Serious limitations of the QTL/microarray approach for QTL gene discovery.
It has been proposed that the use of gene expression microarrays in nonrecombinant parental or congenic strains can accelerate the process of isolating individual genes underlying quantitative trait loci (QTL). However, the effectiveness of this approach has not been assessed. Thirty-seven studies that have implemented the QTL/microarray approach in rodents were reviewed. About 30% of studies showed enrichment for QTL candidates, mostly in comparisons between congenic and background strains. Three studies led to the identification of an underlying QTL gene. To complement the literature results, a microarray experiment was performed using three mouse congenic strains isolating the effects of at least 25 biometric QTL. Results show that genes in the congenic donor regions were preferentially selected. However, within donor regions, the distribution of differentially expressed genes was homogeneous once gene density was accounted for. Genes within identical-by-descent (IBD) regions were less likely to be differentially expressed in chromosome 2, but not in chromosomes 11 and 17. Furthermore, expression of QTL regulated in cis (cis eQTL) showed higher expression in the background genotype, which was partially explained by the presence of single nucleotide polymorphisms (SNP). The literature shows limited successes from the QTL/microarray approach to identify QTL genes. Our own results from microarray profiling of three congenic strains revealed a strong tendency to select cis-eQTL over trans-eQTL. IBD regions had little effect on rate of differential expression, and we provide several reasons why IBD should not be used to discard eQTL candidates. In addition, mismatch probes produced false cis-eQTL that could not be completely removed with the current strains genotypes and low probe density microarrays. The reviewed studies did not account for lack of coverage from the platforms used and therefore removed genes that were not tested. Together, our results explain the tendency to report QTL candidates as differentially expressed and indicate that the utility of the QTL/microarray as currently implemented is limited. Alternatives are proposed that make use of microarray data from multiple experiments to overcome the outlined limitations.


Bronchial artery embolization for massive hemoptysis: long-term follow-up.
Bronchial artery angiography with embolization has become a mainstay in the treatment of massive hemoptysis. Whereas the immediate success rate is high, the reported long-term success rate varies widely among different groups. We aimed to explore the long-term outcome and clinical predictors associated with recurrent bleeding following bronchial artery embolization. We reviewed the clinical characteristics, underlying etiologies, procedure details, and outcome of bronchial artery embolization performed for massive hemoptysis between 1999 and 2012. All 52 consecutive patients treated by bronchial artery embolization during the study period were included. The major etiologies of massive hemoptysis were bronchiectasis (mostly post-infectious) in 53.8%, and primary and metastatic lung cancer in 30.8%. The immediate success rate was high (48/52; 92%). Of 45 patients who survived more than 24 hours following bronchial artery embolization, recurrent bleeding did not occur in 19 (42.2%) during a median follow-up period of 60 months (range 6-130 months). Bleeding recurred in 26 (57.7%); within 30 days in 15 (33.3%) and after 1 month in the other 11 (24.4%). The average time to onset of early and late repeat bleeding was 2 and 506 days, respectively. Idiopathic bronchiectasis and lung cancer were associated with a high likelihood of late bleeding recurrence. Bronchial artery embolization is an effective immediate treatment for massive hemoptysis. Because the bleeding recurrence rate is high in patients with lung cancer or idiopathic bronchiectasis, surgery should be considered in these patients following initial stabilization by bronchial artery embolization. For other underlying etiologies, the long-term outcome is excellent.


Personality traits and risk of lifetime asthma diagnosis.
Traits defined by the Five-Factor Model (FFM) of personality have been linked to physical health, leading to treatment implications and psychophysiological conceptualizations. Previous studies have reported a consistent link between neuroticism and asthma. This study aims to reinforce this finding and further its scope by looking at all five personality traits and lifetime asthma diagnosis. The current study examined associations between personality traits and lifetime asthma diagnosis in a sample of 3993 participants and, for the purposes of replication, a second sample of 1692 participant siblings. Personality was measured at a single time point in adulthood (mean age: 53 years), while asthma diagnosis by a medical professional was self-reported across three time points over a range of 54 years. A binary logistic regression was performed to examine the association between FFM personality traits and the likelihood of having endorsed asthma at any time point. Higher scores in the traits of neuroticism (β = 0.024, p = .03, OR = 1.025) and openness (β = 0.041, p < .001, OR = 1.042) were associated with increased risk of lifetime asthma diagnosis, while the trait of conscientiousness (β = -0.034, p = .009, OR = 0.967) was associated with decreased risk of lifetime asthma diagnosis. The associations with neuroticism and openness were replicated in the sibling sample. These findings suggest that research into certain personality traits might help us better understand psychophysiological connections. Neuroticism, openness, and conscientiousness might be salient factors in developing asthma education and treatment.


Use of the bovine leukaemia virus LTR U3 promoter for expressing antisense antiviral RNAs and competitive inhibition of viral infection in cell culture.
Use of viral inducible promoters which can be activated by virus-specific transactivator proteins to drive expression of antisense (as)RNA genes appears to be an attractive approach to inhibit virus infections in vivo. To this end, we have constructed an asRNA gene expressed from the bovine leukaemia virus (BLV) U3 promoter that is complementary to the R-U5 region of the BLV genome. This is the region that is most susceptible to inhibition by asRNA. With plasmid pLU, which expresses the asRNA gene under the control of the BLV U3 promoter, 75% inhibition of virus replication was attained in CC81 cells (the molar ratio of pLU DNA over BLV proviral DNA in the transfection mixture was 5:1). Plasmid pLT, which contains only the BLV U3 promoter without any asRNA-coding region, also efficiently (up to 60%) inhibited virus replication when cotransfected with BLV proviral DNA at a ratio of 20:1. It was suggested that competition between functional and 'empty' viral promoters for the viral transactivator protein p38tax could account for this inhibition. An immunoblotting assay showed that in the presence of nuclear extracts from CC81 cells exogenous BLV p38tax specifically associates with its responsive sequence located in the BLV U3 promoter. Moreover, the additional expression of p38tax in CC81 cells abolishes the inhibitory effect of the empty viral promoter. These observations suggest a new mechanism of BLV inhibition caused, most probably, by sequestering of the viral transactivator protein.


Dusty plasma cavities: Probe-induced and natural.
A comprehensive exploration of regional dust evacuation in complex plasma crystals is presented. Voids created in three-dimensional crystals on the International Space Station have provided a rich foundation for experiments, but cavities in dust crystals formed in ground-based experiments have not received as much attention. Inside a modified Gaseous Electronics Conference rf cell, a powered vertical probe was used to clear the central area of a dust crystal, producing a cavity with high cylindrical symmetry. Cavities generated by three mechanisms are examined. First, repulsion of micrometer-sized particles by a negatively charged probe is investigated. A model of this effect developed for a dc plasma is modified and applied to explain experimental data in rf plasma. Second, the formation of natural cavities is surveyed; a radial ion drag proposed to occur due to a curved sheath is considered in conjunction with thermophoresis and a flattened confinement potential above the center of the electrode. Finally, cavity formation upon increasing the probe potential above the plasma floating potential is justified by a combination of ion drag and sheath edge modification. The cavities produced by these methods appear similar, but each is shown to be facilitated by fundamentally different processes.


Assembly of enveloped tegument structures (L particles) can occur independently of virion maturation in herpes simplex virus type 1-infected cells.
Cells infected with a number of alphaherpesviruses produce non-infectious virion-related particles, termed L particles, in addition to infectious virions. L particles consist of the tegument and envelope components, but lack the virus capsid and DNA. Using a herpes simplex virus type 1 (HSV-1) temperature-sensitive mutant, ts1201, which fails to produce mature virions, we show that L particle production is independent of virion formation. Moreover, the quantity and protein composition of L particles generated by this mutant at the non-permissive temperature are indistinguishable from those produced in wild-type HSV-1 infections. Electron microscopy studies suggest that the processes governing the assembly of tegument and envelope components into L particles are similar to those involved in virion maturation.


Interaction with epithelial cells modifies airway macrophage response to ozone.
The initial innate immune response to ozone (O3) in the lung is orchestrated by structural cells, such as epithelial cells, and resident immune cells, such as airway macrophages (Macs). We developed an epithelial cell-Mac coculture model to investigate how epithelial cell-derived signals affect Mac response to O3. Macs from the bronchoalveolar lavage (BAL) of healthy volunteers were cocultured with the human bronchial epithelial (16HBE) or alveolar (A549) epithelial cell lines. Cocultures, Mac monocultures, and epithelial cell monocultures were exposed to O3 or air, and Mac immunophenotype, phagocytosis, and cytotoxicity were assessed. Quantities of hyaluronic acid (HA) and IL-8 were compared across cultures and in BAL fluid from healthy volunteers exposed to O3 or air for in vivo confirmation. We show that Macs in coculture had increased markers of alternative activation, enhanced cytotoxicity, and reduced phagocytosis compared with Macs in monoculture that differed based on coculture with A549 or 16HBE. Production of HA by epithelial cell monocultures was not affected by O3, but quantities of HA in the in vitro coculture and BAL fluid from volunteers exposed in vivo were increased with O3 exposure, indicating that O3 exposure impairs Mac regulation of HA. Together, we show epithelial cell-Mac coculture models that have many similarities to the in vivo responses to O3, and demonstrate that epithelial cell-derived signals are important determinants of Mac immunophenotype and response to O3.


The effects of dietary flaxseed supplementation on lipid metabolism in streptozotocin-induced diabetic hamsters.
Vascular complications, such as atherosclerosis, represent an important cause of morbidity and mortality in diabetic patients. The aim of this study was to investigate the effects of dietary flaxseed supplementation, a rich source of lignans, a-linolenic acid and soluble fiber mucilage on serum and hepatic lipid concentrations in streptozotocin-induced diabetes in hamsters. Twenty-four male Golden Syrian hamsters were used in this experiment; diabetes was induced in half of them by intraperitoneal injection of streptozotocin (50 mg/kg body weight), and both diabetic and control groups were divided in 2 subgroups, one fed standard diet, and one fed standard diet supplemented with flaxseed (15%), for 20 weeks. Serum total cholesterol (TC), HDL-cholesterol (HDL-C), triglycerides (TG), cholesterol/HDL-cholesterol ratio and hepatic cholesterol and triglycerides were measured at the end of the experiment. Dietary flaxseed supplementation in diabetic hamsters was associated with significant reductions in serum TC (-24.9%), TC/HDL-C ratio (-60%) and increase in serum HDL-C (+91%) as compared to diabetic group without supplementation. There were no significant differences in serum TG levels between diabetes supplemented with flaxseed and diabetic groups. Also, flaxseed supplementation in diabetes induced significant reductions in hepatic cholesterol (-39.5%) and triglycerides levels (-28.8%). These results suggest that dietary flaxseed supplementation may reduce the incidence of diabetic macrovascular complications through improvement of lipid profile.


Application of clinical value assessment of treatment protocols in guideline development: taking the WFAS Clinical Practice Guideline of Acupuncture and Moxibustion for Migraine as an example.
To enhance the clinical applicability of guidelines and provide more effective guidance for clinical practice, a clinical value assessment was conducted during the development of the World Federation of Acupuncture-Moxibustion Societies (WFAS) Clinical Practice Guideline of Acupuncture and Moxibustion for Migraine, which involved the evaluation of 59 acupuncture and moxibustion treatment protocols from randomized controlled trials (RCTs). This article introduced the methodology, content and results of the clinical value assessment of RCT-based acupuncture and moxibustion treatment protocols, which involved the integration of historical and contemporary medical evidence and expert consensus. It served as a methodological reference for the future development of acupuncture and moxibustion clinical practice guidelines.


Evaluation of Patient-Reported Outcomes in Burn Survivors Undergoing Reconstructive Surgery in the Rehabilitative Period.
Health-related quality of life is decreased in burn survivors, with scars implicated as a cause. The authors aim to characterize the use of reconstructive surgery following hospitalization and determine whether patient-reported outcomes change over time. The authors hypothesized improvement in health-related quality of life following reconstructive surgery. Adult burn survivors undergoing reconstructive surgery within 24 months after injury were extracted from a prospective, longitudinal database from 5 U.S. burn centers (Burn Model System). Surgery was classified by problem as follows: scar, contracture, and open wound. The authors evaluated predictors of surgery using logistic regression. Short Form-12/Veterans RAND 12 health survey outcomes at 6, 12, and 24 months were compared at follow-up intervals and matched with nonoperated participants using propensity score matching. Three hundred seventy-two of 1359 participants (27.4 percent) underwent one or more reconstructive operation within 24 months of injury. Factors that increased the likelihood of surgery included number of operations during index hospitalization (p < 0.001), hand (p = 0.001) and perineal involvement (p = 0.042), and range-of-motion limitation at discharge (p < 0.001). Compared to the physical component scores of peers who were not operated on, physical component scores increased for participants undergoing scar operations; however, these gains were only significant for those undergoing surgery more than 6 months after injury (p < 0.05). Matched physical component scores showed nonsignificant differences following contracture operations. Mental component scores were unchanged or lower following scar and contracture surgery. Participants requiring more operations during index admission were more likely to undergo reconstructive surgery. There were improvements in Short Form-12/Veterans RAND 12 scores for those undergoing scar operations more than 6 months after injury, although contracture operations were not associated with significant differences in Short Form-12/Veterans RAND 12 scores.


In vitro and in vivo evaluation of novel cross-linked saccharide based polymers as bile acid sequestrants.
Bile acid sequestrants (BAS) represent a therapeutic approach for the management of hypercholesterolemia that relies on the cationic polymeric nature of BAS to selectively bind negatively charged bile acids. We hypothesized that the cross-linking of β-cyclodextrin (β-CD) and saccharides such as starch or dextrin with divinyl sulfone (DVS) yields homo- and hetero-polymeric materials with the ability to trap sterols. Our hypothesis was put to test by synthesizing a library of 22 polymers that were screened to evaluate their capability to sequester both cholesterol (CHOL) and cholic and deoxycholic acids (CA and DCA). Three polymers synthesized in high yield were identified as promising. Two were neutral hetero-polymers of β-CD and starch or dextrin and the third was a weakly cationic homo-polymer of starch, highlighting the importance of the cavity effect. They were tested in hypercholesterolemic male Wistar rats and their ability to regulate hypercholesterolemia was similar to that for the reference BAS cholestyramine, but with two additional advantages: (i) they normalized the TG level and (ii) they did not increase the creatinine level. Neither hepatotoxicity nor kidney injury was detected, further supporting them as therapeutical candidates to manage hypercholesterolemia.


Structural stability and Sin a 1 anti-epitope antibody binding ability of yellow mustard (Sinapis alba L.) napin during industrial-scale myrosinase inactivation process.
This study investigated the structural stability of yellow mustard (YM, Sinapis alba L.) napin and the changes of its Sin a 1 anti-epitope antibody-binding ability during myrosinase enzyme inactivation process. The food industry uses myrosinase-inactive non-pungent YM for uses beyond spice applications. Napin was isolated from seeds received from an industrial processor before (YM + M) and after (YM - M) myrosinase inactivation. Secondary and tertiary structural features and surface hydrophobicity parameters of napin were analyzed. The Sin a 1 content in YM seeds and the stability of Sin a 1-containing napin during simulated in vitro gastrointestinal (GI) digestion were determined by a non-competitive indirect enzyme-linked immunosorbent assay using the Sin a 1 anti-epitope antibody (AE-Ab) as the primary Ab. YM napin retained the dominant alpha-helical components of secondary and tertiary structure folds during this process. YM - M napin showed changes in hydrophobicity parameters of the molecules and binding ability of AE-Ab: 2.19 ± 0.48 g per 100 g of YM - M seeds vs. 1.49 ± 0.16 g per 100 g YM + M seeds. YM - M proteins were more susceptible for in vitro GI digestion and also showed a 30% reduction in AE-Ab binding ability upon digestion of napins. This suggests that the myrosinase inactivation process has induced the surface modification of napin, exposing Sin a 1 epitope, leading to an increase in AE-Ab binding. However, the epitope region of YM - M napin showed improved susceptibility for hydrolysis during GI digestion resulting in fewer available epitope regions, suggesting a possible reduction in napin immune reactivity.


Indications for computed tomography in patients with minor head injury.
Computed tomography (CT) is widely used as a screening test in patients with minor head injury, although the results are often normal. We performed a study to develop and validate a set of clinical criteria that could be used to identify patients with minor head injury who do not need to undergo CT. In the first phase of the study, we recorded clinical findings in 520 consecutive patients with minor head injury who had a normal score on the Glasgow Coma Scale and normal findings on a brief neurologic examination; the patients then underwent CT. Using recursive partitioning, we derived a set of criteria to identify all patients who had abnormalities on CT scanning. In the second phase, the sensitivity and specificity of the criteria for predicting a positive scan were evaluated in a group of 909 patients. Of the 520 patients in the first phase, 36 (6.9 percent) had positive scans. All patients with positive CT scans had one or more of seven findings: headache, vomiting, an age over 60 years, drug or alcohol intoxication, deficits in short-term memory, physical evidence of trauma above the clavicles, and seizure. Among the 909 patients in the second phase, 57 (6.3 percent) had positive scans. In this group of patients, the sensitivity of the seven findings combined was 100 percent (95 percent confidence interval, 95 to 100 percent). All patients with positive CT scans had at least one of the findings. For the evaluation of patients with minor head injury, the use of CT can be safely limited to those who have certain clinical findings.


Iatrogenic effects of psychosocial interventions for substance use disorders: prevalence, predictors, prevention.
To examine the prevalence and personal and intervention-related predictors of potential iatrogenic effects associated with psychosocial interventions for substance use disorders and provide a conceptual framework to guide further research on such effects. A review of relevant studies focuses on the prevalence and predictors of potential iatrogenic effects of psychosocial treatment and prevention programs for substance use disorders. Between 7% and 15% of patients who participate in psychosocial treatment for substance use disorders may be worse off subsequent to treatment than before. In addition, several controlled trials of substance use prevention have shown some apparent iatrogenic effects, including more positive expectations about substance use and a rise in alcohol use and alcohol-related problems. Probable person-related predictors of deterioration associated with treatment include younger age and unmarried status, more serious current diagnoses and substance use problems and more psychiatric and interpersonal problems. Probable intervention-related predictors of deterioration include lack of bonding; lack of monitoring; confrontation, criticism and high emotional arousal; deviancy modeling; and stigma, low or inappropriate expectations and lack of challenge. A significant minority of individuals with substance use problems appear to deteriorate during or shortly after participation in treatment or prevention programs. Safety standards and monitoring procedures are needed to routinely identify potential adverse consequences of intervention programs; research is needed to clarify whether deterioration is due to iatrogenic effects of interventions and to identify new approaches to counteract any such effects.


Short Synthetic Terminators for Improved Heterologous Gene Expression in Yeast.
Terminators play an important role both in completing the transcription process and impacting mRNA half-life. As such, terminators are an important synthetic component considered in applications such as heterologous gene expression and metabolic engineering. Here, we describe a panel of short (35-70 bp) synthetic terminators that can be used for modulating gene expression in yeast. The best of these synthetic terminator resulted in 3.7-fold more fluorescent protein output and 4.4-fold increase in transcript level compared to that with the commonly used CYC1 terminator. These synthetic terminators offer several advantages over native sequences, including an easily synthesized short length, minimal sequence homology to native sequences, and similar or better performance characteristics than those of commonly used longer terminators. Furthermore, the synthetic terminators are highly functional in both Saccharomyces cerevisiae and an alternative yeast, Yarrowia lipolytica, demonstrating that these synthetic designs are transferrable between diverse yeast species.


Prevention of conglomerate formation in not-from-concentrate single-cultivar cloudy apple juice by using different treatment methods.
Conglomerates may form at the bottom of bottles containing not-from-concentrate (NFC) cloudy apple juice obtained from a single apple cultivar. Since dissociation or dispersion of these conglomerates cannot be achieved by shaking, the juice appears unsightly, and consumers can mistake the product as being spoilt. Juice from Elstar and Braeburn apples was treated with selected enzymes (gluco-amylase, alpha-amylase, pectin lyase, polygalacturonase and protease) and by using bentonite and a separator. The effects of these treatments on the formation of conglomerates in cloudy apple juice have been studied, and the treatment effects on turbidity and cloud stability have been documented. Conglomerates were observed in juices treated with protease or bentonite and in control juices. However, no conglomerates were observed in the juice samples treated with gluco-amylase, alpha-amylase, pectin lyase or pectin lyase in combination with polygalacturonase. The results obtained after treatment with a separator were not consistent. It is supposed that carbohydrate fractions play a more important role in conglomerate formation than proteins and phenols. Gluco-amylase and alpha-amylase treatment also provides good cloud stability, and thus can be a suitable method for preventing conglomerate formation in single-cultivar NFC cloudy apple juice.


Single-unit responses of serotonergic dorsal raphe neurons to specific motor challenges in freely moving cats.
Serotonin has been hypothesized to play an important role in the central control of motor function. Consistent with this hypothesis, virtually all serotonergic neurons within the medullary nuclei raphe obscurus and raphe pallidus in cats are activated in response to specific motor challenges. To determine whether the response profile of serotonergic neurons in the midbrain is similar to that observed in the medulla, the single-unit activity of serotonergic dorsal raphe nucleus cells was studied during three specific motor activities: treadmill-induced locomotion, hypercarbia-induced ventilatory response and spontaneous feeding. In contrast to the results obtained for medullary raphe cells, none of the serotonergic dorsal raphe cells studied (n=26) demonstrated increased firing during treadmill-induced locomotion. A subset of serotonergic dorsal raphe cells (8/36) responded to the hypercarbic ventilatory challenge with increased firing rates that were directly related to the fraction of inspired carbon dioxide, and a non-overlapping subset of cells (6/31) was activated during feeding. All feeding-on cells demonstrated a rapid activation and de-activation coincident with feeding onset and offset, respectively. Although the proportions of serotonergic cells activated by hypercarbia or feeding in the dorsal raphe nucleus were similar to those found in the medullary raphe, there were several major distinctions in the response characteristics for the two cell groups. In contrast to the medullary serotonergic neurons, only a minority of dorsal raphe nucleus serotonergic neurons responded to a motor challenge. Overall, the above results suggest very different roles for the midbrain and medullary serotonergic neurons in response to motor activities.


[Immunization with Leishmania amazonensis subgenomic libraries protects BALB/c mice against the challenge].
A genomic library of Leishmania amazonensis in expression vector of eukaryote cells (pEF1HisA, pEF1HisB, pEF1HisC) was prepared. Also two subgenomic libraries having each 500 clones approximately were created and BALB/c mice were immunized with 50 mg/0,1 mL of DNA from each. Two immunizations were administered intramuscularly at 15-day interval. Groups of control mice were immunized with DNA from empty plasmid pEF1His, with soluble parasite antigen (100 mg/0,1 mL) and saline solution. The size of lesions was measured for 12 weeks and at the end of the experiment, the parasite load at lesion sites was determined by plaque microtitration method. In mice immunized with subgenomic library DNAI and with soluble antigens,the size of lesions was controlled, which reached an statistical difference (p< 0,05) in relation to the rest of groups whose lesions increased. The parasite load found in lesion sites confirmed the previous results; the number of promastigots was significantly lower in those mice already protected. It was concluded that in subgenomic library DNA1 there should be genes or gene fragments whose in vivo expression induces protective immune response against the challenge in the murine model used.


Partial denture prosthodontic procedures employed by practising graduates of the University of the Witwatersrand, Johannesburg.
This study sought answers to the following two questions related to the teaching of partial denture prosthodontics in the Department of Prosthetic Dentistry at the University of the Witwatersrand, Johannesburg (Wits). Firstly, do practising graduates from Wits assiduously apply, or do they perhaps ignore, the concepts, principles, and practices taught to them at undergraduate level? Secondly, is there any merit in providing additional tutorials on partial denture prosthodontics to undergraduate students at Wits? A questionnaire was mailed to dentists who had graduated at Wits between 1979 and 1986. This sample of 302 subjects was divided into two groups: Group I--those who had graduated between 1979 and 1982; Group II--those who had graduated between 1983 and 1986 and had received additional tutorials on partial denture design. The results suggest that a wide gap exists between faculty beliefs about partial denture design and fabrication and the methods used in general dental practice. Moreover, additional tutorials had some effect on the attitudes and practices of the respondents.


The incidentally discovered asymptomatic adrenal tuberculous mass mimicking malignancy.
Tuberculous adrenal mass without any tuberculous changes in other sites is a rare entity. In this study we describe such a case. A male patient of 47 years with 6 months history of anorexia and weakness was presented. Ultrasonography and computed tomography revealed a mass in the right adrenal gland. It was mistaken as a malignant neoplasm and the diagnosis was confirmed by surgical exploration.


Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis.
The efficacy of exchange transfusion as an adjunct treatment for severe falciparum malaria is controversial. No sufficiently powered, randomized, controlled study has been reported. We analyzed 8 studies that compared survival rates associated with adjunct exchange transfusion with those associated with antimalarial chemotherapy alone. Exchange transfusion was not associated with a higher survival rate than was antimalarial chemotherapy alone (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.7-2.1). However, patients who received transfusions had higher levels of parasitemia and more-severe malaria. Sensitivity analysis found that survival rates were higher among patients with partial immunity to malaria (OR, 0.5; 95% CI, 0.2-1.2) than they were among patients with no immunity (OR, 2.1; 95% CI, 0.9-4.8; P=.007). Exchange transfusion does not appear to increase the survival rate; however, there were significant problems with the comparability of treatment groups in the studies reviewed, and a randomized controlled trial is necessary to determine whether exchange transfusion is beneficial.


Overview of idiopathic pulmonary fibrosis (IPF) and evidence-based guidelines.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive form of interstitial lung disease (ILD), characterized by fibrosis and worsening lung function, that primarily occurs in those 50 years and older. Various causes including genetic susceptibility, environmental risk factors, and exposures have been suggested in the literature. All of these cause repetitive micro-injury to the lung tissue and vasculature, which triggers a cascade of inflammatory response and fibrosis. Symptoms are nonspecific and most patients present several years after the initial radiographic changes occur. Diagnosis requires a high index of clinical suspicion supported by distinct radiographic and/or histopathologic findings. Median survival is estimated at between 2 and 3 years after diagnosis. Other than lung transplantation, no treatment has shown survival benefit. Two most recently approved medications for IPF, pirfenidone and nintedanib, can slow disease progression. Most patients have several comorbid conditions that can affect the course of their disease, including gastroesophageal reflux disease, obstructive sleep apnea, cardiomyopathy, and pulmonary hypertension. Observational studies suggested possible benefits in transplant-free survival and patients' outcomes with these medications. In addition to the new treatment options and optimal management of the comorbidities in patients with IPF, pulmonary rehabilitation remains a critical part of management and has been shown to improve quality of life and functional level. Considering the complexity of the diagnosis and management, the American Thoracic Society and European Respiratory Society published a joint statement on diagnosis and treatment of IPF. This article provides an overview of the epidemiology, pathophysiology, and guideline-recommended approaches for the diagnosis and management of IPF.


Is thrombocytosis a useful prognostic marker in renal cell carcinoma? Results of a single-center retrospective analysis.
Our aim was to determine the correlation of platelet count with stage and grade of renal cell carcinoma (RCC) and to determine whether progression of disease was more likely in those with thrombocytosis. A retrospective review of patients with RCC from January 2004 to December 2011 was undertaken. Patients with no preoperative platelet count and those with multiple tumors were excluded. Disease progression was defined as appearance of local recurrence or distant metastasis on follow-up. Thrombocytosis was defined as a platelet count of >400,000/cumm. Standard tests of significance and multivariate analysis using logistic regression were performed. A total of 322 cases were identified. The median follow-up was 7 months (range, 2-84 months). The platelet count correlated significantly with higher Fuhrmann grade, as well as increasing TNM stage at diagnosis. Patients with a platelet count of >400,000/cumm (n = 35) had a significantly higher mean tumor size and worse grade at diagnosis than those with a normal platelet count (n = 287). Patients with thrombocytosis also had a significantly worse stage at presentation. Progression of disease was seen more often in patients with thrombocytosis (28.6% vs 11.9%, P = 0.07). The median time to progression was significantly faster in patients with thrombocytosis (9 vs 18 months, P = 0.018). However, on multivariate analysis TNM stage was the only significant predictor of time to progression. Rising platelet count correlated significantly with advancing stage and grade of disease. Patients with thrombocytosis were significantly more likely to have advanced tumors at presentation, poorer histological features, and rapid disease progression.


The subgaleal endoscopic browlift.
Most endoscopic browlifts are performed in a subperiosteal plane with or without fixation posterior to the hairline at the incision site. The extent and longevity of browlifting are variable and somewhat unpredictable. We reviewed the literature on endoscopic browlifting techniques and describe herein our technique for the subgaleal endoscopic browlift procedure. It differs from the published reports of subperiosteal endoscopic techniques in the plane of dissection, circumvention of a periosteal release, and suture fixation at the brow level. We have used this technique for browlifting in male and female patients alike, as well as in patients with preoperative brow asymmetries, with consistent results.


Prevalence, distribution, and clinical associations of suspected postictal changes on brain magnetic resonance imaging in epileptic dogs.
To determine the prevalence of presumed postictal changes (PC) on brain MRI in epileptic dogs, describe their distribution, and recognize possible correlations with different epilepsy features. 540 client-owned dogs with epilepsy and a complete medical record that underwent brain MRI at 4 veterinary referral hospitals between 2016 and 2019. Data were collected regarding signalment, seizure type, seizure severity, time between last seizure and MRI, and etiological classification of epilepsy. Postictal changes were considered when solitary or multiple intraparenchymal hyperintense lesions were observed on T2-weighted and fluid-attenuated inversion recovery images and were hypointense or isointense on T1-weighted sequences, which were not confined to a vascular territory and showed no to mild mass effect and no to mild contrast enhancement. Sixty-seven dogs (12.4%) showed MRI features consistent with PC. The most common brain sites affected were the piriform lobe, hippocampus, temporal neocortex, and cingulate gyrus. Dogs having suffered cluster seizures or status epilepticus were associated with a higher probability of occurrence of PC, compared to dogs with self-limiting seizures (OR 2.39; 95% confidence interval, 1.33 to 4.30). Suspected PC were detected both in dogs with idiopathic epilepsy and in those with structural epilepsy. Dogs with unknown-origin epilepsy were more likely to have presumed PC than were dogs with structural (OR 0.15; 95% confidence interval, 0.06 to 0.33) or idiopathic epilepsy (OR 0.42; 95% confidence interval, 0.20 to 0.87). Time between last seizure and MRI was significantly shorter in dogs with PC. MRI lesions consistent with PC were common in epileptic dogs, and the brain distribution of these lesions varied. Occurrence of cluster seizures or status epilepticus, diagnosis of unknown origin epilepsy, and lower time from last seizure to MRI are predictors of suspected PC.


Internal and external constraints in the evolution of morphological allometries in a butterfly.
Much diversity in animal morphology results from variation in the relative size of morphological traits. The scaling relationships, or allometries, that describe relative trait size can vary greatly in both intercept and slope among species or other animal groups. Yet within such groups, individuals typically exhibit low variation in relative trait size. This pattern of high intra- and low intergroup variation may result from natural selection for particular allometries, from developmental constraints restricting differential growth among traits, or both. Here we explore the relative roles of short-term developmental constraints and natural selection in the evolution of the intercept of the allometry between the forewing and hindwing of a butterfly. First, despite a strong genetic correlation between these two traits, we show that artificial selection perpendicular to the forewing-hindwing scaling relationship results in rapid evolution of the allometry intercept. This demonstrates an absence of developmental constraints limiting intercept evolution for this scaling relationship. Mating experiments in a natural environment revealed strong stabilizing selection favoring males with the wild-type allometry intercept over those with derived intercepts. Our results demonstrate that evolution of this component of the forewing-hindwing allometry is not limited by developmental constraints in the short term and that natural selection on allometry intercepts can be powerful.


[The results of a study of the contamination of bodies of water by rotaviruses against a background of gastroenteritis morbidity].
The results of a sanitary virological survey of the prevalence of rotaviruses in water objects in relation to gastroenteritis incidence are presented. Some regularities of the epidemic process of rotavirus infection were discovered: a high portion of infants involved, occurrence of cases of the disease predominantly in the cold periods of the year, a significant portion (23.8%) of rotavirus gastroenteritis in the total incidence of acute intestinal infections, etc. Besides, comparison of the data on the dynamics of rotavirus infection incidence and on the contamination of water objects with rotaviruses revealed a strong correlation between these data. The possibility of using this information for the evaluation of the epidemiological situation is discussed.


Factors associated with falls in the elderly: a community study.
In 2793 respondents aged 65 and over in a survey of a geographically defined community, who were asked about falls in the preceding twelve months, the estimated annual prevalence rate (persons) of falls was 28.0%. Standardized for age, the rate was twice as high in women as in men. Rates increased with age but more steeply in men than in women. Compared with non-fallers, fallers had been in more recent contact with their general practitioner, showed higher prevalence of problems with mobility and daily living, a more frequent history of stroke and heart disease, and had more episodes of non-rotatory vertigo, double vision, faints and blackouts and episodes of weakness or numbness. Fallers also showed more frequent evidence suggestive of cognitive impairment. More fallers than non-fallers were taking diuretics and tranquilizers and these associations merit further study.


Early detection of elevated cardiac biomarkers to optimise risk stratification in patients with COVID-19.
Risk stratification is crucial to optimise treatment strategies in patients with COVID-19. We aimed to evaluate the impact on mortality of an early assessment of cardiac biomarkers in patients with COVID-19. Humanitas Clinical and Research Hospital (Rozzano-Milan, Lombardy, Italy) is a tertiary centre that has been converted to the management of COVID-19. Patients with confirmed COVID-19 were entered in a dedicated database for cohort observational analyses. Outcomes were stratified according to elevated levels (ie, above the upper level of normal) of high-sensitivity cardiac troponin I (hs-TnI), B-type natriuretic peptide (BNP) or both measured within 24 hours after hospital admission. The primary outcome was all-cause mortality. A total of 397 consecutive patients with COVID-19 were included up to 1 April 2020. At the time of hospital admission, 208 patients (52.4%) had normal values for cardiac biomarkers, 90 (22.7%) had elevated both hs-TnI and BNP, 59 (14.9%) had elevated only BNP and 40 (10.1%) had elevated only hs-TnI. The rate of mortality was higher in patients with elevated hs-TnI (22.5%, OR 4.35, 95% CI 1.72 to 11.04), BNP (33.9%, OR 7.37, 95% CI 3.53 to 16.75) or both (55.6%, OR 18.75, 95% CI 9.32 to 37.71) as compared with those without elevated cardiac biomarkers (6.25%). A multivariate analysis identified concomitant elevation of both hs-TnI and BNP as a strong independent predictor of all-cause mortality (OR 3.24, 95% CI 1.06 to 9.93). An early detection of elevated hs-TnI and BNP predicts mortality in patients with COVID-19. Cardiac biomarkers should be systematically assessed in patients with COVID-19 at the time of hospital admission in order to optimise risk stratification.


N-methyl-D-aspartate receptor agonists modulate homocysteine-induced developmental abnormalities.
We showed previously that the induction of neural crest (NC) and neural tube (NT) defects is a general property of N-methyl-D-aspartate receptor (NMDAR) antagonists. Since homocysteine induces NC and NT defects and can also act as an NMDAR antagonist, we hypothesized that the mechanism of homocysteine-induced developmental defects is mediated by competitive inhibition of the NMDAR by homocysteine. If this hypothesis is correct, homocysteine-induced defects will be reduced by NMDAR agonists. To test the hypothesis, we treated chicken embryos during the process of neural tube closure with sufficient homocysteine thiolactone to induce NC and NT defects in approximately 40% of survivors or with homocysteine thiolactone in combination with each of a selected set of NMDAR agonists in 0. 05-5000 nmol doses. Glutamate site agonists selected were L-glutamate and N-methyl-D-aspartate. Glycine site agonists were glycine, D-cycloserine, and aminocyclopropane-carboxylic acid. Glycine was the most effective overall, reducing defects significantly at two different doses (each P>0.001). These results support the hypothesis that homocysteine may affect NC and NT development by its ability to inhibit the NMDAR. One potentially important consequence of this putative mechanism is that homocysteine may interact synergistically with other NMDAR antagonists to enhance its effect on development.


Prognostic Value of DNA Damage Response Genomic Alterations in Relapsed/Advanced Urothelial Cancer.
DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03-4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31-0.8; p = .003). Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.


The Role of Heparin in Embryo Implantation in Women with Recurrent Implantation Failure in the Cycles of Assisted Reproductive Techniques (Without History of Thrombophilia).
Several studies have shown the improving effect of heparin on the outcomes of ART. Moreover, it has been reported that adding heparin in non-thrombophilia patients with RIF is useful.The aim of this study was to evaluate the beneficial effects of heparin on ART outcomes in women with history of recurrent implantation failure (RIF) and without history of congenital or acquired thrombophilia in a randomized, controlled clinical trial (RCT). In this study, 100 patients with a history of two or more failures in implantation in cycles of ART were randomly subdivided into two groups of study and control. Patients of the control group just received the luteal phase support. In the patients of study group, in addition to the routine support of luteal phase following in vitro fertilization (IVF) or intra cytoplasmic sperm injection (ICSI), 5000 units of subcutaneous heparin was administered for 15 days from the day of oocyte pick up. Pregnancy test (β-HCG) was done for patient of two groups 15 days after IVF. In the study group, pregnancy test was positive in 16 (32%) patients and negative in 34 (68%) patients. In the control group, pregnancy test was positive in 15 (30%) patients and negative in 35 (70%) patients. There was no significant difference between two groups for the role of heparin in the pregnancy rate (p = 0.5). Although the effect of heparin on pregnancy was not statistically significant in this study, with regard to the numerous benefits of this agent, it is recommended to study its effects in further studies with lager sample size.


Associations between animal and herd management factors, serological response to three respiratory pathogens and pluck lesions in finisher pigs on a farrow-to-finish farm.
Serological screening is a common method to monitor antibody response to pathogen exposure, but results could vary due to several factors. This study aimed to quantify animal and management related factors associated with variation in antibody levels in finisher pigs at slaughter, in an Irish farrow-to-finish farm endemically infected with Actinobacillus pleuropneumonia (App), Mycoplasma hyopneumoniae (Mhyo) and swine influenza virus (SIV). A second objective was to estimate differences in antibody levels in pigs presenting pluck lesions. This was an observational study whereby pigs were managed as per routine farm practice. Data on sow parity, number of born alive (NBA) pigs per litter, cross-fostering status, birth and weaning body weight were recorded from 1016 pigs born from one farrowing batch. At slaughter, blood samples were collected for serological analysis and pigs were inspected for presence of enzootic pneumonia (EP)-like lesions, pleurisy, pericarditis and heart condemnations. Pigs were retrospectively classified into three production flows, depending on time spent in each production stage: flow 1 (F1; pigs followed the normal production flow); flow 2 (F2; pigs which were delayed by 1 week from advancing forward); and flow 3 (F3; pigs delayed by > 1 week from advancing forward). A nested case-control design was applied by matching pigs from each flow by sow parity, birth weight and NBA. Pigs born from primiparous sows had higher antibody levels for App than those born to parity ≥5 sows (P < 0.05) and there was no association between any of the pathogens investigated and other early life indicators (P > 0.05). Pigs in F1 had lower antibody levels for App but higher antibody levels for SIV than F2 and F3 pigs (P < 0.05). There was no association between pluck lesions and respiratory pathogens (P > 0.05), except for increased antibody levels for Mhyo when EP-like lesions were present (P = 0.006). Results indicate that offspring from primiparous sows develop higher antibody levels for App IV toxin when exposed to this disease and that enforcement of a strict all-in/all-out production system would reduce on-farm disease circulation. A high percentage of pigs were affected with EP-like lesions which were associated with higher antibody levels for Mhyo.


Survival and quality of life after minimally invasive esophagectomy: a single-surgeon experience.
Reports on quality of life (QOL) after minimally invasive esophagectomy (MIE) have been limited. This report compares perioperative outcomes, survival, and QOL after MIEs with open transthoracic esophagectomy (TTE) and open transhiatal esophagectomy (THE). After institutional review board approval, retrospective review of a prospectively maintained database identified patients who underwent esophageal resection for esophageal cancer at Creighton University between August 2003 and August 2010. Patients with preoperative stage 4 disease, emergent procedures, laparoscopic transhiatal esophagectomies, or esophagojeujunostomies were excluded from the study. The study patients were categorized as having undergone open TTE, open THE, or MIE. Overall survival (OS) was the interval between diagnosis and death or follow-up assessment. Disease-free survival (DFS) was the interval between surgery and recurrence, death, or follow-up assessment. For the patients who survived at least 1 year after surgery, QOL was assessed using European Organization for Research and Treatment of Cancer (EORTC-QLQ, version 3.0) and esophageal module (EORTC-QLQ OES 18) questionnaires. The study criteria were satisfied by 104 patients. Lymph node harvest with MIE (median = 20) was similar to that with open TTEs (median = 19) and significantly higher (P < 0.001) than that with open THEs (median = 12). The percentage of patients requiring intraoperative blood transfusion in the MIE group (23.4%) was significantly lower (P < 0.001) than in the open TTE (73.1%) and THE (67.7%) groups. The volume of intraoperative blood product transfusion was significantly lower for the MIE patients (median = 0 ml) than for the open TTE (median = 700 ml) and THE (median = 700 ml) patients. The incidence of respiratory complications with MIEs (10.64%) was significantly lower than with open TTEs (34.61%) and THEs (32.26%). The groups did not differ significantly in terms of R0 resection rates, OS, DFS, or QOL. MIEs offer a safe and viable alternative to open esophagectomies because they reduce the need and volume of intraoperative blood product transfusion and postoperative respiratory complications without compromising oncological clearance, survival, and QOL.


Localization of two fibronectin-binding glycoproteins in rat liver and primary hepatocytes. Co-distribution in vitro of integrin (alpha 5 beta 1) and non-integrin (AGp110) receptors in cell-substratum adhesion sites.
We have compared the localization of integrin alpha 5 beta 1 and AGp110 (apical glycoprotein of Mr 110 x 10(3]] in rat liver parenchyma and in primary hepatocyte cultures. Integrin alpha 5 beta 1 is a heterodimeric fibronectin receptor. AGp110 is a newly described monomeric glycoprotein of the apical (bile canalicular) membrane domain of liver parenchyma that binds in an RGD-independent manner to fibronectin and mediates spreading of hepatocytes onto fibronectin-coated substrata. Using Western blotting of fractionated liver membranes and immunocytochemistry of liver sections at light- and electron-microscope levels, we have confirmed that AGp110 is a canalicular glycoprotein and have established that integrin is located in approximately equal proportions in the sinusoidal, lateral and canalicular membrane domains. In the canalicular surface domain both glycoproteins are associated with microvilli. Examination of immunolabelled primary hepatocytes spread on fibronectin-coated substrata by light and laser scanning confocal microscopy revealed colocalization of AGp110, integrin, actin and vinculin in substratum-attached microextensions at the periphery of the basal cell surface. Actin filaments that terminated at these cell processes originated from circular sub-cortical actin fibres. Interference reflection microscopy revealed focal adhesive contacts at the edge of the basal cell periphery at the same location where AGp110 and integrin were observed by immunofluorescence. In vitro, a proportion of the primary hepatocytes seeded onto fibronectin-coated substrata aggregated into colonies of several cells with intercellular contacts between neighbouring cells. Cell-substratum contacts containing integrin, AGp110, actin and vinculin followed the contours of these colonies in the same manner as they delineated the basal periphery of single, substratum-attached cells. We conclude that both integrin and AGp110 contribute to hepatocyte-fibronectin adhesive interactions and that intercellular adhesion and cooperation among hepatocytes in their response to fibronectin matrices leads to colony formation and morphological differentiation of parenchymal cell monolayers in vitro.


[Malaria prevention for long-term travelers].
The risk of malaria increases with the duration of stay. Long-term travelers need to know the risk of malaria and the effective measures to reduce this risk: personal protective measures against mosquito bites and chemoprophylaxis. The use of insecticide-impregnated mosquito nets and window screens should be emphasized. When chemoprophylaxis is indicated it should be prescribed at least for the first 3 to 6 months. Then, alternative strategies can be discussed with the traveler: continuous chemoprophylaxis, seasonal chemoprophylaxis and/or standby emergency treatment.


Global expression profiling of globose basal cells and neurogenic progression within the olfactory epithelium.
Ongoing, lifelong neurogenesis maintains the neuronal population of the olfactory epithelium in the face of piecemeal neuronal turnover and restores it following wholesale loss. The molecular phenotypes corresponding to different stages along the progression from multipotent globose basal cell (GBC) progenitor to differentiated olfactory sensory neuron are poorly characterized. We used the transgenic expression of enhanced green fluorescent protein (eGFP) and cell surface markers to FACS-isolate ΔSox2-eGFP(+) GBCs, Neurog1-eGFP(+) GBCs and immature neurons, and ΔOMP-eGFP(+) mature neurons from normal adult mice. In addition, the latter two populations were also collected 3 weeks after olfactory bulb ablation, a lesion that results in persistently elevated neurogenesis. Global profiling of mRNA from the populations indicates that all stages of neurogenesis share a cohort of >2,100 genes that are upregulated compared to sustentacular cells. A further cohort of >1,200 genes are specifically upregulated in GBCs as compared to sustentacular cells and differentiated neurons. The increased rate of neurogenesis caused by olfactory bulbectomy had little effect on the transcriptional profile of the Neurog1-eGFP(+) population. In contrast, the abbreviated lifespan of ΔOMP-eGFP(+) neurons born in the absence of the bulb correlated with substantial differences in gene expression as compared to the mature neurons of the normal epithelium. Detailed examination of the specific genes upregulated in the different progenitor populations revealed that the chromatin modifying complex proteins LSD1 and coREST were expressed sequentially in upstream ΔSox2-eGFP(+) GBCs and Neurog1-eGFP(+) GBCs/immature neurons. The expression patterns of these proteins are dynamically regulated after activation of the epithelium by methyl bromide lesion.


Treatment of pityriasis versicolor with topical application of essential oil of Cymbopogon citratus (DC) Stapf - therapeutic pilot study.
Pityriasis versicolor is a fungal infection caused by Malassezia spp. that has frequent relapses. The main objective of this research was to perform phase I and II clinical studies, using formulations containing essential oil of Cymbopogon citratus in patients with pityriasis versicolor. Phase I study included twenty volunteers to ascertain the safety of the formulations. In phase II, 47 volunteers randomly received essential oil formulations at 1.25 μL/mL concentration, for forty days. The shampoo should be applied three times a week and the cream twice a day. A control group in phase II, consisting of 29 volunteers, received the same formulations but with 2% ketoconazole as the active ingredient. No significant adverse events were observed in volunteers during Phase I. In Phase II, 30 (63.83%) volunteers using essential oil and 18 (62.07%) using ketoconazole remained until the end of the study. We observed a predominance of lesions in disseminated form, with M. sympodialis detected as the predominant agent identified in cultures. After 40 days of treatment, the rate of mycological cure was 60% (p <0.05) for the group treated with essential oil of C. citratus and over 80% (p <0.05) for the group treated with ketoconazole formulations. Notwithstanding the safety and antifungal effects observed in this study after application of formulations containing the essential oil of C. citratus, further studies with larger populations should be performed to confirm the actual potential of these formulations in the treatment of patients with Pityriasis versicolor.


Comparison Of Health Insurance Coverage For Hearing Aids And Other Services In Alberta.
Of the several barriers associated with uptake and adherence to hearing services, cost is the most commonly identified barrier in Canada. This study evaluated health insurance plans for hearing care coverage within Alberta, Canada, and subsequent out-of-pocket expenses that would result if an individual chose to pursue treatment. An investigation of eight companies that provide supplementary health coverage in Alberta was conducted. Categories of health service coverage included hearing, vision, speech-language pathology (S-LP), physical therapy related (PT-R; including massage therapy and chiropractic therapy) and alternative medicine related (AM-R; including osteopathy, acupuncture and naturopathy). All coverage amounts were corrected to a four-year term for comparison purposes. For a four-year term, the coverage amounts for hearing services were CAD 300-750; for vision services were CAD 0-900; for S-LP services were CAD 0-2,400; for PT-R services were CAD 1,400-10,200; and for AM-R services were CAD 0-10,200 per four-year term. The expected out-of-pocket expense for vision ranged from CAD 0 to CAD 2,766, whereas for hearing, it ranged from CAD 250 to CAD 11,700. A considerable range and discrepancy were reported between hearing care and most paramedical services. In addition, the coverage amounts for hearing care were inconsistent with treatment costs, resulting in considerable out-of-pocket expenses for most consumers. The potential implications of such cost-related barriers on public health are an important consideration as our understanding of the impact of untreated hearing impairment continues to increase.


Active focus stabilization for upright selective plane illumination microscopy.
Due to its sectioning capability, large field of view, and minimal light exposure, selective plane illumination microscopy has become the preferred choice for 3D time lapse imaging. Single cells in a dish can be conveniently imaged using an upright/inverted configuration. However, for measurements on long time scales (hours to days), mechanical drift is a problem; especially for studies of mammalian cells that typically require heating to 37°C which causes a thermal gradient across the instrument. Since the light sheet diverges towards the edges of the field of view, such a drift leads to a decrease in axial resolution over time. Or, even worse, the specimen could move out of the imaging volume. Here, we present a simple, cost-effective way to stabilize the axial position using the microscope camera to track the sample position. Thereby, sample loss is prevented and an optimal axial resolution is maintained by keeping the sample at the position where the light sheet is at its thinnest. We demonstrate the virtue of our approach by measurements of the light sheet thickness and 3D time lapse imaging of a cell monolayer at physiological conditions.


Prevalence, causes and impact of musculoskeletal impairment in Malawi: A national cluster randomized survey.
There is a lack of accurate information on the prevalence and causes of musculoskeletal impairment (MSI) in low income countries. The WHO prevalence estimate does not help plan services for specific national income levels or countries. The aim of this study was to find the prevalence, impact, causes and factors associated with musculoskeletal impairment in Malawi. We wished to undertake a national cluster randomized survey of musculoskeletal impairment in Malawi, one of the UN Least Developed Countries (LDC), that involved a reliable sampling methodology with a case definition and diagnostic criteria that could clearly be related to the classification system used in the WHO International Classification of Functioning, Disability and Health (ICF). A sample size of 1,481 households was calculated using data from the latest national census and an expected prevalence based on similar surveys conducted in Rwanda and Cameroon. We randomly selected clusters across the whole country through probability proportional to size sampling with an urban/rural and demographic split that matched the distribution of the population. In the field, randomization of households in a cluster was based on a ground bottle spin. All household members present were screened, and all MSI cases identified were examined in more detail by medical students under supervision, using a standardized interview and examination protocol. Data collection was carried out from 1st July to 30th August 2016. Extrapolation was done based on study size compared to the population of Malawi. MSI severity was classified using the parameters for the percentage of function outlined in the WHO International Classification of Functioning (ICF). A loss of function of 5-24% was mild, 25-49% was moderate and 50-90% was severe. The Malawian version of the EQ-5D-3L questionnaire was used, and EQ-5D index scores were calculated using population values from Zimbabwe, as a population value set for Malawi is not currently available. Chi-square test was used to test categorical variables. Odds ratio (OR) was calculated with a linear regression model adjusted for age, gender, location and education. A total of 8,801 individuals were enumerated in 1,481 households. Of the 8,548 participants that were screened and examined (response rate of 97.1%), 810 cases of MSI were diagnosed of which 18% (108) had mild, 54% (329) had moderate and 28% (167) had severe MSI as classified by ICF. There was an overall prevalence of MSI of 9.5% (CI 8.9-10.1). The prevalence of MSI increased with age, and was similar in men (9.3%) and women (9.6%). People without formal education were more likely to have MSI [13.3% (CI 11.8-14.8)] compared to those with formal education levels [8.9% (CI 8.1-9.7), p<0.001] for primary school and [5.9% (4.6-7.2), p<0.001] for secondary school. Overall, 33.2% of MSIs were due to congenital causes, 25.6% were neurological in origin, 19.2% due to acquired non-traumatic non-infective causes, 16.8% due to trauma and 5.2% due to infection. Extrapolation of these findings indicated that there are approximately one million cases of MSI in Malawi that need further treatment. MSI had a profound impact on quality of life. Analysis of disaggregated quality of life measures using EQ-5D showed clear correlation with the ICF class. A large proportion of patients with moderate and severe MSI were confined to bed, unable to wash or undress or unable to perform usual daily activities. This study has uncovered a high prevalence of MSI in Malawi and its profound impact on a large proportion of the population. These findings suggest that MSI places a considerable strain on social and financial structures in this low-income country. The Quality of Life of those with severe MSI is considerably affected. The huge burden of musculoskeletal impairment in Malawi is mostly unattended, revealing an urgent need to scale up surgical and rehabilitation services in the country.


Expression of RESP18 in peptidergic and catecholaminergic neurons.
We examined the expression of regulated endocrine-specific protein of 18-kD (RESP18) in selected peptidergic and catecholaminergic neurons of adult rat brain. In the hypothalamic paraventricular, supraoptic, and accessory nuclei, RESP18 mRNA was highly expressed in neurons immunostained for oxytocin and vasopressin. RESP18 mRNA was also highly expressed in paraventricular nucleus neurons immunostained for corticotropin-releasing hormone, thyrotropin-releasing hormone, and somatostatin. RESP18 mRNA was expressed in POMC cells of the arcuate nucleus, in neuropeptide Y cells of the dorsal tegmental nucleus, lateral reticular nucleus, and hippocampus, and in brainstem catecholaminergic neurons. RESP18 mRNA expression was high in all paraventricular and arcuate neurons, but RESP18 protein was detectable in the perikarya of a subset of these neurons, suggesting an important post-transcriptional component to the regulation of RESP18 expression. RESP18 antisera immunostained perikarya but not axon fibers or terminals. Sub-cellular fractionation of homogenates of several hypothalamic nuclei identified RESP18 protein in fractions enriched in endoplasmic reticulum. The presence of 22- and 24-kD RESP18 isoforms in the neural lobe of the pituitary indicated that some RESP18 protein exited the endoplasmic reticulum. The post-transcriptional regulation of RESP18 expression and localization of RESP18 protein primarily to the endoplasmic reticulum suggests that RESP18 plays a regulatory role in peptidergic neurons.


Exposure of Women With and Without Disabilities to Violence and Discrimination: Evidence from Cross-sectional National Surveys in 29 Middle- and Low-Income Countries.
There is a paucity of robust nationally representative data from low- and middle-income countries (LMICs) on the prevalence and risk factors associated with exposure of women with/without disability to either discrimination or violence. We undertook secondary analysis of data collected in Round 6 of UNICEF's Multiple Indicator Cluster Surveys (MICS) involving nationally representative data from 29 countries with a total sample size of 320,426 women aged 18 to 49 years. We estimated: (1) prevalence rates for exposure to discrimination and violence among women with/without disabilities in the previous year in a range of LMICs; (2) the relative risk of exposure when adjusted for demographic and contextual characteristics; (3) the relative risk of exposure associated with specific functional difficulties associated with disabilities; and (4) the association between country-level estimates and national wealth and human development potential. Our results indicated that women with disabilities were approximately twice as likely as women without disabilities to be exposed to violence and discrimination in the past year, and approximately one-third more likely to feel unsafe in either their home or local neighbourhood and to be at greater risk of domestic violence. Risk of exposure was associated with national characteristics (national wealth, human development potential) and within country factors, especially relative household wealth and level of education. These results must be of concern on two counts. First, they attest to the ongoing violation of the human rights of women with disabilities. Second, they point to increased exposure among women with disabilities to several well-documented social determinants of poorer health.


Intraocular pressure assessment in gas-filled eyes following vitrectomy.
The accuracy and precision of tonometric methods in measuring intraocular pressure (IOP) was assessed in 24 eye-bank eyes subjected to pars plana lensectomy/vitrectomy and air-fluid exchange. Intraocular pressure was measured in masked fashion with a Perkins' applanation tonometer, pneumatic applanation tonometer; a mercury manometer served as a reference standard. Pneumatic tonometry underestimated actual IOP by as much as 25%, and Schiotz' indentation tonometry underestimated actual IOP by as much as 79%. Perkins' applanation tonometry was significantly more accurate in estimating actual IOP in gas-filled eyes than pneumatic tonometry or Schiotz' indentation tonometry.


The new frontier of epigenetic heterogeneity in B-cell neoplasms.
There is mounting evidence that heterogeneity of the epigenome is a feature of many cancers, including B-cell lymphomas, and presents important clinical implications. The purpose of this review is to explain the biological and clinical relevance of this epigenetic phenomenon in B-cell neoplasms. Here, we summarize new findings demonstrating that B-cell lymphomas display increased DNA methylation heterogeneity compared to their normal counterparts. This plasticity of cytosine methylation manifests both as intertumor and intratumor heterogeneity and is associated with worse prognosis and poor clinical outcome in lymphoma patients. Recent studies of different subtypes of B-cell lymphomas have revealed that epigenetic aberrations and heterogeneous cytosine methylation patterning are common features of all neoplasms derived from B-lymphocytes, irrespective of maturation stage. With regard to mechanisms driving this process, recent reports suggest that cytosine methylation heterogeneity arises through passive and active processes. One factor implicated in active generation of cytosine methylation heterogeneity is activation-induced cytidine deaminase, which mediates DNA methylation changes and introduces epigenetic heterogeneity in normal germinal center B cells, the cells of origin of mature B-cell neoplasms such as diffuse large B-cell lymphoma and follicular lymphoma. Understanding the scope and mechanism of epigenetic heterogeneity in cancer is of paramount importance to our understanding of clonal plasticity and treatment responses in B-cell lymphomas.


Effects of oregano essential oil with or without feed enzymes on growth performance, digestive enzyme, nutrient digestibility, lipid metabolism and immune response of broilers fed on wheat-soybean meal diets.
1. The study was conducted to determine the effects of dietary supplementation of enzyme and oregano essential oil at two levels, alone or together, on performance, digestive enzyme, nutrient digestibility, lipid metabolism and immune response of broilers fed on wheat-soybean meal based diets. 2. The following dietary treatments were used from d 0 to 21. Diet 1 (control, CONT): a commercial diet containing no enzyme or oregano essential oil, diet 2 (ENZY): supplemented with enzyme, diet 3 (EO250): supplemented with essential oil at 250 mg/kg feed, diet 4 (EO500): supplemented with essential oil at 500 mg/kg feed, diet 5 (ENZY + EO250): supplemented with enzyme and essential oil at 250 mg/kg, and diet 6 (ENZY + EO500): supplemented with enzyme and essential oil at 500 mg/kg. 3. Birds fed on diets containing ENZY, EO250 and ENZY + EO250 had significantly higher weight gain than those given CONT diet from d 0 to 7. No significant effects on feed intake, feed conversion ratio, mortality, organ weights except for jejunum weight and intestinal lengths was found with either enzyme or essential oil, alone or in combination, over the 21-d growth period. The supplementation of essential oil together with enzyme decreased jejunum weight compared with essential oil alone. 4. Supplementation with enzyme significantly decreased viscosity and increased dry matter of digesta, but did not alter pH of digesta. There was no effect of essential oil alone at either concentration on viscosity, dry matter or pH of digesta. A significant decrease in viscosity of digesta appeared when essential oil was used with together enzyme. 5. The supplementation of essential oil at both levels with or without enzyme significantly increased chymotrypsin activity in the digestive system, and improved crude protein digestibility. 6. The higher concentration of essential oil with and without enzyme significantly increased serum total cholesterol concentrations. No significant effect on immune response was found with either enzyme or essential oil, alone or together. 7. Enzymes and essential oil had different modes of actions. The supplementation of enzyme with essential oil in diets is likely more effective in view of performance, nutrient digestibility, enzyme activities and immune system.


Impact of Treatment Strategy on Outcomes in Isolated Pulmonary Artery of Ductal Origin.
Isolated pulmonary artery (PA) of ductal origin (IPADO) is a rare cardiac defect which requires surgical repair, with or without preceding palliation. We sought to determine the impact of treatment strategy on outcomes. Retrospective study of consecutive patients with IPADO that underwent staged or primary repair from 1/05 to 9/16 at 6 Congenital Cardiac Research Collaborative centers. Patients with single ventricle physiology, major aortopulmonary collaterals, or bilateral IPADO were excluded. Primary outcome was isolated PA z-score at late follow-up. Secondary outcomes included PA symmetry index (isolated:confluent PA diameter) and reintervention burden. Propensity score adjustment was used to account for baseline differences. Of 60 patients in the study cohort, 26 (43%) underwent staged and 34 (57%) primary repair. The staged and primary repair groups differed in weight at diagnosis and presence of other heart disease but not in baseline PA dimensions. Staged patients underwent ductal stent (n = 16) or surgical shunt (n = 10) placement followed by repair at 210 vs. 21 days in the primary repair group (p < 0.001). At median follow-up of 4.5 years post-repair, after adjustment, isolated PA z-score (- 0.74 [- 1.75, - 0.26] vs. - 1.95 [- 2.91, - 1.59], p = 0.012) and PA symmetry index (0.81 [0.49, 1.0] vs. 0.55 [0.48, 0.69], p = 0.042) significantly favored the staged repair group. Freedom from PA reintervention was not different between groups (adjusted HR 0.78 [0.41, 1.48]; p = 0.445). A staged approach to repair of IPADO is associated with superior isolated PA size and symmetry at late follow-up. Consideration should be given to initial palliation in IPADO patients, when feasible.


Disseminated Coccidioidomycosis Following Insufficient Treatment at Initial Presentation: Case Report.
A 35-year-old male presented to our university hospital with night sweats, fevers, ulcerated skin lesions to the lower mouth and posterior neck, shortness of breath, and an enlarging cervical lymph node. The patient was evaluated 2 months prior for respiratory symptoms, cervical lymphadenopathy, and skin lesions resulting in a diagnosis of primary pulmonary coccidioidomycosis and was treated with a 4-week course of fluconazole. On presentation to our hospital, initial laboratory test results revealed leukocytosis, increased liver enzymes, elevated inflammatory markers, and hypercalcemia. Computed tomography scan of the chest revealed lung nodules in a miliary pattern and prominent mediastinal lymphadenopathy. Magnetic resonance imaging revealed multiple vertebral and iliac bone lesions, as well as bilateral psoas muscle lesions. Serum ELISA (enzyme linked immunosorbent assay) detected elevated serological markers against coccidioides, and sputum culture revealed coccidioides arthroconidia, confirming the presence of an acute coccidioides infection. Biopsy of the right iliac crest and cervical lymph node revealed spherules resembling coccidioides, escalating the diagnosis to disseminated coccidioidomycosis. The patient's hospital course was complicated by septic shock, acute respiratory distress syndrome requiring several days of mechanical ventilation, and acute kidney injury. He was ultimately treated with several weeks of voriconazole and liposomal amphotericin-B. He made a full recovery and was discharged on an extended course of oral voriconazole. Our case highlights the importance of recognition and appropriate treatment duration of disseminated coccidioidomycosis at initial presentation. Failure to do so may lead to increased morbidity and mortality.


Projected climate impacts for the amphibians of the Western hemisphere.
Given their physiological requirements, limited dispersal abilities, and hydrologically sensitive habitats, amphibians are likely to be highly sensitive to future climatic changes. We used three approaches to map areas in the western hemisphere where amphibians are particularly likely to be affected by climate change. First, we used bioclimatic models to project potential climate-driven shifts in the distribution of 413 amphibian species based on 20 climate simulations for 2071-2100. We summarized these projections to produce estimates of species turnover. Second, we mapped the distribution of 1099 species with restricted geographic ranges. Finally, using the 20 future climate-change simulations, we mapped areas that were consistently projected to receive less seasonal precipitation in the coming century and thus were likely to have altered microclimates and local hydrologies. Species turnover was projected to be highest in the Andes Mountains and parts of Central America and Mexico, where, on average, turnover rates exceeded 60% under the lower of two emissions scenarios. Many of the restricted-range species not included in our range-shift analyses were concentrated in parts of the Andes and Central America and in Brazil's Atlantic Forest. Much of Central America, southwestern North America, and parts of South America were consistently projected to experience decreased precipitation by the end of the century. Combining the results of the three analyses highlighted several areas in which amphibians are likely to be significantly affected by climate change for multiple reasons. Portions of southern Central America were simultaneously projected to experience high species turnover, have many additional restricted-range species, and were consistently projected to receive less precipitation. Together, our three analyses form one potential assessment of the geographic vulnerability of amphibians to climate change and as such provide broad-scale guidance for directing conservation efforts.


Associations between OPA1, MFN1, and MFN2 polymorphisms and primary open angle glaucoma in Polish participants of European ancestry.
Glaucomatous optic nerve damage is caused by selective death of retinal ganglion cells (RGCs). Another condition with underlying loss of RGCs is autosomal dominant optic atrophy (ADOA). Majority of ADOA patients have mutations in OPA1, gene responsible for mitochondrial fusion final steps. Clinical resemblance between the two diseases make genes involved in mitochondrial fusion good candidates as glaucoma genes. In this study, we investigated if selected polymorphisms of OPA1, MFN1, and MFN2 were associated with glaucoma in Polish population. Four OPA1 (rs166850, rs10451941, rs7624750, rs9851685), one MFN1 (rs2111534), and two MFN2 (rs873458, rs2295281) single nucleotide polymorphisms were investigated in 304 primary open angle glaucoma patients (204 with normal tension glaucoma, 100 with high-tension glaucoma) and 258 control subjects using RT-PCR method. There was a significant difference in genotype frequencies of rs9851685 and rs2111534 polymorphisms between glaucoma patients and control subjects. Several genotype combinations comprising SNPs at OPA1 and MFN1 were significantly differently distributed in a three-way comparison between controls, patients with NTG and patients with HTG. None of the studied MFN2 polymorphisms was significantly associated with HTG or NTG. In studied population, genotype CC and allele C of rs9851685 OPA1 polymorphism are NTG risk factors, whereas TT genotype and T allele of this polymorphism are protective factors against NTG. Genotype GA of rs2111534 MFN1 polymorphism is an HTG risk factor and AA genotype of this polymorphism is a protective factor against HTG. Several OPA1 and MFN2 genotype combinations are significantly associated with either increased or decreased risk of glaucoma in this population.


Biodistribution and therapeutic efficacy of (125/131)I-, (186)Re-, (88/90)Y-, or (177)Lu-labeled monoclonal antibody MN-14 to carcinoembryonic antigen in mice with small peritoneal metastases of colorectal origin.
Therapeutic efficacy in radioimmunotherapy depends, among other things, on the choice of the radionuclide. The aim of the present study was to determine the most suitable radionuclide for radioimmunotherapy with monoclonal antibody MN-14 to carcinoembryonic antigen in an experimental model of small peritoneal metastases of colorectal origin. In nude mice with intraperitoneal LS174T tumors (diameter, 1-3 mm), the biodistributions of MN-14 labeled with (131)I ((131)I-MN-14), (186)Re-mercaptoacetyltriglycine ((186)Re-MN-14), and (88)Y-diethylenetriaminepentaacetic acid (DTPA) ((88)Y-MN-14) after intravenous and intraperitoneal administration were determined. Subsequently, the therapeutic efficacies of equally toxic activity doses of (131)I-MN-14 (9.25 MBq per mouse), (186)Re-MN-14 (9.25 MBq per mouse), (90)Y-MN-14 (3.15 MBq per mouse), and MN-14 labeled with (177)Lu-DTPA ((177)Lu-MN-14) (8.33 MBq per mouse) after intraperitoneal administration were determined. Each of the radioimmunoconjugates preferentially accumulated in tumor nodules, both after intravenous administration and after intraperitoneal administration. Values for clearance from blood were similar for all radioimmunoconjugates. The uptake of (88)Y-MN-14 in the liver and spleen was significantly higher than the uptake of (131)I-MN-14 or (186)Re-MN-14. Maximal uptake values (mean +/- SD) in tumors were 58 +/- 7 percentage injected dose per gram of tissue (%ID/g) for (131)I-MN-14 (24 h after administration), 83 +/- 19 %ID/g for (186)Re-MN-14 (72 h after administration), and 148 +/- 89 %ID/g for (88)Y-MN-14 (192 h after administration). Dosimetric analysis of the biodistribution data estimated that the radiation doses guided to the tumor by intraperitoneally administered (131)I-MN-14, (186)Re-MN-14, (90)Y-MN-14, and (177)Lu-MN-14 were 150, 100, 45, and 200 Gy, respectively. The median survival time of control mice, treated with unlabeled MN-14, was 42 d, whereas the median survival times of mice treated with (131)I-MN-14, (186)Re-MN-14, (90)Y-MN-14, and (177)Lu-MN-14 were 100 d (range, 58-142; P < 0.0001), 72 d (range, 46-84; P = 0.0002), 82 d (range, 46-142; P < 0.0001), and 136 d (range, 56-142; P < 0.0001), respectively. At the completion of the experiment (142 d after tumor cell inoculation), no residual disease was found in 8 of 9 long-term survivors ((131)I, n = 3; (90)Y, n = 1; and (177)Lu, n = 4). The uptake of (88)Y-MN-14 in small peritoneal LS174T xenografts was higher than the uptake of (131)I-MN-14 or (186)Re-MN-14. The present study indicates that (131)I and (177)Lu are the most suitable radionuclides for the radioimmunotherapy of small peritoneal metastases.


Adjuvant Chemotherapy and Radiotherapy in Resected Pancreatic Ductal Adenocarcinoma: A Systematic Review and Clinical Practice Guideline.
Pancreatic cancer is the seventh leading cause of cancer deaths worldwide, accounting for 4.7% of all cancer deaths, and is expected to climb significantly over the next decade. The purpose of this systematic review and guidance document was to synthesize the evidence surrounding the role of adjuvant treatment (chemotherapy and chemoradiation therapy [CRT], and stereotactic body radiation therapy [SBRT]) in resected pancreatic ductal adenocarcinoma (PDAC). Systematic literature searches of MEDLINE, EMBASE, and 11 guideline databases were conducted. Both direct and indirect comparisons indicate adjuvant chemotherapy offers a survival advantage over surgery alone. The optimal regimens recommended are mFOLFIRINOX with alternative options of gemcitabine plus capecitabine, gemcitabine alone, or S-1 (which is not available in North America). Trials comparing a CRT strategy to modern chemotherapy regimens are lacking. However, current evidence demonstrates that the addition of CRT to chemotherapy does not result in a survival advantage over chemotherapy alone and is therefore not recommended. Trials evaluating SBRT in PDAC are also lacking. SBRT should only be used within a clinical trial or multi-institutional registry.


Changes in the perceived head transversal plane and the subjective visual horizontal induced by Coriolis stimulation during gondola centrifugation.
For studying the influence of the vertical semicircular canals on spatial orientation in roll, the subjective visual horizontal (SVH) and the subjective transversal plane of the head (STP) were measured in a situation where the vertical canals sense a roll-velocity stimulus while the otolith organs persistently signal that the head is upright in roll. During gondola centrifugation (resultant gravitoinertial force vector 2.5 G, gondola inclination 66 degrees) subjects were exposed to controlled rotational head movements (angular speed 27 degrees/s, magnitude 40 degrees) about the yaw (body z-) axis, produced by means of a motor-driven helmet. This causes a roll-plane Coriolis stimulus to the canals, while the otoliths persistently sense upright head position in roll. The subjects reported intense sensations of rotation and tilt in the roll plane. This was reflected in tilts of both the SVH and STP. The initial tilt of the SVH was 13.0 +/- 9.7 degrees (mean +/- S.D., n=10). The STP was changed in the opposite direction. The initial tilt was 23.8 +/- 12.2 degrees (mean +/- S.D., n=5). The changes in the SVH and STP were not of equal magnitude. A few subjects who had almost no deviations in the SVH showed pronounced tilts of the STP. The time constant for exponential decay of the tilts of the SVH and STP was on average approximately 1 minute. These findings indicate that a difference in activity of the vertical canals in the right versus left ear may cause substantial tilts of the SVH even if there is no asymmetry in the activity of the otolith system. Further, the canal stimulus may induce a tilt of the fundamental egocentric frame of reference.


[Mental adaptation disorders in duodenal ulcer patients].
Mental adptation disorders that appeared as a result of the stressogenic factor effect include two interrelated processes concurrently: processes of the development of the acute stage of ulcer (pathogenesis) and mechanisms of recovery (sanogenesis). Pathogenetic processes prevail over sanogenetic ones at the beginning of the acute stage--pains and ulcerous defects in the duodenal bulb occur more frequently in case of a mental adaptation disorder than in case of its absence. The incipient recovery (disappearance of pains and appearance of a postulcerous scar on the spot of the former ulcer) represents a turn to the prevalence of sanogenetic mechanisms. However, disappearance of the mental adaptation disorder is a more inert process, as compared to the dynamics of clinical and morphological data, which can be explained by the organism's striving for maintaining sanogenetic processes for some time in order to produce a stabler compensation of former disorders. The treatment of the acute stage of ulcers in some patients is insufficiently effective, which can be apparently explained by the excessive intensity of mental adaptation disorders having a negative effect on the recovery processes.


Effects of rhG-CSF plus dexamethasone on hemostatic parameters in healthy granulocyte donors: role of u-PA and nitric oxide.
Granulocyte colony-stimulating factor (G-CSF) is widely used to reduce the risk of infection resulting from neutropenias and to mobilize and collect CD34+ hematopoetic progenitor cells (HPCs) for autologous and allogenic transplantation. The safety of recombinant human G-CSF (rhG-CSF) administration in healthy donors has been investigated in several studies. However, there are limited cumulative data about the effects of rhG-CSF on hemostasis. Hemostatic parameters, including urokinase-type plasminogen activator antigen (u-PA:Ag) and nitric oxide in 17 healthy granulocyte apheresis donors who donated for neutropenic patients were evaluated. rhG-CSF (single dose, 10 microg/kg subcutaneously) and dexamethasone (8 mg, single dose oral) were given to donors 12 hours before granulocyte apheresis. Two blood samples were drawn at time 0 (T(0)) before rhG-CSF and dexamethasone administration and at time 1 (T1), immediately before the apheresis. A statistically significant rise in coagulant factor VIII (FVIII) and von Willebrand factor (vWF), and slightly rise in u-PA:Ag were observed after G-CSF plus dexamethasone administration. In addition, there were positive correlations between vWF-D-dimer and FVIII-D-dimer. A significant decrease in mean total nitric oxide (NOx), nitrite, and nitrate levels was also found after G-CSF plus dexamethasone administration. Moreover, there was a strong negative correlation between nitrite and D-dimer levels (r = -0.611; P = .009). Even if partially compensated with u-PA and protein C, increased FVIII and vWF activity, and decreased nitric oxide levels may still partially contribute to progress of thrombosis risk in rhG-CSF plus dexamethasone administered healthy granulocyte donors. Large numbers of healthy donors exposed to G-CSF plus dexamethasone will be needed to evaluate the risk of thrombosis in this population.


Green synthesis of 3D core-shell SnS2/SnS-Cd0.5Zn0.5S multi-heterojunction for efficient photocatalytic H2 evolution.
Low charge carrier separation efficiency is one of the key factors restricting photocatalytic hydrogen evolution performance. It is an effective strategy to build heterojunctions to steer charge migration. Herein, a series of x-SnS2/SnS-Cd0.5Zn0.5S (x-SS-CZS) nanosphere composites with varying mass ratios of SnS2/SnS (SS) were prepared through in situ hydrothermal synthesis. Moreover, XRD, TEM, and XPS were used to characterize the 3D core-shell SS-CZS multi-heterojunction composite. The 5-SS-CZS heterojunction composite with 5 wt% content of SS exhibits a remarkable hydrogen evolution rate of 168.85 mmol g-1 h-1, which is 5.4 times higher than that of pristine twin CZS (31.08 mmol g-1 h-1) and 1.9 times higher than that of 5-SnS2-CZS (88.21 mmol g-1 h-1). Furthermore, the composite catalyst showed excellent photostability after four cycles of reactions under visible light illumination. The apparent quantum yield at λ = 420 nm could reach up to 24.78%. The excellent hydrogen evolution performance of 5-SS-CZS nanospheres is ascribed to the following factors: (1) a core-shell catalyst with broad spectral absorption improves light utilization efficiency, (2) hybrid material with large surface area provides more active sites and shows the highest H2 activity, (3) a multi-heterojunction composite extends the lifetime of photoinduced carriers and accelerates charge separation and migration, and (4) SS as a hole trapping agent enhances the photocatalytic stability performance. This work proposes a possible photocatalytic mechanism, while also providing a novel approach for the synthesis of highly active and stable photocatalysts.


Membrane blebbing is associated with Ca2+-activated hyperpolarizations induced by serum and alpha 2-macroglobulin.
We have reported previously that serum and alpha 2-macroglobulin (alpha 2M) induce Ca2+-activated hyperpolarizations in the membrane potential of a clonal rat osteosarcoma cell line (ROS 17/2) (Dixon and Aubin, J. Cell, Physiol., 132:215-225, 1987). In this report, we describe morphological changes that accompany these hyperpolarizations. Both cell surface blebbing (zeiosis) and transient hyperpolarizations were induced by application of 10% fetal bovine serum (FBS) or alpha 2M; neither was induced by serum-free medium, a suspension of latex beads, or purified bovine serum albumin. Following a brief application of FBS or alpha 2M at time 0, electrical activity typically occurred between 7-40 s and was always followed by blebbing activity that began at 30 s and persisted for 3-5 min. In contrast, continuous exposure to FBS resulted in the persistence of both blebbing activity and transient hyperpolarizations for periods of at least several hours. Scanning electron microscopy (SEM) revealed that the blebs appeared concomitantly with the disappearance of microvilli and the appearance of surface pits that measured 100-300 nm in diameter. Coated pits and vesicles, similar in size to the pits observed by SEM, were observed using transmission electron microscopy (TEM). By TEM, blebs were found to contain few organelles other than centrally located free ribosomes. Fluorescence microscopy of nitrobenzooxadizole-phallacidin-labeled cells indicated that blebs contained filamentous actin and that microfilament bundles remained primarily on the substratum side of blebbed cells. We propose that blebbing results from a dynamic local reorganization of microfilaments initiated by ligand-induced transient increases in intracellular Ca2+.


Saturation of the human phenome.
The phenome is the complete set of phenotypes resulting from genetic variation in populations of an organism. Saturation of a phenome implies the identification and phenotypic description of mutations in all genes in an organism, potentially constrained to those encoding proteins. The human genome is believed to contain 20-25,000 protein coding genes, but only a small fraction of these have documented mutant phenotypes, thus the human phenome is far from complete. In model organisms, genetic saturation entails the identification of multiple mutant alleles of a gene or locus, allowing a consistent description of mutational phenotypes for that gene. Saturation of several model organisms has been attempted, usually by targeting annotated coding genes with insertional transposons (Drosophila melanogaster, Mus musculus) or by sequence directed deletion (Saccharomyces cerevisiae) or using libraries of antisense oligonucleotide probes injected directly into animals (Caenorhabditis elegans, Danio rerio). This paper reviews the general state of the human phenome, and discusses theoretical and practical considerations toward a saturation analysis in humans. Throughout, emphasis is placed on high penetrance genetic variation, of the kind typically asociated with monogenic versus complex traits.