Coagulation status in coronary artery disease patients with type II diabetes mellitus compared with non-diabetic coronary artery disease patients using the PFA-100® and ROTEM®.
Previous investigations in patients with coronary artery disease (CAD) revealed differences in thromboelastographic parameters indicating different states of coagulability. The aim of the present study was to investigate the coagulation status of patients with documented CAD and type II diabetes mellitus (DM) and non-diabetic patients with coronary artery disease with the PFA-100® and the ROTEM®. No differences were found in platelet function as measured with collagen/epinephrine (263.6 ± 70.6 s vs. 254.6 ± 65.3 s) and collagen/ADP cartridges (105.3 ± 63.2 s vs. 90.6 ± 47.3 s) in CAD patients with DM and CAD patients without DM. Measured with the EXTEM reagent of the ROTEM®, mean maximum clot elasticity (MCE) in patients with CAD and DM (233.6 ± 86.9) was significantly longer than in CAD patients without DM (186.7 ± 54.5), (p = 0.03). A similar result was seen using the INTEM reagent; patients with CAD and DM (234.4 ± 83.9) showed a higher value for MCE than CAD patients without DM (190.8 ± 57.8) which was of borderline significance (p = 0.053). Moreover, a weak trend for higher maximum clot firmness (MCF) was seen in CAD patients with DM compared with CAD patients without DM with the EXTEM reagent (68.1 ± 7.5 vs. 63.6 ± 8.6, p = 0.08) and the INTEM reagent (68.4 ± 7.2 vs. 64.1 ± 8.2, p = 0.09). The ROTEM® analysis indicates increased coagulability in patients with coronary artery disease and diabetes mellitus compared to non-diabetic CAD patients. Moreover, the ROTEM® device seems to be an appropriate and easy-to-use tool to describe the coagulation status in these patients groups.


Osteoarthritis year in review 2021: mechanics.
Osteoarthritis (OA) has a complex, heterogeneous and only partly understood etiology. There is a definite role of joint cartilage pathomechanics in originating and progressing of the disease. Although it is still not identified precisely enough to design or select targeted treatments, the progress of this year's research demonstrates that this goal became much closer. On multiple scales - tissue, joint and whole body - an increasing number of studies were done, with impressive results. (1) Technology based instrument innovations, especially when combined with machine learning models, have broadened the applicability of biomechanics. (2) Combinations with imaging make biomechanics much more precise & personalized. (3) The combination of Musculoskeletal & Finite Element Models yield valid personalized cartilage loads. (4) Mechanical outcomes are becoming increasingly meaningful to inform and evaluate treatments, including predictive power from biomechanical models. Since most recent advancements in the field of biomechanics in OA are at the level of a proof op principle, future research should not only continue on this successful path of innovation, but also aim to develop clinical workflows that would facilitate including precision biomechanics in large scale studies. Eventually this will yield clinical tools for decision making and a rationale for new therapies in OA.


SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release.
SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in a minority of patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes and macrophages are sentinel immune cells in the blood and tissue, respectively, that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that expression quantitative trait loci (eQTLs) linked to higher GSDMD expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). We find that about 10% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on viral antibody opsonization and uptake of opsonized virus by the Fc receptor CD16. After uptake, SARS-CoV-2 begins to replicate in monocytes, as evidenced by detection of double-stranded RNA and subgenomic RNA and expression of a fluorescent reporter gene. However, infection is aborted, and infectious virus is not detected in infected monocyte supernatants or patient plasma. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of the NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial cells, from COVID-19 lung autopsy specimens showed evidence of inflammasome activation. These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to severe COVID-19 disease pathogenesis.


Prevalence and molecular heterogeneity of glucose-6-phosphate dehydrogenase (G6PD) deficiency in the Senoi Malaysian Orang Asli population.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder characterized by reduced G6PD enzyme levels in the blood. This condition is common in populations exposed to malaria; an acute febrile disease caused by Plasmodium parasites. G6PD-deficient individuals may suffer from acute hemolysis following the prescription of Primaquine, an antimalarial treatment. The population at risk for such a condition includes the Senoi group of Orang Asli, a remote indigenous community in Malaysia. This study aimed to elucidate the G6PD molecular heterogeneity in this subethnic group which is important for malaria elimination. A total of 662 blood samples (369 males and 293 females) from the Senoi subethnic group were screened for G6PD deficiency using a quantitative G6PD assay, OSMMR2000-D kit with Hb normalization. After excluding the family members, the overall prevalence of G6PD deficiency in the studied population was 15.2% (95% CI: 11-19%; 56 of 369), with males (30 of 172; 17.4%) outnumbering females (26 of 197; 13.2%). The adjusted male median (AMM), defined as 100% G6PD activity, was 11.8 IU/gHb. A total of 36 participants (9.6%; 26 male and 10 female) were deficient (<30% of AMM) and 20 participants (5.4%; 4 male and 16 female) were G6PD-intermediate (30-70% of AMM). A total of 87 samples were genotyped, of which 18 showed no mutation. Seven mutations were found among 69 genotyped samples; IVS11 T93C (47.1%; n = 41), rs1050757 (3'UTR +357A>G)(39.1%; n = 34), G6PD Viangchan (c.871G>A)(25.3%; n = 22), G6PD Union (c.1360C>T)(21.8%; n = 19), c.1311C>T(20.7%; n = 18), G6PD Kaiping (c.1388G>A)(8.0%; n = 7), and G6PD Coimbra (c.592C>T)(2.3%; n = 2). Our analysis revealed 27 hemizygote males, 18 heterozygote females, 7 homozygote females, and 2 compound heterozygote females. This study confirms the high prevalence of G6PD deficiency among the Senoi Malaysian Orang Asli, with a significant degree of molecular heterogeneity. More emphasis should be placed on screening for G6PD status and proper and safe use of Primaquine in the elimination of malaria among this indigenous population.


OsEIN2 is a positive component in ethylene signaling in rice.
EIN2 is a central signal transducer in the ethylene-signaling pathway, and a unique membrane-anchored protein. By screening a cDNA library, we have isolated a cDNA clone (OsEIN2) that encodes the rice EIN2 homolog. The full-length ORF clone was obtained by reverse transcriptase-polymerase chain reaction. OsEIN2 shares significant amino acid sequence similarity with Arabidopsis EIN2 (57% similarity and 42% identity). Both the numbers and positions of introns and exons in the OsEIN2 and AtEIN2 coding regions are also conserved. To address whether this structural similarity is indicative of functional conservation of the corresponding proteins, we also generated transgenic lines expressing the antisense construct of OsEIN2. Those plants were stunted and shoot elongation was severely inhibited. Their phenotypes were similar to that found with wild-type rice seedlings that were treated with AgNO3, an ethylene signal inhibitor. In the OsEIN2 antisense plants, the expression levels of two ethylene-responsive genes, SC129 and SC255, were decreased compared with the wild types. These results suggest that OsEIN2 is a positive component of the ethylene-signaling pathway in rice, just as AtEIN2 is in Arabidopsis: Our antisense transgenic plants produced approximately 3.5 times more ethylene than the wild-type plants. Expression analysis of rice ACS and ACO genes showed that the transcript levels of OsACS1 and OsACO1 were elevated in the transgenic plants.


Glutamic acid decarboxylase (anti-GAD) & tissue transglutaminase (anti-TTG) antibodies in patients with thyroid autoimmunity.
Several autoimmune disorders have been reported to be associated with autoimmune thyroiditis and may coexist with other organ-specific autoantibodies. The aim of the present study was to evaluate the presence of tissue transglutaminase (anti-TTG) and glutamic acid decarboxylase (anti-GAD) antibodies in patients suffering from autoimmune thyroiditis as diagnosed by anti-thyroid peroxidase (anti-TPO) antibodies, which may indicate high risk for developing celiac disease or type 1 diabetes mellitus. Five thousand children and 2800 adults were screening as part of a general health examination done on a voluntary basis in four different parts of Delhi. A total of 577 subjects positive for anti-TPO antibody constituted the cases. Equal number of age and sex matched anti-TPO antibody negative controls were randomly selected from the same cohort to form paired case control study. The cases and controls were further divided into two groups as follows: group-1 (children and adolescent <18 yr), group-2 (adults >18 yr). Serum samples of cases and controls were analysed for thyroid function test (FT3, FT4, and TSH), anti-TTG and anti-GAD antibodies. A total of 1154 subjects (577 cases and 577 controls) were included in this study. Hypothyroidism was present in 40.2 per cent (232) cases compared to only 4.7 per cent (27) in controls (P<0.001). Anti-TTG and anti-GAD antibodies were present in 6.9 and 12.5 per cent subjects among cases compared to 3.5 per cent (P=0.015) and 4.3 per cent (P=0.001) in controls, respectively. Only anti-GAD antibody were significantly positive in cases among children and adolescents (P =0.0044) and adult (P=0.001) compared to controls. Levels of anti-TTG and anti-GAD antibodies increased with increasing titre of anti-TPO antibody. Our findings showed high positivity of anti-GAD and anti-TTG antibodies among subjects with thyroid autoimmunity. It is, therefore, important to have high clinical index of suspicion for celiac disease or type 1 diabetes mellitus in patients with autoimmune thyroiditis.


Early life exposure to 1959-1961 Chinese famine exacerbates association between diabetes and cardiovascular disease.
We aimed to assess whether early life exposure to the Chinese famine (1959-1961) modifies the association between type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in adulthood. Data from 4247 adults born between 1954 and 1964 from the 2011 and 2015 China Health and Retirement Longitudinal Study (CHARLS) were analyzed. CVD in 2011 and 2015 was based on self-reported doctor's diagnosis of cardiac events (heart attack, coronary heart disease, angina, congestive heart failure, or other heart problems) and stroke. Diabetes in 2011 was defined by fasting blood glucose, HbA1C, or known diabetes. Diabetes in 2011 was cross-sectionally associated with an increase of CVD risk in 2011 (OR 1.91, 95%CI 1.53-2.40, P < 0.001) after adjusting for age and gender. Famine exposure changed the association between diabetes and CVD in areas severely affected by famine. The odds ratios (OR) of diabetes in 2011 for CVD in 2015 were 1.24 (95%CI 0.73-2.10), 1.27 (95%CI 0.72-2.24), 2.25 (95%CI 1.29-3.91), 4.31 (95%CI 2.07-8.97) and 1.72 (95%CI 0.84-3.51) among adults in late childhood-, mid-childhood-, early childhood-, fetal-, and nonexposed cohorts in severe famine areas, respectively. T2DM is associated with the risk of CVD among Chinese adults. Fetal and early childhood exposure to the Chinese famine exacerbated the associated risk.


Predictive value of dysplasia grading and DNA ploidy in malignant transformation of oral potentially malignant disorders.
Dysplasia grading is widely used to assess risk of transformation in oral potentially malignant disorders despite limited data on predictive value. DNA ploidy analysis has been proposed as an alternative. This study examines the prognostic value for both tests used in a routine diagnostic setting to inform clinical management. A retrospective study of conventional dysplasia grading was conducted on 1,401 patients. DNA ploidy analysis was conducted on a subset of 273 patients and results correlated with clinical information, pathologic diagnosis, and outcome over 5 to 15 years. Malignant transformation occurred in 32 of 273 patients (12%) and, of these, 20 (63%) of preexisting index lesions were aneuploid. Of 241 patients not developing carcinoma, only 39 (16%) of index lesions were aneuploid. Epithelial dysplasia correlated with DNA ploidy status (P < 0.001). The overall positive predictive value for malignant transformation by DNA aneuploidy was 38.5% (sensitivity 65.2% and specificity 75%) and by severe dysplasia grade 39.5% (sensitivity 30% and specificity 98%). DNA diploid and tetraploid status had negative predictive value of 90% to 96%. Combining DNA ploidy analysis with dysplasia grading gives a higher predictive value than either technique alone. Each of three traditional dysplasia grades predicts a significantly different risk of carcinoma development and time to transformation. DNA ploidy analysis had equivalent predictive value and also detected additional risk lesions in the absence of dysplasia.


The hazards of internal fixation in podiatry.
There are several ways to avoid the iatrogenic complications or hazards of internal fixation. The surgical approach should be planned well in advance. The instruments and materials to be used intraoperatively should be checked before beginning the operation to assure that there are adequate materials of appropriate length and thickness. Also, all materials should be checked for major defects (see Fig. 11A). Good tissue dissection and atraumatic surgical technique is essential to limit excessive tissue destruction. Reduction of the fracture fragments should be obtained prior to fixation. While applying fixation devices, the fragments should be held stable. Intraoperative radiographs are necessary to demonstrate appropriate positioning of the internal fixation device and the proper alignment of the fracture fragments. If the alignment is not satisfactory, repositioning of the devices can and should be made. Preoperative practice and familiarity with the fixation devices is an essential part of shortening the operative time and helping to assure optimum fixation stability. A poor time to learn the techniques for internal fixation is during surgery. Good postoperative care is essential to optimize fracture fragment healing results.


Travelers' Diarrhea and Other Gastrointestinal Symptoms Among Boston-Area International Travelers.
AbstractThis prospective cohort study describes travelers' diarrhea (TD) and non-TD gastrointestinal (GI) symptoms among international travelers from the Boston area, the association of TD with traveler characteristics and dietary practices, use of prescribed antidiarrheal medications, and the impact of TD and non-TD GI symptoms on planned activities during and after travel. We included adults who received a pre-travel consultation at three Boston-area travel clinics and who completed a three-part survey: pre-travel, during travel, and post-travel (2-4 weeks after return). TD was defined as self-reported diarrhea with or without nausea/vomiting, abdominal pain, or fever. Demographic and travel characteristics were evaluated by χ2 test for categorical and Wilcoxon rank-sum test for continuous variables. Analysis of dietary practices used logistic generalized estimating equation models or logistic regression models. Of 628 travelers, 208 (33%) experienced TD and 45 (7%) experienced non-TD GI symptoms. Of 208 with TD, 128 (64%), 71 (36%), and 123 (62%) were prescribed ciprofloxacin, azithromycin, and/or loperamide before travel, respectively. Thirty-nine (36%) of 108 took ciprofloxacin, 20 (38%) of 55 took azithromycin, and 28 (28%) of 99 took loperamide during travel. Of 172 with TD during travel, 24% stopped planned activities, and 2% were hospitalized. Of 31 with non-TD GI symptoms during travel, six (13%) stopped planned activities. International travelers continue to experience diarrhea and other GI symptoms, resulting in disruption of planned activities and healthcare visits for some. Although these illnesses resulted in interruption of travel plans, a relatively small proportion took prescribed antibiotics.


Spatial and temporal changes in microbial community structure associated with recharge-influenced chemical gradients in a contaminated aquifer.
In a contaminated water-table aquifer, we related microbial community structure on aquifer sediments to gradients in 24 geochemical and contaminant variables at five depths, under three recharge conditions. Community amplified ribsosomal DNA restriction analysis (ARDRA) using universal 16S rDNA primers and denaturing gradient gel electrophoresis (DGGE) using bacterial 16S rDNA primers indicated: (i). communities in the anoxic, contaminated central zone were similar regardless of recharge; (ii). after recharge, communities at greatest depth were similar to those in uncontaminated zones; and (iii). after extended lack of recharge, communities at upper and lower aquifer margins differed from communities at the same depths on other dates. General aquifer geochemistry was as important as contaminant or terminal electron accepting process (TEAP) chemistry in discriminant analysis of community groups. The Shannon index of diversity (H) and the evenness index (E), based on DGGE operational taxonomic units (OTUs), were statistically different across community groups and aquifer depths. Archaea or sulphate-reducing bacteria 16S rRNA abundance was not clearly correlated with TEAP chemistry indicative of methanogenesis or sulphate reduction. Eukarya rRNA abundance varied by depth and date from 0 to 13% of the microbial community. This contaminated aquifer is a dynamic ecosystem, with complex interactions between physical, chemical and biotic components, which should be considered in the interpretation of aquifer geochemistry and in the development of conceptual or predictive models for natural attenuation or remediation.


Self-assembly, self-sorting, and electronic properties of a diketopyrrolopyrrole hydrogelator.
We show here the first example of a hydrogel formed from a symmetrically functionalised diketopyrrolopyrrole aromatic core. Gelation is triggered by change in pH. Not only does this gelator form aggregated, entangled structures at low pH, but it also forms worm-like micelles at high pH. The structures at high pH can be aligned using shear to provide conductive materials.


Variations in the use of medication for the treatment of childhood asthma in the Michigan Medicaid population, 1980 to 1986.
Asthma is a leading cause of morbidity in the United States and is a leading cause of disability in children. Prevalence has been shown to be highest in male children, blacks, and urban residents. Racial and residential differences have been attributed to economics. Medicaid claims data allow for the comparison of asthma morbidity and treatment of patients with different demography but of low socioeconomic status. Michigan Medicaid claims data for recipient children between 5 and 14 years of age were used to ascertain demographic factors associated with asthma treatment from 1980 through 1986. A cross-sectional analysis was used. Black asthmatics were found to receive medical care more frequently, but to obtain asthma drugs less frequently than other groups. The prevalence of different prescription asthma preparations also varied by race and residence. Black, urban residents obtained fixed-combination drugs more frequently and steroids less frequently than other groups. Rural patients, in general, had fewer medical contacts but obtained more prescription products per provider contact, whether black or white. Possible reasons for this variation are discussed.


Trends of lung cancer mortality in Mexico.
Lung cancer (LC) is one of the most important public health problems in the world; 1,035,000 annual deaths are estimated each year and more than 80% of these are attributed to tobacco. The trend of lung cancer mortality in Mexico City from 1979 - 1993 was determined, as was the rate ratio of lung cancer mortality in 31 states in Mexico, taking Mexico City as a reference by means of a Poisson model. A strong linear regression model was used to evaluate the rate, where the dependent variable was LC mortality rate and the independent variable the year observed. In 15 years, 73,807 deaths from LC were reported, with an increase in mortality from 5.01 - 7.25 per 100,000 inhabitants. Mortality increases significantly after 60 years of age (B not equal to 0), p<.05) in men and in women. Mortality from LC was 70% in men, and more than 60% of deaths were reported after 65 years of age. Mortality risk is higher in the northern states of the country (e.g., Sonora, RR=2.40) than in the southern region (e.g., Oaxaca RR=0.40). In Mexico, almost 10,000 deaths by LC are estimated for the year 2010. Therefore, changes in lifestyle should be encouraged in order to decrease the smoking habit. The governmental tax on cigarettes should be increased, smoking restricted in squares and public spaces, and the risks should be announced on cigarette packages, among other measures. With respect to other emergent risk factors, the sources of industrial pollution and toxic emissions should be regulated.


Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats.
The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD:NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I-IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.


Analysis of component findings in 79 patients diagnosed with VACTERL association.
VACTERL association is a relatively common condition, though the causes remain poorly understood. We present data on 79 patients diagnosed with VACTERL association and perform statistical analysis on a selected subset of 60 patients with at least three component features, and who, after review, did not meet criteria for a likely alternate diagnosis. Considered individually, no two component features are significantly associated, but several multivariate statistical techniques suggest novel patterns of the co-occurrence of component features, and latent class cluster analysis demonstrates the presence of five major subgroups of patients. These findings have implications for both our understanding of VACTERL association and for the approach to research involving this condition.


Comparative Genomic Characterization of the Multimammate Mouse Mastomys coucha.
Mastomys are the most widespread African rodent and carriers of various diseases such as the plague or Lassa virus. In addition, mastomys have rapidly gained a large number of mammary glands. Here, we generated a genome, variome, and transcriptomes for Mastomys coucha. As mastomys diverged at similar times from mouse and rat, we demonstrate their utility as a comparative genomic tool for these commonly used animal models. Furthermore, we identified over 500 mastomys accelerated regions, often residing near important mammary developmental genes or within their exons leading to protein sequence changes. Functional characterization of a noncoding mastomys accelerated region, located in the HoxD locus, showed enhancer activity in mouse developing mammary glands. Combined, our results provide genomic resources for mastomys and highlight their potential both as a comparative genomic tool and for the identification of mammary gland number determining factors.


Cicatricial alopecia: classification and histopathology.
Primary cicatricial alopecias are a diagnostically challenging group of disorders characterized by folliculocentric inflammation resulting in destruction of hair follicles and irreversible hair loss. They are classified according to a consensus-issued classification scheme based on the predominant cell type present: lymphocytic, neutrophilic, or mixed. Histopathology is a pivotal component of the diagnostic evaluation. Early diagnosis is critical since timely institution of treatment can halt progression of permanent hair loss. Salient histopathologic findings are presented in this review, along with adjunctive clues derived from interpretation of special stains and direct immunofluorescence studies. Despite careful evaluation, accurate diagnosis may remain elusive in some instances. The primary cicatricial alopecias often share overlapping features. The highest diagnostic yield is procured when histology is correlated with the clinical presentation.


Possible effect of time on renal allograft rejection.
The change in plasma creatinine concentrations from decreasing values after successful renal transplantation to increasing values after the onset of rejection occurs as a sudden event. Twenty-two such episodes in 16 renal allograft recipients were studied by extrapolating sequential measurements of plasma creatinine concentrations to see when the change occurred. Seventeen of the episodes occurred between 2300 and 1100 and the rest at other times. This difference was significant. The results suggest that rejection is more common at night and apparently has a circadian rhythm, being likely to first influence creatinine clearance at around 0600.


Carrion fly-derived DNA metabarcoding is an effective tool for mammal surveys: Evidence from a known tropical mammal community.
Metabarcoding of vertebrate DNA derived from carrion flies has been proposed as a promising tool for biodiversity monitoring. To evaluate its efficacy, we conducted metabarcoding surveys of carrion flies on Barro Colorado Island (BCI), Panama, which has a well-known mammal community, and compared our results against diurnal transect counts and camera trapping. We collected 1,084 flies in 29 sampling days, conducted metabarcoding with mammal-specific (16S) and vertebrate-specific (12S) primers, and sequenced amplicons on Illumina MiSeq. For taxonomic assignment, we compared blast with the new program protax, and we found that protax improved species identifications. We detected 20 mammal, four bird, and one lizard species from carrion fly metabarcoding, all but one of which are known from BCI. Fly metabarcoding detected more mammal species than concurrent transect counts (29 sampling days, 13 species) and concurrent camera trapping (84 sampling days, 17 species), and detected 67% of the number of mammal species documented by 8 years of transect counts and camera trapping combined, although fly metabarcoding missed several abundant species. This study demonstrates that carrion fly metabarcoding is a powerful tool for mammal biodiversity surveys and has the potential to detect a broader range of species than more commonly used methods.


E test versus agar dilution for antimicrobial susceptibility testing of viridans group streptococci.
Viridans group streptococci (VGS) are commonly isolated from the blood of hospitalized patients. The E test represents a convenient method for determining the MICs for VGS, but for this purpose it has not been well validated against reference methods. In this study, 180 unselected VGS isolates were identified to a species level, and the MICs of penicillin, cefuroxime, cefotaxime, and vancomycin were determined by both agar dilution and the E test. Available data regarding demographic and laboratory variables for each VGS bacteremic episode were collected, the significance of each VGS isolate was assessed, and the associations between and among laboratory and clinical variables were investigated. Among all VGS isolates, 68.3% (median of three runs) were found to be fully susceptible to penicillin by agar dilution. The E test and agar dilution showed average agreements (within +/-1 dilution) of 92.2% for penicillin, 95.7% for cefuroxime 91.3% for cefotaxime, and 86.7% for vancomycin. Agreements over serial E tests and serial agar dilutions were excellent for beta-lactam agents (intraclass correlation coefficients, >0.9) but less impressive for vancomycin. Very major error rates for the E test were </=0.7%, and combined major and minor error rates were within acceptable limits for all antimicrobial agents tested. Lysis-centrifugation culture methods were more often associated with clinically insignificant VGS isolates; otherwise, no associations between clinical and laboratory variables were noted.


Phase change and the regulation of developmental timing in plants.
Plants produce different types of organs at different times in shoot development. Along with the major changes in organ morphology that take place during developmental transitions, more gradual patterns of variation occur. The identity of organs produced at a particular position on the shoot is determined by interactions between several independently regulated, temporally coordinated processes. Two of these processes are organ production and the specification of organ identity. Coordination of these processes is accomplished in part by a thermal clock and by signal transduction pathways that mediate the response of plants to light.


Risk of Inflammatory Bowel Disease in Patients With Atopic Dermatitis.
Data on the association between atopic dermatitis (AD) and inflammatory bowel disease (IBD) are inconsistent. Few studies have examined the association of AD or AD severity with risk of ulcerative colitis (UC) and Crohn disease (CD) separately. To examine the risk of new-onset IBD, UC, and CD in children and adults with AD. This population-based cohort study assessed patients with AD matched with up to 5 controls on age, practice, and index date. Treatment exposure was used as a proxy for AD severity. Data were retrieved from The Health Improvement Network, a UK electronic medical record database, for January 1, 1994, to February 28, 2015. Data analysis was performed from January 8, 2020, to June 30, 2023. Outcomes of interest were incident IBD, UC, and CD. Logistic regression was used to examine the risk for each outcome in children and adults with AD compared with controls. A total of 1 809 029 pediatric controls were matched to 409 431 children with AD (93.2% mild, 5.5% moderate, and 1.3% severe). The pediatric cohort ranged in median age from 4 to 5 years (overall range, 1-10 years), was predominantly male (936 750 [51.8%] controls, 196 996 [51.6%] with mild AD, 11 379 [50.7%] with moderate AD, and 2985 [56.1%] with severe AD), and with similar socioeconomic status. A total of 2 678 888 adult controls were matched to 625 083 adults with AD (65.7% mild, 31.4% moderate, and 2.9% severe). The adult cohort ranged in median age from 45 to 50 years (overall range, 30-68 years) and was predominantly female (1 445 589 [54.0%] controls, 256 071 [62.3%] with mild AD, 109 404 [55.8%] with moderate AD, and 10 736 [59.3%] with severe AD). In fully adjusted models, children with AD had a 44% increased risk of IBD (hazard ratio [HR], 1.44; 95% CI, 1.31-1.58) and a 74% increased risk of CD (HR, 1.74; 95% CI, 1.54-1.97), which increased with worsening AD; however, they did not have increased risk of UC (HR, 1.09; 95% CI, 0.94-1.27) except for those with severe AD (HR, 1.65; 95% CI, 1.02-2.67). Adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk of IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk of CB, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk of UC, with risk increasing with worsening AD. In this cohort study, children and adults with AD had an increased risk of IBD, with risk varying by age, AD severity, and IBD subtype. These findings provide new insights into the association between AD and IBD. Clinicians should be aware of these risks, particularly when selecting systemic treatments for AD in patients who may have coincident gastrointestinal symptoms.


A comparison of analytical methods for genetic association studies.
The explosion of genetic information over the last decade presents an analytical challenge for genetic association studies. As the number of genetic variables examined per individual increases, both variable selection and statistical modeling tasks must be performed during analysis. While these tasks could be performed separately, coupling them is necessary to select meaningful variables that effectively model the data. This challenge is heightened due to the complex nature of the phenotypes under study and the complex underlying genetic etiologies. To address this problem, a number of novel methods have been developed. In the current study, we compare the performance of six analytical approaches to detect both main effects and gene-gene interactions in a range of genetic models. Multifactor dimensionality reduction, grammatical evolution neural networks, random forests, focused interaction testing framework, step-wise logistic regression, and explicit logistic regression were compared. As one might expect, the relative success of each method is context dependent. This study demonstrates the strengths and weaknesses of each method and illustrates the importance of continued methods development.


Needs for and barriers to correctional mental health services: inmate perceptions.
Because of increasing numbers of mentally ill offenders without concomitant increases in mental health staffing, issues of service utilization and priority populations have become paramount. The aim of this study was to expand upon previous studies of correctional mental health service utilization by examining the underlying factor structure of problems for which inmates may seek services and by examining the barriers hindering inmates' willingness to seek services. Additionally, this study investigated whether previous treatment experiences had an impact on inmates' willingness to seek services or barriers to seeking services. Participants consisted of 418 incarcerated adult males who voluntarily participated in this study and were from three security levels (that is, reception and diagnostic unit, minimum security, and maximum security). Participants completed a three-page survey inquiring about use of mental health services before and during incarceration. Factor analysis indicated five types of problems for which inmates may request mental health services (behavioral dyscontrol, physical health concerns, negative affect, interpersonal relationships, and institutional relations) and four types of potential barriers to service utilization (self-preservation concerns, procedural concerns, self-reliance, and professional service provider concerns). Inmates with no prior history of mental health service use were more likely to present with self-preservation concerns about services and present as self-reliant. Results of this study provide an overarching conceptualization of barriers hindering inmates' willingness to seek services, as well as the types of problems for which they are likely to seek services. Also, inmates' mental health treatment history affected their current perceptions of services.


Dental Caries and the Erosive Tooth Wear Status of 12-Year-Old Children in Jakarta, Indonesia.
Indonesia has the largest population of all countries in southeast Asia. However, little information is available on the oral health status of Indonesian children. The aims of this study were to assess dental caries and erosive tooth wear in 12-year-old children in Jakarta, Indonesia and to investigate the associated risk factors. Samples were selected using cluster sampling. Parents were asked to complete a self-administered questionnaire regarding their oral health knowledge, demographic information, their child's dietary habits, and oral health-related behaviors. Experience of caries and erosive tooth wear were recorded using the Decayed, Missing (due to caries), and Filled Teeth (DMFT) index and the Basic Erosive Wear Examination (BEWE) index, respectively. Of 779 children invited, 696 participated in the survey. Of these, 61% had experienced caries, and the mean DMFT score was 1.58. Almost all decay was untreated. Children who were female, who had a high frequency of soft drink intake, and whose father's educational level was low were more likely to have dental caries. Most children had at least one lesion of erosive tooth wear. Children whose mother's educational level was low were more likely to have erosive tooth wear. The prevalence of dental caries and erosive tooth wear was high in 12-year-old children in Jakarta. Their dietary habits and parental level of education were associated with the presence of these dental conditions.


Development of a monoclonal antibody against a tumor-associated antigen.
A monoclonal antibody-producing hybrid cell line was obtained by fusing mouse myeloma cells with spleen cells from a mouse immunized with C6 glioma cells. This antibody binds to a specific cell-surface antigen that is present on C6 rat glioma cells, transformed astrocytes and oligodendrocytes, and a human glioma cell line but is absent on a normal glial cell line, fibroblasts, and primary cultures of astrocytes and oligodendrocytes. The antigen also appears on tumor tissue of transformed oligodendrocytes but not on normal brain tissue.


Premixed vs basal-bolus insulin regimen in Type 2 diabetes: comparison of clinical outcomes from randomized controlled trials and real-world data.
To evaluate the concordance between data derived from randomized controlled trial (RCT) and real-world estimates of HbA1c and weight change after 24 weeks of initiation of a basal-bolus compared with a premixed insulin regimen in people with Type 2 diabetes. Data eight RCTs were pooled after a systematic review of studies examining basal-bolus (n = 1893) or premixed (n = 1517) regimens. Real-world data were extracted from the UK primary care dataset for people on basal-bolus (n = 7483) or premixed insulin regimens (n=10 744). The mean differences between HbA1c and weight from baseline were calculated using t-tests, while analysis of variance was used to compare the two treatment regimens. Linear regression analyses were used to determine the predictors of this change. Both insulin regimens were associated with HbA1c reductions (real-world data -0.28%; RCT data, -1.4%) and weight gain (real-world data, +0.27 kg; RCT data, +2.96 kg) but there were no significant differences between basal-bolus and premixed insulin. Discordances in the pattern of treatment response were observed, however, between real-world and RCT data for both insulin regimens. For any given baseline HbA1c concentration, the change in HbA1c in the RCTs was greater than in real-world conditions and for those with baseline weight above ~60 kg, RCT data showed overall weight gain in contrast to slight weight loss in the real-world population. Lastly, for both randomized controlled trial and real-world populations, while greater baseline weight was associated with reduced response to treatment, the association was much steeper in the RCT than in the real-world population. In addition, greater baseline weight was associated with greater weight reductions in both premixed insulin and basal-bolus insulin regimens, although to a lesser extent with the latter. These results highlight specific discrepancies in the HbA1c reduction and weight change in insulin regimen between real world versus RCT populations; with greater reduction in HbA1c and greater increase in weight observed in the RCT population than in the real-world population. Also, the basal-bolus regimens in both real-world and RCT populations showed greater reduction in HbA1c compared to the premix regimen (though more marked in RCTs), while the premix regimen showed greater increase in weight in real-world, as against basal-bolus in the RCT population.


Association Between Trust and Mental, Social, and Physical Health Outcomes in Veterans and Active Duty Service Members With Combat-Related PTSD Symptomatology.
Background: Trust represents a complex emotion and interpersonal concept which assumes abandoning control over a given situation or set of circumstances, in turn yielding such control to another party. Advances in our knowledge of post-traumatic stress disorder and moral injury have underscored the need to more closely examine how trust stands to impact health outcomes in these disorders. The aim of the present study is to examine and identify relationships linking general trust with select health outcomes in a mixed sample of Veterans and Service members with a self-reported history of deployment to a combat theater and PTSD symptomatology. Methods: This study applied a cross-sectional methodology, surveying n = 427 participants recruited across six sites. This included 373 Veterans and 54 active duty Service members in the United States. Measures included demographic characteristics, combat exposure, general trust, post-traumatic stress disorder symptomatology, depressive/anxiety symptomatology, alcohol use, social involvement, religiosity, and physical health. Data were analyzed descriptively as well as using Pearson correlations, Student's t-test, and multivariate regression. Results: Several significant relationships were identified, indicating an inverse relationship between trust and PTSD, depressive, and anxiety symptomatology. Greater levels of trust were also significantly associated with increased social interaction and religiosity. Lastly, no significant associations were identified with either physical functioning or pain level. Conclusion: The findings suggest that trust is correlated with a variety of health outcomes in Veterans and Service members affected by combat-related PTSD. Additional, hypothesis-driven research, informed by longitudinal data, is needed to better understand how trust stands to impact health outcomes, including the development of strategies and intervention options for repairing trust.


[Local treatment of malignant pleural effusion in gynecologic tumors].
Pleural effusions are a frequent complication of malignant gynecologic diseases, especially in breast cancer with an incidence of about 50%. Pleural effusions usually occur at a stage of the disease where no further curative therapeutic options exist. Therefore, the treatment should be effective and have a low side effect profile. The intrapleural administration of mitoxantrone in comparison with other pleurodesis techniques has been demonstrated to meet these requirements.


Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial.
Inhaled nitric oxide has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). To determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department or hospital for care. Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled nitric oxide gas vs inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004, and December 22, 2008. Intervention Inhaled nitric oxide gas vs inhaled nitrogen placebo. The primary end point was the time to resolution of painful crisis, defined by (1) freedom from parenteral opioid use for 5 hours; (2) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0-10 scale); (3) ability to walk; and (4) patient's and family's decision, with physician consensus, that the remaining pain could be managed at home. There was no significant change in the primary end point between the nitric oxide and placebo groups, with a median time to resolution of crisis of 73.0 hours (95% confidence interval [CI], 46.0-91.0) and 65.5 hours (95% CI, 48.1-84.0), respectively (P = .87). There were no significant differences in secondary outcome measures, including length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of acute chest syndrome. Inhaled nitric oxide was well tolerated, with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed adherence and randomization but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. Among patients with SCD hospitalized with VOC, the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution. clinicaltrials.gov Identifier: NCT00094887.


Facilitation of dissociation reaction of nucleotides bound to Mycobacterium tuberculosis DnaA.
Acidic phospholipids have been shown to promote dissociation of bound nucleotides from Mycobacterium tuberculosis DnaA (DnaA(TB)) purified under denaturing conditions [Yamamoto et al., (2002) Modulation of Mycobacterium tuberculosis DnaA protein-adenine-nucleotide interactions by acidic phospholipids. Biochem. J., 363, 305-311]. In the present study, we show that a majority of DnaA(TB) in non-overproducing cells of M. tuberculosis is membrane associated. Estimation of phospholipid phosphorus following chloroform: methanol extraction of soluble DnaA(TB) purified under native conditions (nDnaA(TB)) confirmed the association with phospholipids. nDnaA(TB) exhibited weak ATPase activity, and rapidly exchanged ATP for bound ADP in the absence of any added phospholipids. We suggest that the outcome of intra-cellular DnaA(TB)-nucleotide interactions, hence DnaA(TB) activity, is influenced by phospholipids.


Charge-based detection of small molecules by plasmonic-based electrochemical impedance microscopy.
Charge-based detection of small molecules is demonstrated by plasmonic-based electrochemical impedance microscopy (P-EIM). The dependence of surface plasmon resonance (SPR) on surface charge density is used to detect small molecules (60-120 Da) printed on a dextran-modified sensor surface. Local variations in charge density on an electrode surface are manifest in an optical SPR signal. The SPR response to an applied ac potential measures the sensor surface impedance which is a function of the surface charge density. This optical signal is comprised of a dc and an ac component, and is measured with high spatial resolution. The dc element of the SPR signal represents conventional SPR imaging information. The amplitude and phase of local surface impedance is provided by the ac component. The phase signal of the small molecules is a function of their charge status, which is manipulated by the pH of a solution. Small molecules with positive, neutral, and negative charge are detected by P-EIM. This technique is used to detect and distinguish small molecules based on their charge status, thereby circumventing the mass limitation (~100 Da) of conventional SPR measurement.


Reliability of performance of elite Olympic weightlifters.
There are no published data on the reliability of competitive strength performance, even though it has a pronounced effect on athletes' medal prospects and the ability of coaches and athletes to identify factors that affect competitive performance. The purpose of this investigation was to analyze the reliability of elite olympic weightlifters over a series of international weightlifting meets. We obtained official results of international competitions over an 18-month period from 1999 until the 2000 Olympic Games at the International Weightlifting Federation website. The measure of reliability was the typical within-athlete variation, derived as the coefficient of variation (CV) by 2-way analysis of variance of log-transformed weights lifted for the snatch, clean and jerk, and total. The results of this analysis were (a) within-athlete variations were as follows: snatch, 2.7% (95% likely range, 2.4-3.2%); clean and jerk, 2.3% (1.7-3.6%); total weight lifted, 2.5% (2.2-2.9%); (b) men and women: the variation was higher for the women compared with the men in both snatch (ratio of CV, 1.4) and clean and jerk (ratio of CV, 1.5), and for the total weight lifted (ratio of CV, 1.3); and (c) the top 5 athletes were almost always more reliable than the bottom-half athletes. Recent work has shown that the smallest worthwhile performance is about half the within-athlete variation, so coaches and sport scientists should focus on enhancements of as little as 1.2% in total weight lifted for elite olympic weightlifters.


Investigation of diagnostic performance of five urinary cholesterol metabolites for Niemann-Pick disease type C.
Niemann-Pick disease type C (NPC) is an autosomal recessive disorder characterized by progressive nervous degeneration. Because of the diversity of clinical symptoms and onset age, the diagnosis of this disease is difficult. Therefore, biomarker tests have attracted significant attention for earlier diagnostics. In this study, we developed a simultaneous analysis method for five urinary conjugated cholesterol metabolites, which are potential diagnostic biomarkers for a rapid, convenient, and noninvasive chemical diagnosis, using LC/MS/MS. By the method, their urinary concentrations were quantified and the NPC diagnostic performances were evaluated. The developed LC/MS/MS method showed high accuracy and satisfied all analytical method validation criteria. When the urine of healthy controls and patients with NPC was analyzed, three of five urinary conjugated cholesterol metabolite concentrations corrected by urinary creatinine were significantly higher in the patients with NPC. As a result of receiver operating characteristics analysis, these urinary metabolites might have excellent diagnostic marker performance. 3β-Sulfooxy-7β-hydroxy-5-cholenoic acid showed particularly excellent diagnostic performance with both 100% clinical sensitivity and specificity, suggesting that it is a useful NPC diagnostic marker. The urinary conjugated cholesterol metabolites exhibited high NPC diagnostic marker performance and could be used for NPC diagnosis.


How Can Service-Learning Shape the Political Perspectives of Pre-Service Teachers? A Program in the Field of Physical Education.
Active and democratic citizenship promotion has become a critical challenge for higher education, and civic engagement is a fundamental axis not only in education but also in fostering democratic systems. Consequently, teacher educators held a prominent role through their own teaching practices to generate contexts promoting critical thinking, skills and attitudes. The aim of this study was to analyze the learning related to the political dimension developed by pre-service teachers (n = 123) after participating in a Service-Learning program through physical education with children at risk or/and student with educational needs. This research followed a qualitative research approach and we based the analysis of reflective diaries on Gorham's (2005) categories regarding political learning: Critical political thinking, Interest in politics, Deliberation and Political judgment. The findings show a development in learning such as civic attitudes, critical political thinking, awareness of social justice problems, increased civic compromise and responsibility. The Service-Learning program, therefore, may have been an adequate option to develop pre-service teachers' learning related to a political perspective. Therefore, these findings let us understand how Service-Learning may foster equity and social justice among future teachers.


The muskrat (Ondatra zibethicus) as a new reservoir for puumala-like hantavirus strains in Europe.
We have used an indirect immunofluorescent assay (IFA) and reverse transcription-PCR (RT-PCR) to screen the sera and tissues of muskrats (Ondatra zibethica) caught in the northwest of Brandenburg and in the northeast of Saxony-Anhalt, Germany, for hantavirus infection. Kidney and/or lung tissue from 6 (3.1%, CI = 1.1-6.5%) out of 197 muskrats were found to be positive for genomic sequences of hantavirus by RT-PCR. We could also demonstrate that 14 (5%, CI = 2.9-8.7%) out of 266 muskrat's sera available for testing contained hantavirus-specific antibodies in IFA. Thus, a total of 8% of the investigated muskrat population was found to be positive for hantavirus infection by RT-PCR and IFA. None of the animals was found positive in both tests. Further analysis of the RT-PCR amplified fragments by genomic sequencing revealed sequences mostly related to the puumala (PUU) S segment sequence of the Hällnäs B1 hantavirus strain (97-99% similarity). Our data therefore demonstrate that Ondatra zibethicus serves as an additional reservoir for puumala-like hantavirus strains in Europe. The epidemiological implications of this finding for hantavirus infection in Europe and elsewhere are discussed.


Orthodontic treatment in patient with idiopathic root resorption: a case report.
Multiple idiopathic external root resorption is a rare pathological condition usually detected as an incidental radiographic finding. External root resorption of permanent teeth is a multifactorial process related to several local and systemic factors. If an etiological factor cannot be identified for root resorption, the term "idiopathic" is applied. This report presents a case of multiple idiopathic apical root resorption. The condition was found in a young female patient seeking orthodontic treatment due to malocclusion. This kind of resorption starts apically and progresses coronally, causing a gradual shortening and rounding of the remaining root. Patients with this condition are not the ideal candidates for orthodontic treatment; however, the aim of this report is to describe an unusual case of idiopathic root resorption involving the entire dentition, and to present the orthodontic treatment of this patient. It describes the progress and completion of orthodontic therapy with satisfactory end results.


Mapping the Gene Expression Spectrum of Mediator Subunits in Response to Viroid Infection in Plants.
The mediator (MED) represents a large, conserved, multi-subunit protein complex that regulates gene expression through interactions with RNA polymerase II and enhancer-bound transcription factors. Expanding research accomplishments suggest the predominant role of plant MED subunits in the regulation of various physiological and developmental processes, including the biotic stress response against bacterial and fungal pathogens. However, the involvement of MED subunits in virus/viroid pathogenesis remains elusive. In this study, we investigated for the first time the gene expression modulation of selected MED subunits in response to five viroid species (Apple fruit crinkle viroid (AFCVd), Citrus bark cracking viroid (CBCVd), Hop latent viroid (HLVd), Hop stunt viroid (HSVd), and Potato spindle tuber viroid (PSTVd)) in two model plant species (Nicotiana tabacum and N. benthamiana) and a commercially important hop (Humulus lupulus) cultivar. Our results showed a differential expression pattern of MED subunits in response to a viroid infection. The individual plant MED subunits displayed a differential and tailored expression pattern in response to different viroid species, suggesting that the MED expression is viroid- and plant species-dependent. The explicit evidence obtained from our results warrants further investigation into the association of the MED subunit with symptom development. Together, we provide a comprehensive portrait of MED subunit expression in response to viroid infection and a plausible involvement of MED subunits in fine-tuning transcriptional reprogramming in response to viroid infection, suggesting them as a potential candidate for rewiring the defense response network in plants against pathogens.


A-296G variant of THBS1 gene (rs1478605) is associated with a lower frequency of stroke in a Brazilian population with sickle cell anemia.
Stroke is a devastating clinical outcome that significantly contributes to the morbidity and mortality of sickle cell anemia (SCA) patients. Despite its advantages in predicting stroke risk, transcranial Doppler screening has limitations that restrict its applicability, highlighting the need for emerging prognostic tools. Thrombospondin-1 plays a crucial role in endothelial injury, platelet adhesion, and nitric oxide metabolism and may be implicated in stroke pathophysiology. Here, we aimed to evaluate the association of THBS1 genetic variations with the occurrence of stroke in SCA patients MATERIALS AND METHODS: By real-time PCR, 512 SCA patients were fully genotyped for THBS1 A-296G (rs1478605) polymorphism RESULTS: THBS1 GG genotype was associated with a lower risk for stroke occurrence [odds ratio (OR): 0.30; 95% confidence interval (CI): 0.11-0.78; P = 0.011], although these findings were not consistent with multivariate logistic regression analysis (OR: 0.73, 95% CI: 0.12 - 4.37; P = 0.736). In agreement, the cumulative incidence of stroke for patients with AG/AA genotypes was higher when compared to the GG genotype (P = 0.018). However, the association was not maintained in the multivariate proportional hazards model (hazard ratio: 0.67, 95% CI: 0.12-3.61; P = 0.643) CONCLUSIONS: In summary, the present study shows that the THBS1 A-296G (rs1478605) polymorphism may be a potential modifier for stroke in SCA.


delta 9-tetrahydrocannabinol in clinical oncology.
After anecdotal reports of marijuana's providing antiemetic activity in cancer chemotherapy patients refractory to standard agents, orally administered delta 9-tetrahydrocannabinol (THC) was formally studied by a number of investigators. In six of seven well-controlled studies, orally administered THC was a superior antiemetic agent compared with control agents. The THC toxic effects are notable but manageable. Patients rarely require hospitalization after the development of THC-induced dysphorias. However, serious toxic effects are uncommon and the most frequently noted effects are somnolence, conjunctivitis, and tachycardias. Because certain subgroups of patients are more prone to have toxicities develop, careful selection of the candidates to receive this agent is mandatory. Overall, the benefits of orally administered THC use represent a major advance in antiemetic therapy.


Factors influencing completion of multi-dose vaccine schedules in adolescents: a systematic review.
Completion of multiple dose vaccine schedules is crucial to ensure a protective immune response, and maximise vaccine cost-effectiveness. While barriers and facilitators to vaccine uptake have recently been reviewed, there is no comprehensive review of factors influencing subsequent adherence or completion, which is key to achieving vaccine effectiveness. This study identifies and summarises the literature on factors affecting completion of multi-dose vaccine schedules by adolescents. Ten online databases and four websites were searched (February 2014). Studies with analysis of factors predicting completion of multi-dose vaccines were included. Study participants within 9-19 years of age were included in the review. The defined outcome was completion of the vaccine series within 1 year among those who received the first dose. Overall, 6159 abstracts were screened, and 502 full texts were reviewed. Sixty one studies were eligible for this review. All except two were set in high-income countries. Included studies evaluated human papillomavirus vaccine, hepatitis A, hepatitis B, and varicella vaccines. Reported vaccine completion rates, among those who initiated vaccination, ranged from 27% to over 90%. Minority racial or ethnic groups and inadequate health insurance coverage were risk factors for low completion, irrespective of initiation rates. Parental healthcare seeking behaviour was positively associated with completion. Vaccine delivery in schools was associated with higher completion than delivery in the community or health facilities. Gender, prior healthcare use and socio-economic status rarely remained significant risks or protective factors in multivariate analysis. Almost all studies investigating factors affecting completion have been carried out in developed countries and investigate a limited range of variables. Increased understanding of barriers to completion in adolescents will be invaluable to future new vaccine introductions and the further development of an adolescent health platform. PROSPERO reg# CRD42014006765.


Do smokers' harm perceptions of cigarillos differ by modified use of the tobacco product? Findings from waves 3 and 4 of the PATH study.
The harm perceptions of individuals who smoke either blunts or the Black & Mild (B&M) brand, which is often "freaked," have seldom been investigated. Since these practices could affect users' perceived health risks of the cigarillo, this study was intended to compare such risks among cigarillo users by modified use of the tobacco product. Adult cigarillo and blunt smokers were selected from the Population Assessment of Tobacco and Health Study for cross-sectional (Wave 4; n = 3,331) and longitudinal (Waves 3-4; n = 1,898) analyses of predictors of general and relative harm perceptions of cigarillos. Ordinal and multinomial logistic regression methods were employed for testing whether adjusted odds of perceiving cigarillo harms were greater in blunt versus cigarillo smokers. In a separate model (n = 1,258), preference for B&M cigarillos was examined as a correlate of harm perception due to the perceived health benefits of removing the inner tobacco liner. Cross-sectional estimates indicated that blunt smokers, mixed cigarillo/blunt smokers, and those who preferred B&M brand perceived significantly more risk than conventional cigarillo smokers. Longitudinal estimates indicated that among those who underwent a transition in use, former blunt and former cigarillo smokers had significantly greater odds of reporting an increase in perceived harm compared to new users. The change in blunt smokers' harm perceptions upon transitioning in blunt use suggests acknowledgment of the harm of using cigarillos in some form. Given their high perceived risk of cigarillos, blunt smokers might be receptive to replacing the tobacco product with a nontobacco wrap. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


[Surgical treatment of patients with purulent cholangitis in cholelithiasis].
Results of treatment of 89 patients with cholelithiasis complicated by obstructive jaundice and purulent cholangitis using the minimally invasive technologies are analyzed. The advantages of two-stages surgical treatment of these patients are demonstrated. The decompression of biliary tract are performed as the first stage, radical operations by laparoscopy or minilaparotomy--as the second stage. This method permits to refuse the large and traumatic operations and to improve significantly the nearest and long-term results of treatment.


A recurrent 14q32.2 microdeletion mediated by expanded TGG repeats.
Nearly all recurrent microdeletion/duplication syndromes described to date are characterized by the presence of flanking low copy repeats that act as substrates for non-allelic homologous recombination (NAHR) leading to the loss, gain or disruption of dosage sensitive genes. We describe an identical 1.11 Mb heterozygous deletion of 14q32.2 including the DLK1/GTL2 imprinted gene cluster in two unrelated patients. In both patients, the deleted chromosome 14 was of paternal origin, and consistent with this both exhibit clinical features compatible with uniparental disomy (UPD) (14)mat. Using a high-resolution oligonucleotide array, we mapped the breakpoints of this recurrent deletion to large flanking (TGG)(n) tandem repeats, each approximately 500 bp in size and sharing > or =88% homology. These expanded (TGG)(n) motifs share features with known fragile sites and are predicted to form strong guanine quadruplex secondary structures. We suggest that this recurrent deletion is mediated either by NAHR between the TGG repeats, or alternatively results from their inherent instability and/or strong secondary structure. Our results define a recurrent microdeletion of the 14q32.2 imprinted gene cluster mediated by flanking (TGG)(n) repeats, identifying a novel mechanism of recurrent genomic rearrangement. Our observation that expanded repeats can act as catalysts for genomic rearrangement extends the role of triplet repeats in human disease, raising the possibility that similar repeat structures may act as substrates for pathogenic rearrangements genome-wide.


Protein-encapsulated gold cluster aggregates: the case of lysozyme.
We report the evolution and confinement of atomically precise and luminescent gold clusters in a small protein, lysozyme (Lyz) using detailed mass spectrometric (MS) and other spectroscopic investigations. A maximum of 12 Au(0) species could be bound to a single Lyz molecule irrespective of the molar ratio of Lyz : Au(3+) used for cluster growth. The cluster-encapsulated protein also forms aggregates similar to the parent protein. Time dependent studies reveal the emergence of free protein and the redistribution of detached Au atoms, at specific Lyz to Au(3+) molar ratios, as a function of incubation time, proposing inter-protein metal ion transfer. The results are in agreement with the studies of inter-protein metal transfer during cluster growth in similar systems. We believe that this study provides new insights into the growth of clusters in smaller proteins.


Gallium nitride micro-light-emitting diode structured light sources for multi-modal optical wireless communications systems.
Gallium nitride-based light-emitting diodes (LEDs) have revolutionized the lighting industry with their efficient generation of blue and green light. While broad-area (square millimetre) devices have become the dominant LED lighting technology, fabricating LEDs into micro-scale pixels (micro-LEDs) yields further advantages for optical wireless communications (OWC), and for the development of smart-lighting applications such as tracking and imaging. The smaller active areas of micro-LEDs result in high current density operation, providing high modulation bandwidths and increased optical power density. Fabricating micro-LEDs in array formats allows device layouts to be tailored for target applications and provides additional degrees of freedom for OWC systems. Temporal and spatial control is crucial to use the full potential of these micro-scale sources, and is achieved by bonding arrays to pitch-matched complementary metal-oxide-semiconductor control electronics. These compact, integrated chips operate as digital-to-light converters, providing optical signals from digital inputs. Applying the devices as projection systems allows structured light patterns to be used for tracking and self-location, while simultaneously providing space-division multiple access communication links. The high-speed nature of micro-LED array devices, combined with spatial and temporal control, allows many modes of operation for OWC providing complex functionality with chip-scale devices. This article is part of the theme issue 'Optical wireless communication'.


A multicentre analysis of abiraterone acetate in Canadian patients with metastatic castration-resistant prostate cancer.
The COU-AA-301 trial showed that abiraterone acetate (abiraterone), an oral cytochrome p450 CYP17 inhibitor, improved survival for men with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel. To better understand the non-clinical trial experience with abiraterone, we undertook a multicentre retrospective analysis of Canadian mCRPC patients treated with abiraterone. Consecutive patients with mCRPC who received abiraterone post-docetaxel were identified using centralized pharmacy records. These patients came from 5 Canadian tertiary cancer centres. Patients who received abiraterone for approved indications were included. Demographics, prognostic factors, treatment outcomes and adverse events were abstracted. We included 187 patients who initiated abiraterone between January 2011 and June 2012. The median age at diagnosis and abiraterone start was 65 and 73 years, respectively. Seventy-three (39%) patients had metastatic disease at diagnosis. The Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 and 3 was noted in 17, 96, 39 and 8 patients, respectively. The median prostate-specific antigen (PSA) at abiraterone start was 132, with a median PSA doubling time of 2.8 months. The median follow-up of patients still on active follow-up was 13 months. The proportion of patients achieving a ≥50% PSA reduction was 64/177 (36%). PSA progression-free survival was 3.5 months (95% confidence interval [CI], 3.0, 4.0). Median overall survival from start of abiraterone was 11 months (95% CI, 8.0, 13) and 38 months (95% CI, 31, 41) from date of mCRPC. Anemia and fatigue were the most commonly reported adverse events. This study carries the inherent limitations of a retrospective chart review. The outcomes in this series of men treated with abiraterone in a non-trial setting were expected, considering previous clinical trials. Our results, therefore, support the generalizability of the COU-AA-301 study results.


Information needs about medication according to patients discharged from a general hospital.
Medication regimens change during hospital admission, and these discrepancies can lead to an increased risk of patient harm after hospital discharge. Information about medication according to the patient's needs may contribute to patient safety by improvement of knowledge and adherence. The goal of this study is to explore the patient's needs on information about medication at hospital discharge. Qualitative, semi-structured interviews were performed with 31 patients from the pulmonology, internal medicine and cardiology departments who were discharged with at least one prescribed drug from the hospital to primary care in the Netherlands. Interviews were analysed with content analysis. Patients had variable needs concerning information about discharge medication. Most patients wanted to receive basic information about their medication, alternatives for the prescribed medication and side effects. Some patients did not need basic information or explicitly mentioned that information about side effects would negatively influence their attitude towards medication. Patients preferred a combination of oral instructions and written information. Information at discharge should be tailored to the individual needs of the patient. In the process of providing patient information at hospital discharge, the preference of some patients for non-disclosure of information should be recognised.


Withholding the Heimlich Maneuver: Ethical Considerations.
The topic of withholding the Heimlich maneuver as part of a do-not-attempt-to-resuscitate (DNAR) order or an advance directive has not been widely discussed in the clinical ethics literature. This discussion addresses a request by family members to withhold the Heimlich maneuver from a patient in a long-term care facility. A request to forgo the Heimlich maneuver seems to have prima facie categorical similarities to justifications for withholding life-saving treatments such as cardiopulmonary resuscitation (CPR). Further examination reveals significant distinctions. Such distinctions call into question the ethical appropriateness of including the Heimlich maneuver among interventions to be withheld as part of end-of-life care planning, and encourages a broader discussion of an increasingly uncritical deference to autonomy in end-of-life decision making. Most notably, the Heimlich maneuver is the only intervention known to effectively relieve the distressing symptoms of accidental choking. The Heimlich maneuver serves a palliative function and is the standard of care for accidental choking. The Heimlich maneuver should not be conflated with other life-prolonging interventions that may be withheld as part of end-of-life care planning.


Differential nuclear protein binding to 5-azacytosine-containing DNA as a potential mechanism for 5-aza-2'-deoxycytidine resistance.
A clonal cell line (56-42) that was stably and exclusively resistant to the toxic effects of the antileukemic agent 5-aza-2'-deoxycytidine (5-aza-CdR) was derived from C3H 10T1/2 C18 cells after multiple treatments with 5-aza-CdR. The 50% lethal dose of 5-aza-CdR for these cells was 1.3 microM, which was 15-fold greater than that for the parental cells. Cell line 56-42 was slightly cross-resistant to the ribo-analog 5-azacytidine, but was sensitive to the nucleoside analog 1-beta-D-arabinofuranosylcytosine and to colcemid. Both parental and resistant cell lines incorporated equimolar amounts of 5-aza-CdR into DNA. Resistance was therefore not due to decreased activation, increased detoxification, or reduced incorporation of the drug. The overall level of cytosine methylation in the resistant clone was 80% lower than the level in the sensitive cells. Therefore, the potential number of hemimethylated sites created by the incorporation of equivalent amounts of 5-aza-CdR into the DNA of the two cell types was much greater in the sensitive cells. Furthermore, 5-azacytosine-substituted DNA from the sensitive cells bound 100% more nuclear protein in the form of highly stable complexes. The incorporation of 5-aza-CdR opposite methylated cytosine residues in DNA of the sensitive cells thus resulted in increased nuclear protein binding at hemimethylated sites. This relative increase in tight-binding protein complexes was shown to occur in living cells and may well disrupt replication and transcription and instigate cell death. The differential binding of proteins to hypomethylated, azacytosine-containing DNA may thus mediate a novel mechanism of drug resistance.


Protein-rich diet attenuates cyclosporin A-induced renal tubular damage in rats.
The objective of the present study was to look at the effect of a protein-rich diet on cyclosporine A (CsA)-induced acute nephrotoxicity in rodents using markers of tubular damage. Female Sprague-Dawley rats were conditioned to either a standard or a casein-rich diet for 2 weeks. Then, they were given CsA intraperitoneally (25 mg/kg/24 h or an equivalent volume of vehicle (Cremophor EL; Sigma Chemical Co, St. Louis, MO) for 7 days at 7 AM. During CsA treatment, bodyweight, caloric consumption, water intake, and urine output were not significantly different in animals fed with the standard Rat Chow and those on the high-protein feeding. On days 1 and 7, the 24-hour urine excretion of N-acetyl-beta-d-glucosaminidase (NAG) and beta-galactosidase (beta-GAL) were significantly (P < .001) lower in CsA-treated rats on the high-protein diet than in those on the standard Rat Chow. After 7 days of treatment with CsA, no significant difference in the renal function level was found between rats fed with the standard or the casein-rich diet. The post-necrotic cellular regeneration in renal cortex was significantly lower (p<0.001) in CsA-treated rats on the high-protein than on the standard diet. In CsA-treated rats on the standard diet, immunogold labeling showed a massive and specific concentration of the drug into lysosomes of proximal tubular cells. Contrastingly, no gold particle was found over the lysosomes of animals given the rich-protein feeding. In our current experimental conditions, a protective effect of high-casein diet against CsA-induced proximal tubular damage was observed in Sprague-Dawley rats.


Cerebral abscess in children.
We reviewed 94 consecutive episodes of pyogenic brain abscess seen at Children's Hospital Medical Center, Boston, between 1945 and 1980. After 1970, the mortality as reduced from 36% to 14%. Predisposing factors included congenital heart disease, otitic and sinus infections, closed head injuries, and cystic fibrosis. There were seven patients younger than 5 months of age. In one patient with Fallot's tetralogy, an abscess recurred at the site of retained thorium dioxide (Thorotrast) after an 11-year interval. The continuing substantial mortality is attributed to the presence of coma at the time of treatment, hemorrhagic complications of tapping abscesses, and the location of abscesses in deep brain structures. The early detection and successful treatment of brain abscesses in children remains a clinical challenge.


Alpha 1-adrenergic and H1-histamine receptor control of intracellular Ca2+ in a muscle cell line: the influence of prior agonist exposure on receptor responsiveness.
Activation of alpha 1-adrenergic receptors in BC3H-1 muscle cells has been shown previously to mobilize intracellular Ca2+, which can be monitored as enhanced 45Ca2+ unidirectional efflux. We report here that histamine also stimulates 45Ca2+ efflux in these cells (Kact = 5.50 microM, nH = 0.94 +/- 0.04), reflecting mobilization of intracellular Ca2+ from a source similar to that accessed by alpha 1-adrenergic receptor activation. In addition, histamine stimulates substantial transmembrane 45Ca2+ influx into BC3H-1 cells. The actions of histamine are inhibited by the H1-selective antagonist, diphenhydramine (IC50 = 1.01 microM), but are unaffected by the H2-selective antagonist, cimetidine (1 nM-10 microM) indicating that histamine regulates cellular Ca2+ via a functional H1 receptor. The presence of independent receptor types which mobilize Ca2+ originating from common intracellular stores has been exploited in order to evaluate the determinants of receptor responsiveness following prior agonist exposure. After exposure with 45Ca2+ to achieve radioisotopic equilibrium, 30 min incubation with increasing concentrations of norepinephrine reduces to similar extents (30-40%) the unidirectional 45Ca2+ efflux responses to subsequent challenges by maximally effective concentrations of norepinephrine or histamine. The decrement in response following norepinephrine exposure appears to reflect an altered disposition of agonist-sensitive intracellular Ca2+, whereas the concentration dependence for alpha 1-adrenergic receptor activation remains unchanged. Prior exposure of cells to increasing concentrations of histamine also reduces the efflux response to norepinephrine challenge (approximately 30% decrease), whereas the response to subsequent histamine challenge is specifically and completely abolished. The loss of histamine responsiveness is accompanied by a marked shift in the concentration dependence for histamine receptor activation toward higher histamine concentrations. These results indicate that substantial alpha 1-receptor responsiveness is maintained following agonist exposure and that the observed reduction in response occurs distally to the receptor itself at some point common to alpha 1- and H1-receptor-effector coupling. By contrast, the H1-histamine receptor exhibits refractoriness, indicative of agonist-induced receptor desensitization.


Plasmodium falciparum Calcium-Dependent Protein Kinase 2 Is Critical for Male Gametocyte Exflagellation but Not Essential for Asexual Proliferation.
Drug development efforts have focused mostly on the asexual blood stages of the malaria parasite Plasmodium falciparum Except for primaquine, which has its own limitations, there are no available drugs that target the transmission of the parasite to mosquitoes. Therefore, there is a need to validate new parasite proteins that can be targeted for blocking transmission. P. falciparum calcium-dependent protein kinases (PfCDPKs) play critical roles at various stages of the parasite life cycle and, importantly, are absent in the human host. These features mark them as attractive drug targets. In this study, using CRISPR/Cas9 we successfully knocked out PfCDPK2 from blood-stage parasites, which was previously thought to be an indispensable protein. The growth rate of the PfCDPK2 knockout (KO) parasites was similar to that of wild-type parasites, confirming that PfCDPK2 function is not essential for the asexual proliferation of the parasite in vitro The mature male and female gametocytes of PfCDPK2 KO parasites become round after induction. However, they fail to infect female Anopheles stephensi mosquitoes due to a defect(s) in male gametocyte exflagellation and possibly in female gametes.IMPORTANCE Despite reductions in the number of deaths it causes, malaria continues to be a leading infectious disease of the developing world. For effective control and elimination of malaria, multiple stages of the parasite need to be targeted. One such stage includes the transmission of the parasite to mosquitoes. Here, we demonstrate the successful knockout of PfCDPK2, which was previously thought to be indispensable for parasite growth in red blood cells. The PfCDPK2 KO parasites are incapable of establishing an infection in mosquitoes. Therefore, our study suggests that targeting PfCDPK2 may be a good strategy to control malaria transmission in countries with high transmission. Moreover, molecular understanding of the signaling pathway of PfCDPK2 may provide additional targets for malaria control.


The effects of 2 µg and 4 µg doses of dexmedetomidine in combination with intrathecal hyperbaric bupivacaine on spinal anesthesia and its postoperative analgesic characteristics.
To compare the postoperative analgesic characteristics and side effects of two different doses of intrathecal dexmedetomidine in combination with hyperbaric bupivacaine, and to evaluate the effects of these combinations on spinal anesthesia. After obtaining approval from the local ethics committee, 60 male patients who were undergoing inguinal surgery and were classified as American Society of Anesthesiologists physical status class I were included in the study. The present study was conducted in 2003 in a military hospital with a capacity of 100 beds. The patients were randomly assigned to three groups of 20 patients: group 1, 0.5 mL saline added to 3 mL (15 mg) hyperbaric bupivacaine; and groups 2 and 3, 2 µg dexmedetomidine and 4 µg dexmedetomidine added to 3 mL (15 mg) hyperbaric bupivacaine, respectively. Medications were administered by intrathecal injection in a total volume of 3.5 mL. The postoperative analgesic characteristics, effects on spinal anesthesia and side effects were recorded. Demographic characteristics were similar among the groups. The mean (±SD) time to onset of pain was 220.75±112.7 min in group 1, 371.5±223.5 min in group 2 and 1042.50±366.78 min in group 3. Time to first pain sensation in group 3 was significantly longer than that in groups 1 and 2 (P<0.001). Two different doses of dexmedetomidine, an α2-adrenoceptor agonist with analgesic effects, resulted in an increased duration of analgesia and efficacy, decreased postoperative analgesic use and was associated with no notable adverse effects.


EPR characterization of photosystem II from different domains of the thylakoid membrane.
We report electron paramagnetic resonance (EPR) studies on photosystem II (PSII) from higher plants in five different domains of the thylakoid membrane prepared by sonication and two-phase partitioning. The domains studied were the grana core, the entire grana stack, the grana margins, the stroma lamellae and the purified stromal fraction, Y100. The electron transport properties of both donor and acceptor sides of PSII such as oxygen evolution, cofactors Y D, Q A, the CaMn 4-cluster, and Cytb 559 were investigated. The PSII content was estimated on the basis of oxidized Y D and Q A (-) Fe (2+) signal from the acceptor side vs Chl content (100% in the grana core fraction). It was found to be about 82% in the grana, 59% in the margins, 35% in the stroma and 15% in the Y100 fraction. The most active PSII centers were found in the granal fractions as was estimated from the rates of electron transfer and the S 2 state multiline EPR signal. In the margin and stroma fractions the multiline signal was smaller (40 and 33%, respectively). The S 2 state multiline could not be induced in the Y100 fraction. In addition, the oxidized LP Cytb 559 prevailed in the stromal fractions while the HP form dominated in the grana core. The margins and entire grana fractions have Cytb 559 in both potential forms. These data together with previous analyses indicate that the sequence of activation of the PSII properties can be represented as: PSII content > oxygen evolution > reduced Cytb 559 > dimerization of PSII centers in all fractions of the thylakoid membrane with the gradual increase from stromal fractions via margin to the grana core fraction. The results further support the existence of a PSII activity gradient which reflects lateral movement and photoactivation of PSII centers in the thylakoid membrane. The possible role of the PSII redox components in this process is discussed.


Stomach Cancer Following Hodgkin Lymphoma, Testicular Cancer and Cervical Cancer: A Pooled Analysis of Three International Studies with a Focus on Radiation Effects.
To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.


[Application of the methods of the mathematical theory of experiments to the development of multicomponent radioprotective preparations].
A study was made of the possibility of using a mathematical theory of experiment in developing effective many-component radioprotective preparations. The preparations composed of cystamine or S-(omega-aminopropyl)-beta-aminoethyl thiophosphate, as the basis, and mexamine, ethyron and gutimine were used as an example to prove the adequacy of such an approach in solving the problems of optimization of composing the radioprotective complexes according to their efficiency and toxicity.


Tyrosine replacement in P-selectin glycoprotein ligand-1 affects distinct kinetic and mechanical properties of bonds with P- and L-selectin.
Selectins are adhesion molecules that initiate tethering and rolling of leukocytes on the vessel wall. Rolling requires rapid formation and breakage of selectin-ligand bonds that must have mechanical strength to resist premature dissociation by the forces applied in shear flow. P- and L-selectin bind to the N-terminal region of P-selectin glycoprotein ligand-1 (PSGL-1), a mucin on leukocytes. To define determinants on PSGL-1 that contribute to the kinetic and mechanical properties of bonds with selectins, we compared rolling of transfected preB cells expressing P- or L-selectin on transfected cell monolayers expressing wild-type PSGL-1 or PSGL-1 constructs with substitutions in targeted N-terminal residues. Rolling through P- or L-selectin required a Thr or Ser at a specific position on PSGL-1, the attachment site for an essential O-glycan, but required only one of three nearby Tyr residues, which are sites for Tyr-SO(3) formation. The adhesive strengths and numbers of cells rolling through P- or L-selectin were similar on wild-type PSGL-1 and on each of the three PSGL-1 constructs containing only a single Tyr. However, the cells rolled more irregularly on the single-Tyr forms of PSGL-1. Analysis of the lifetimes of transient tethers on limiting densities of PSGL-1 revealed that L-selectin dissociated faster from single-Tyr than wild-type PSGL-1 at all shears examined. In sharp contrast, P-selectin dissociated faster from single-Tyr than wild-type PSGL-1 at higher shear but not at lower shear. Thus, tyrosine replacements in PSGL-1 affect distinct kinetic and mechanical properties of bonds with P- and L-selectin.


HHV-8-positive and EBV-positive intravascular lymphoma: an unusual presentation of extracavitary primary effusion lymphoma.
Intravascular lymphomas are rare and aggressive hematolymphoid tumors. Here, we describe a human herpesvirus type-8 (HHV-8)/Kaposi sarcoma-associated herpesvirus-positive and Epstein-Barr virus (EBV)-positive intravascular lymphoma. The patient was a 59-year-old human immunodeficiency virus-positive man who presented with diarrhea, abdominal pain, fevers, night sweats, and weight loss. Radiographic studies of the abdomen and pelvis revealed numerous subcentimeter nodules within the subcutaneous fat that lacked connection to the skin. An excisional biopsy demonstrated large atypical cells within vessels in the deep subcutaneous fat, and many of the vessels contained extensive organizing thrombi. The atypical cells lacked strong expression of most B-cell markers but were positive for MUM-1 and showed partial expression of several T-cell markers. An immunohistochemical stain for HHV-8 and an in situ hybridization for EBV were both positive in the neoplastic cells. The disease had a rapidly progressive and fatal course. This lymphoma appears to represent an entirely intravascular form of primary effusion lymphoma and highlights the propensity for HHV-8 and EBV-positive lymphoid neoplasms to show aberrant expression of T-cell markers, illustrates the utility of skin biopsies for the diagnosis of intravascular lymphoma, and suggests that biopsies to evaluate for intravascular lymphoma should be relatively deep and include subcutaneous fat.


Clonal non-malignant hematological disorders: unraveling molecular pathogenic mechanisms to develop novel targeted therapeutics.
Clonal non-malignant hematological disorders are a heterogeneous group of diseases that are particularly challenging for hematologists. Indeed, most obvious and frequent hematological diseases include a broad spectrum of malignancies, such as leukemias, lymphomas, myeloma, and other myeloproliferative or lymphoproliferative disorders. In recent years, all these diseases have been categorized by the WHO according to a novel classification of myeloid and lymphoid malignancies, which takes in account the outstanding progress in our understanding of molecular defects underlying hematological malignancies. Regardless of a number of novel technologies, hematologists continue to deal daily with conditions where a clear diagnosis of a malignancy is missing: this is the case of several clonal hematological disorders, which are considered bona fide non-malignant. Some myelodysplastic syndromes, chronic T and NK disorders of granular lymphocytes, myelofibrosis, monoclonal gammopathies, monoclonal B-cel lymphocytosis, mastocytosis and paroxysmal nocturnal hemoglobinuria are paradigmatic examples of how clonal disorders are clearly different from cancers, even if they may share with hematological malignancies similar molecular, genetic, epigenetic and immunological processes. Indeed, it is not entirely clear whether in individual conditions such pathogenic mechanisms may represent initial step(s) of malignant transformation, making a bridge between these clonal non-malignant disorders and typical hematological cancers. Some of these non-malignant disorders imply specific pathogenic mechanisms and/or clinical course, and so they have been definitely established with their own biological and clinical identity. However, the obvious question whether some of these clonal non-malignant hematological diseases form some a kind of disease-continuum with their corresponding malignant counterpart is still to be answered.


Glutamine is highly effective in preventing in vivo cobalt-induced oxidative stress in rat liver.
To evaluate the in vivo effect of glutamine on cobalt-generated oxidative stress and (HO-1) induction in rat liver. Fasted female Wistar rats received a single injection of cobalt chloride (375 micromol/kg body weight) and then were killed at different times. Lipid peroxidation and soluble and enzymatic antioxidant defense system (reduced glutathione (GSH), catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD)) were measured in liver homogenates. Ferritin and ferritin iron contents as well as heme oxygenase-1 (HO-1) activity and expression were also determined. The antioxidant properties of glutamine (Gln) were also evaluated. Cobalt chloride increased lipid peroxidation (50% over control values) 1 h after treatment. GSH reached a minimum at 3 h (40%) increasing thereafter. Twelve hours after CoCl2 injection, the antioxidant enzymes CAT, GSH-Px and SOD also diminished by about 30%. Heme oxygenase-1 induction was observed 6 h after treatment reaching a maximum value of 14-fold over the controls, 12 h after cobalt treatment. A 1.7-fold increase in ferritin and ferritin-bound iron 24 h after treatment were also obtained. Administration of glutamine (300 mg/kg body weight) by gavage 24 h before CoCl2 treatment entirely prevented the increase in thiobarbituric acid reactive substances (TBARS) content, the decrease in GSH levels, and partially reverted heme oxygenase-1 induction. These results suggested that a natural product such as glutamine prevents glutathione depletion and consequently heme oxygenase induction.


Victimization and substance use among adolescents in residential child care.
Adolescents in Residential Child Care (RCC) report high levels of victimization. This has been linked to mental health problems and a higher risk of substance use and substance use problems. The present study aimed to evaluate the specific impact of different forms of victimization on alcohol and cannabis use problems among adolescents in RCC, attending to sex differences. 321 adolescents from 38 residential therapeutic care facilities in Spain participated in the study. Thirty-six different forms of victimization were evaluated, as well as alcohol and cannabis use problems. Impact of polyvictimization and specific forms of victimization on alcohol and cannabis use problems and disorders were calculated using Analysis of Variance (ANOVA) and logistic regression models. Girls in RCC reported significantly more experiences of victimization. Polyvictimization was associated with alcohol use problems but not cannabis use problems. Property, domestic and community victimization showed the highest predictive role regarding alcohol and cannabis use disorders, with significant interactions with sex and migrant family background. Adolescents in RCC reported considerably high levels of victimization and alcohol and cannabis use problems. In this population, property victimization, as well as indirect domestic and community victimization were predictors of further substance use problems, with girls being particularly sensitive to victimization. Migrant family backgrounds can also have an influence on the impact of some victimization forms on substance use. Victimization associated to high-risk environments and families could contribute to explain the high levels of substance use problems in this population.