Prognostic Effects of Predominant Histologic Subtypes in Resected Pulmonary Adenocarcinomas
Predominant histologic subtypes have been reported as predictors of survival of patients with pulmonary adenocarcinoma. To evaluate the predictive value of histologic classification in resected lung adenocarcinoma using the classification systems proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and World Health Organization (2015). Cross-sectional study. The histologic classification of a large cohort of 491 patients with resected lung adenocarcinoma (stages I-III) was retrospectively analyzed. The tumors were classified according to their predominant component (lepidic, acinar, papillary, solid, micropapillary, and mucinous), and their predictive values were assessed for clinicopathologic characteristics and overall survival. The patient cohort comprised 158 (32.2%) patients with solid predominant, 150 (30.5%) with acinar predominant, 80 (16.3%) with papillary predominant, 75 (15.3%) with lepidic predominant, 22 (4.5%) with mucinous, and 5 (1.0%) with micropapillary subtype, and 1 (0.2%) with adenocarcinoma in situ. Overall 5-year survival of 491 patients was found to be 51.8%. Patients with lepidic, acinar, and mucinous adenocarcinoma had 70.9%, 59.0%, and 66.6% 5-year survival, respectively, and there was no statistically significant difference between them. Whereas patients with solid, papillary, and micropapillary predominant adenocarcinoma had 41.0%, 40.5%, and 0.0% 5-year survival, respectively. Compared to other histologic subtypes, patients with solid and papillary predominant adenocarcinoma had significantly lower survival than those with lepidic (p<0.001, p=0.002), acinar (p<0.001, p=0.008), and mucinous (p=0.048, p=0.048) subtypes, respectively. The survival difference between patients with solid subtype and those with papillary subtype was not statistically significant (p=0.67). Solid and papillary histologic subtypes are poor prognostic factors in resected invasive lung adenocarcinoma.


Older patients undergoing emergency laparotomy: observations from the National Emergency Laparotomy Audit (NELA) years 1-4.
older patients aged ≥65 years constitute the majority of the National Emergency Laparotomy Audit (NELA) population. To better understand this group and inform future service changes, this paper aims to describe patient characteristics, outcomes and process measures across age cohorts and temporally in the 4-year period (2014-2017) since NELA was established. patient-level data were populated from the NELA data set years 1-4 and linked with Office of National Statistics mortality data. Descriptive data were compared between groups delineated by age, NELA year and geriatrician review. Primary outcomes were 30- and 90-day mortality, length of stay (LOS) and discharge to care-home accommodation. in total, 93,415 NELA patients were included in the analysis. The median age was 67 years. Patients aged ≥65 years had higher 30-day (15.3 versus 4.9%, P < 0.001) and 90-day mortality (20.4 versus 7.2%, P < 0.001) rates, longer LOS (median 15.2 versus 11.3 days, P < 0.001) and greater likelihood of discharge to care-home accommodation compared with younger patients (6.7 versus 1.9%, P < 0.001). Mortality rate reduction over time was greater in older compared with younger patients. The proportion of older NELA patients seen by a geriatrician post-operatively increased over years 1-4 (8.5 to 16.5%, P < 0.001). Post-operative geriatrician review was associated with reduced mortality (30-day odds ratio [OR] 0.38, confidence interval [CI] 0.35-0.42, P < 0.001; 90-day OR 0.6, CI 0.56-0.65, P < 0.001). older NELA patients have poorer post-operative outcomes. The greatest reduction in mortality rates over time were observed in the oldest cohorts. This may be due to several interventions including increased perioperative geriatrician input.


TWEAK and Fn14 in the Neurovascular Unit.
The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells (EC), a basement membrane (BM), perivascular astrocytes (PA), pericytes, and surrounding neurons. The NVU regulates the passage of substances and cellular elements from the intravascular space into the brain parenchyma. This function, also known as blood-brain barrier (BBB), is regulated by the integrity of tight junctions proteins between EC, and the interaction between PA and the basal lamina. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are abundantly expressed in the NVU. Here we will review data indicating that the interaction between TWEAK and Fn14 in the endothelial cell-BM-astrocyte interface regulates the function of the BBB following an ischemic/hypoxic injury, and that pharmacological inhibition of TWEAK-Fn14 is a promising target for the treatment of patients with neurological diseases that have a direct impact on the structure and function of the NVU.


Diffusion alterations in corpus callosum of patients with HIV.
Diffusion alterations have been identified in the corpus callosum and frontal white matter of patients infected with human immunodeficiency virus (HIV), though the relevance of these findings to cognitive deterioration has not yet been determined. This study tested the hypothesis that diffusion tensor imaging can detect tissue status alterations in these regions in cognitively impaired patients infected with HIV and the acquired measurements correlate with the severity of cognitive impairment. Fractional anisotropy (FA) and mean diffusivity (MD) were determined for corpus callosum (genu and splenium) and frontal white matter (FWM). The DTI measurements were compared in 11 HIV and 11 control participants. Patterns of relationship were examined with cognitive status measures from concurrent neurologic and neuropsychologic evaluations. FA values for the splenium were significantly reduced in the patients infected with HIV and correlated with dementia severity and deficits in motor speed. MD values for the splenium were significantly increased in the patients infected with HIV and correlated with deficits in motor speed. FA measurements were also significantly correlated with performance on visual memory (genu), visuoconstruction (FWM), and verbal memory (FWM) tasks. Diffusion abnormalities were identified in the splenium of the corpus callosum in patients infected with HIV, and these alterations were associated with dementia severity and motor speed losses. In vivo assessment of callosal integrity by using quantitative neuroimaging may have potential utility as a marker of brain injury in patients infected with HIV.


Butyrate supplementation regulates expression of chromosome segregation 1‑like protein to reverse the genetic distortion caused by p53 mutations in colorectal cancer.
The chromosome segregation 1‑like (CSE1L) protein, which regulates cellular mitosis and apoptosis, was previously found to be overexpressed in colorectal cancer (CRC) cells harboring mutations. Therefore, regulating CSE1L expression may confer chemotherapeutic effects against CRC. The gut microflora can regulate gene expression in colonic cells. In particular, metabolites produced by the gut microflora, including the short‑chain fatty acid butyrate, have been shown to reduce CRC risk. Butyrates may exert antioncogenic potential in CRC cells by modulating p53 expression. The present study evaluated the association between CSE1L expression and butyrate treatment from two non‑transformed colon cell lines (CCD‑18Co and FHC) and six CRC cell lines (LS 174T, HCT116 p53+/+, HCT116 p53‑/‑, Caco‑2, SW480 and SW620). Lentiviral knockdown of CSE1L and p53, reverse transcription‑quantitative PCR (CSE1L, c‑Myc and p53), western blotting [CSE1L, p53, cyclin (CCN) A2, CCNB2 and CCND1], wound healing assay (cell migration), flow cytometry (cell cycle analysis) and immunofluorescence staining (CSE1L and tubulin) were adopted to verify the effects of butyrate on CSE1L‑expressing CRC cells. The butyrate‑producing gut bacteria Butyricicoccus pullicaecorum was administered to mice with 1,2‑dimethylhydrazine‑induced colon tumors before the measurement of CSE1L expression. The effects of B. pullicaecorum on CSE1L expression were then assessed by immunohistochemical staining for CSE1L and p53 in tissues from CRC‑bearing mice. Non‑cancerous colon cells with the R273H p53 mutation or CRC cells haboring p53 mutations were found to exhibit significantly higher CSE1L expression levels. CSE1L knockdown in HCT116 p53‑/‑ cells resulted in G1‑and G2/M‑phase cell cycle arrest. Furthermore, in HCT116 p53‑/‑ cells, CSE1L expression was already high at interphase, increased at prophase, peaked during metaphase before declining at cytokinesis but remained relatively high compared with that in HCT116 expressing wild‑type p53. Significantly decreased expression levels of CSE1L were also observed in HCT116 p53‑/‑ cells that were treated with butyrate for 24 h. In addition, the migration of HCT116 p53‑/‑ cells was significantly decreased after CSE1L knockdown or butyrate treatment. Tumors with more intense nuclear p53 staining and weaker CSE1L staining were found in mice bearing DMH/DSS‑induced CRC that were administered with B. pullicaecorum. Taken together, the results indicated that butyrate can impair CSE1L‑induced tumorigenic potential. In conclusion, butyrate‑producing microbes, such as B. pullicaecorum, may reverse the genetic distortion caused by p53 mutations in CRC by regulating CSE1L expression levels.


Essential nutrients: food or supplements? Where should the emphasis be?
The consumption of adequate levels and proper balance of essential nutrients is critical for maintaining health. The identification, isolation, and purification of nutrients in the early 20th century raised the possibility that optimal health outcomes could be realized through nutrient supplementation. Recent attempts using this approach for cardiovascular disease and lung cancer have been disappointing, as demonstrated with vitamin E and beta carotene. Moreover, previously unrecognized risks caused by nutrient toxicity and nutrient interactions have surfaced during intervention studies. The most promising data in the area of nutrition and positive health outcomes relate to dietary patterns, not nutrient supplements. These data suggest that other factors in food or the relative presence of some foods and the absence of other foods are more important than the level of individual nutrients consumed. Finally, unknown are the implications on public health behavior of shifting the emphasis away from food toward nutrient supplements. Notwithstanding the justification for targeting recommendations for nutrient supplements to certain segments of the population (eg, the elderly), there are insufficient data to justify an alteration in public health policy from one that emphasizes food and diet to one that emphasizes nutrient supplements.


Epithelial-specific keratin gene expression: identification of a 300 base-pair controlling segment.
To elucidate the elements required for regulation of keratin expression in epidermis, we have linked a short, 300 base pair segment, corresponding to the promoter region of a human K#14 gene, to the chloramphenicol-acetyl-transferase gene. This construct was introduced into various mammalian cell lines and primary cultures via Ca3(PO4)2 precipitation. The 300 base pair segment from the keratin gene promoter region was active in all epithelial cells studied including transformed, simple epithelial cells such as HeLa and ME-180, cell lines derived from stratified epithelium, such as SCC-12, as well as primary cultures of epithelial cells. The construct was inactive in all non-epithelial cells tested including fibroblasts and melanocytes. The segment does not function as a silencer in nonepithelial cells but it can function as an enhancer in epithelial cells. Using the polymerase chain reaction we have constructed a series of deletions of the promoter and have localized an essential function within a 40 bp sequence. We conclude that we have identified the keratin gene promoter that is sufficient to confer epithelial-specific expression.


Prospects of human malaria and Bancroftian filariasis infections in the Lower Rufiji Basin, Tanzania. I. Malaria.
Surveys for human malaria infections were conducted in the Lower Rufiji Basin in Tanzania, before and after the long rains in 1981. A multipurpose water resources development project has been planned in the area. Overall asexual malaria parasite, gametocyte and spleen rates of 38.6%, 3.8% and 21.1% respectively were observed before the long rains whilst respective parameters after the long rains were 44.5%, 2.8% and 17.3%. Malaria parasite species percentages of 95.5, 1.0, 0.2 and 3.4 were observed in respect of P. falciparum, P. malariae, P. ovale and mixed infections respectively for both periods. Malaria endemicity in the Lower Rufiji Basin ranges between mesoendemic to hyperendemic. Following implementation of the project, malaria is likely to become holoendemic.


Probing the regulation of TASK potassium channels by PI4,5P₂ with switchable phosphoinositide phosphatases.
TASK channels are background K+ channels that contribute to the resting conductance in many neurons. A key feature of TASK channels is the reversible inhibition by Gq-coupled receptors, thereby mediating the dynamic regulation of neuronal activity by modulatory transmitters. The mechanism that mediates channel inhibition is not fully understood. While it is clear that activation of Gαq is required, the immediate signal for channel closure remains controversial. Experimental evidence pointed to either phospholipase C (PLC)-mediated depletion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) as the cause for channel closure or to a direct inhibitory interaction of active Gαq with the channel. Here, we address the role of PI(4,5)P2 for G-protein-coupled receptor (GPCR)-mediated TASK inhibition by using recently developed genetically encoded tools to alter phosphoinositide (PI) concentrations in the living cell.When expressed in CHO cells, TASK-1- and TASK-3-mediated currents were not affected by depletion of plasma membrane PI(4,5)P2 either via the voltage-activated phosphatase Ci-VSP or via chemically triggered recruitment of a PI(4,5)P2-5'-phosphatase. Depletion of both PI(4,5)P2 and PI(4)P via membrane recruitment of a novel engineered dual-specificity phosphatase also did not inhibit TASK currents. In contrast, each of these methods produced robust inhibition of the bona fide PI(4,5)P2-dependent channel KCNQ4. Efficient depletion of PI(4,5)P2 and PI(4)P was further confirmed with a fluorescent phosphoinositide sensor. Moreover, TASK channels recovered normally from inhibition by co-expressed muscarinic M1 receptors when resynthesis of PI(4,5)P2 was prevented by depletion of cellular ATP. These results demonstrate that TASK channel activity is independent of phosphoinositide concentrations within the physiological range. Consequently, Gq-mediated inhibition of TASK channels is not mediated by depletion of PI(4,5)P2.


Microdifferentiation in historical Massachusetts: a comparison of migration matrix and isonymy analyses.
Historical studies of population structure allow assessment of the effects of demographic change on genetic variation among and within populations. This paper investigates the degree of microdifferentiation among four towns in north-central Massachusetts during the 18th and 19th centuries, a time of rapid population growth. Migration matrices were derived from 4,223 marriage records from 1785 through 1849 and then used to estimate genetic kinship using the methods of Imaizumi et al. (Genetics 66:569-582, 1970) and Harpending and Jenkins (In: Genetic Distance. New York: Plenum Press, 1974). Kinship matrices based on isonymy were also derived using the surnames of 4,039 marriages according to Morton's (In: Genetic Structure of Populations. Honolulu: University Press of Hawaii, 1973) methods. In addition, an isonymy distance matrix was constructed based on 4,659 marriage records from 1741 through 1849 to compare surname frequencies across space and time simultaneously. For both migration and isonymy matrices, the degree of micro-differentiation among the four towns, RST, was computed for each of six time cohorts. Both migration and isonymy show a reduction in among-group variation over time, reflecting population growth and stable, but high, rates of long-distance migration. Estimates of RST from migration and isonymy are very similar. The one notable exception reflects known historical events. Comparison of the kinship estimates for individual towns (rii) also shows close correspondence between migration and isonymy. The differences seem to reflect a tendency for migration matrices to overestimate kinship in earlier generations relative to isonymy. A principal coordinates analysis of the isonymy distance matrix shows the relative isolation of towns from one another in all time periods but with a reduction in differentiation over time.


Chronic Alcohol Consumption is Inversely Associated with Insulin Resistance and Fatty Liver in Japanese Males.
We aimed to elucidate the effect of chronic alcohol consumption on fatty liver. We assessed the consumption of alcohol in 2429 Japanese males (mean age: 54.2 ± 9 years); they were classified according to average consumption into non-drinkers (ND), light drinkers (LD), moderate drinkers (MD), and heavy drinkers (HD). The prevalence of fatty liver was the lowest in the MD and highest in the ND group (p < 0.001), while obesity was not significantly different among the groups (p = 0.133). Elevated levels of alanine aminotransferase (ALT) were the lowest in the MD group (p = 0.011) along with resistance to insulin (homeostasis model assessment-insulin resistance (HOMA-IR)), which was highest in the ND group (p = 0.001). Chronic consumption of alcohol was independently and inversely associated with fatty liver and insulin resistance after adjusting for obesity, hypertension, fasting hyperglycemia, habit of drinking sweet beverages, physical activity, and age (odds ratios are as follows: ND, 1; LD, 0.682; MD, 0.771; HD, 0.840 and ND, 1; LD, 0.724; MD, 0.701; HD, 0.800, respectively). We found that regardless of the type of alcoholic beverage, chronic consumption of alcohol is inversely associated with insulin resistance and fatty liver in Japanese males. This study had limitations, most notably the lack of investigation into diet and nutrition.


X-ray fluorescence microscopy reveals accumulation and secretion of discrete intracellular zinc pools in the lactating mouse mammary gland.
The mammary gland is responsible for the transfer of a tremendous amount of zinc ( approximately 1-3 mg zinc/day) from maternal circulation into milk during lactation to support the growth and development of the offspring. When this process is compromised, severe zinc deficiency compromises neuronal development and immune function and increases infant morbidity and/or mortality. It remains unclear as to how the lactating mammary gland dynamically integrates zinc import from maternal circulation with the enormous amount of zinc that is secreted into milk. Herein we utilized X-ray fluorescence microscopy (XFM) which allowed for the visualization and quantification of the process of zinc transfer through the mammary gland of the lactating mouse. Our data illustrate that a large amount of zinc first accumulates in the mammary gland during lactation. Interestingly, this zinc is not cytosolic, but accumulated in large, discrete sub-cellular compartments. These zinc pools were then redistributed to small intracellular vesicles destined for secretion in a prolactin-responsive manner. Confocal microscopy identified mitochondria and the Golgi apparatus as the sub-cellular compartments which accumulate zinc; however, zinc pools in the Golgi apparatus, but not mitochondria are redistributed to vesicles destined for secretion during lactation. Our data directly implicate the Golgi apparatus in providing a large, mobilizable zinc storage pool to assist in providing for the tremendous amount of zinc that is secreted into milk. Interestingly, our study also provides compelling evidence that mitochondrial zinc pools expand in the mammary gland during lactation which we speculate may play a role in regulating mammary gland function.


Computational Vibrational Spectroscopy.
Vibrational spectroscopy is a powerful technique to characterize the near-equilibrium dynamics of molecules in the gas and the condensed phase. This contribution summarizes efforts from computer-based methods to gain insight into the relationship between structure and spectroscopic response. Methods for this purpose include physics-based and machine-learned energy functions, and methods that separate sampling conformational space and determining the data for spectral analysis such as map-based techniques.


[Use of dielectrophoresis for the preparative separation of thermotolerant yeast cells].
Dielectrophoresis as a new method for preparative separation of cells is being presented. This method responds to differences in the polarization of cells, which correlate with a number of complex physiological properties of cells. It is shown that yeast cells of different thermotolerant properties can be differentiated by dielectrophoresis. Moreover, the application of this method permitted to separate cells with a high selectivity, which produce more biomass at a temperature of 40 degrees C than the initial population. Investigations on the ability of cells to survive in an inhomogeneous a.c. field have shown that the number of dead cells at frequencies of 10(5) cps and 10(6) cps and at field strengths (on the surface of the central electrode) below 2.4 X 10(5) V/m is small. This fact should be considered when picking out suitable separation conditions.


Venous thromboembolic events following foot and ankle surgery in the English National Health Service.
Diagnostic and operative codes are routinely collected for every patient admitted to hospital in the English NHS. Data on post-operative complications following foot and ankle surgery have not previously been available in large numbers. Data on symptomatic venous thromboembolism events and mortality within 90 days were extracted for patients undergoing fixation of an ankle fracture, first metatarsal osteotomy, hindfoot fusions and total ankle replacement over a period of 42 months. For ankle fracture surgery (45 949 patients), the rates of deep-vein thrombosis (DVT), pulmonary embolism and mortality were 0.12%, 0.17% and 0.37%, respectively. For first metatarsal osteotomy (33 626 patients), DVT, pulmonary embolism and mortality rates were 0.01%, 0.02% and 0.04%, and for hindfoot fusions (7033 patients) the rates were 0.03%, 0.11% and 0.11%, respectively. The rate of pulmonary embolism in 1633 total ankle replacement patients was 0.06%, and there were no recorded DVTs and no deaths. Statistical analysis could only identify risk factors for venous thromboembolic events of increasing age and multiple comorbidities following fracture surgery. Venous thromboembolism following foot and ankle surgery is extremely rare, but this subset of fracture patients is at a higher risk. However, there is no evidence that thromboprophylaxis reduces this risk, and these national data suggest that prophylaxis is not required in most of these patients.


The effect of inbreeding and population hybridization on developmental instability in petals and leaves of the rare plant silene diclinis (Caryophyllaceae)
Studies of fluctuating asymmetry (FA), a measure of developmental instability (DI), may provide insights into the importance of genetic factors in the long-term survival of small and isolated populations. In the present study of the rare, endemic plant Silene diclinis, I tested how moderate inbreeding within populations (full-sib crosses) and hybridization between populations influenced levels of developmental instability of petals and leaves, using plants derived from controlled crosses and raised under uniform growth conditions. The area and length of petals and leaves were digitized and measured with an image analysis system, but only bifid petals could be tested for true fluctuating asymmetry (normally distributed left-minus-right values with a mean of zero). Based on a bootstrap procedure, I found little evidence for directional asymmetry and antisymmetry in the area and length of the two lobes of the petals. Only the length measurements showed a significant leptokurtic distribution, which may reflect limited resolution (too few classes) in the image analysis system. Randomization tests were performed to test for differences between crossing treatments. Levels of FA of petal area and petal length were significantly higher for both the inbred and the interpopulation hybrid progenies relative to offspring from crosses between unrelated plants from the same population (control). There was no significant treatment effect on DI of leaves. Comparison of plants in the control group revealed that DI of leaf area was significantly higher than FA of petal area, and that these parameters were uncorrelated. This study demonstrates that FA of petals in Silene diclinis is sensitive to moderate levels of inbreeding and outbreeding, and therefore might serve as an indicator of genetic stress.


In vitro effects of plant essential oils on non-specific immune parameters of red drum, Sciaenops ocellatus L.
Phytochemicals such as plant essential oils (EOs) have been reported to favour various activities in the innate immune system of fish. Thus, the aim of this study was to verify the in vitro effect of three different plant EOs (Ocimum americanum, Cymbopogon flexuosus and Melaleuca alternifolia) on non-specific immune parameters and erythrocyte osmotic fragility of red drum, Sciaenops ocellatus. Concentrations of each plant EO evaluated in preparations of head-kidney macrophages, blood leucocytes and blood plasma were as follows: 0.0 (control), 1.0, 2.0, 4.0, 8.0, and 16.0 μg/ml. Red drum head-kidney macrophages significantly increased extracellular superoxide anion production when exposed (20 h) to O. americanum EO (1.0-8.0 μg/ml) and C. flexuosus EO (2.0 and 4.0 μg/ml). The respiratory burst of blood leucocytes (NBT test) significantly increased in all concentrations when compared to the respective control group, for all EOs. At the highest concentration (16.0 μg/ml), C. flexuosus EO significantly inhibited the haemolytic activity of complement system in red drum blood after 1 h exposure. None of the tested concentrations significantly altered plasma lysozyme activity or erythrocyte osmotic fragility after exposing (1 h) red drum whole blood to each EO. This study demonstrated that these plant EOs are capable of triggering superoxide anion production in red drum leucocytes (head-kidney macrophages and/or blood leucocytes). In vivo studies are warranted to address their potential as immunostimulants in the diet of red drum and other aquacultured species.


[Parameters of binding of fluorescent probe pyrrone red with human serum albumin].
The constant of binding of a new fluorescent probe pyrrone red to human serum albumin (Kb = 4.7.10(5) M-1) and the number of binding sites (N = 2) were determined by the method of double fluorimetric titration at a Fex/Fem intensity ratio of 560/625 nm. The affinity of pyrrone red for albumin was by 20% lower than that of 8-anilinonaphthalenesulfonate and 2.4 times higher than that of another probe K35. Thus, pyrrone red is almost identical to amlinonaphthalenesulfonate in affinity for albumin and can be considered as a long-wavelength "red" analogue of anilinonaphthalenesulfonate.


Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. The American Society of Hematology ITP Practice Guideline Panel.
To develop guidelines for the diagnosis and management of idiopathic thrombocytopenic purpura (ITP) and to document the extent to which those guidelines are based on either scientific evidence or opinion, the AMerican Society of Hematology established a panel composed of 13 hematologists with expertise in ITP, a clinical epidemiologist, and a practice guidelines methodologist. A comprehensive review was done of all published English-language studies that met explicit inclusion criteria and that evaluated the natural history of ITP or the effectiveness of testing and treatment options for ITP. The quality of each study was graded by two reviewers using formal methodologic rules. In subject areas for which data was inadequate, recommendations were based on opinion and were derived by using a formal screening procedure. Confidential questionnaires were used to survey the hematologists on the panel about the appropriateness of testing and treatment options in hundreds of clinical scenarios. Practice recommendations were derived from the mean appropriateness scores for each indication. Voting was kept confidential to give each panel member an equal voice and to limit biases introduced by group dynamics. The recommendations were peer reviewed by eight outside experts. This report focuses on data and on recommendations for adults with ITP. Little high-quality scientific evidence with which to assess the efficacy of diagnostic tests and treatments for ITP is available. The opinion of the panel was that most diagnostic tests are unnecessary in the routine work-ups of patients suspected of having ITP and that ITP accompanied by severe bleeding requires treatment with glucocorticoids, intravenous immunoglobin, and other measures. However, treatment and hospitalization is often unnecessary when patients have only mild or moderate thrombocytopenia or minimal bleeding. Special therapeutic measures are sometimes indicated in pregnant women with ITP.


Cthrc1 is a novel inhibitor of transforming growth factor-beta signaling and neointimal lesion formation.
We identified collagen triple helix repeat containing-1 (Cthrc1) as a novel gene expressed in the adventitia and neointima on arterial injury and found that it functionally increases cell migration while reducing collagen deposition. To address the in vivo role of Cthrc1, we generated transgenic mouse lines that constitutively overexpress Cthrc1. An intercross of 2 transgenic lines produced offspring with brittle bones caused by a reduction in collagenous bone matrix. Hemizygous Cthrc1 transgenic mice developed normally but neointimal lesion formation and adventitial collagen deposition in response to carotid artery ligation were significantly reduced compared with wild-type littermates. In 75% of Cthrc1 transgenic mice, cartilaginous metaplasia of medial smooth muscle cells was observed as assessed by Alcian blue staining and expression of the chondrocyte marker collagen type II. Transforming growth factor-beta signaling was reduced in smooth muscle cells of Cthrc1 transgenic arteries, as demonstrated by reduced phospho-Smad2/3 immunoreactivity, whereas Smad signaling related to bone morphogenetic proteins was unaffected. Similarly, primary smooth muscle cells and PAC1 smooth muscle cells overexpressing Cthrc1 had reduced levels of phospho-Smad2/3 as well as procollagen. Furthermore, Cthrc1 inhibited transforming growth factor-beta-sensitive reporter constructs in smooth muscle but not endothelial cells. These data indicate that Cthrc1 is a cell-type-specific inhibitor of transforming growth factor-beta, which in turn impacts collagen type I and III deposition, neointimal formation, and dedifferentiation of smooth muscle cells.


NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas.
Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis. Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m2/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses. Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings. To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m2/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.


[Prostate cancer and androgen deprivation: benefits of psychological counseling].
Androgen deprivation is a therapeutic option for patients with prostate cancer, however with a range of side effects that negatively affects their physical and psychological condition. A multidisciplinary care program, ADAPP ("Androgenic deprivation in prostate cancer patients"), has been created with a special focus on managing these side effects. This article describes the intervention of the liaison psychiatry within this program, with care options ranging from psychological support to intensive psychotherapy to address patients' intrapsychic dynamics throughout this care program. Clinical cases are reported to illustrate the relevance and the necessity of this specialized counselling.


Mesalazine causes a mitotic arrest and induces caspase-dependent apoptosis in colon carcinoma cells.
Non-steroidal anti-inflammatory drugs (NSAID) may inhibit colon cancer development through affecting proliferation and apoptosis. However, their use in cancer chemoprevention is still limited due to toxicities. There is longstanding clinical experience with the aminosalicylate mesalazine in the treatment of patients with inflammatory bowel disease with very few side effects. So far, most studies on the cellular effects of mesalazine were focused on its anti-inflammatory properties. Recent data, however, indicate that mesalazine may also reduce cell growth in vivo. We therefore investigated the growth inhibitory effect of mesalazine on human colon cancer cells in vitro compared with established chemopreventive agents. We also wished to determine the underlying cellular mechanisms of the effect. Here we show that mesalazine dose- and time-dependently inhibited the proliferation of colon cancer cells. Mesalazine was less potent in reducing cell growth than sulindac sulfide or indomethacin but growth effective mesalazine concentrations were comparable with concentrations achievable in vivo under standard mesalazine treatment. While other NSAID induced a robust G(1) arrest, mesalazine specifically blocked cells in mitosis although microtubule polymerization or spindle orientation was not affected. In addition, mesalazine induced apoptosis in colon cancer cells possibly through activation of caspase-3 whereas the levels of bcl-2 family proteins were not altered. We conclude that mesalazine inhibits growth of colon cancer cells largely through a mitotic arrest, which has not been reported for NSAID so far. Mesalazine also induces apoptosis through partial activation of caspases similar to, although weaker than, established chemopreventive agents. These findings may suggest a potential of mesalazine as a chemopreventive agent for colorectal cancer.


Heterophile reactive antigen in infectious mononucleosis.
Specific heterophile reactive antigen has been localized by means of indirect immunofluorescence in 12 of 13 kidney biopsy specimens obtained during the acute phase of infectious mononucleosis. I feel that this may represent the identification of infectious agent antigen. Evidence is also presented for the possible existence of two different strains of the agent of infectious mononucleosis.


Enhancement of class I HLA antigen expression by cytomegalovirus: role in amplification of virus infection.
We have investigated the effect of cytomegalovirus (CMV) infection on the expression of class I HLA antigens on fibroblasts in vitro. Scanning and integrating microdensitometry was used to quantitate the level of cytoplasmic class I antigen expression, and an antibody binding assay was used to quantitate cell surface expression of class I HLA molecules. CMV infection resulted in a significant increase in the level of cytoplasmic and cell surface class I HLA antigen expression of fibroblast monolayers. The maximal effect was seen at 72 hours postinfection and was observed with both the laboratory strain of CMV, strain AD169, and with CMV purified directly from clinical specimens. Part of the increased HLA expression was mediated by interferon released from infected cells; however, an additional direct effect of the virus itself has not been ruled out. Interferon-induced increased expression of class I HLA antigens was accompanied by increased binding of CMV to the cells, consistent with our recent demonstration that class I HLA molecules can function as a cellular receptor for CMV.


Survival by sex and HIV status in patients with anal cancer in the USA between 2001 and 2019: a retrospective cohort study.
The risk of anal cancer is increased among people with HIV, particularly men who have sex with men. Estimating survival by HIV status and sex and identifying groups at high risk is crucial for documenting prognostic differences between populations. We aimed to compare all-cause and anal cancer-specific survival in patients with anal cancer with and without HIV, stratified by sex, and to identify predictors of survival, stratified by HIV status. In this retrospective cohort study, we used data from the HIV/AIDS Cancer Match Study of 13 population-based HIV and cancer registries throughout the USA. We included individuals aged 20-79 years diagnosed with invasive anal cancer between 2001 and 2019. To estimate associations between HIV status and both all-cause and anal cancer-specific mortality overall, we used Cox proportional hazards models, adjusting for year of and age at diagnosis, sex, race and ethnicity, histology, cancer stage, region, and treatment. We also calculated sex-specific adjusted hazard ratios (HRs). By HIV status, we identified characteristics associated with mortality. Models among people with HIV were further adjusted for AIDS status and HIV transmission risk group. Between Jan 1, 2001, and Dec 31, 2019, 1161 (43·6%) of 2662 patients with anal cancer and HIV and 7722 (35·4%) of 21 824 patients without HIV died. HIV was associated with a 1·35 times (95% CI 1·24-1·47) increase in all-cause mortality among male patients and a 2·47 times (2·10-2·90) increase among female patients. Among patients with HIV, all-cause mortality was increased among non-Hispanic Black individuals (adjusted HR 1·19, 95% CI 1·04-1·38), people with AIDS (1·36, 1·10-1·68), people who inject drugs (PWID; 1·49, 1·17-1·90), patients with adenocarcinoma (2·74, 1·82-4·13), and those with no or unknown surgery treatment (1·34, 1·18-1·53). HIV was associated with anal cancer-specific mortality among female patients only (1·52, 1·18-1·97). Among patients with HIV, anal cancer-specific mortality was increased among patients with adenocarcinoma (3·29, 1·89-5·72), those with no or unknown treatment (1·59, 1·17-2·17), and PWID (1·60, 1·05-2·44). HIV was associated with all-cause mortality among patients with anal cancer, especially women. Anal cancer-specific mortality was elevated among female patients with HIV. As screening for anal cancer becomes more widespread, examining the effects of screening on survival by HIV status and sex is crucial. US National Cancer Institute Intramural Research Program.


Parallels between two geographically and ecologically disparate cave invasions by the same species, Asellus aquaticus (Isopoda, Crustacea).
Caves are long-known examples of evolutionary replications where similar morphologies (troglomorphies) evolve independently as the result of strong natural selection of the extreme environment. Recently, this paradigm has been challenged based on observations that troglomorphies are inconsistent across taxa and different subterranean habitats. We investigated the degree of replicated phenotypic change in two independent cave invasions by the freshwater isopod Asellus aquaticus; the first in a sulphidic aquifer in Romania, the second in a sinking river in the Dinaric Karst in Slovenia. Both ancestral surface populations still live alongside the subterranean ones. Phylogenetic analyses show independence of the two colonization events, and microsatellite analysis shows no evidence of ongoing genetic exchange between surface and subterranean ecomorphs. The overall morphology has changed dramatically at both sites (50 of 62 morphometric traits). The amount of phenotypic change did not reflect differences in genetic diversity between the two ancestral populations. Multivariate analyses revealed divergent evolution in caves, not parallel or convergent as predicted by the current paradigm. Still, 18 traits changed in a parallel fashion, including eye and pigment loss and antennal elongation. These changes might be a consequence of darkness as the only common ecological feature, because Romanian caves are chemoautotrophic and rich in food, whereas Slovenian caves are not. Overall, these results show that morphologically alike surface populations can diverge after invading different subterranean habitats, and that only about one-third of all changing traits behave as troglomorphies in the traditional sense.


Outcomes of an intermediate respiratory care unit in the COVID-19 pandemic.
15% of COVID-19 patients develop severe pneumonia. Non-invasive mechanical ventilation and high-flow nasal cannula can reduce the rate of endotracheal intubation in adult respiratory distress syndrome, although failure rate is high. To describe the rate of endotracheal intubation, the effectiveness of treatment, complications and mortality in patients with severe respiratory failure due to COVID-19. Prospective cohort study in a first-level hospital in Madrid. Patients with a positive polymerase chain reaction for SARS-CoV-2 and admitted to the Intermediate Respiratory Care Unit with tachypnea, use of accessory musculature or SpO2 <92% despite FiO2> 0.5 were included. Intubation rate, medical complications, and 28-day mortality were recorded. Statistical analysis through association studies, logistic and Cox regression models and survival analysis was performed. Seventy patients were included. 37.1% required endotracheal intubation, 58.6% suffered medical complications and 24.3% died. Prone positioning was independently associated with lower need for endotracheal intubation (OR 0.05; 95% CI 0.005 to 0.54, p = 0.001). The adjusted HR for death at 28 days in the group of patients requiring endotracheal intubation was 5.4 (95% CI 1.51 to 19.5; p = 0.009). The rate of endotracheal intubation in patients with severe respiratory failure from COVID-19 was 37.1%. Complications and mortality were lower in patients in whom endotracheal intubation could be avoided. Prone positioning could reduce the need for endotracheal intubation.


An In Vitro Model for the Ocular Surface and Tear Film System.
Dry eye is a complicated ocular surface disease whose exact pathogenesis is not yet fully understood. For the therapeutic evaluation and pathogenesis study of dry eye, we established an in vitro three-dimensional (3D) coculture model for the ocular surface. It is composed of rabbit conjunctival epithelium and lacrimal gland cell spheroids, and recapitulates the aqueous and mucin layers of the tear film. We first investigated the culture conditions for both cell types to optimize their secretory functions, by employing goblet cell enrichment, air-lifting culture, and 3D spheroid formation techniques. The coculture of the two cell components leads to elevated secretion and higher expression of tear secretory markers. We also compared several coculture systems, and found that direct cell contact between the two cell types significantly increased tear secretion. Inflammation was induced to mimic dry eye disease in the coculture model system. Our results showed that the coculture system provides a more physiologically relevant therapeutic response compared to monocultures. Our work provides a complex 3D model as a recapitulation of the ocular surface and tear film system, which can be further developed as a model for dry eye disease and therapeutic evaluation.


The decreasing incidence of diaphragmatic dysfunction in liver transplantation: a probable advantage of the piggy-back liver transplant technique.
Pediatric orthotopic liver transplantation (OLT) has a low mortality. Some children, however, have an adverse outcome defined as a prolonged ventilatory support requirement and protracted pediatric intensive care unit (PICU) stay. The aim of this study was to determine if that adverse outcome related to the child's condition pre-OLT and/or the development of a pleural effusion or diaphragmatic dysfunction. The study included 210 children with a median age at transplantation of 45.5 months (range 0.2-252 months). Fourteen had undergone retransplantation. The duration of ventilatory support (intermittent positive pressure ventilation [IPPV]) and PICU admission and development of a pleural effusion and/or diaphragmatic dysfunction were documented for each child. The patients were divided into three groups according to whether they had acute liver failure (ALF), chronic liver disease at home (CHOM), or chronic liver failure sufficiently ill to be in the hospital awaiting transplantation (CHOSP). The 36 children with ALF were of similar age to the 138 CHOM and 36 CHOSP children but required longer IPPV (P < 0.0001) and PICU stay (P < 0.0001). Overall, 17 children developed diaphragmatic dysfunction and 138 pleural effusions; affected children required longer IPPV and PICU stay (P <0.01). Regression analysis demonstrated that diaphragmatic dysfunction, but not pleural effusion development, was associated with prolonged ventilation (P <0.01) and protracted PICU stay (P <0.05). Other risk factors were ALF (P <0.01), retransplantation (P <0.01), and young age (P <0.05). Diaphragmatic dysfunction adversely influences PICU morbidity after OLT. Early assessment of diaphragmatic function, and if necessary aggressive management, might improve outcome.


Randomized controlled trial of brief cognitive-behavioural interventions for insomnia in recovering alcoholics.
To test the efficacy of a cognitive-behavioural approach to treating disturbed sleep in abstinent alcoholics. Sixty recovering alcoholics with insomnia were assigned randomly to individual therapy, self-help with telephone support or waiting-list control. Participants were volunteers recruited from out-patient treatment programs and through the media. Outcomes were assessed at post-treatment, 3-month and 6-month follow-ups using sleep diaries, the Pittsburgh Sleep Quality Index, wrist actigraphs and time-line follow-back interviews. Five sessions of out-patient cognitive-behavioural therapy for insomnia or a self-help manual with five telephone support calls. Treatment duration was 7 weeks. Treated participants were significantly more improved than control participants on diary measures of sleep quality, sleep efficiency, awakenings and time to fall asleep. No significant differences between the individual therapy and self-help treatment conditions on measures of insomnia severity were evident at post-treatment. Self-reported improvement in sleep was corroborated by clinician and spousal ratings of insomnia severity, but not by actigraph recordings of nocturnal activity. At 3- and 6-month follow-up assessments treatment gains were reasonably maintained in both treatment groups, although individual therapy was associated with a higher rate of clinically significant improvement. At the 6-month follow-up, 60% participants who were regular users of sedative medication at baseline discontinued the use of their medication. Treatment appeared to have little impact in preventing relapses to alcohol. Recovering alcoholics with insomnia can achieve better sleep by applying cognitive-behavioural strategies.


Coordinated social communication in toddlers with and without autism spectrum disorder during a home observation.
Social communication and language skills have been found to be important predictors of long-term outcomes in individuals with autism spectrum disorder (ASD). However, the development of coordinated social communication (i.e., gestures and sounds or words) remains relatively understudied in young children with ASD and developmental delays (DD). This study used a prospective, longitudinal design and granular observational coding to document the coordination of gestures, sounds, and words in a large, heterogeneous sample of toddlers identified with ASD, DD, or typical development (TD) during a naturalistic home observation. Specific aims were: (1) to compare rates per minute and proportions of coordinated child communicative acts across groups; (2) to examine concurrent relationships between coordinated communication and measures of social communication and autism symptoms; and (3) to examine prospective relationships between coordinated communication, receptive and expressive language skills, and autism symptoms collected at 3 years of age. At a mean age of 20.3 months (SD = 2.0), 211 children (nASD = 121; nDD = 46; nTD = 44) participated in everyday activities with a parent during an hourlong home observation. Rates per minute and proportions of gestures, sounds and words, as well as temporally overlapping gesture + sound, gesture + word, and gesture + phrase combinations, were compared using one-way ANOVA. Pearson product moment correlations between coordinated communicative acts and measures of social communication, language, and autism symptoms were examined. On average, children with ASD used sounds and gesture + sounds at significantly lower rates than DD and TD groups, who did not differ. Children with ASD and DD coordinated gesture + single words and gesture + phrases at significantly lower rates than the TD group. Groups did not differ with respect to the rate per minute at which they used gestures alone. Children with TD used a smaller proportion of sounds alone and higher proportions of words and phrases, with and without coordinated gestures, than ASD and DD groups. Children with ASD and DD used a significantly higher proportion of gestures alone than children with TD. Rates per minute and proportions of single words and gesture + words had significant correlations with measures of social communication, language skills, and autism symptoms. Results suggest that a significantly lower rate per minute of sounds and gesture + sound combinations was a distinguishing feature of ASD in our sample. Further, limited use of single words and gesture + single words was observed in children ASD and DD. Significant prospective relationships between single words and gesture + words with language skills measured over a year later underscores the importance of acquiring these forms. Results support the idea that clinicians should include opportunities to observe and encourage coordinated social communication while screening and assessing young children for DD and ASD in the home environment. The significant associations between rate of single words and gesture + word combinations with language development over a year later have implications for incorporating intervention targets that encourage the use of gesture-speech combinations.


A chronometric model of the relationship between frontal midline theta functional connectivity and human intelligence.
Individual differences in cognitive control have been suggested to act as a domain-general bottleneck constraining performance in a variety of cognitive ability measures, including but not limited to fluid intelligence, working memory capacity, and processing speed. However, owing to psychometric problems associated with the measurement of individual differences in cognitive control, it has been challenging to empirically test the assumption that individual differences in cognitive control underlie individual differences in cognitive abilities. In the present study, we addressed these issues by analyzing the chronometry of intelligence-related differences in midfrontal global theta connectivity, which has been shown to reflect cognitive control functions. We demonstrate in a sample of 98 adults, who completed a cognitive control task while their electroencephalogram was recorded, that individual differences in midfrontal global theta connectivity during stages of higher-order information-processing explained 65% of the variance in fluid intelligence. In comparison, task-evoked theta connectivity during earlier stages of information processing was not related to fluid intelligence. These results suggest that more intelligent individuals benefit from an adaptive modulation of theta-band synchronization during the time-course of information processing. Moreover, they emphasize the role of interregional goal-directed information-processing for cognitive control processes in human intelligence and support theoretical accounts of intelligence, which propose that individual differences in cognitive control processes give rise to individual differences in cognitive abilities. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Replacing traditional pretreatment in one-step UF with natural short-distance riverbank filtration: Continuous contaminants removal and TMP increase relief.
Scientists have been focusing on applying more natural processes instead of industrial chemicals in drinking water treatment to achieve the purpose of carbon emissions reduction. In this study, we shortened the infiltration range of riverbank filtration, a natural water purification process, to form the short-distance riverbank filtration (sRBF) which retained its ability in water quality improvement and barely influenced the groundwater environment, and integrated it with ultrafiltration (UF) to form a one-step sRBF-UF system. This naturalness-artificiality combination could realize stable contaminants removal and trans-membrane pressure (TMP) increase relief for over 30 days without dosing chemicals. Generally, both sRBF and UF played the important role in river water purification, and the interaction between them made the one-step sRBF-UF superior in long-term operation. The sRBF could efficiently remove contaminants (90 % turbidity, 60 % total nitrogen, 30 % ammonia nitrogen, and 25 % total organic carbon) and reduce the membrane fouling potential of river water under its optimum operation conditions, i.e., a hydraulic retention time of 48 h, an operation temperature of 20 °C, and a synergistic filter material of aquifer and riverbank soil. Synergistic adsorption, interception, and microbial biodegradation were proved to be the mechanisms of contaminants and foulants removal for sRBF. The sequential UF also participated in the reduction of impurities and especially played a role in intercepting microbial metabolism products and possibly leaked microorganisms from sRBF, assuring the safety of product water. To date, the one-step sRBF-UF was a new attempt to combine a natural process with an artificial one, and realized a good and stable product quality in long-term operation without doing industrial chemicals, which made it a promised alternative for water purification for cities alongside the river.


Viz.ai Implementation of Stroke Augmented Intelligence and Communications Platform to Improve Indicators and Outcomes for a Comprehensive Stroke Center and Network.
Comprehensive stroke centers continually strive to narrow neurointerventional time metrics. Although process improvements have been put in place to streamline workflows, complex pathways, disparate imaging locations, and fragmented communications all highlight the need for continued improvement. This Quality Improvement Initiative (VISIION) was implemented to assess our transition to the Viz.ai platform for immediate image review and centralized communication and their effect on key performance indicators in our comprehensive stroke center. We compared periods before and following deployment. Sequential patients having undergone stroke thrombectomy were included. Both direct arriving large-vessel occlusion and Brain Emergency Management Initiative telemedicine transfer large-vessel occlusion cases were assessed as were subgroups of OnHours and OffHours. Text messaging thread counts were compared between time periods to assess communications. Mann-Whitney U and Student t tests were used. Eighty-two neurointerventional cases were analyzed pre vs. post time periods: (DALVO-OnHours 7 versus 7, DALVO-OffHours 10 versus 5, BEMI-OnHours 13 versus 6, BEMI-OffHours 17 versus 17). DALVO-OffHours had a 39% door-to-groin reduction (157 versus 95 minutes, P = .009). DALVO-All showed a 32% reduction (127 versus 86 minutes, P = .006). BEMI-All improved 33% (42 versus 28 minutes, P = .036). Text messaging thread counts improved 30% (39 versus 27, P = .04). There was an immediate improvement following Viz.ai implementation for both direct arriving and telemedicine transfer thrombectomy cases. In the greatest opportunity subset (direct arriving large-vessel occlusion-OffHours: direct arriving cases requiring team mobilization off-hours), we noted a 39% improvement. With Viz.ai, we noted that immediate access to images and streamlined communications improved door-to-groin time metrics for thrombectomy. These results have implications for future care processes and can be a model for centers striving to optimize workflow and improve thrombectomy timeliness.


A model for estimating the economic impact of secondhand smoke exposure: a study in Indiana.
This study estimated the economic cost of health services and premature loss-of-life costs from secondhand smoke (SHS) exposure in Indiana. Costs of SHS-related mortality and morbidity were estimated using national attributable risk values for diseases that are causally related to SHS exposure both for adults and children. Estimated direct costs included hospital inpatient costs, loss-of-life costs, and ambulatory care costs where available, based on the most currently available Indiana hospital discharge data, vital statistics, census data, and nationally published research. Attributable risk values were applied to the number of deaths and hospital discharges in Indiana in 2008 and 2010, respectively, to estimate the number of individuals impacted by SHS exposure. All cost estimates were adjusted to 2010 US dollar values. The direct cost of health care and premature loss of life in Indiana attributed to SHS was estimated to be $1.3 billion in 2010--$237.8 million in health care costs and $879.0 million in premature loss of life for adults and $89.4 million in health care costs and $98.6 million in premature loss of life for children. The estimated population for Indiana in 2010 was 6 483 802 resulting in SHS-related costs of $201 per capita. This study demonstrated a model that could be used to estimate the costs of health care and premature mortality from exposure to SHS at a state or local level. These data may be used to support the education of the public, community leaders, and state policy makers regarding the magnitude of the problem and the compelling need to implement interventions to better protect the health of citizens and their economic prosperity.


Smooth muscle adherens junctions associated proteins are stable at the cell periphery during relaxation and activation.
This study was performed to determine the stability of the adherens junction (AJ)-associated proteins at the smooth muscle cell (SMC) plasma membrane during relaxing and activating conditions. Dog stomach, ileum, colon, and trachea tissues were stored in Ca2+-free PSS or regular PSS or were activated in 10 muM carbachol in PSS before rapid freezing. The tissues were subsequently sectioned and immunoreacted using antibodies for vinculin, talin, fibronectin, and caveolin to determine their cellular distribution in these tissues under these conditions. In all four tissues and under all three conditions, the distribution of these four proteins remained localized to the periphery of the cell. In transverse tissue sections, the AJ-associated proteins formed a distinct punctate pattern around the periphery of the SMCs at the plasma membrane. These domains alternated with the caveolae (as identified by the presence of caveolin). In longitudinal tissue sections, the AJ-associated proteins formed continuous tracks or staves, while the caveolae remained punctate in this dimension as well. Caveolin is not present in the tapered ends of the SMCs, where the AJ-associated proteins appear continuous around the periphery. Densitometry of the fluorophore distribution of these proteins showed no shift in their localization from the SMC periphery when the tissues were relaxed or when they were activated before freezing. These results suggest that under physiologically relaxing and activating conditions, AJ-associated proteins remain stably localized at the plasma membrane.


The subunits of cholera toxin: structure, stoichiometry, and function.
The toxin of Vibrio cholerae dissociates into subunit A and an aggregate of subunit B (choleragenoid); the dissociation is rapid under denaturing conditions and slow at neutral pH. Subunit A has a molecular weight of 27,000 daltons (measured by sedimentation equilibrium or gel chromatography) and has two polypeptide chains (mol wt, approximately 22,000 and 5,000 daltons) joined by disulfide bonds. The molecular weight of subunit B in 6 M guanidine hydrochloride is 14,000 daltons when determined by sedimentation equilibrium or gel chromatography, although dodecylsulfate gel electrophoresis suggests a lower value. These results suggest a structure of AB4 for the toxin; studies of cross-linking with methyl-4-mercaptobutyrimidate confirm this structure. The properties of antibodies both to cholera toxin and to choleragenoid are compatible with this structure, but subunit A has very low immunogenicity. Subunit A by itself is active, and this activity is abolished by a large excess of antitoxin but not by choleragenoid, anticholeragenoid, or ganglioside GM1 (galactosyl-N-acetylgalactosaminyl [sialosyl] lactosyl ceramide; GGnSLC). It is suggested that the function of subunit B is not to interact directly with the adenylate cyclase system, but to bind to the cell membrane and facilitate the interaction of subunit A.


Macrolide-resistant Mycoplasma pneumoniae: characteristics of isolates and clinical aspects of community-acquired pneumonia.
Mycoplasma pneumoniae is one of the main pathogens causing community-acquired respiratory tract infections in children and adults. Macrolide (ML) antibiotics are recognized generally as first-choice agents for M. pneumoniae infections, and these antibiotics were thought to have excellent effectiveness against M. pneumoniae for many years. In 2000, however, M. pneumoniae showing resistance to macrolides was isolated from clinical samples obtained from Japanese pediatric patients with community-acquired pneumonia (CAP). Since then, prevalence of ML-resistant M. pneumoniae isolates in pediatric patients has increased rapidly. In 2007, ML-resistant M. pneumoniae isolates were obtained from Japanese adults with CAP; numbers of such isolates also have gradually increased in Japan. Recently, similar antimicrobial resistance in M. pneumoniae has begun to emerge worldwide. In this review, we focus on changes of ML-resistant M. pneumoniae from year to year and consider resistance mechanisms as well as clinical features of patients with resistant M. pneumoniae infection.


Hymen care for unmarried Muslim females: role of the forensic consultant in gynaecology interventions.
This case series illustrates the role of the forensic consultant in hymen care for unmarried Muslim females exposed to gynaecology interventions. The age range of the 12 females attending University of Jordan Hospital in Amman was 35 days to 28 years. Gynaecology interventions included the use of a vaginoscope, circular resection of the hymen in cases of congenital imperforate hymen, evacuation of perineal abscess and evaluation of a torn hymen. The forensic consultant provides a valuable role in reassuring patients and parents about procedures used to avoid rupturing the hymen, and in protecting the gynaecologist's and patients' rights by providing reports of the status of the hymen before and after intervention in cases where damage is unavoidable.


Bayesian analysis of misclassified binary data from a matched case-control study with a validation sub-study.
Bayesian methods are proposed for analysing matched case-control studies in which a binary exposure variable is sometimes measured with error, but whose correct values have been validated for a random sample of the matched case-control sets. Three models are considered. Model 1 makes few assumptions other than randomness and independence between matched sets, while Models 2 and 3 are logistic models, with Model 3 making additional distributional assumptions about the variation between matched sets. With Models 1 and 2 the data are examined in two stages. The first stage analyses data from the validation sample and is easy to perform; the second stage analyses the main body of data and requires MCMC methods. All relevant information is transferred between the stages by using the posterior distributions from the first stage as the prior distributions for the second stage. With Model 3, a hierarchical structure is used to model the relationship between the exposure probabilities of the matched sets, which gives the potential to extract more information from the data. All the methods that are proposed are generalized to studies in which there is more than one control for each case. The Bayesian methods and a maximum likelihood method are applied to a data set for which the exposure of every patient was measured using both an imperfect measure that is subject to misclassification, and a much better measure whose classifications may be treated as correct. To test methods, the latter information was suppressed for all but a random sample of matched sets.


Phase I and pharmacokinetic study of mitomycin C and celecoxib as potential modulators of tumor resistance to irinotecan in patients with solid malignancies.
Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-kappaB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies. Initially, patients received MMC on day 1 and irinotecan on days 2, 8, 15 and 22, every 6 weeks. MMC dose was fixed at 6 mg/m(2) and cumulative doses of >36 mg/m(2) were not permitted. Irinotecan was escalated in 25 mg/m(2) increments. Due to late-onset diarrhea, the schedule was subsequently shortened to 4 weeks, omitting irinotecan on days 15 and 22. In the second part of the study, celecoxib 400 mg orally twice daily was added to irinotecan/MMC regimen. Potential pharmacokinetic interactions and Topo-1 and DT-diaphorase (NQ01) gene expressions in peripheral-mononuclear cells were evaluated. Forty-five patients were enrolled. Irinotecan 125 mg/m(2) on days 2 and 8 in combination with MMC 6 mg/m(2) on day 1 every 4 weeks is recommended for future studies; myelosuppression and diarrhea are dose-limiting. The addition of celecoxib resulted in unacceptable toxicities despite reductions on irinotecan's dose. No relevant pharmacokinetic interactions occurred between irinotecan and MMC, and mean increases in Topo-1, were observed. Sixteen of 36 patients evaluable for response-assessment had discernable anti-tumor activity, including 1 complete, 4 partial, 10 minor and 1 tumor marker response. Four patients had prolonged (>4 months) disease-stability (stable disease, not included in CR or PR). Patients experiencing complete and partial responses had higher increments in Topo-1 expression. Modulation of irinotecan by MMC is feasible, devoid of pharmacological interactions and active in solid malignancies. The lack of improvement in therapeutic index does not support the addition of celecoxib.


Coxsackievirus B transmission and possible new roles for extracellular vesicles.
Coxsackievirus B1, a member of the Picornaviridae family is a non-enveloped single-stranded RNA virus associated with human diseases including myocarditis and pancreatitis. Infection of the intestinal mucosa, lined by polarized epithelial cells, requires interaction of coxsackievirus with apically located DAF (decay-accelerating factor) before transport to the basolaterally located CAR (coxsackie and adenovirus receptor), where entry is mediated by endocytosis. As with many other non-enveloped viruses, coxsackievirus has to induce lysis of host cells in order to perpetuate infection. However, recent evidence indicates that virus spread to secondary sites is not only achieved by a lytic mechanism and a non-lytic cell-cell strategy has been suggested for coxsackievirus B3. A physical interaction between infected and non-infected cells has been shown to be an efficient mechanism for retroviral transmission and one type of extracellular vesicle, the exosome, has been implicated in HIV-1 transmission. HIV-1 also takes advantage of depolymerization of actin for spread between T-cells. Calpain-mediated depolymerization of the actin cytoskeleton, as a result of increases in intracellular calcium concentration during coxsackievirus infection, would result in a release of host cell-derived microvesicles. If so, we speculate that maybe such microvesicles, increasingly recognized as major vehicles mediating intercellular communication, could play a role in the intercellular transmission of non-enveloped viruses.


Acetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulates transcription.
Promoter clearance and transcriptional processivity in eukaryotic cells are fundamentally regulated by the phosphorylation of the carboxy-terminal domain of RNA polymerase II (RNAPII). One of the kinases that essentially performs this function is P-TEFb (positive transcription elongation factor b), which is composed of cyclin-dependent kinase 9 (CDK9) associated with members of the cyclin T family. Here we show that cellular GCN5 and P/CAF, members of the GCN5-related N-acetyltransferase family of histone acetyltransferases, regulate CDK9 function by specifically acetylating the catalytic core of the enzyme and, in particular, a lysine that is essential for ATP coordination and the phosphotransfer reaction. Acetylation markedly reduces both the kinase function and transcriptional activity of P-TEFb. In contrast to unmodified CDK9, the acetylated fraction of the enzyme is specifically found in the insoluble nuclear matrix compartment. Acetylated CDK9 associates with the transcriptionally silent human immunodeficiency virus type 1 provirus; upon transcriptional activation, it is replaced by the unmodified form, which is involved in the elongating phase of transcription marked by Ser2-phosphorylated RNAPII. Given the conservation of the CDK9 acetylated residues in the catalytic task of virtually all CDK proteins, we anticipate that this mechanism of regulation might play a broader role in controlling the function of other members of this kinase family.


Glucose Control During Breakthrough SARS-CoV-2 Infections in Vaccinated Patients With Type 1 Diabetes.
This study aims at evaluating the trend of glycemic control metrics during the infection of SARS-CoV-2 in individuals with Type 1 Diabetes (T1D) using a Continuous Glucose Monitoring (CGM) system and vaccinated against COVID-19. This is a retrospective study of T1D subjects who got a breakthrough SARS-CoV-2 infection between November 2021 and February 2022. Data of glycemic control of CGM-derived metrics were compared 14 days before COVID-19 (Time 1), 14 days during COVID-19 (Time 2) and 14 days after COVID-19 (Time 3). A total of 106 patients with T1D and breakthrough SARS-CoV-2 infection was included in the analysis. A significant reduction of GMI [%, 7.41 ± 1.60 vs 7.52 ± 1.63, P = 0.006)] and increase of TIR [%, 54.6 ± 20.4 vs 52.1 ± 19.7, P = 0.026] were observed at Time 3 as compared with Time 2. There was a significant reduction of SD (P < 0.001) and CV (P < 0.001) at Time 3 and Time 2 as compared with Time 1, associated with significant changes of mean glucose levels, TBR level 1 and total daily insulin doses. Breakthrough SARS-CoV-2 infection did not worsen glycemic control in vaccinated people with T1D.


Expression and nucleotide diversity of the maize RIK gene.
The K homology (KH) domain is a conserved sequence present in a wide variety of RNA-binding proteins. The rough sheath2-interacting KH domain (RIK) protein of maize has been implicated in the maintenance of the repressed chromatin state of knox genes during leaf primordia initiation. The amino acid sequences of the publicly available plant RIK proteins contain a splicing factor 1 (SF1)-like KH domain core sequence motif that distinguishes them from all other SF1-like KH domain-containing proteins. We demonstrate that the maize RIK gene exhibits surprisingly little nucleotide sequence diversity among Zea species and subspecies. Microarray hybridization experiments demonstrate that RIK has a higher level of expression in the shoot apical meristem as compared with 14-day seedling. Reverse transcriptase-polymerase chain reaction analysis of RIK indicates that the gene is expressed in many tissues, albeit at lower levels in older leaf samples. Taken together, these data suggest that the RIK protein may be involved in the maintenance of an inactive chromatin state of knox and possibly other genes in nonmeristematic tissues.


Enhancement of haematopoiesis-directed suppressor activity in mice following Bordetella pertussis vaccine.
A single injection of killed whole-cell pertussis vaccine (strain 5374) into CBA mice (H-2k) was shown to induce a drastic depletion of cells in the thymus accompanied by the enhancement of suppressor T-cell activity. Thymus cells obtained from pertussis vaccine-treated mice were shown to inhibit the endogenous and exogenous colony formation in the spleen by haematopoietic stem cells (CFUs). Treatment of thymus cells with the anti-I-Jk alloantiserum against a specific marker of suppressor T-cells plus complement abolished the inhibitory effect on CFUs proliferation and had a stimulatory action on the capacity of the marrow CFUs to form macroscopic haematopoietic colonies in the spleen as compared to controls. These results suggest probable involvement of I-J-bearing suppressor T-cells in haematopoietic disorders induced by pertussis vaccine.


Tissue-specific metabolite profiling of Turmeric by using laser micro-dissection, ultra-high performance liquid chromatography-quadrupole time of fight-mass spectrometry and liquid chromatography-tandem mass spectrometry.
Curcuma longa L. is recognized for its therapeutic and culinary uses both in Ayurveda and traditional Chinese medicine and is considered to be a boon to mankind. It has been extensively studied for its benefits and still continues to be an important drug with continued potential for further exploration and research. We studied the tissue-specific distribution of secondary metabolites to establish the validity of the use of rhizome samples from India and China, as substitutes for each other, based upon their metabolite profiles and curcumin contents. Laser microdissection was used for the isolation of microscopic tissues, such as cork, cortex and leaf-trace vascular bundles from rhizomes. Metabolite profiling was carried out by ultra-high performance liquid chromatography-quadrupole time of fight-mass spectrometry and curcumin content was estimated by a method validated as per the Harmonized Tripartite Guidelines. The cortex and cork revealed the presence of a higher number of secondary metabolites than in the leaf-trace vascular bundles. The curcumin contents in rhizome samples from both the countries, estimated with the help of a precise and accurate validated method, were found to be comparable. Based on the results, we conclude that turmeric rhizomes grown in India and China are qualitatively and quantitatively indistinguishable and therefore can be used as substitutes. The developed method can be widely applied for microscopic identification, authentication and analysis of the distribution of phytoconstituents in other botanical species of interest or of species with a significant commercial and therapeutic value.


Thrombocytopenia in pregnancy with different diagnoses: Differential clinical features, treatments, and outcomes.
To investigate the clinical features and perinatal treatment of thrombocytopenia induced by different causes during pregnancy.Clinical data from 195 pregnant women with thrombocytopenia attending 2 tertiary hospitals from January 2014 to October 2016 were retrospectively studied. The obtained data were analyzed with SPSS 19.0 software.There were 117 (60.0%), 55 (28.2%), and 23 cases (11.8%) of pregnancy-associated thrombocytopenia (PAT), idiopathic thrombocytopenia (ITP), and hypertensive disorder in pregnancy (PIH), respectively. The percentage of nulliparous women, gestational age at delivery, date of diagnosis of thrombocytopenia, and delivery mode significantly differed between the patients in these 3 groups (P < .05). Patients with PIH had a higher percentage of premature delivery and of lower birth weight infants than patients in the other 2 groups. The 3 groups had similar incidences of postpartum hemorrhage, rates of stillbirth, and neonatal Apgar scores at 5 minutes. PAT and PIH patients had different platelet counts after delivery compared with at diagnosis, whereas the platelet counts of the ITP patients were similar at diagnosis and after delivery. ITP patients in the nontreatment group and the treatment group had significantly different platelet counts (P < .05), and in the treatment group, the maternal platelet count did not differ for treatment with intravenous immunoglobulin (IVIg) versus corticosteroids.The causes of thrombocytopenia in pregnancy are diverse, and the clinical features vary widely. Timely analysis is needed to determine the primary cause of thrombocytopenia, and appropriate therapy should then be selected to effectively improve the prognosis of pregnancies.


Emotional fluctuations in Bob Dylan's lyrics measured by the dictionary of affect accompany events and phases in his life.
Lyrics for Bob Dylan's songs between 1962 and 2001 (close to 100,000 words) were scored with the help of the Dictionary of Affect in Language (Whissell, 2006). Means for Pleasantness, Activation, and Imagery are reported for 22 Blocks characterizing this time span. Significant but weak differences across Blocks were found for all three measures at the level of individual words. Emotional fluctuations in words included in Bob Dylan's lyrics accompanied events and phases in his life, although they were not entirely dictated by these events. Dylan used more highly Imaged and more Active words at times when his work was critically acclaimed. More Passive word choices characterized times of prolonged stress, and more Pleasant choices times of experimentation. Dylan's three popularity peaks were used to divide the singer's career into three stages (rhetor, poet, sage) which differed in terms of pronouns used.


Inhibition of angiogenesis by growth factor receptor bound protein 2-Src homology 2 domain bound antagonists.
Growth factor receptor bound protein 2 (Grb2) is an intracellular adaptor protein that participates in the signal transduction cascades of several angiogenic factors, including hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor. We described previously the potent blockade of hepatocyte growth factor-stimulated cell motility, matrix invasion, and epithelial tubulogenesis by synthetic Grb2-Src homology 2 (SH2) domain binding antagonists. Here, we show that these binding antagonists block basic morphogenetic events required for angiogenesis, including hepatocyte growth factor-, vascular endothelial growth factor-, and basic fibroblast growth factor-stimulated endothelial cell proliferation and migration, as well as phorbol 12-myristate 13-acetate-stimulated endothelial cell migration and matrix invasion. The Grb2-SH2 domain binding antagonists also impair angiogenesis in vitro, as shown by the inhibition of cord formation by macrovascular endothelial cells on Matrigel. We further show that a representative compound inhibits angiogenesis in vivo as measured using a chick chorioallantoic membrane assay. These results suggest that Grb2 is an important mediator of key proangiogenic events, with potential application to pathologic conditions where neovascularization contributes to disease progression. In particular, the well-characterized role of Grb2 in signaling cell cycle progression together with our present findings suggests that Grb2-SH2 domain binding antagonists have the potential to act as anticancer drugs that target both tumor and vascular cell compartments.


[Rational diuretic therapy in patients with liver cirrhosis].
When ascites develops in a patient with liver cirrhosis his probability to survive the following two years amounts to 50%. It is determined essentially by the residual functional capacity of the liver. In 80 to 90% of patients ascites due to portal hypertension can be managed by salt restriction and diuretics. A daily reduction of body weight of 0.5 to 0.75 kg should not be exceeded because prerenal failure may become a threat. Aldosterone-antagonists are more efficient and have fewer side-effects than loop diuretics. The urinary ratio of Na/K may be used to adjust the therapy. They may lower portal hypertension by an additional direct effect on the vasculature. If diuretics are insufficient or when a rapid therapeutic success is needed, paracentesis of 4-6 l is a safe option if intravascular volume is substituted simultaneously with albumin. Only in the few patients whose ascites is intractable by the forementioned measures, alternatives such as peritoneo-, venous or porto-systemic shunts (nowadays mostly by interventional techniques via a transjugular catheter) should be evaluated. The only treatment which not only attacks ascites symptomatically but also corrects the underlying disease is liver transplantation.


Hyperthermic Intraperitoneal Chemotherapy for Primary or Recurrent Adrenocortical Carcinoma. A Single Center Study.
This study explores the impact of Hypertermic Intra PEritoneal Chemotherapy (HIPEC) on adrenocortical carcinoma (ACC) management through a safety analysis completed by a preliminary evaluation of survival performances. Retrospective chart review of 27 patients submitted to surgical treatment completed by HIPEC for primary (SP, 13 patients) or recurrent (SR, 14 patients, 17 treatments) ACC. Safety was evaluated by means of procedural morbidity and mortality. Survival performances included multiple end points: local/peritoneal disease-free survival (l/pDFS), overall progression-free survival (OPFS), and overall survival (OS). In the SP group, mortality was nil and morbidity was 46% (major 23%). At a median follow-up of 25 months, the median value for all the different survival measures had not been reached. Mortality was also nil in the SR group. However, morbidity was 77% (major 18%). Median l/pDFS and OPFS were 12 ± 4 and 8 ± 2 months, respectively. At a median follow-up of 30 months, median OS had not been reached. Surgery and HIPEC is an invasive procedure. Its employment in the surgery for primary setting deserves attention as it may affect oncologic outcomes positively. Its value in the management of recurrences seems less appreciable, albeit it may find its place in the multimodal management of a rare disease for which multiple therapeutic options do not yet exist.


Recombinant laminin-8 (alpha(4)beta(1)gamma(1)). Production, purification,and interactions with integrins.
Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. Functional studies on these laminins have been hampered by poor availability of the protein in pure and soluble forms. To facilitate studies on laminin-8, recombinant laminin-8 was produced in a mammalian expression system, purified and shown to form native Y-shaped molecules in rotary shadowing electron microscopy. Integrins mediating cell adhesion to laminin-8 were identified using function-blocking mAbs. The integrin specificities were found to differ somewhat from that of laminin-1. Integrin alpha(6)beta(1) was found to be a major mediator of adhesion of HT-1080 and cultured capillary endothelial cells to laminin-8. Considering the expression patterns of laminin-8 and integrin alpha(6)beta(1) it is likely that the former is a ligand for the latter in vivo as well.


Genetic susceptibility factors of Type 1 diabetes in Asians.
Type 1 diabetes is a multifactorial disease in which the insulin producing beta-cells of the pancreas are destroyed by the immune system, a process determined by the activity of major histocompatibility complex (MHC)-restricted T lymphocytes. Progress has been made in elucidating genetic factors involved in Type 1 diabetes in Caucasians, with less data available from Asia. For Asians, the human MHC locus (HLA region), especially the class II region, is the major susceptibility interval. The role of IDDM2, the insulin locus, has been questioned in Asia. In contrast to Caucasians, Asian populations have a very low incidence of Type 1 diabetes (0.4-1.1 cases/year/100 000 individuals). This low incidence rate in the Asian population may be related to the population frequency distribution of susceptible Type 1 diabetes genes, especially of HLA. The overall risk for Type 1 diabetes from HLA DR and DQ is determined by polymorphic residues (alleles) and particular combinations of alleles (haplotypes and genotypes) in a given individual. In Asians, it is very common that a protective DR4 allele is associated with susceptible DQ alleles while neutral/protective DQ alleles are associated with the susceptible DR4 alleles. Our analyses indicate that the counterbalancing between susceptible DRB1 and protective DQB1, and vice versa, is a factor that may contribute to the low incidence of diabetes in Asians. We find that identical HLA DRB1-DQB1 haplotypes of Asians and Caucasians have similar transmission to diabetic children and similar associations with diabetes. Moreover, the association with diabetes and transmission to a diabetic offspring of DR4 haplotypes varies depending on the haplotype borne on the homologous chromosome. This might contribute not only to the synergistic effect of DR3/4, but also to the susceptibility influence of DQB1*0401 haplotypes confined to DR4/X. High-risk DR4 subtypes were predominant in DR4/X, whereas protective DR4 subtypes were observed mainly in the DR3/4 genotype. Since in Asians DQB1*0401 is in linkage disequilibrium (LD) with DRB1*0405, we find more DRB1*0405-DQB1*0401 haplotypes in patients with DR4/X than in patients with DR3/4, suggesting that the contribution of the DRB1 locus may be greater in DR4/X than in DR3/4 genotypes. Several genome scans suggested additional susceptibility intervals and provided supporting evidence for several previously reported linkages. Other studies focused on the confirmation of linkage using multipoint sib-pair analyses with densely spaced markers and multiethnic collection of families. Although significant and consistent linkage evidence was reported for the susceptibility intervals IDDM12 (on 2q33) even in Asia, evidence for most other intervals varies in different data sets. LD mapping has become an increasingly important tool for both confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations. The examination of large and ethnically varied data sets including those of Asia has allowed identification of haplotypes that differ only at a single codon in a single locus. As more data become available, the study of pairs of haplotypes which differ at a single polymorphic site, but have different effects on disease susceptibility, should allow more precise definition of the polymorphisms involved in the disease process.


Cervicovaginal and anal self-sampling for HPV testing in a transgender and gender diverse population assigned female at birth: comfort, difficulty, and willingness to use.
Transgender and gender diverse (TGD) people assigned female at birth (AFAB) face numerous barriers to preventive care, including for HPV and cervical cancer screening. Self-sampling options may expand access to HPV testing for TGD people AFAB. We recruited TGD individuals AFAB to collect cervicovaginal and anal specimens at-home using self-sampling for HPV testing, and individuals reported their perceptions of self-sampling. Associations between demographic and health characteristics and each of comfort of use, ease of use, and willingness to use self-sampling were estimated using robust Poisson regression. The majority of the 101 participants who completed the study reported that the cervicovaginal self-swab was not uncomfortable (68.3%) and not difficult to use (86.1%), and nearly all (96.0%) were willing to use the swab in the future. Fewer participants found the anal swab to not be uncomfortable (47.5%), but most participants still found the anal swab to not be difficult to use (70.2%) and were willing to use the swab in the future (89.1%). Participants were more willing to use either swab if they had not seen a medical professional in the past year. About 70% of participants who reported negative experiences with either self-swab were still willing to use that swab in the future. TGD AFAB individuals were willing to use and preferred self-sampling methods for cervicovaginal and anal HPV testing. Developing clinically approved self-sampling options for cancer screening could expand access to HPV screening for TGD AFAB populations.


Parasitization of commercially available parasitoid species against the lettuce aphid, Nasonovia ribisnigri (Hemiptera: Aphididae).
The lettuce aphid, Nasonovia ribisnigri (Mosley), is an economically important pest of lettuce worldwide. Little documentation exists for the control efficacy of aphid parasitoids against N. ribisnigri. This laboratory study evaluated three commercially available parasitoid species: Aphidius colemani (Viereck), Lysiphlebus testaceipes (Cresson), and Aphelinus abdominalis (Dalman) for their mortality impact on N. ribisnigri. The green peach aphid Myzus persicae (Sulzer) was included as a reference aphid. The study showed that A. abdominalis successfully parasitized 39 and 13% of the offered N. ribisnigri and M. persicae, respectively, within a 24-h exposure period. In contrast, none of the lettuce aphids exposed to Ap. colemani or L. testaceipes were successfully parasitized, whereas 60 and 3.5% of M. persicae, respectively, were successfully parasitized within a 6-h exposure period. Lettuce aphid mortality due to incomplete parasitization was 26 and 31% when exposed to Ap. colemani and L. testaceipes, respectively, with corresponding values for M. persicae being 5 and 10%, respectively. Mortality as a result of incomplete parasitization when aphids were exposed to A. abdominalis was low for both aphid species. The total mortality inflicted by A. abdominalis within a 24-h exposure period was 51% for the lettuce aphids and significantly less (19%) for green peach aphids. In contrast, Ap. colemani inflicted a higher mortality in M. persicae (65%) compared with N. ribisnigri (26%) within a 6-h exposure period. L. testaceipes caused a greater mortality in N. ribisnigri as compared with M. persicae. This study concludes that A. abdominalis has the potential to be used against N. ribisnigri in inoculative biocontrol programs as compared with the other parasitoid species based on successful parasitization.


Three-dimensional image reconstruction of helical aggregates of trypsin modified elongation factor EF-Tu from Escherichia coli: comparison with the reconstructed image of intact EF-Tu.
The three-dimensional structure of trypsin-modified EF-Tu polymers was analyzed to a resolution of 30 A with electron image reconstruction techniques after negative staining. In a 70% saturated ammonium sulfate solution the modified protein forms cylindrical aggregates with a diameter of about 340 A. The repeat distance of the structure along the cylindrical axis is 448 A. The large number of subunits in one repeat hampers the assessment of the helical symmetry. The Fourier analysis and three-dimensional synthesis were therefore carried out with three different selection rules. The three reconstructed density distributions show marked differences. In all of them twofold axes perpendicular to the cylindrical axis are present. The half unit cell content of one of the reconstructions shows a striking similarity with the shape of intact EF-Tu.GDP previously proposed in a similar study. We suggest that in the assemblies investigated here dimers of trypsin-modified EF-Tu.GDP are arranged along a one-start basic helix with 15.4 subunits per turn and a pitch of 64 A. The shape of the monomeric proteolyzed EF-Tu.GDP in this helical arrangement is very similar to that of the intact molecule in cylindrical assemblies studied at this resolution.


Discrepancies in the evaluation of incapacity for work in a patient with epidermolysis bullosa acquisita between public pension fund and occupational medicine expert raise the issue of competencies.
Abstrat A 50-year-old female patient suffering from a severe form of epidermolysis bullosa acquisita (EBA) took legal action against the Croatian Pension Insurance Institute (CPII) in an attempt to overturn their assessment that she was no longer capable of working as a seamstress but still capable of doing administrative jobs. Her claim was that she was not capable of doing any job at all. She was first diagnosed EBA in 2000, and the disease progressed slowly with intermittent remissions. In 2012, skin erosions appeared on her feet, followed by the loss of all toenails and lesions and infiltrations on the tongue and oral mucosa. Her whole body was covered in oozing wounds, she was in pain, and parts of her skin would stick to fabric while changing clothes or bandages. The most recent findings showed oesophageal stricture. She can consume only liquid food and is on the waiting list for receiving a feeding tube. The occupational health expert witness confirmed that the patient was generally incapable of work and was fighting her life. The judge and CPII lawyers fully accepted this report and the earlier assessment was overturned. To avoid incompetent assessments of working (in)capacity in the future, CPII and similar institutions should engage occupational medicine specialists to work in their assessment teams.


Design, synthesis, and spasmolytic activity of thiophene-based derivatives via Suzuki cross-coupling reaction of 5-bromothiophene-2-carboxylic acid: their structural and computational studies.
In the current research work, a facile synthesis of a series of novel thiophene-based derivatives of 5-bromothiophene-2-carboxylic acid ( 1 ) have been synthesized. All analogs ( 5a - 5e , 10a - 10f ) were obtained from the coupling reaction of 5-bromothiophene-2-carboxylic acid ( 1 ) and different arylboronic acids with moderate-to-good yields under controlled and optimal conditions. The structures of the newly synthesized compounds were characterized through spectral analysis and their spasmolytic activity, and most of the compounds exhibited potentially good spasmolytic effect. Among the synthesized analogs, compound phenethyl 5-(3,4-dichlorophenyl)thiophene-2-carboxylate ( 10d ) particular showed an excellent spasmolytic effect with an EC 50 value of 1.26. All of the compounds were also studied for their structural and electronic properties by density functional theory (DFT) calculations. Through detailed insight into frontier molecular orbitals of the compounds and their different reactivity descriptors, it was found that the compounds 10c and 5c are the most reactive, while 10a is the most stable in the series. Furthermore, compounds 10c and 5c showed a very good NLO response with the highest β values.


Perturbation of BRMS1 interactome reveals pathways that impact metastasis.
Breast Cancer Metastasis Suppressor 1 (BRMS1) expression is associated with longer patient survival in multiple cancer types. Understanding BRMS1 functionality will provide insights into both mechanism of action and will enhance potential therapeutic development. In this study, we confirmed that the C-terminus of BRMS1 is critical for metastasis suppression and hypothesized that critical protein interactions in this region would explain its function. Phosphorylation status at S237 regulates BRMS1 protein interactions related to a variety of biological processes, phenotypes [cell cycle (e.g., CDKN2A), DNA repair (e.g., BRCA1)], and metastasis [(e.g., TCF2 and POLE2)]. Presence of S237 also directly decreased MDA-MB-231 breast carcinoma migration in vitro and metastases in vivo. The results add significantly to our understanding of how BRMS1 interactions with Sin3/HDAC complexes regulate metastasis and expand insights into BRMS1's molecular role, as they demonstrate BRMS1 C-terminus involvement in distinct protein-protein interactions.