differences in adverse event incidence warrant further investigation.


Lymphocyte function-associated antigen-1 binding residues in intercellular adhesion molecule-2 (ICAM-2) and the integrin binding surface in the ICAM subfamily.
The crystal structure of intercellular adhesion molecule-2 (ICAM-2) revealed significant differences in the presentation of the critical acidic residue important for integrin binding between I and non-I-domain integrin ligands. Based on this crystal structure, we mutagenized ICAM-2 to localize the binding site for the integrin lymphocyte function-associated antigen-1 (LFA-1). The integrin binding site runs diagonally across the GFC beta-sheet and includes residues on the CD edge of the beta-sandwich. The site is oblong and runs along a flat ridge on the upper half of domain 1, which is proposed to dock to a groove in the I domain of LFA-1, with the critical Glu-37 residue ligating the Mg2+ in the I domain. Previous mutagenesis of ICAM-1 and ICAM-3, interpreted in light of the recently determined ICAM-1 and ICAM-2 structures, suggests similar binding sites. By contrast, major differences are seen with vascular cell adhesion molecule-1 (VCAM-1), which binds alpha4 integrins that lack an I domain. The binding site on VCAM-1 includes the lower portion of domain 1 and the upper part of domain 2, whereas the LFA-1 binding site on ICAM is confined to the upper part of domain 1.


Preoperative Octenidine Application in Breast Reconstruction Surgery.
Postoperative infection in implant-based reconstructive breast surgery is a common problem. The preoperative application of a disinfecting washing agent may reduce postoperative infection rates. This retrospective analysis aimed to evaluate whether preoperative Octenisan® application yields a reduction in postoperative complications or infection rates in breast reconstructive surgery. Between 2016 and 2019, 127 women received implant-based breast reconstruction at the municipal hospital of Cologne, Holweide, Germany. A total of 197 treatments were performed. After giving consent, patients were asked to use Octenisan® wash lotion for five days before breast reconstructive surgery. All patients were asked by a simple questionnaire whether they performed showering and washing according to the proposed protocol. In 96 cases patients did adhere to the protocol. In 101 cases they did not. Patient cohorts were then divided into patients who had applied Octenisan® wash lotion and patients who had not. Endpoints were defined as minor complications with no implant loss and major complications with consecutive implant loss. Patient adherence to the application regimen was 48.7%. Overall minor complications occurred in 34.4% with preoperative Octenidine usage and 36.6% without preoperative Octenidine usage. Major complications happened in 7% with preoperative Octenidine and 5% without Octenidine. Overall, there was no significant difference concerning minor or major complication rates. Preoperative washing protocols involving the Octenisan® wash lotion is relatively cheap and easy to follow. There is evidence that washing protocols result in a reduction of S. aureus infections leading to a better perioperative outcome. Octenisan® is safe to use in implant-based breast reconstructive surgery and is not associated with higher risks for patients. Our study did not yield any significant reduction in perioperative and postoperative complication and infection rates. This is attributed to a relatively low study population. Wash lotion compliance was only 48.7%. Proper patient education is crucial. With those preliminary data, it is now possible to design a larger analysis since patient adherence to washing protocol with Octenisan® wash lotion has been established.


Amebic liver abscess.
Amebic liver abscess was seen in 35 patients over a ten-year period at Cook County and the University of Illinois hospitals, Chicago; 32 had immigrated from an area of endemic amebiasis, but three were natives of Chicago. Typically they had right upper-quadrant abdominal pain and fever of short duration (nine days); on physical examination, upper abdominal tenderness and hepatomegaly were usually present. The diagnosis was confirmed by liver scan, serologic studies, aspiration of "anchovy paste" from the abscess, and/or a favorable response to specific antiamebic therapy. Most were solitary abscesses in the right lobe of the liver. Metronidazole treatment alone was adequate in 24 of 29 patients (83%). Nine patients underwent percutaneous or surgical drainage of the abscess owing to incorrect diagnosis (three), persistent pain and fever after medical treatment (three), expanding left lobe abscess (two), and for diagnosis (one). Mortality was 5.7% (two patients). Owing to current immigration patterns amebic liver abscess should be considered in the differential diagnosis of patients with right upper-quadrant pain and fever. The diagnosis should be confirmed with a liver scan and serologic study for amebiasis.


Infant safety seat use. Reaching the hard to reach.
We crafted an interactive video infant safety seat (ISS) education program for presentation to postpartum mothers. This program was designed to reach all socioeconomic groups with the message that consistent, correct ISS use is important. The program was further designed to be physically portable, versatile, and affordable and to narrow previously observed differences in correct ISS use between groups of high and low socioeconomic status exposed to the same educational message. Observed ISS use at an examination after four months confirmed the utility of this program in meeting the experimental goals. While also reaching other program goals, the interactive video program (64.6% correct use) was found to be at least as effective as a control education program (63.9% correct use).


Instillation of allogeneic lung antigen-presenting cells deficient in expression of major histocompatibility complex class I or II antigens have differential effects on local cellular and humoral immunity and on pathology in recipient murine lungs.
Recognition of allogeneic major histocompatibility complex (MHC) molecules expressed on donor lung antigen-presenting cells (APCs) by host T lymphocytes is believed to stimulate lung allograft rejection. However, the specific roles of donor MHC molecules in the rejection response is unknown. We report a murine model in which instilling allogeneic lung APCs into recipient lungs induces pathology analogous to acute rejection, and the production of interferon (IFN)-gamma, immunoglobulin (Ig) G2a, and alloantibodies in recipient lungs. Using allogeneic lung APCs (C57BL/6, I-a(b), H-2(b)) deficient in MHC class I, II, or both for instillation into lungs of BALB/c mice (I-a(d), H-2(d)), the purpose of the current study was to determine the specific roles of donor MHC molecules in stimulating local alloimmune responses. The data show that MHC class I or II on donor APCs induced IFN-gamma and IgG2a synthesis locally, though less than that induced by wild-type cells. Both MHC class I and II were required to induce alloantibody production. Instillation of wild-type or class I- or class II-deficient APCs induced comparable pathologic lesions in recipient lungs, and more severe than that induced by MHC-deficient cells. These data show that donor MHC class I and II molecules have differential effects in the stimulation of local alloimmune responses.


Movement Disorders and Mortality in Severely Mentally Ill Patients: The Curacao Extrapyramidal Syndromes Study XIV.
There is a substantial gap in life expectancy between patients with severe mental illness (SMI) and the general population and it is important to understand which factors contribute to this difference. Research suggests an association between tardive dyskinesia (TD) and mortality; however, results are inconclusive. In addition, studies investigating associations between parkinsonism or akathisia and mortality are rare. We hypothesized that TD would be a risk factor for mortality in patients with SMI. We studied a cohort of 157 patients diagnosed predominantly with schizophrenia on the former Netherlands Antilles. TD, parkinsonism, and akathisia were assessed with rating scales on eight occasions over a period of 18 years. Twenty-four years after baseline, survival status and if applicable date of death were determined. Associations between movement disorders and survival were analyzed using Cox regression. Sex, age, antipsychotics, antidepressants and benzodiazepines at each measurement occasion were tested as covariates. Parkinsonism was a significant risk factor with an HR of 1.02 per point on the motor subscale of the Unified Parkinson's Disease Rating Scale (range 0-56). TD and akathisia were not significantly associated with mortality. Parkinsonism may be an important risk factor for mortality in SMI patients. This finding calls for more follow-up and intervention studies to confirm this finding and to explore whether treatment or prevention of parkinsonism can reduce excess mortality.


Analgesic and anti-inflammatory properties of the leaf extracts of Anacardium occidentalis in the laboratory rodents.
Anacardium occidentalis (family: Anacardiaceae) is a plant of the tropical climate widely used by folklore to treat pain and inflammation. This study was conducted to evaluate the analgesic and anti-inflammatory effects of the leaf extracts in rat and mice using different models in other to confirm folkloric claims. The aqueous, hexane, dichloromethane and methanol extracts (AEAO, HEAO, DEAO and MEAO respectively) were investigated for analgesic effects in acetic acid induced pain in mice. They significantly reduced the number of writhing (p<0.001) and the highest analgesic effect was seen in DEAO extract. DEAO was further studied on various analgesic and anti-inflammatory models in graded doses. The extract significantly reduced writhing induced by acetic acid and the number and time of paw licking induced by formalin in a dose related manner. It inhibited the neurogenic and inflammatory phases of formalin. Analgesia was shown in the inhibition of nociception induced by tail immersion in 55oC hot water. The extract prolonged the latencies of tail withdrawal to a similar degree as pentazocine. The extract caused significant inhibition of carrageenan induced paw oedema in rats in a dose dependent manner. These findings suggest that the leaf extracts of Anacardium occidentalis are highly potent analgesic and anti-inflammatory agents. Phytochemical analysis showed that the leaf extracts contain alkaloids, tannins, saponins and cardenolides.


Genomic Characterization of Antimicrobial Resistance, Virulence, and Phylogeny of the Genus Ochrobactrum.
Ochrobactrum is a ubiquitous Gram-negative microorganism, mostly found in the environment, which can cause opportunistic infections in humans. It is almost uniformly resistant to penicillins and cephalosporins through an AmpC-like β-lactamase enzyme class (OCH). We studied 130 assembled genomes, of which 5 were animal-derived isolates recovered in Israel, and 125 publicly available genomes. Our analysis focused on antimicrobial resistance (AMR) genes, virulence genes, and whole-genome phylogeny. We found that 76% of Ochrobactrum genomes harbored a blaOCH β-lactamase gene variant, while 7% harbored another AmpC-like gene. No virulence genes other than lipopolysaccharide-associated genes were found. Core genome multilocus sequence typing clustered most samples to known species, but neither geographical clustering nor isolation source clustering were evident. When analyzing the distribution of different blaOCH variants as well as of the blaOCH-deficient samples, a clear phylogenomic clustering was apparent for specific species. The current analysis of the largest collection to date of Ochrobactrum genomes sheds light on the resistome, virulome, phylogeny, and species classification of this increasingly reported human pathogen. Our findings also suggest that Ochrobactrum deserves further characterization to underpin its evolution, taxonomy, and antimicrobial resistance.


Pattern of statin use changes following media coverage of its side effects.
The media plays a role in shaping opinions about medical decisions, for example, whether to initiate or stop treatment. An association between negative media attention and statin discontinuation has been demonstrated, but it may differ depending on the reason for prescription and whether the user is new (incident) or long term (prevalent). The aim of this study is to explore whether a Danish newspaper article featuring the side effects of statins affects statin discontinuation in incident versus prevalent users, with the reason for prescription also taken into account. The study relies on a quasi-experimental design and uses registry data on statin purchases to explore discontinuation and treatment duration. As a proxy for reason for prescription, data on filled prescriptions and hospital diagnoses from a Danish registry were used. We compared statin discontinuation in all statin users in Denmark in 2007 before the media event (n=343,438) and after it in 2008 (n=404,052). Compared to 2007, statin discontinuation among prevalent users in 2008 increased by 2.97 percentage points (pp). The change in discontinuation varied with the indication for statin use. Those with myocardial infarction had the smallest increase (1.98 pp) and those with hypercholesterolemia or primary hypertension had the largest increase (3.54 pp). Incident statin users had a higher level of discontinuation and a larger difference in discontinuation between 2007 and 2008. Compared to 2007, more people (5.52 pp) discontinued statin treatment in 2008. Again, those with myocardial infarction had the smallest decrease in statin discontinuation (1.49 pp), while those with a potential atherosclerotic condition (7.05 pp) and hypercholesterolemia or primary hypertension (6.10 pp) had the largest increase. Statin discontinuation increased in 2008 following a media event, but especially among individuals prescribed statins for primary prevention and among new statin users.


Reducing relative food reinforcement of infants using a music enrichment program: a randomized, controlled trial.
Food reinforcement or one's motivation to eat may be established early in life; it might not be the food reinforcement per se that drives weight gain, but rather the imbalance between food and nonfood reinforcement. We implemented a 2-y randomized, controlled trial to assess the effects of a music enrichment program (music, n = 45) compared with an active play date control (control, n = 45) in 9- to 15-mo-old healthy infants who were strongly motivated to eat. The 12-mo intensive intervention phase included 4 semesters of Music Together® or a play date program (Winter, Spring, Summer, and Fall), comprised of once per week group meetings, followed by a 12-mo maintenance phase with monthly meetings. Parents were encouraged to listen to the Music Together® program CD or play with the play date group's toy with their infants at home, respectively. We performed a modified intention-to-treat analysis using all randomly assigned, non-excluded subjects for the outcome measures [relative reinforcing value of food (RRVfood), food reinforcement, music reinforcement, and weight-for-length z-score (WLZ)]. There were significant differential group changes across time for RRVfood (group × month; P = 0.016; Cohen's f2 = 0.034). The music group had significantly greater RRVfood decreases than the control group from baseline to the end of the intensive intervention phase (music change = -0.211; control change = -0.015; P = 0.002; Cohen's D = 0.379). However, these differences were not maintained during months 12-24 (music change = -0.187; control change = -0.143; P = 0.448; D = 0.087). We observed an overall moderation effect by sex for food reinforcement and WLZ. Boys in the music group had a significant attenuation in food reinforcement and WLZ compared with boys in the control group. This study extends our knowledge in infant eating behavior by providing insight into the role of nonfood alternatives in altering one's motivation to eat. There may be sex differences in altering one's motivation to eat.This trial was registered at clinicaltrials.gov as NCT02936284.