Czechoslovak cardiosurgery.
Similarly as in all war-ravaged countries of Europe, in Czechoslovakia, too, cardiosurgery did not begin being systematically developed until after 1945. Patent ductus arteriosus was first treated surgically in this country in 1947, the year 1951 saw the launching of surgical therapy for mitral stenosis (commissurotomy on the closed heart), 1955 - the introduction into clinical practice of open-heart surgery for simple heart defects (DSS, pulmonary artery stenosis and aortic stenosis) with the patient in 28 degrees C hypothermia and with the blood circulation arrested for brief periods of time. In the years 1958-1959, four Czechoslovak cardiosurgical centres began to provide surgical treatment for congenital and acquired heart defects in extracorporeal circulation. Considering the war-inflicted material and personnel shortcomings prevailing in those times, Czechoslovak cardiosurgery managed relatively soon to attain the standard of cardiosurgery of the western countries, thus testifying to the viability of the country's post-war health care services. At present, there are six cardiosurgical centres in this country systematically engaged in the surgical treatment of congenital and acquired heart defects and providing the diagnosis and surgical correction of heart defects on a professional scale equal to that in countries with advanced health care systems. While the care provided at Czechoslovak cardiosurgical centres is comparable in terms of quality, the productivity of those centres leaves much to be desired. Ways and means of coping early with this inadequacy are looked for with the help of the Ministry of Health.


Herb-partitioned moxibustion alleviates colon injuries in ulcerative colitis rats.
To observe the effect of herb-partitioned moxibustion (HPM) on expression of colonic cytokines in ulcerative colitis (UC) rats. A UC rat model was established by protein immunization in combination with topical chemical stimulation. Rats in the HPM group (n = 8) received HPM at bilateral Tianshu (ST25) points. The gross injury and pathological scores of the colon were recorded. The expression profile of colonic cytokines was assayed using the protein microarray technique. Specific differential cytokines were selected and verified by ELISA. The corresponding UniProt Accessions of the differentially expressed cytokines were retrieved in the UniProt database. The pathways involved were analyzed with the help of the KEGG PATHWAY database. The DAVID database was used for functional cluster and pathway analysis. HPM improved colon injuries in UC rats, manifested by accelerated repair of ulcers and alleviation of inflammation, and the gross injury and pathological scores both significantly decreased (P < 0.01). Fold change > 1.3 or < 0.77 was taken as the screening standard. There were 77 down-regulated and 9 up-regulated differentially expressed colonic cytokines in the HPM group compared with the model group, and expression of 20 differed significantly (P < 0.05). Twelve of the 20 significantly differentially expressed cytokines [β-catenin, interleukin-1 receptor 6 (IL-1R6), IL-1β, B7-1, nerve growth factor receptor, AMP-activated protein kinase-α1, neuropilin-2, orexin A, adipocyte differentiation-related protein, IL-2, Fas and FasL] were up-regulated in the model group (n = 3, compared with the normal group) but down-regulated in the HPM group (n = 3, compared with the model group). Functional cluster analysis showed that the differentially expressed colonic cytokines in the HPM group regulated apoptosis and protein phosphorylation. KEGG pathway analysis showed that 52 down-regulated and 7 up-regulated differentially expressed colonic cytokines in the HPM group had pathways. The pathways that interacted between the cytokines and their receptors accounted for the largest proportion (28 of the down-regulated and 5 of the up-regulated cytokines). HPM promotes the repair of colon injuries in UC rats, which is related to the regulation of several abnormally expressed cytokines.


Cushing's syndrome due to ectopic production of corticotropin-releasing hormone in an infant with ganglioneuroblastoma.
To report the first recognized case of Cushing's syndrome due to a corticotropin-releasing hormone (CRH)-secreting ganglioneuroblastoma, which was found in an 18-month-old boy with hypertensive encephalopathy. The clinical, biochemical, and immunohistochemical characteristics of this rare syndrome are described, and the relevant literature is reviewed. An 18-month-old boy with a history of recent weight gain was admitted because of sudden onset of right fixed esotropia and left facial palsy after episodes of emesis. Magnetic resonance imaging showed old left frontal lobe and right hypothalamic infarcts. The patient had generalized obesity, decelerated linear growth, hypertrichosis, hypertension (144/103 mm Hg), hypokalemia, and proteinuria. The 24-hour urinary excretion of free cortisol, catecholamines, and metanephrines was increased. The serum cortisol concentration after a 1-mg overnight dexamethasone suppression test (DST) was 53.7 mg/dL (normal, <5). The serum adrenocorticotropic hormone (ACTH) concentration was 7 pg/mL (normal, 10 to 60), and the CRH level was 439 pg/mL (normal, 24 to 40). An overnight high-dose DST (8 mg) failed to suppress serum cortisol; however, both cortisol and ACTH were responsive to ovine CRH stimulation. Despite discordant dynamic endocrine testing and negative somatostatin receptor scintigraphy, computed tomography showed a right 3.6- by 3.0-cm extra-adrenal retroperitoneal mass with central calcification extending 7 cm cephalocaudally. The patient underwent exploratory laparotomy, followed by chemotherapy. Findings on light microscopic and immunohistochemical examination of the retroperitoneal mass were consistent with a ganglioneuroblastoma that expressed CRH, pro-opiomelanocortin, and ACTH. The evaluation of Cushing's syndrome is one of the most complex endocrine challenges. In this case, it was due to ectopic production of CRH by a ganglioneuroblastoma. Because most CRH-producing tumors also secrete ACTH, the ectopic production may represent a paracrine phenomenon in addition to an endocrine phenomenon. The ectopic CRH may also indirectly provoke pituitary ACTH secretion. This dual mechanism may explain the resistance of the tumor to feedback inhibition and a CRH-stimulation response indistinguishable from that observed in pituitary-dependent Cushing's syndrome.


[Hemodynamic effects of changes in the heart rate].
The effects of the variations in heart rate (HR) within the range of 80 and 180 beats/min were studied in open-chest dogs with complete AV block. Left ventricular systolic pressure (LVSP) and the maximal velocities of development (+P) and fall (-P), left ventricular end diastolic pressure (LVEDP), cardiac output (CO) and duration of ejection (DE) were recorded and analyzed. Contractility was assessed by the force developed by an isometric segment of the left ventricular wall (DT) and the maximal velocities of rise (+T) and fall (-T). Stroke volume (SV), stroke work (SW), stroke power (SP), +P/-P and +T/-T ratios, the time constant of LV pressure fall during isovolumic relaxation (T tau), and mean rate of ejection of left ventricle (MRE) were calculated from the precedent data. LVSP, LVEDP and -P did not show any statistically significant difference, while +P fell by 10 +/- 5% and 16 +/- 4% at 160 and 180 beats/min, respectively. +P/-P ratios were 1.25 +/- 0.07 at 80 beats/min; 1.08 +/- 0.06 at 140 beats/min (P less than 0.01); 1.03 +/- 0.05 at 160 beats/min (P less than 0.01) and 1.02 +/- 0.06 at 180 beats/min (P less than 0.01). CO remained unchanged and due to this SV fell significantly when HR increased. DT, +T, -T, +T/-T and T (tau) were unchanged. DE fell significantly at 120, 140, 160 and 180 beats/min with respect to the initial HR. SW fell significantly at every HR studied. MRE was 147 +/- 13 ml/sec at 80 beats/min and 100 +/- 8 and 93 +/- 7 ml/sec at 160 and 180 beats/min, respectively (P less than 0.01 with respect to control). SP was 161.7 +/- 19.3 g X m X sec-1 at 80 beats/min, and 122.3 +/- 13.2 and 103.8 +/- 9.2 g X m X sec-1 at 160 and 180 beats/min, respectively (P less than 0.01 with respect to control). We may come to the following conclusions: 1) When HR changed in our experimental conditions, CO remained unchanged and due to this the SV fell significantly, showing the difficulty of the heart pump to regulate the CO by itself. 2) The process of relaxation is not affected within the used HR range. 3) In our experiments the inotropic effect due to increments of heart rate ("Bowditch staircase phenomenon") was not detected. However, it might become evident in preparations with more depressed contractility.


[Hybrid tumor of the penis: is this denomination correct?].
Few cases of verrucous carcinoma of the penis with foci of invasive squamous cell carcinoma have been reported and denominated "hybrid tumors". The accuracy of this term is discussed in this paper. A huge penile mass in a patient that had undergone three previous operations for lesions diagnosed as verrucous carcinoma is reported. Partial penectomy was performed. Histological examination showed a very well-differentiated squamous cell carcinoma. PCR (polymerase chain reaction) did not detect any type of human papillomavirus (HPV) in the tumor. Verrucous carcinoma is a strictly-defined lesion with a different biological behaviour from that of squamous carcinoma. Preoperative deep biopsy may miss the squamous cell carcinoma. Definitive diagnosis can only be achieved by histological examination of the surgical specimen. In future, DNA studies could possibly support preoperative diagnosis of this lesion.


Longstanding rhinolith leading to anatomical alterations of the ipsilateral inferior nasal meatus and turbinate.
Rhinoliths consist of a central nidus with calcification resulting in calcareous concretions within the nasal cavity. They are uncommon in the literature despite a propensity particularly in children to insert foreign bodies into their nose and ears. We present the case of a 62-year-old woman with a longstanding undetected rhinolith with mild uncharacteristic symptoms. Radiographic examination revealed anatomical alteration of the inferior turbinate that was attributed to the long presence of the rhinolith in the nasal cavity. The management of the rhinolith and a review of the literature are presented.


The detection and discovery of glycan motifs in biological samples using lectins and antibodies: new methods and opportunities.
Recent research has uncovered unexpected ways that glycans contribute to biology, as well as new strategies for combatting disease using approaches involving glycans. To make full use of glycans for clinical applications, we need more detailed information on the location, nature, and dynamics of glycan expression in vivo. Such studies require the use of specimens acquired directly from patients. Effective studies of clinical specimens require low-volume assays, high precision measurements, and the ability to process many samples. Assays using affinity reagents-lectins and glycan-binding antibodies-can meet these requirements, but further developments are needed to make the methods routine and effective. Recent advances in the use of glycan-binding proteins involve improved determination of specificity using glycan arrays; the availability of databases for mining and analyzing glycan array data; lectin engineering methods; and the ability to quantitatively interpret lectin measurements. Here, we describe many of the challenges and opportunities involved in the application of these new approaches to the study of biological samples. The new tools hold promise for developing methods to improve the outcomes of patients afflicted with diseases characterized by aberrant glycan expression.


Chromosome-level genomes of three key Allium crops and their trait evolution.
Allium crop breeding remains severely hindered due to the lack of high-quality reference genomes. Here we report high-quality chromosome-level genome assemblies for three key Allium crops (Welsh onion, garlic and onion), which are 11.17 Gb, 15.52 Gb and 15.78 Gb in size with the highest recorded contig N50 of 507.27 Mb, 109.82 Mb and 81.66 Mb, respectively. Beyond revealing the genome evolutionary process of Allium species, our pathogen infection experiments and comparative metabolomic and genomic analyses showed that genes encoding enzymes involved in the metabolic pathway of Allium-specific flavor compounds may have evolved from an ancient uncharacterized plant defense system widely existing in many plant lineages but extensively boosted in alliums. Using in situ hybridization and spatial RNA sequencing, we obtained an overview of cell-type categorization and gene expression changes associated with spongy mesophyll cell expansion during onion bulb formation, thus indicating the functional roles of bulb formation genes.


Rational peptide design for targeting cancer cell invasion.
Cell invasion is an important process in cancer progression and recurrence. Invasion and implantation of cancer cells from their original place to other tissues, by disabling vital organs, challenges the treatment of cancer patients. Given the importance of the matter, many molecular treatments have been developed to inhibit cancer cell invasion. Because of their low production cost and ease of production, peptides are valuable therapeutic molecules for inhibiting cancer cell invasion. In recent years, advances in the field of computational biology have facilitated the design of anti-cancer peptides. In our investigation, using computational biology approaches such as evolutionary analysis, residue scanning, protein-peptide interaction analysis, molecular dynamics, and free energy analysis, our team designed a peptide library with about 100 000 candidates based on A6 (acetyl-KPSSPPEE-amino) sequence which is an anti-invasion peptide. During computational studies, two of the designed peptides that give the highest scores and showed the greatest sequence similarity to A6 were entered into the experimental analysis workflow for further analysis. In experimental analysis steps, the anti-metastatic potency and other therapeutic effects of designed peptides were evaluated using MTT assay, RT-qPCR, zymography analysis, and invasion assay. Our study disclosed that the IK1 (acetyl-RPSFPPEE-amino) peptide, like A6, has great potency to inhibit the invasion of cancer cells.


Allelic diversity in the host genetic background may be an important determinant in tumor metastatic dissemination.
Metastasis, the spread and growth of tumors at secondary sites, is an extremely important clinical event, since the majority of cancer mortality is associated with the metastatic tumors rather than the primary tumor. In spite of the importance of metastasis in the clinical setting, the actual process is extremely inefficient. Millions of tumor cells can be shed into the vasculature daily yet few secondary tumors are formed. To successfully colonize a distant site tumor cells must overcome a series of barriers. Failure to complete any single step in the metastatic cascade abrogates the ability to form a secondary lesion. A variety of theories have been proposed to explain the inefficiency of the metastatic process. The most commonly accepted, the progression theory, posits a series of random mutational occurs within a primary tumor to generate a small subpopulation that acquires full metastatic capability. While significant evidence supports this model, recent discoveries demonstrating the ability to predict metastatic propensity from gene expression profiles in bulk tumor tissue are not consistent with only a small subpopulation of cells in the primary tumor acquiring metastatic ability. A second theory of metastatic inefficiency, the transient compartment theory, is more consistent with the microarray data, but does not completely explain observations like metastasis associated loss-of-heterozygosity events. To reconcile the observed results additional variables need to be added to the model of metastatic inefficiency. One possible variable that might explain the discrepancies is genetic background effects. Studies have demonstrated that the genetic background a tumor arises on can have significant affects on the ability of the tumor to metastasize and on gene expression profiles. Thus the observations could be reconciled by combining the theories, with genetic background influencing both metastatic efficiency and predictive gene expression profiles, upon which subsequently occur metastasis-promoting mutational and epigenetic events. If the genetic background is an important determinant of metastatic efficiency it would have significant implications for the clinical prediction and treatment of metastatic disease, as well as for the design of potential prevention strategies.


What can we do to improve physical function in older persons with type 2 diabetes?
Older persons with type 2 diabetes are at higher risk for functional impairment than are their age-matched counterparts without-diabetes. We therefore sought to identify factors associated with impaired physical function in older persons with type 2 diabetes by using a cross-sectional study design. We studied 1238 persons with type 2 diabetes who were 55 years of age or older and enrolled in the Type II Diabetes Patient Outcomes Research Team (PORT) project. Subjects were primary care patients at a large staff model health maintenance organization who had completed a mailed survey that collected information about demographics (age, race, marital status, income, education, gender, and body mass index [BMI]), health behaviors (exercise, smoking, and alcohol), care and control of diabetes (therapy, self-reported glucose control, home glucose monitoring, and disease duration), mood (Center for Epidemiologic Studies--Depression Scale [CES-D]), comorbidity, and the Short-Form-36 health survey (SF-36). We evaluated the bivariate relationships between the PFI- 10, a 10-item measure of physical function from the SF-36, and candidate independent variables from the domains described previously. Variables that were significant at an a level of .10 were entered into a multiple linear regression model. There were eight independent predictors of impaired physical function (all p < .05, R2 = .40). Factors associated with impaired function in order of their relative importance were as follows: a higher comorbidity score, older age, obesity, lack of regular exercise, CES-D score higher than 20, taking insulin, lower formal education, and abstinence from alcohol. Increased comorbidity and older age are associated with poorer function, as is the severity of diabetes and less formal education. Exercise, lower BMI, and better mood are associated with better function. Therefore, promoting regular exercise and weight loss, in addition to treating depression, are likely to preserve or even improve the functional status of older persons with type 2 diabetes. Moderate alcohol use may be beneficial as well. The extent to which these relationships persist in prospective studies or clinical trials remains to be evaluated.


Cloning of the cyclodextrin glucanotransferase gene from alkalophilic Bacillus sp. A2-5a and analysis of the raw starch-binding domain.
The cyclodextrin glucanotransferase (CGTase) gene of alkalophilic Bacillus sp. A2-5a was cloned and expressed in Bacillus subtilis ANA-1 as a host. The DNA region included an open reading frame encoding a 704-amino-acid polypeptide with a typical raw starch-binding motif in its C-terminal region. The CGTase purified from Bacillus sp. A2-5a bound to raw starch as strongly as porcine pancreas alpha-amylase, as expected from the sequence motif. A chromosomal region (a DNA fragment of about 14.1 kbp) including the CGTase gene was also cloned and the nucleotide sequence was determined. Possible cyclodextrinase and putative cyclodextrin-binding protein genes were found in the flanking region of the CGTase gene, which implied that the novel starch-degradation pathway postulated for a gram-negative bacterium [Klebsiella oxytoca; Fiedler et al. (1996) J Mol Biol 256: 279-291] also exists in a gram-positive bacterium i.e. Bacillus.


[Results of arthroscopically assisted refixation of fractures of the intercondylar eminence].
In order to restore ACL function and therefore knee joint stability, the surgical refixation of anterior cruciate ligament avulsion fractures is a consistent recommendation in literature. The objective of this study was to evaluate the clinical results after arthroscopic fixation of dislocated avulsion fracture of the intercondylar eminence depending on patient age and refixation technique. 24 patients (50% below 16 years) with anterior cruciate ligament avulsion fractures were treated either with arthroscopic screw fixation (n = 17) or transtibial suture refixation (n = 7). Clinical follow-up examination was conducted on average 4.1 years after operation. 17% of the patients presented with additional intra-articular lesions. Osseous integration of the avulsion fragment was documented on plain radiographs on average 6.1 weeks after surgery in adults and after 3.9 weeks in children. Free range of motion was accomplished after 11.3 weeks. The choice of surgical technique did not show any influence on healing period or rehabilitation. The complication rate was 16.6% in skeletally immature patients and 8.3 % in adults. IKDC scores: A10, B2 in children; A9, B3 in adults. Tegner scores: children 5.8, adults 4.1. Lysholm scores: children 93, adults 88. Neither the patients' age nor the refixation technique selected yielded a significant correlation to the accomplished clinical score. Both arthroscopic screw fixation and transtibial suture fixation are appropriate surgical procedures regarding results and complication rate.


Age-related differences in glycaemic control, cardiovascular disease risk factors and treatment in patients with type 2 diabetes: a cross-sectional study from the Australian National Diabetes Audit.
To compare the glycaemic control and cardiovascular risk factor profiles of younger and older patients with type 2 diabetes. Cross-sectional analysis of data from the 2015 Australian National Diabetes Audit was undertaken. Data were obtained from adults with type 2 diabetes presenting to Australian secondary/tertiary diabetes centres. Logistic regression examined associations with glycated haemoglobin A1c (HbA1c) >7% (53 mmol/mol) and cardiovascular risk factors. Data from 3492 patients were analysed. Mean (±SD) age was 62.9±12.5 years, mean diabetes duration 13.5±9.4 years and mean HbA1c 8.2%±1.8%. Mean HbA1c was 8.6%±2.1% and 8.0%±1.6% for the younger (<60 years) and older subgroups (≥60 years), respectively (p<0.001). The adjusted OR (aOR) of HbA1c above >7.0% was 1.5 times higher (95% CI 1.22 to 1.84) for younger patients compared with older patients after adjustment for gender, smoking, diabetes duration, renal function and body mass index. Younger patients were also more likely to have dyslipidaemia (aOR 2.02, 95% CI 1.53 to 2.68; p<0.001), be obese (aOR 1.25, 95% CI 1.05 to 1.49; p<0.001) and be current smokers (aOR 2.13 95% CI 1.64 to 2.77; p<0.001) than older patients. Younger age was associated with poorer glycaemic control and adverse cardiovascular risk factor profiles. It is imperative to optimise and monitor treatment in order to improve long-term outcomes.


Lack of transparency of clinical trials on endometriosis.
To estimate patterns of publication of clinical trials of endometriosis registered in ClinicalTrials.gov and their associated characteristics. Information on interventional clinical trials on endometriosis that were registered at ClinicalTrials.gov and updated as having been completed by October 25, 2012, was retrieved and the publication status and time to publication in Medline-indexed journals were ascertained by searching PubMed and by sending e-mail inquiries to the principal investigators listed by the registry. Seventy-one interventional trials of endometriosis, testing various drugs and biologicals, were identified. Among them, 49.3% (35/71) were completed by October 25, 2012, 21.1% were either stopped or inactive in the past 2 years, and the remaining 29.6% were ongoing. Among the 35 completed trials, 25 (71.4%) were sponsored by industry and results were published for only 11 (31.4%; five industry-sponsored, and six nonindustry-sponsored). Trials sponsored by industry were nearly four times less likely to publish their results than nonindustry-sponsored trials, even though these trials typically had larger sample sizes and were completed faster. Compared with the publication rate of 20% found 4 years ago, the current rate has increased only marginally but still lies significantly below the reported 66.3% surveyed recently among 546 completed nonendometriosis trials registered at ClinicalTrials.gov (P<.001). Despite mounting pressure on more transparency of clinical trials, the current state of transparency or lack thereof of clinical trials on endometriosis is worrisome and does not benefit the trial sponsor or the public. Thus, we again call for more transparency for endometriosis trials.


Webbing of the pharyngeal recess in adults with cleft palate.
The limited literature on the lateral pharyngeal recess of Rosenmüller and the various presentations of pharyngeal webbing are reviewed. Webbing across the lateral pharyngeal recess is described in 28 of 31 adults with cleft palate examined. The phenomenon has not been reported before and does not appear to be a feature of the nasopharyngeal wall in noncleft individuals.


Imaging Exocytosis with Total Internal Reflection Microscopy (TIRFM).
INTRODUCTIONAlthough electrophysiological techniques such as membrane capacitance measurements, electrochemical detection, and post-synaptic recordings are powerful ways of studying exocytosis, information concerning any steps prior to vesicle fusion must be inferred indirectly. Total internal reflection fluorescence microscopy (TIRFM) is a powerful technique for studying events that, like exocytosis, occur near a cell surface. The technique allows selective imaging of fluorescent molecules that are closest to a high refractive index substance such as glass. In this protocol, TIRFM is used to investigate the steps leading up to vesicle fusion in both retinal bipolar neurons and chromaffin cells by directly imaging synaptic vesicles and dense core granules prior to and including exocytosis.


Severity of frailty as a significant predictor of mortality for hemodialysis patients: a prospective study in China.
Background: Frailty is known to be highly prevalent in older hemodialysis (HD) patients. We studied the prevalence of frailty and its associated factors in Chinese HD patients. We further studied if frailty could predict survival in HD patients. Methods: This is a prospective study involving patients receiving maintenance HD in the dialysis center of Xuanwu Hospital, Beijing. Study subjects were enrolled from October to December, 2017 and followed up for two years. Demographic data, comorbidities and biological parameters were collected. Frailty was assessed using the Fried frailty phenotype at baseline. Cox regression analysis was performed to identify the relationship between frailty and mortality in HD patients. Kaplan-Meier was plotted using the cutoff value obtained by ROC curve to evaluate survival rates in different frailty status. Results: Total of 208 HD patients were enrolled with a mean age of 60.5±12.7 years. According to the frailty criteria, at baseline the prevalence of robust, pre-frail and frail in HD patients was 28.7%, 45.9%, and 25.4%, respectively. The two-year all-cause mortality was 18.8% (39/207) and underlying causes of death included coronary artery disease (CAD), cerebrovascular disease (CVD), hyperkalemia, severe infection, malignant tumor and others. Survival curve showed the patients with frailty score ≥4 to have significantly shorter survival time as compared to patients with frailty score ≤ 3. Frailty predicted two-year mortality when frailty score ≥4 with a sensitivity of 70% and a specificity of 83.67% with an AUC of 0.819. Frailty score was positively associated with age and ratio of ultrafiltration volume to dry weight, while negatively associated with levels of serum albumin, uric acid and diastolic blood pressure after HD. Conclusions: Our results confirm frailty to be very common among HD patients and severity of frailty was a significant predictor of mortality for HD patients. Factors such as age, malnutrition and low blood pressure are the factors to be associated with frailty. Interdialytic weight gain inducing excessive ultrafiltration volume is an important risk factor.


Current and emerging treatment strategies for cutaneous T-cell lymphoma.
Cutaneous T-cell lymphomas (CTCLs) are a rare group of mature T-cell lymphomas presenting primarily in the skin. The most common subtypes of CTCL are mycosis fungoides and its leukaemic variant Sézary's syndrome. Patients with early-stage disease frequently have an indolent clinical course; however, those with advanced stages have a shortened survival. For the treating physician, the question of how to choose a particular therapy in the management of CTCL is important. These diseases span the disciplines of dermatology, medical oncology and radiation oncology. Other than an allogeneic stem cell transplant, there are no curative therapies for this disease. Hence, many treatment modalities need to be offered to the patient over the course of their life. An accepted treatment approach has been to delay traditional chemotherapy, which can cause excessive toxicity without durable benefit. More conservative treatment strategies in the initial management of CTCL have led to the development of newer biological and targeted therapies. These therapies include biological immune enhancers such as interferon alpha and extracorporeal photopheresis that exert their effect by stimulating an immune response to the tumour cells. Retinoids such as bexarotene have been shown to be effective and well tolerated with predictable adverse effects. The fusion toxin denileukin diftitox targets the interleukin-2 receptor expressed on malignant T cells. Histone deacetylase inhibitors such as vorinostat and romidepsin (depsipeptide) may reverse the epigenetic states associated with cancer. Forodesine is a novel inhibitor of purine nucleoside phosphorylase and leads to apoptosis of malignant T cells. Pralatrexate is a novel targeted antifolate that targets the reduced folate carrier in cancer cells. Lastly, systemic chemotherapy including transplantation is used when rapid disease control is needed or if all other biological therapies have failed. As response rates to most of the biological agents used to treat CTCL are 25-30%, it is also reasonable to consider clinical trials with novel agents if one or two front-line therapies have failed, especially before considering chemotherapy. CTCL is largely an incurable disease with significant morbidity and more active agents are needed.


Two-dimensional few-layered PC3 as a promising photocatalyst for overall water splitting.
Recently, 2D carbon phosphides (PCs) have attracted much attention due to their superior electronic and photovoltaic properties suitable for potential applications in field effect transistors and photodetectors. In this work, we systematically investigate the stability, electronic properties, optical absorption and photocatalytic water splitting performance of few-layered PC3 by using the first principles calculation method. Numerical results indicate that both monolayered and bilayered PC3 can serve as efficient photocatalysts for overall water splitting due to their high stability, moderate band gaps, suitable band edge positions, anisotropic high carrier mobilities and strong capacity of solar absorption. Compared with monolayered PC3, bilayered PC3 displays higher carrier mobilities (2500-23 000 cm2 V-1 s-1) and a wider optical absorption spectrum. Moreover, by applying an in-plane biaxial strain, the utilization of solar energy and the pH range suitable for overall water splitting can be improved effectively for both monolayered and bilayered PC3. Our work reliably expands the potential application of 2D few-layered PC3 in the field of nano-electronics and nano-optoelectronics.


Assessing the market viability of a packaged intensive health behavior and lifestyle treatment.
In the USA, more than 14 million children are impacted by obesity. Despite intensive health behavior and lifestyle treatments being found effective, gaps exist in moving these interventions into widespread use. Focusing on market viability could improve the dissemination and sustainment of interventions. The purpose of this paper is to outline the process and results of our market viability assessment for the Healthy Weight Clinic (HWC), a Centers for Disease Control and Prevention-recognized Family Health Weight Program. We conducted a market viability assessment using the Speeding Research-test INTerventions (SPRINT) program to gain insights into the commercialization and marketplace for the HWC. Through the process of customer discovery, we interviewed 50 stakeholders to test our hypotheses pertaining to our business model. Key takeaways were the need for packaged interventions that offer support and training for providers, and interventions that are multidisciplinary and located within the medical home. We also learned that (i) the intervention goals must align with the healthcare organization's performance metrics; (ii) services need to be reimbursable; and (iii) the importance of understanding different customer segments (i.e. program users vs. organization decision-makers) and their unique needs. The market viability assessment is a critical step to transforming the HWC into a viable commercial product. The process we have outlined is replicable by others and by encouraging other teams to design for dissemination we can increase the number of evidence-based, packaged IHBLTs available to children with obesity.


Mutant isolation and gene transfer as tools in study of transport proteins.
Somatic cell and molecular genetic concepts, techniques, and approaches relevant to the analysis of a complex mechanism such as a mammalian ion transport system are reviewed and illustrated with examples taken from studies of K+ transport mutants. The reasons for undertaking a study of mutants and mutations are stated and followed by directly applicable approaches to transport mutant isolation. Examples of the types of information that can be extracted from a characterization of such mutants is then presented. The parasexual system of somatic cell hybridization is reviewed, again, followed by applicable approaches and examples of how data from such studies can be used. Finally, the technique of DNA-mediated gene transfer is presented as a method that allows the actual isolation of a transporter gene which has been characterized as above.


Temporal evolution of biomedical research grant collaborations across multiple scales--a CTSA baseline study.
The evolution of biomedical research grant collaborations (BRGC) across time (2006, 2009) and hierarchically related scales (Staff, Department) at the University of Arkansas for Medical Sciences (UAMS) is investigated using network abstractions. This baseline study is a part of the Clinical Translational Science Award (CTSA) efforts in promoting team science and exploring network science approaches for CTSA evaluation. The BRGC data were retrieved from the internally developed grants management system (Automated Research Information Administrator, ARIA). Our analysis revealed the BRGC networks to be disconnected with mutually exclusive research clusters. However, a dominant weakly-connected cluster with positively skewed degree centrality and betweenness distribution was observed across scales and time. Variation in the centrality measures, clustering coefficient, and the impact of perturbing the most-influential nodes as a function of time and scale is investigated. The results presented provide novel insights into the complex nature of BRGC networks that may persist across similar settings.


Roles and regulation of the transcription factor CREB in pancreatic β -cells.
The preservation of a functional pancreatic β-cell mass has become a major point of research in type 2 diabetes (T2D) and the future therapies of T2D notably aim at protecting the β-cell from dysfunction and apoptotic death. β-cell proliferation, survival and insulin secretion are regulated by crucial transcription factors which are activated by signalling pathways engaged by nutrients, G-protein coupled receptors or tyrosine kinase receptors. Among these factors, the cAMP-responsive element-binding protein (CREB) has emerged as a key transcriptional element for the maintenance of an efficient glucose sensing, insulin exocytosis, insulin gene transcription and β-cell survival. CREB activates the transcription of target genes within the β-cells in response to a diverse array of stimuli including glucose, incretin hormones such as the glucagon-like peptide-1 (GLP-1) or the gastric inhibitory polypeptide (GIP), the pituitary adenylate cyclase-activating polypeptide (PACAP), or growth factors such as the insulin like growth factor-1 (IGF-1). All these stimuli phosphorylate CREB at a particular residue, serine 133, which is required for CREB-mediated transcription. However, the molecular mechanisms by which CREB activates gene transcription in β-cells vary according to the nature of the stimulus. These mechanisms involve different protein kinases, scaffold proteins and cofactors which allow CREB to specifically regulate the expression of crucial genes such as insulin, BCL-2, cyclin D1, cyclin A2 or IRS-2. In this review, we summarize the signalling pathways that lead to CREB phosphorylation in β-cells and the molecular features of each signalling pathway that rise specificity at the level of CREB activation and regulation.


Conservation of the putative methyltransferase domain: a hallmark of the 'Sindbis-like' supergroup of positive-strand RNA viruses.
Computer-assisted comparisons of the large proteins involved in the replication of viral RNA have revealed a novel domain located near the N termini of these proteins and conserved throughout the so-called 'Sindbis-like' supergroup of positive-strand RNA viruses. This domain encompasses four distinct conserved motifs, with motifs I, II and IV containing an invariant His residue, the AspXXArg signature and an invariant Tyr residue, respectively. Each of the two large groups of viruses within this supergroup, the 'altovirus' group (alphaviruses, tobamoviruses, tobraviruses, hordeiviruses, tricornaviruses, furoviruses, hepatitis E virus and probably rubiviruses), and the 'typovirus' group (tymoviruses, potexviruses, carlaviruses and apple chlorotic leaf spot virus), can be characterized by additional conserved sequence motifs. Based on the available results of biochemical studies and site-directed mutagenesis of the alphavirus proteins, it is hypothesized that this domain may be involved in methylation of the cap during viral RNA maturation. Unlike the other conserved domains, the RNA-dependent RNA polymerase and the RNA helicase, the motifs typical of the putative methyltransferase domain are universal within the Sindbis-like supergroup but are not found in the proteins of any other viruses, constituting a distinctive hallmark of this supergroup.


Foot-related pain and disability and spatiotemporal parameters of gait during self-selected and fast walking speeds in people with gout: A two-arm cross sectional study.
To examine gait parameters in people with gout during different walking speeds while adjusting for body mass index (BMI) and foot-pain, and to determine the relationship between gait parameters and foot-pain and disability. Gait parameters were measured using the GAITRite™ walkway in 20 gout participants and 20 age- and sex-matched controls during self-selected and fast walking speeds. Foot-pain and disability was measured using the Manchester Foot Pain and Disability Index (MFPDI) which contains four domains relating to function, physical appearance, pain and work/leisure. At the self-selected speed, gout participants demonstrated increased step time (p=0.017), and stance time (p=0.012), and reduced velocity (p=0.031) and cadence (p=0.013). At the fast speed, gout participants demonstrated increased step time (p=0.007), swing time (p=0.005) and stance time (p=0.019) and reduced velocity (p=0.036) and cadence (p=0.009). For participants with gout, step length was correlated with total MFPDI (r=-0.62, p=0.008), function (r=-0.65, p=0.005) and physical appearance (r=-0.50, p=0.041); stride length was correlated with total MFPDI (r=-0.62, p=0.008), function (r=-0.65, p=0.005) and physical appearance (r=-0.50, p=0.041); and velocity was correlated with total MFPDI (r=-0.60, p=0.011), function (r=-0.63, p=0.007) and work/leisure (r=-0.53, p=0.030). Gait patterns exhibited by people with gout are different from controls during both self-selected and fast walking speeds, even after adjusting for BMI and foot-pain. Additionally, gait parameters were strongly correlated with patient-reported functional limitation, physical appearance and work/leisure difficulties, while pain did not significantly influence gait in people with gout.


FEV(1)/FEV(6) to diagnose airflow obstruction. Comparisons with computed tomography and morbidity indices.
FVC is a difficult maneuver for many patients, and forced expiratory volume in 6 seconds (FEV6) has been proposed as a surrogate for FVC for the diagnosis of chronic obstructive pulmonary disease (COPD). Previous studies have performed head-to-head comparisons of these thresholds but did not examine their relationships with structural lung disease, symptoms, or exacerbations. To compare FEV1/FEV6 with FEV1/FVC in the diagnosis of COPD-related morbidity and structural lung disease as assessed by CT. We analyzed data from a large multicenter cohort study (COPDGene) that included current and former smokers (age 45-80 yr). Accuracy and concordance between the two ratios in diagnosing structural COPD was compared using CT measures of emphysema and airway disease and COPD-related morbidity to assess how the two ratios compare in defining disease. A total of 10,018 subjects were included. FEV1/FEV6 showed excellent accuracy in diagnosing airflow obstruction using FEV1/FVC < 0.70 as a reference (area under curve, 0.99; 95% confidence interval [CI], 0.989-0.992; P < 0.001). FEV1/FEV6 < 0.73 had the best sum of sensitivity (92.1%; 95% CI, 90.8-92.4) and specificity (97.3%; 95% CI, 97.3-98.1). There was excellent agreement between the two diagnostic cutoffs (κ = 0.90; 95% CI, 0.80-0.91; P < 0.001). In comparison with control subjects and those positive by FEV1/FVC alone, subjects positive by FEV1/FEV6 alone had greater gas trapping and airway wall thickness, worse functional capacity, and a greater number of exacerbations on follow-up. These relationships held true when disease definitions were made using the lower limits of normal. FEV1/FEV6 can be substituted for FEV1/FVC in diagnosing airflow obstruction and may better predict COPD-related pathology and morbidity.


[The role of the medial preoptic area in the organization of paradoxical sleep].
Influence of electrical stimulation of the medial preoptic area of cats on characteristics of paradoxical sleep and activity of medial preoptic neurons were studied in the course of sleep-waking cycle. Low-frequency stimulation of this structure in the state of slow-wave sleep evoked short-latency electrocortical desynchronization and induced transition to paradoxical sleep or paradocical sleep-like state. The same stimulation during the whole period of paradoxical sleep results in a reduction of its duration, practically complete disappearance of tonic stage, and increase in the density of rapid eye movements in phasic stage. The vast majority of meurons in the medial preoptic area decreased their firing rates during quiet waking and slow-wave sleep and dramatically increased their activity during paradoxical sleep. More than 50% of such neurons displayed activation 20-70 s prior to the appearance of electrocorticographic correlates of paradoxical sleep. Some neurons were selectively active during paradoxical sleep. Approximately 50% of cells increased their firing rates a few seconds prior to and/or during series of rapid eye movements. The results suggest that the medial preoptic area contains the units of the executive system (network) of paradoxical sleep and are involved in the mechanisms of neocortical desynchronization.


Alternating hemiplegia of childhood: clinical manifestations and long-term outcome.
We present our analysis of 44 patients with alternating hemiplegia of childhood. The clinical course usually consisted of three phases. The first was dominated by abnormal eye movements and dystonic episodes, the second by hemiplegic spells and psychomotor regression, and the third by persistent developmental delay and fixed neurologic deficits. The age of onset was 0-54 months (mean = 7.9 +/- 13 months). The presenting signs included abnormal ocular movements in 65%, dystonia in 60%, and hemiplegia in 32%. Patients with an early onset of the disorder and an early appearance of hemiplegic spells faired the poorest developmentally. Developmental delay was present in 91%, ataxia in 68%, choreoathetosis in 50%, and seizures in 18%. Laboratory investigations suggested mitochondrial abnormalities and cerebrovascular dysfunction in several patients. Numerous therapies were largely ineffective. Flunarizine reduced the duration, severity, and frequency of the hemiplegic attacks in 78%. Patients who received flunarizine did not differ developmentally from those who did not. Our data suggest that flunarizine does not adversely affect and may favorably influence the outcome in patients with alternating hemiplegia of childhood. Additionally, the occurrence of autosomal-dominant cases of the syndrome, although rare, suggests that, in addition to mitochondrial dysfunction, genetic factors may be important.


B lymphoblastic leukemia with ETV6 amplification.
We present a case of acute lymphoblastic leukemia caused by ETV6 amplification. Although the cytogenetic result revealed complex karyotype, multicolor fluorescence in situ hybridization and high-resolution multicolor banding supported amplification of a gene on 12p13. Fluorescence in situ hybridization with ETV6 probe confirmed the amplification. ETV6 generally plays as tumor-suppressor gene in leukemia. Their expression is decreased or missed by deletion or mutation. Otherwise, ETV6 protein overexpression was verified in this case by immunohistochemistry. Any translocation or mutation involving ETV6 was not detected. This experience strongly supports the hypothesis that the amplification of ETV6 is a possible mechanism of leukeogenesis as oncogene.


RNA-Seq Reveals Sex Differences in Gene Expression during Peripheral Neuropathic Inflammation and in Pain Relief from a COX-2 Inhibiting Theranostic Nanoemulsion.
Given decades of neuroinflammatory pain research focused only on males, there is an urgent need to better understand neuroinflammatory pain in females. This, paired with the fact that currently there is no long-term effective treatment for neuropathic pain furthers the need to evaluate how neuropathic pain develops in both sexes and how it can be relieved. Here we show that chronic constriction injury of the sciatic nerve caused comparable levels of mechanical allodynia in both sexes. Using a COX-2 inhibiting theranostic nanoemulsion with increased drug loading, both sexes achieved similar reduction in mechanical hypersensitivity. Given that both sexes have improved pain behavior, we specifically explored differential gene expression between sexes in the dorsal root ganglia (DRG) during pain and relief. Total RNA from the DRG revealed a sexually dimorphic expression for injury and relief caused by COX-2 inhibition. Of note, both males and females experience increased expression of activating transcription factor 3 (Atf3), however, only the female DRG shows decreased expression following drug treatment. Alternatively, S100A8 and S100A9 expression appear to play a sex specific role in relief in males. The sex differences in RNA expression reveal that comparable behavior does not necessitate the same gene expression.


Trends in gonorrhoea infection and overseas sexual contacts among females attending a sexual health centre in Melbourne, Australia, 2008-2015.
There has been a steady increase in gonorrhoea cases among females in Australian major cities but the reasons remain unclear. The aim of this study was to identify the risk factors associated with gonorrhoea among females attending a sexual health centre in Melbourne. Analysis of retrospective electronic patient records of females aged 16 to 80 years old attending the Melbourne Sexual Health Centre, Australia between 1st January 2008 and 20th March 2015. East and South-East Asian countries were considered as higher-prevalence countries for gonorrhoea. Logistic regression with a generalised estimating equation was used to identify the risk factors associated with gonorrhoea among females. Gonorrhoea positivity by culture among females increased from 0.3% in 2008 to 1.2% in 2015 (ptrend =0.004). The rise in positivity was greatest in females reporting sex in a higher-prevalence country (0% to 7.4%, p trend =0.026) but only moderate (0.2% to 0.4%, ptrend =0.049) in those reporting sex in Australia and/or in lower-prevalence countries. There was no association between gonorrhoea positivity and age, country of birth, number of male partners, condomless sex, or injecting drug use behaviours in the multivariable analysis. Gonorrhoea positivity by culture was significantly associated with presenting as a contact of gonorrhoea (aOR: 74.79; 95% CI: 44.07-126.93) or having sex with someone from a higher-prevalence country (aOR: 2.46; 95% CI: 1.15-5.25) after adjusting for potential confounding factors. There has been a recent four-fold increase in gonorrhoea among females attending a sexual health centre in Melbourne. Females who have sex with a partner from a country with higher-prevalence gonorrhoea (i.e. East and South-East Asian countries) are at higher risk of acquiring gonorrhoea. Public health interventions such as safe sex messages targeting travellers are required.


Mitogen-activated protein kinase ERK1/2 regulates the class II transactivator.
The expression of major histocompatibility class II genes is necessary for proper antigen presentation and induction of an immune response. This expression is initiated by the class II transactivator, CIITA. The establishment of the active form of CIITA is controlled by a series of post-translational events, including GTP binding, ubiquitination, and dimerization. However, the role of phosphorylation is less clearly defined as are the consequences of phosphorylation on CIITA activity and the identity of the kinases involved. In this study we show that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) interact directly with CIITA, targeting serine residues in the amino terminus of the protein, including serine 288. Inhibition of this phosphorylation by dominant-negative forms of ERK or by treatment of cells with the ERK inhibitor PD98059 resulted in the increase in CIITA-mediated gene expression from a class II promoter, enhanced the nuclear concentration of CIITA, and impaired its ability to bind to the nuclear export factor, CRM1. In contrast, inhibition of ERK1/2 activity had little effect on serine-to-alanine mutant forms of CIITA. These data suggest a model whereby ERK1/2-mediated phosphorylation of CIITA down-regulates CIITA activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.


Robust inference on effects attributable to mediators: A controlled-direct-effect-based approach for causal effect decomposition with multiple mediators.
Effect decomposition is a critical technique for mechanism investigation in settings with multiple causally ordered mediators. Causal mediation analysis is a standard method for effect decomposition, but the assumptions required for the identification process are extremely strong. Moreover, mediation analysis focuses on addressing mediating mechanisms rather than interacting mechanisms. Mediation and interaction for mediators both contribute to the occurrence of disease, and therefore unifying mediation and interaction in effect decomposition is important to causal mechanism investigation. By extending the framework of controlled direct effects, this study proposes the effect attributable to mediators (EAM) as a novel measure for effect decomposition. For policymaking, EAM represents how much an effect can be eliminated by setting mediators to certain values. From the perspective of mechanism investigation, EAM contains information about how much a particular mediator or set of mediators is involved in the causal mechanism through mediation, interaction, or both. EAM is more appropriate than the conventional path-specific effect for application in clinical or medical studies. The assumptions of EAM for identification are considerably weaker than those of causal mediation analysis. We develop a semiparametric estimator of EAM with robustness to model misspecification. The asymptotic property is fully realized. We applied EAM to assess the magnitude of the effect of hepatitis C virus infection on mortality, which was eliminated by controlling alanine aminotransferase and treating hepatocellular carcinoma.


Can Glaucomatous Visual Field Progression be Predicted by Structural and Functional Measures?
The aim of this study was to compare the predictive value of retinal nerve fiber layer thickness (RNFLT) measurements obtained by optical coherence tomography (OCT), morphometric parameters of confocal scanning laser ophthalmoscopy (CSLO), and frequency-doubling technique perimetry to predict visual field conversion of normal individuals, ocular hypertensive subjects, and early preperimetric glaucoma patients as determined by standard automated perimetry (SAP). This longitudinal single-center study included 107 eyes of 56 controls, 164 eyes of 98 patients with ocular hypertension, and 169 eyes of 110 patients with preperimetric glaucoma. At baseline, all patients and controls underwent OCT (Spectralis OCT), CSLO (Heidelberg Retina Tomograph) examination, optic disc photography, and frequency-doubling technique perimetry. At baseline SAP was normal in all participants. Univariate and multivariate hazard ratios (HRs) were measured to model the conversion-free survival including morphometric functional and clinical variables. The median follow-up period was 6.9 years. In total, 48 eyes (10.9%) demonstrated visual field conversion in the follow-up. RNFLT temporal-inferior outside normal limits demonstrated the highest HR with 1.2 (95% confidence interval, 1.1-1.4) per 10 μm loss for OCT, and Glaucoma probability score global outside normal limits demonstrated the highest HR with 1.3 (95 % confidence interval, 1.1-1.5) per 0.1 increase for CSLO in a multivariate model adjusted for photograph-based glaucoma staging, central corneal thickness, and SAP pattern SD. Both measurement of RNFLT by OCT and Glaucoma probability score by CSLO are highly predictive of future visual field conversion and provide independent predictive information beyond optic disc assessment, central corneal thickness, and SAP pattern SD.


Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment.
There are two known mRNA degradation pathways, 3' to 5' and 5' to 3'. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a splice site variant (c.636+1G>A) that results in an in-frame insertion of 45 nucleotides and a missense variant (c.947C>T; p.Thr316Met). DCPS decaps the cap structure generated by 3' to 5' exonucleolytic degradation of mRNA. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS. In another family, we identified a homozygous mutation (c.161T>C; p.Phe54Ser) in EDC3 in two affected children. EDC3 stimulates DCP2, which decaps mRNAs at the beginning of the 5' to 3' degradation pathway. In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. We show that individuals with biallelic mutations in these genes of seemingly central functions are viable and that these possibly lead to impairment of neurological functions linking mRNA decapping to normal cognition. Our results further affirm an emerging theme linking aberrant mRNA metabolism to neurological defects.


Marked Practice Variation in Antithrombotic Care with the Berlin Heart EXCOR Pediatric Ventricular Assist Device.
Management of antithrombotic therapy (ATT) for pediatric ventricular assist devices is challenging, and the Berlin EXCOR remains the only Food and Drug Administration (FDA)-approved option. Among those on the EXCOR, 28% have neurologic complications and major bleeding occurs in 50%. The Edmonton Protocol was developed to guide ATT, but the adverse event rate remains high, leading most centers to make modifications. The objective of this study is to characterize antithrombotic practice variation among North American pediatric ventricular assist device programs, in order to guide future research. In this descriptive cross-sectional study, a survey assessing antithrombotic (AT) practices was distributed by Berlin Heart Inc. to centers that implanted ≥1 EXCOR between January 2012 and January 2016. Practices were compared at high- versus low-volume centers. High volume was defined as ≥14 implants in this period. Seventeen of 38 centers (44.7%) participated; 4 were high volume. At half of all centers (9/17), ≤2 clinicians managed all AT decisions. Although 47.1% (8/17) followed the protocol "extremely/very closely," only 5.9% (1/17) felt it to be "very effective." Most centers (10/15; 66.7%) deviated in ≥2 protocol aspects. Over half modified either recommended antiplatelet agents (5/15) or anticoagulants (4/15). Adjunct medication use was highly variable. Most (11/17; 64.7%) deviated from protocol in either timing or type of AT lab monitoring. Despite widespread use of Thromboelastography (TEG)/Platelet Mapping (PM), concerns of inaccuracy were common. Most high-volume centers (3/4; 75%) abandoned TEG/PM as a primary tool. These practice variation analyses have identified areas in ATT that are amenable to care standardization and further research. Systematic study of optimal AT medication dosing and monitoring is needed.


Why East Asians but not South Asians are underrepresented in leadership positions in the United States.
Well-educated and prosperous, Asians are called the "model minority" in the United States. However, they appear disproportionately underrepresented in leadership positions, a problem known as the "bamboo ceiling." It remains unclear why this problem exists and whether it applies to all Asians or only particular Asian subgroups. To investigate the mechanisms and scope of the problem, we compared the leadership attainment of the two largest Asian subgroups in the United States: East Asians (e.g., Chinese) and South Asians (e.g., Indians). Across nine studies (n = 11,030) using mixed methods (archival analyses of chief executive officers, field surveys in large US companies, student leader nominations and elections, and experiments), East Asians were less likely than South Asians and whites to attain leadership positions, whereas South Asians were more likely than whites to do so. To understand why the bamboo ceiling exists for East Asians but not South Asians, we examined three categories of mechanisms-prejudice (intergroup), motivation (intrapersonal), and assertiveness (interpersonal)-while controlling for demographics (e.g., birth country, English fluency, education, socioeconomic status). Analyses revealed that East Asians faced less prejudice than South Asians and were equally motivated by work and leadership as South Asians. However, East Asians were lower in assertiveness, which consistently mediated the leadership attainment gap between East Asians and South Asians. These results suggest that East Asians hit the bamboo ceiling because their low assertiveness is incongruent with American norms concerning how leaders should communicate. The bamboo ceiling is not an Asian issue, but an issue of cultural fit.


[Definition of low respiratory tract infections].
Lower respiratory tract infection is easily suggested on clinical signs (cough and sputum) associated with fever. To discriminate between pneumonia and acute bronchitis is crucial because of the mortality associated with pneumonia and of its specific management. Chest X-ray is a key exam for the diagnosis and should be performed on the basis of validated clinical signs that are however of weak diagnostic value. Clinical as well as radiological signs cannot be reliably used to identify the causative germ. Sputum examination, the search for pneumococcal and legionella urinary antigens are of good diagnostic value. An associated COPD may lead to an acute respiratory failure. Acute exacerbation of chronic bronchitis results from various causes but infection is involved in about 50% of the cases, mostly viral and most often due to a rhinovirus. Viral infection can be associated to bacterial infection and the most frequently isolated germs are Streptococcus pneumoniae, Haemophilus influenzae, and B. catarrhalis. Severity assessment relies on the value of basal FEV1 that is often non available. Therefore Afssaps suggests using a dyspnea index to assess exacerbation severity.


[The prevention of postresection disorders in the surgical treatment of cancer of the distal stomach].
Four hundred and forty-seven patients who had undergone various surgical procedures for stage II-III cancer of the distal part of the stomach and 35 operated cases of chronic gastric ulcer were followed for three years. The study showed distal subtotal resection of the stomach using transversal gastroenteroanastomosis with a long loop and additional transversal enteroenteric anastomosis to offer functional advantage in cancer patients. These valve anastomoses prevented reflux of duodenal contents to the gastric stump, assured a stepwise emptying of the resected stomach and precluded passing of food to efferent intestine thus preventing dumping and afferent loop syndromes.


HLA alleles and IDDM in children in Hungary: a comparison with Finland.
It has been postulated that variation in the distribution of human leukocyte antigen (HLA)-encoded susceptibility alleles for insulin-dependent diabetes mellitus (IDDM) is the genetic basis for variation in the incidence of the disease between populations. The aim of this study was to characterize HLA-encoded susceptibility to IDDM in Hungary and to identify whether HLA-DRB1/DQ-encoded susceptibility could account for the five times lower incidence of disease in Hungary compared with Finland. The haplotypes DRB1*03-DQA1*05-DQB1*02 (DRB1*03-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DRB1*04-DQ8) were significantly associated with disease in both populations. Three genotypes incorporating either or both of these haplotypes accounted for over 70% of the diabetic population in both races. The combined background frequency and the degree of risk as measured by odds ratios of these HLA-DRB1-DQ genotypes were not significantly different in the two countries. Comparison of the DRB1*0401-DQ8 haplotype between the two races suggested a role for HLA-B alleles in susceptibility. These data indicate that the susceptibility associated with high risk DRB1-DQ genotypes alone is insufficient to account for the fivefold variation in incidence of IDDM between Hungary and Finland. Other genetic and/or environmental influences must be involved.


Organ models in wound ballistics: experimental study.
Effects of various types and diameters of guns and related treatment principles are different. Our study was performed to experimentally demonstrate the effects of different gunshots in body tissues. 9x19 mm hand-gun and 7.62x51 mm G-3 infantry rifle were used in the study. Injury models were created through hand-gun and rifle shootings at isolated soft tissue, lower extremity, liver and intestine tissue simulants made of ballistic candle. High-speed cameras were used to capture 1000 frames per second. Images were examined and wound mechanisms were evaluated. It was observed that the colon content distributed more within the surrounding tissues by the rifle shootings comparing with hand-gun shootings and could be an infection source due to the large size of the cavity in the colon. Especially when the bullets hitting the bone were investigated, it was seen that much more tissue injury occurs with high speed bullets due to bullet deformation and fragmentation. However, no significant difference was found between the effect of hand-gun and rifle bullets passing through the extremity without hitting the bone. To know the type of the gun that caused the injury and its characteristics will allow to estimate severity and size of the injury before the treatment and to focus on different alternatives of treatment. Therefore, use of appropriate models is required in experimental studies.


Three year results of the prostatic urethral L.I.F.T. study.
To report the three year results of a multi-center, randomized, patient and outcome assessor blinded trial of the Prostatic Urethral Lift (PUL) in men with bothersome lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). At 19 centers in North America and Australia, 206 subjects = 50 years old with International Prostate Symptom Score (IPSS) ≥ 13, peak flow rate (Qmax) ≤ 12 mL/s, and prostate volume between 30 cc-80 cc were randomized 2:1 to the PUL procedure or sham control. PUL involved placing permanent UroLift implants into the lateral lobes of the prostate to enlarge the urethral lumen. After randomized comparison at 3 months, PUL patients were followed to 3 years. LUTS severity (IPSS), quality of life, Qmax, sexual function, and adverse events were assessed throughout follow up. The therapeutic effect of PUL regarding IPSS was 88% greater than sham at 3 months. Average improvements from baseline through 3 years were significant for total IPSS (41.1%), quality of life (48.8%), Qmax (53.1%), and individual IPSS symptoms. Symptomatic improvement was independent of prostate size. There were no de novo, sustained ejaculatory or erectile dysfunction events and all sexual function assessments showed average stability or improvement after PUL. Fifteen of the 140 patients originally randomized to PUL required surgical reintervention for treatment failure within the first 3 years. PUL offers rapid improvement in voiding and storage symptoms, quality of life and flow rate that is durable to 3 years. Patients demonstrated a level of symptom relief that is associated with significant patient satisfaction. PUL, a minimally invasive procedure, is very effective in treating bothersome LUTS secondary to benign prostatic obstruction (BPO) and is unique in its ability to preserve total sexual function while offering a rapid return to normal physical activities.


The Relationship between Dialysis Metrics and Patient-Reported Cognition, Fatigue, and Physical Function.
The impact of achieving hemodialysis laboratory and hemodynamic quality metrics on patient-reported outcomes (PROs) is unknown. To determine if meeting dialysis laboratory quality of care measures is associated with improved PROs. In this cross-sectional study, we measured the relationship between dialysis patients' Patient Reported Outcome Measurement Information System (PROMIS) scores and commonly used dialysis quality of care measures. PROMIS surveys were administered to 92 dialysis patients. The mean ± SD scores demonstrated higher fatigue (55.0 ± 9.8) and lower physical function (37.9 ± 7.9) but similar cognition (50.3 ± 10.9) compared to general population normative scores of 50 ± 10. Dialysis patients meeting Kt/V goals had no better scores than those who did not. Meeting the hemoglobin (Hgb) value of ≥10 g/dL was associated with a lower fatigue score, but no difference in cognitive or physical function scores. Meeting the serum albumin goal of ≥4.0 mg/dL was associated with a higher physical function score but made no difference for cognitive function or fatigue score. As a continuous variable, a higher Hgb was associated with lower reported fatigue (HR -1.74 95%, CI [-3.09, -0.39]), but no other measures were associated with PRO scores when adjusted for demographics and comorbidities. We found little association between measures currently used to assess the quality of dialysis care and PROs. Encouraging improved utilization of PROs and incorporating PROs into quality measurements might give a more robust assessment of quality of care. Future studies should assess the benefits of this approach.


Transtympanic versus tympanic membrane electrocochleography in examining cochleovestibular disorders.
The use of electrocochleography (EcoG) is considered to be of clinical value in otological diagnosis. Non-invasive ear canal (EC) and tympanic membrane (TM) EcoG recording techniques, and invasive transtympanic (TT) technique are the methods used for objective assessment of cochlear function. In this study, eight adults (16 ears) with suspected Meniere's disease were examined using a newly designed, disposable tympanic electrode and a traditional, thin transtympanic needle. The amplitudes of the TT electrode responses were 4-6-fold larger than those produced by the TM electrode. The morphology of the waveforms for the two recording techniques was nearly identical. The mean amplitudes of the action potential (AP) obtained with the TM electrode were 2.39-3.73 microV, and with the TT electrode 14.08-19.60 microV, depending on the stimulus intensity. For the summating potential (SP), the TM and TT electrodes had mean amplitudes of 0.82-1.60 microV and 3.53-5.81 microV respectively. The SP/AP ratios were larger with the TM electrode than with the TT electrode. They were inconsistent in four ears (25%) when measured with the TM and TT electrodes. All patients were more satisfied with the TT examination, since it was quite painless, unlike the TM examination. The authors recommend the use of the TT recording technique as a painless examination in which the electrode is close to the inner ear, allowing a good signal-to-noise ratio and large amplitudes. Diagnostic interpretations are easier and more reliable with the TT electrode than with the TM electrode.


Isolation and characterization of Vibrio parahaemolyticus causing infection in Iberian toothcarp Aphanius iberus.
High mortality among laboratory cultured Iberian toothcarp Aphanius iberus occurred in February 1997 in Valencia (Spain). The main signs of the disease were external haemorrhage and tail rot. Bacteria isolated from internal organs of infected fish were biochemically homogeneous and identified as Vibrio parahaemolyticus. The bacteria were haemolytic against erythrocytes from eel Anguilla anguilla, amberjack Seriola dumerili, toothcarp A. iberus and humans, and were Kanagawa-phenomenon-negative. Infectivity tests showed that the virulence for A. iberus was dependent on salinity. Finally, all strains were virulent for amberjack and eel.


Leveraging the Electronic Health Record to Create an Automated Real-Time Prognostic Tool for Peripheral Arterial Disease.
Background Automated individualized risk prediction tools linked to electronic health records ( EHR s) are not available for management of patients with peripheral arterial disease. The goal of this study was to create a prognostic tool for patients with peripheral arterial disease using data elements automatically extracted from an EHR to enable real-time and individualized risk prediction at the point of care. Methods and Results A previously validated phenotyping algorithm was deployed to an EHR linked to the Rochester Epidemiology Project to identify peripheral arterial disease cases from Olmsted County, MN, for the years 1998 to 2011. The study cohort was composed of 1676 patients: 593 patients died over 5-year follow-up. The c-statistic for survival in the overall data set was 0.76 (95% confidence interval [CI], 0.74-0.78), and the c-statistic across 10 cross-validation data sets was 0.75 (95% CI, 0.73-0.77). Stratification of cases demonstrated increasing mortality risk by subgroup (low: hazard ratio, 0.35 [95% CI, 0.21-0.58]; intermediate-high: hazard ratio, 2.98 [95% CI, 2.37-3.74]; high: hazard ratio, 8.44 [95% CI, 6.66-10.70], all P<0.0001 versus the reference subgroup). An equation for risk calculation was derived from Cox model parameters and β estimates. Big data infrastructure enabled deployment of the real-time risk calculator to the point of care via the EHR . Conclusions This study demonstrates that electronic tools can be deployed to EHR s to create automated real-time risk calculators to predict survival of patients with peripheral arterial disease. Moreover, the prognostic model developed may be translated to patient care as an automated and individualized real-time risk calculator deployed at the point of care.


Arginine and citrulline and the immune response in sepsis.
Arginine, a semi-essential amino acid is an important initiator of the immune response. Arginine serves as a precursor in several metabolic pathways in different organs. In the immune response, arginine metabolism and availability is determined by the nitric oxide synthases and the arginase enzymes, which convert arginine into nitric oxide (NO) and ornithine, respectively. Limitations in arginine availability during inflammatory conditions regulate macrophages and T-lymfocyte activation. Furthermore, over the past years more evidence has been gathered which showed that arginine and citrulline deficiencies may underlie the detrimental outcome of inflammatory conditions, such as sepsis and endotoxemia. Not only does the immune response contribute to the arginine deficiency, also the impaired arginine de novo synthesis in the kidney has a key role in the eventual observed arginine deficiency. The complex interplay between the immune response and the arginine-NO metabolism is further underscored by recent data of our group. In this review we give an overview of physiological arginine and citrulline metabolism and we address the experimental and clinical studies in which the arginine-citrulline NO pathway plays an essential role in the immune response, as initiator and therapeutic target.


Measurement of nitrous oxide concentrations in a simulated post anesthesia care unit environment.
The postanesthesia care unit (PACU) nurse works in close proximity to patients during early stages of recovery. It is during this time that the patient exhales the highest levels of anesthetic gases. The National Institute for Occupational Health and Safety has established standards for exposure to waste anesthetic gases which state that sampling should be done in the breathing zone of those most heavily exposed. Thus, it is important that a sampling methodology, data acquisition system, and statistical analysis technique be developed which accurately measures waste anesthetic gas levels at a point representing the breathing zone of nurses providing bedside care. A study was conducted to obtain an understanding of how the concentration of nitrous oxide varies with distance from a recovering patient. The study found that concentration of nitrous oxide decreases with distance from the patient; the patient's respiration increases the level of nitrous oxide at the location of the nurse; and the respiration of the nurse pulls the flow field toward them, increasing their exposure to the gas. The results show the inadequacy of attempting to measure levels of gas exposure for PACU nurses by a sampling protocol which calls for samples taken at random points in the room.


Biomarkers of sepsis.
Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate's effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high.


Different human copper-zinc superoxide dismutase mutants, SOD1G93A and SOD1H46R, exert distinct harmful effects on gross phenotype in mice.
Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of fatal neurodegenerative diseases characterized by a selective loss of motor neurons in the brain and spinal cord. Creation of transgenic mice expressing mutant Cu/Zn superoxide dismutase (SOD1), as ALS models, has made an enormous impact on progress of the ALS studies. Recently, it has been recognized that genetic background and gender affect many physiological and pathological phenotypes. However, no systematic studies focusing on such effects using ALS models other than SOD1(G93A) mice have been conducted. To clarify the effects of genetic background and gender on gross phenotypes among different ALS models, we here conducted a comparative analysis of growth curves and lifespans using congenic lines of SOD1(G93A) and SOD1(H46R) mice on two different genetic backgrounds; C57BL/6N (B6) and FVB/N (FVB). Copy number of the transgene and their expression between SOD1(G93A) and SOD1(H46R) lines were comparable. B6 congenic mutant SOD1 transgenic lines irrespective of their mutation and gender differences lived longer than corresponding FVB lines. Notably, the G93A mutation caused severer disease phenotypes than did the H46R mutation, where SOD1(G93A) mice, particularly on a FVB background, showed more extensive body weight loss and earlier death. Gender effect on survival also solely emerged in FVB congenic SOD1(G93A) mice. Conversely, consistent with our previous study using B6 lines, lack of Als2, a murine homolog for the recessive juvenile ALS causative gene, in FVB congenic SOD1(H46R), but not SOD1(G93A), mice resulted in an earlier death, implying a genetic background-independent but mutation-dependent phenotypic modification. These results indicate that SOD1(G93A)- and SOD1(H46R)-mediated toxicity and their associated pathogenic pathways are not identical. Further, distinctive injurious effects resulted from different SOD1 mutations, which are associated with genetic background and/or gender, suggests the presence of several genetic modifiers of disease expression in the mouse genome.


Does Surgeon Sex Matter?: Practice Patterns and Outcomes of Female and Male Surgeons.
We sought to compare postoperative outcomes of female surgeons (FS) and male surgeons (MS) within general surgery. FS in the workforce are increasing in number. Female physicians provide exceptional care in other specialties. Differences in surgical outcomes of FS and MS have not been examined. We linked the AMA Physician Masterfile to discharge claims from New York, Florida, and Pennsylvania (2012 to 2013) to examine practice patterns and to compare surgical outcomes of FS and MS. We paired FS and MS operating at the same hospital using cardinality matching with refined balance and compared inpatient mortality, any postoperative complication, and prolonged length of stay (pLOS) in FS and MS. Overall practice patterns differed between the 663 FS and 3219 MS. We identified 2462 surgeons (19% FS, 81% MS) at 429 hospitals who met inclusion criteria for outcomes analysis. FS were younger (mean age ± SD FS: 48.5 ± 8.4 years, MS: 54.3 ± 9.4y; P < 0.001) with less clinical experience (mean years ± SD FS: 11.6 ± 8.3 y, MS: 17.6 ± 10.0 years; P < 0.001) than MS before matching. FS had lower rates of inpatient mortality (FS: 1.51%, MS: 2.30%; P < 0.001), any postoperative complication (FS: 12.6%, MS: 16.1%; P < 0.001), and pLOS (FS: 18.4%, MS: 20.7%; P < 0.001) before matching. After matching, FS and MS outcomes were equivalent. Surgeon practice patterns vary by sex and experience. FS and MS with similar characteristics who treat similar patients at the same hospital have equivalent rates of inpatient morality, postoperative complications, and prolonged length of hospital stay. Patients should select the surgeon who is the best fit for them regardless of sex.


Begg appliance management of a moderately crowded Angle Class 11 Division 2 malocclusion.
A case is presented that shows Begg appliance management of an Angle Class II division 2 malocclusion. The judicious use of anchorage bends and Class II elastics enabled the successful treatment of the poor posterior and anterior relationships, at the same time addressing the chief complaint of crooked front teeth.


Increasing organ yield through a lung management protocol.
Gift of Life Michigan determined that the largest gap between the number of organ donors and the number of organs transplanted has been in the number of lungs transplanted. The literature was reviewed for lung donor management strategies and other organ procurement organizations were surveyed for existing donor management guidelines to improve lung function. On the basis of pulmonary physiology and the knowledge gained from the literature search, Gift of Life Michigan developed a lung donor management protocol that has been very effective. In 4 years, the number of lungs transplanted has increased from 37 to 135, representing a 265% improvement.


Spectral analysis of climate dynamics with operator-theoretic approaches.
The Earth's climate system is a classical example of a multiscale, multiphysics dynamical system with an extremely large number of active degrees of freedom, exhibiting variability on scales ranging from micrometers and seconds in cloud microphysics, to thousands of kilometers and centuries in ocean dynamics. Yet, despite this dynamical complexity, climate dynamics is known to exhibit coherent modes of variability. A primary example is the El Niño Southern Oscillation (ENSO), the dominant mode of interannual (3-5 yr) variability in the climate system. The objective and robust characterization of this and other important phenomena presents a long-standing challenge in Earth system science, the resolution of which would lead to improved scientific understanding and prediction of climate dynamics, as well as assessment of their impacts on human and natural systems. Here, we show that the spectral theory of dynamical systems, combined with techniques from data science, provides an effective means for extracting coherent modes of climate variability from high-dimensional model and observational data, requiring no frequency prefiltering, but recovering multiple timescales and their interactions. Lifecycle composites of ENSO are shown to improve upon results from conventional indices in terms of dynamical consistency and physical interpretability. In addition, the role of combination modes between ENSO and the annual cycle in ENSO diversity is elucidated.


Alcohol Consumption during Pregnancy: Analysis of Two Direct Metabolites of Ethanol in Meconium.
Alcohol consumption in young women is a widespread habit that may continue during pregnancy and induce alterations in the fetus. We aimed to characterize prevalence of alcohol consumption in parturient women and to assess fetal ethanol exposure in their newborns by analyzing two direct metabolites of ethanol in meconium. This is a cross-sectional study performed in September 2011 and March 2012 in a series of women admitted to an obstetric unit following childbirth. During admission, socio-demographic and substance use (alcohol, tobacco, cannabis, cocaine, and opiates) during pregnancy were assessed using a structured questionnaire and clinical charts. We also recorded the characteristics of pregnancy, childbirth, and neonates. The meconium analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect the presence of ethyl glucuronide (EtG) and ethyl sulfate (EtS). Fifty-one parturient and 52 neonates were included and 48 meconium samples were suitable for EtG and EtS detection. The median age of women was 30 years (interquartile range (IQR): 26-34 years); EtG was present in all meconium samples and median concentration of EtG was 67.9 ng/g (IQR: 36.0-110.6 ng/g). With respect to EtS, it was undetectable (<0.01 ng/g) in the majority of samples (79.1%). Only three (6%) women reported alcohol consumption during pregnancy in face-to-face interviews. However, prevalence of fetal exposure to alcohol through the detection of EtG and EtS was 4.2% and 16.7%, respectively. Prevention of alcohol consumption during pregnancy and the detection of substance use with markers of fetal exposure are essential components of maternal and child health.


Beat-to-beat cycle length variability of spontaneously beating guinea pig sinoatrial cells: relative contributions of the membrane and calcium clocks.
The heartbeat arises rhythmically in the sino-atrial node (SAN) and then spreads regularly throughout the heart. The molecular mechanism underlying SAN rhythm has been attributed by recent studies to the interplay between two clocks, one involving the hyperpolarization activated cation current If (the membrane clock), and the second attributable to activation of the electrogenic NaCa exchanger by spontaneous sarcoplasmic releases of calcium (the calcium clock). Both mechanisms contain, in principle, sources of beat-to-beat cycle length variability, which can determine the intrinsic variability of SAN firing and, in turn, contribute to the heart rate variability. In this work we have recorded long sequences of action potentials from patch clamped guinea pig SAN cells (SANCs) perfused, in turn, with normal Tyrode solution, with the If inhibitor ivabradine (3 µM), then back to normal Tyrode, and again with the ryanodine channels inhibitor ryanodine (3 µM). We have found that, together with the expected increase in beating cycle length (+25%), the application of ivabradine brought about a significant and dramatic increase in beat-to-beat cycle length variability (+50%). Despite the similar effect on firing rate, ryanodine did not modify significantly beat-to-beat cycle length variability. Acetylcholine was also applied and led to a 131% increase of beating cycle length, with only a 70% increase in beat-to-beat cycle length variability. We conclude that the main source of inter-beat variability of SANCs firing rate is related to the mechanism of the calcium clock, whereas the membrane clock seems to act in stabilizing rate. Accordingly, when the membrane clock is silenced by application of ivabradine, stochastic variations of the calcium clock are free to make SANCs beating rhythm more variable.


Reduced tumorigenicity of rat glioma cells in the brain when mediated by hygromycin phosphotransferase.
A variant of C6 glioma cells, C6R-G/H cells express hygromycin phosphotransferase (HPT) and appear to have reduced tumorigenicity in the embryonic brain. The goal of this study was to investigate their reduced capacity to generate tumors in the adult rat brain. Cell lines were implanted into rat brains and tumorigenesis was evaluated. After 3 weeks, all rats with C6 cells showed signs of neurological disease, whereas rats with C6R-G/H cells did not and were either killed then or allowed to survive until later. Histological studies were performed to analyze tumor size, malignancy, angiogenesis, and cell proliferation. Cells isolated from rat brain tumors were analyzed for mutation to HPT by testing their sensitivity to hygromycin. The results indicate that HPT suppresses tumor formation. Three weeks after implantation, only 44% of animals implanted with C6R-G/H cells developed tumors, whereas all animals that received C6 glioma cells developed high-grade gliomas. The C6R-G/H cells filled a 20-fold smaller maximal cross-sectional area than the C6 cells, and exhibited less malignant characteristics, including reduced angiogenesis, mitosis, and cell proliferation. Similar results were obtained in the brain of nude rats, indicating that the immune system did not play a significant role in suppressing tumor growth. The combination of green fluorescent protein (GFP) and HPT was more effective in suppressing tumorigenesis than either plasmid by itself, indicating that the GFP may protect against inactivation of the HPT. Interestingly. hygromycin resistance was lost in tumor cells that were recovered from a group of animals in which C6R-G/H cells formed tumors, confirming the correlation of HPT with reduced tumorigenicity.


Isolation of mutants of an animal virus in bacteria.
Mutants of animal viruses can be isolated in bacteria by recombinant DNA methods. Since no viral functions are required for propagation of recombinants in bacteria, viral mutants with lethal changes in cis- or trans-acting elements can be isolated, as well as partially or conditionally defective mutants. In the cases of viruses with small DNA genomes, such as the tumorigenic simian virus 40 (SV40), the entire viral DNA can be inserted into the bacterial plasmid pBR322 and cloned in Escherichia coli. Recombinant plasmids with a single copy of SV40 DNA cause morphological transformation of mouse cells in culture with the same efficiency as SV40 DNA isolated from virus-infected monkey cells, but the recombinant DNA is noninfectious and replicates poorly in permissive cells. However, SV40 DNA excised from the plasmid replicates as well as authentic viral DNA and is fully infectious. SV40 mutants with small deletions or base substitutions have been isolated by in vitro site-specific or random local mutagenesis of recombinant DNA followed by cloning in E. coli. Many of the mutants thus isolated are defective in specific viral functions.


Extracorporeal carbon dioxide removal performed with surface-heparinized equipment in patients with ARDS.
To avoid the drawbacks of systemic anticoagulation during prolonged extracorporeal circulation in patients with adult respiratory distress syndrome (ARDS) a heparinization technique has been developed by which partially degraded heparin can be covalently end-point attached to the surface of the equipment constituting the extracorporeal circuit (Carmeda Bio-Active Surface, CBAS) thereby localizing the anticoagulatory effect. Since 1986 we have used extracorporeal circuits and membrane lungs coated with the CBAS for extracorporeal lung assistance (ECLA) in 14 patients suffering from ARDS. The patients were on ECLA for 3 to 55 days with a survival rate of 43%. Our experience so far is that by using equipment coated with CBAS it is possible to perform long-term extracorporeal circulation with a minimum of intravenously administered heparin, thus avoiding the risk of major coagulation defects.


Predictors of treatment intensification in uncontrolled hypertension.
Prior studies have shown that treatment intensification for patients presenting with uncontrolled hypertension (HTN) rarely occurs, even during visits to the patient's own primary care physicians (PCPs). In this article, we identified predictors of treatment intensification for uncontrolled HTN. We conducted a cross-sectional study using nationally representative survey data on visits by patients aged 18 or above with uncontrolled HTN, defined as a recorded SBP at least 140 and/or a DBP at least 90 using data from the National Ambulatory Medical Care Survey (NAMCS) 2008-2018. Our outcome is treatment intensification defined as the addition of a new blood pressure medication. We analyzed 22 559 visits to PCPs where uncontrolled HTN was noted, representing 801 023 786 visits nationally. Among these encounters, 2138 (10.3%) of the visits resulted in treatment intensification. Visits with the patient's own PCP had higher rates of treatment intensification than visits to another PCP (10.8 vs. 5.9%, P < 0.0001). Visits for patients previously on antihypertensive medications had lower rates of treatment intensification (11% for no medications, 10.4% for one medication, 6.6% for ≥2 medications, P < 0.0001), but there were no statistically significant differences in rates of intensification for those with relevant comorbidities (9.4% for no chronic conditions, 10.8% for one to two chronic conditions, 8.9% for at least three chronic conditions, P = 0.12). Multivariable adjusted results were similar to the unadjusted findings. Visits for patients with uncontrolled HTN rarely result in treatment intensification. Substantial opportunity exists to improve management of HTN, particularly for patients on fewer medications or seen by a covering provider.


Ligand-independent dimerization of the human prolactin receptor isoforms: functional implications.
Prolactin (PRL) contributes to the growth of normal and malignant breast tissues. PRL initiates signaling by engaging the PRL receptor (PRLr), a transmembrane (TM) receptor belonging to the cytokine receptor family. The accepted view has been that PRL activates the PRLr by inducing dimerization of the receptor, but recent reports show ligand-independent dimerization of other cytokine receptors. Using coimmunoprecipitation assays, we have confirmed ligand-independent dimerization of the PRLr in T47D breast cancer and HepG2 liver carcinoma cells. In addition, mammalian cells transfected with differentially epitope-tagged isoforms of the PRLr indicated that long, intermediate, and DeltaS1 PRLrs dimerized in a ligand-independent manner. To determine the domain(s) involved in PRLr ligand-independent dimerization, we generated PRLr constructs as follows: (1) the TM-ICD, which consisted of the TM domain and the intracellular domain (ICD) but lacked the extracellular domain (ECD), and (2) the ECD-TM, which consisted of the TM domain and the ECD but lacked the ICD. These constructs dimerized in a ligand-independent manner in mammalian cells, implicating a significant role for the TM domain in this process. These truncated PRLrs were functionally inert alone or in combination in cells lacking the PRLr. However, when introduced into cells containing endogenous PRLr, the ECD-TM inhibited human PRLr signaling, whereas the TM-ICD potentiated human PRLr signaling. These studies indicate that the ECD-TM and the TM-ICD are capable of modulating PRLr function. We also demonstrated an endogenous TM-ICD in T47D cells, suggesting that these findings are relevant to PRL-signaling pathways in breast cancer.


Inertial effects on the assessment of performance in isokinetic dynamometry.
Moments due to acceleration and deceleration periods influence the joint moment (torque) in isokinetic dynamometry. The purpose of this study was to evaluate the differences in the peak moment and the moment development during the initial acceleration period of isokinetic concentric knee extension before and after correction for inertial effects, and evaluate their relationship. The moment development was expressed by the work produced during the initial 0.125 s of the movement. Five male and five female healthy young adults participated in the study. Seven concentric knee extensions at 1.04, 3.14 and 5.24 rad/s were performed on a Biodex dynamometer. Inertial moments were calculated using acceleration data derived from the Biodex software angular displacement data. After inertial correction, the maximum errors in the original peak moment and the moment development at the inital 0.125 s were 7 and 16%, respectively, and were recorded at 5.24rad/s. At slower velocities (1.04 and 3.14 rad/s) the effects of inertial moments on the peak moment and the work at the initial 0.125 s were negligible. Inertial moments did not influence the relationship between the examined parameters at the three velocities. In conclusion, inertial moments affect the peak moment and moment development during the initial acceleration period at high velocities of isokinetic testing and therefore these effects should be considered in order to obtain valid results in isokinetic dynamometry.