Cannabis alters epigenetic integrity and endocannabinoid signalling in the human follicular niche.
Do phytocannabinoids (PCs) affect follicular endocannabinoid signalling and the epigenome in the surrounding granulosa cells (GCs)? Exposure to PCs increases the expression of endocannabinoid receptors and reduces DNA methylation enzyme expression and global DNA methylation in naïve GCs. Cannabis plant derivatives, known as PCs, are used for medicinal and recreational purposes. The main PC, tetrahydrocannabinol (THC), is the third most commonly used substance by women of childbearing age, hence knowledge of the effect it has on reproduction is of utmost importance. THC exerts its effects via receptors of the endocannabinoid system (ECS) and can interfere with folliculogenesis, oocyte development and ovulation. Endocannabinoids have been measured in follicular fluid (FF) obtained during oocyte retrieval and are implicated in controlling folliculogenesis. It has been established that in the placenta, PCs disrupt endocannabinoid homeostasis via impairment of the synthetic and degrading enzymes, leading to a net increase of endocannabinoid levels. Finally, previous studies have shown that THC alters methylation and histone modifications in sperm, brain and blood cells. This study included an in vivo cohort assessment of cannabis exposure and its effects on the follicle and in vitro assays conducted to validate the in vivo findings and to explore possible mechanisms of action. A total of 318 FF samples, from 261 patients undergoing IVF treatment at a private fertility clinic who consented for biobanking biological waste material between January 2018 and July 2019, were included in this study. Concentrations of PCs and endocannabinoids were assessed in FF by liquid chromatography-mass spectrometry (LC-MS/MS). Exposure to PCs was determined based on these measured levels. Levels of both endocannabinoid receptors (CB1R, CB2R) and the de novo DNA methylating enzyme, DNMT3b, in GCs were assessed by flow cytometry both in vitro and in vivo and global DNA methylation was assessed in vitro by ELISA. In vivo effects were assessed by comparing samples positive for at least one PC, with samples negative for all measured PCs. In vitro effects were determined in naive GCs, obtained concurrently with FF samples that had tested negative for all PCs. These GCs were treated with different combinations of the main three PCs. Overall, 17 patients (6.4%) were positive for cannabis consumption. Furthermore, the prevalence of cannabis positivity in the FF increased from 4% of the tested samples that were collected prior to national legalisation in October 2018 to 12% of those collected following legalisation. Of note, 59% of patients who tested positive for PCs (10 of 17) reported previous or ongoing exposure to cannabis upon their initial intake. Endocannabinoid levels were not affected by the presence of PCs. CB2R was more prevalent than CB1R in GCs and its expression increased following acute and chronic in vitro exposure to PCs. The expression of DNMT3b and global methylation decreased following exposure, suggesting that cannabis may affect the epigenome in the follicular niche. The acute changes were sustained throughout chronic treatment. N/A. Our study is limited by lack of details regarding mode, frequency and timing of PC consumption. Moreover, we were not able to adequately assess the effect of PCs on immediate or long-term clinical outcomes, due to the small sample size and the lack of follow up. Future, large-scale studies should focus on assess the clinical implications of cannabis exposure, validate our findings, and determine to what extent cannabis affects the epigenome ovarian follicle and the developing oocyte. To our knowledge, this is the first study measuring PCs in FF by LC-MS/MS. We show that consuming cannabis alters the ECS in the developing follicle, and directly affects DNMT expression and global DNA methylation levels. Cannabis legalisation and use is increasing worldwide, therefore further understanding its role in female fertility and folliculogenesis is critical. All funding was provided by CReATe Fertility Centre through the reinvestment of clinical earnings. The authors declare no competing interests.


Erythrocyte factors concerned in the inhibition of ALA-D by lead.
Erythrocyte factors are concerned in the inhibition of delta-aminolaevulinic acid dehydratase (ALA-D) by lead at 20 to 100 nM concentrations. The activity of the factors in detected in Hb fractions from Sephadex G-200 gel filtration of erythrocyte supernatant. After gel filtration of erythrocyte supernatant from a lead worker, 50% of lead is found in ALA-D fractions, although the fractions recover from ALA-D inhibition. The recovered activity is reinhibited if the enzyme fraction is preincubated with Hb fraction obtained from the same chromatography. Similarly obtained enzyme from a normal subject is also inhibited when it is preincubated with normal Hb fraction and lead acetate at 20 to 100 nM concentrations. The extent of the inhibition depends on the concentrations of Hb fraction and lead acetate preincubated. Reinhibition of lead worker enzyme with normal Hb fraction may be deleted not only by heating but also by zinc or DTT as well. Hb fraction heated at 60 degrees C for 5 min is also able to induce the lead-inhibition of the activity in ALA-D fraction. Half life of the factors is 26 min at 60 degrees C and 3 min at 80 degrees C.


The introduction of DRG funding and hospital nurses' changing perceptions of their practice environment, quality of care and satisfaction: comparison of cross-sectional surveys over a 10-year period.
As other countries which have introduced diagnosis-related groups (DRGs) to pay their hospitals Germany initially expected that quality of care could deteriorate. Less discussed were potential implications for nurses, who might feel the efficiency-increasing effects of DRGs on their daily work, which in turn may lead to an actual worsening of care quality. To analyze whether the DRG implementation in German acute hospitals (as well as other changes over the 10-year period) had measurable effects on (1) the nurse work environment (including e.g. an adequate number of nursing staff to provide quality patient care), (2) quality of patient care and safety (incl. confidence into patients' ability to manage care when discharged), and (3) whether the effects from (1) and (2)--if any--impacted on the nurses themselves (satisfaction with their current job and their choice of profession as well as emotional exhaustion). Two rounds of nurse surveys with the Practice Environment Scale of the Nursing Work Index (PES-NWI), five years before DRG implementation (i.e. in 1998/1999; n=2681 from 29 hospitals) and five years after (i.e. in 2009/2010; n=1511 from 49 hospitals). The analysis utilized 15 indicators as outcomes for (1) practice environment, (2) quality of patient care and safety, as well as (3) nurses' satisfaction and emotional exhaustion. Multivariate analyses were performed for all three sets of outcomes using SPSS version 20. Aspects of the practice environment (especially adequate staffing and supportive management) worsened within the examined time span of 10 years, which as a consequence had significant negative impact on the nurse-perceived quality of care (except for patient safety, which improved). Both the aspects of the practice environment and the quality aspects impacted substantially on satisfaction and emotional exhaustion among nurses. The DRG implementation in Germany has apparently had measurable negative effects on nurses and nurse-perceived patient outcomes, however, not as distinct as often assumed.


Mutational analysis of the role of the distal histidine and glutamine residues of prostaglandin-endoperoxide synthase-2 in peroxidase catalysis, hydroperoxide reduction, and cyclooxygenase activation.
Site-directed mutants of prostaglandin-endoperoxide synthase-2 (PGHS-2) with changes in the peroxidase active site were prepared by mutagenesis, expressed in Sf-9 cells, and purified to homogeneity. The distal histidine, His193, was mutated to alanine and the distal glutamine, Gln189, was changed to asparagine, valine, and arginine. The guaiacol peroxidase activities of H193A, Q189V, and Q189R were drastically reduced to levels observed in the absence of protein; only Q189N retained wild-type PGHS-2 (wtPGHS-2) activity. The mechanism of hydroperoxide reduction by the PGHS-2 mutants was investigated using 15-hydroperoxyeicosatetraenoic acid (15-HPETE), a diagnostic probe of hydroperoxide reduction pathways. The hydroperoxide reduction activity of Q189V and Q189R was reduced to that of free Fe(III) protoporphyrin IX levels, whereas Q189N catalyzed more reduction events than wtPGHS-2. The percentage of two-electron reduction events was identical for wtPGHS-2 and Q189N. The number of hydroperoxide reductions catalyzed by H193A was reduced to approximately 60% of wtPGHS-2 activity, but the majority of products were the one-electron reduction products, 15-KETE and epoxyalcohols. Thus, mutation of the distal histidine to alanine leads to a change in the mechanism of hydroperoxide reduction. Reaction of wtPGHS-2, Q189N, and H193A with varying concentrations of 15-HPETE revealed a change in product profile that suggests that 15-HPETE can compete with the reducing substrate for oxidation by the peroxidase higher oxidation state, compound I. The ability of the PGHS-2 proteins to catalyze two-electron hydroperoxide reduction correlated with the activation of cyclooxygenase activity. The reduced ability of H193A to catalyze two-electron hydroperoxide reduction resulted in a substantial lag phase in the cyclooxygenase assay. The addition of 2-methylimidazole chemically reconstituted the two-electron hydroperoxide reduction activity of H193A and abolished the cyclooxygenase lag phase. These observations are consistent with the involvement of the two-electron oxidized peroxidase intermediate, compound I, as the mediator of the activation of the cyclooxygenase of PGHS.


An unexpected role for ion channels in brain tumor metastasis.
Over the past two decades it has become apparent that essentially all living cells express voltage-activated ion channels. While the role of ion channels for electrical signaling between excitable cells is well known, their function in non-excitable cells is somewhat enigmatic. Research on cancer cells suggests that certain ion channels, K+ channels in particular, may be involved in aberrant tumor growth and channel inhibitors often lead to growth arrest. An unsuspected role for K+ and Cl(-) channels has now been documented for primary brain tumors, glioma, where the concerted activity of these channels promotes cell invasion and the formation of brain metastasis. Specifically, Ca2+-activated K+ (BK) channels colocalize with ClC-3 Cl(-) channels to the invading processes of these tumor cells. Upon a rise in intracellular Ca2+, these channels activate and release K+ and Cl(-) ions together with obligated water causing a rapid shrinkage of the leading process. This in turn facilitates the invasion of the cell into the narrow and tortuous extracellular brain spaces. The NKCC1 cotransporter accumulates intracellular Cl(-) to unusually high concentrations, thereby establishing an outward directed gradient for Cl(-) ions. This allows glioma cells to utilize Cl(-) as an osmotically active anion during invasion. Importantly, the inhibition of Cl(-) channels retards cell volume changes, and, in turn, compromises tumor cell invasion. These findings have led to the clinical evaluation of a Cl(-) channel blocking peptide, chlorotoxin, in patients with malignant glioma. Data from this clinical trial shows remarkable tumor selectivity for chlorotoxin. The experimental therapeutic was well tolerated and is now evaluated in a multi-center phase II clinical trial. A similar role for Cl(-) and K+ channels is suspected in other metastatic cancers, and lessons learned from studies of gliomas may pave the way towards the development of novel therapeutics targeting ion channels.


Dietary (Poly)phenols and Cognitive Decline: A Systematic Review and Meta-Analysis of Observational Studies.
This study aims to systematically review observational studies investigating the relation between dietary (poly)phenol consumption and various cognitive outcomes. Embase and PubMed databases are searched from inception to April 2023 for observational studies investigating the relation between dietary (poly)phenol intake and cognitive outcomes. For quantitative analyses, random effects models, subgroup analyses, and dose-response analyses are performed. A total of 37 studies are included in the systematic review. Among (poly)phenols, a higher intake of flavonoids is associated with better cognitive function and lower odds of cognitive decline (although with some exceptions). A quantitative meta-analysis shows an overall inverse association with cognitive impairment and reduced association with the incidence of dementia or related disorders for total flavonoids (relative risk (RR) = 0.83, 95% confidence interval (CI): 0.76, 0.89), anthocyanins (RR = 0.73, 95% CI: 0.60, 0.89), flavones (RR = 0.77, 95% CI: 0.63, 0.94), flavan-3-ols (RR = 0.86, 95% CI: 0.82, 0.91), and flavonols (RR = 0.88, 95% CI: 0.80, 0.96). Data on other (poly)phenolic compounds (i.e., phenolic acids) are promising but too preliminary. Habitual inclusion of flavonoids in the diet may play a preventive role against cognitive disorders.


The PAWPER tape: A new concept tape-based device that increases the accuracy of weight estimation in children through the inclusion of a modifier based on body habitus.
Weight estimations in children, which are required when actual weight cannot be measured, are often very inaccurate because of variations in body habitus not accounted for in the estimating methodology. This study was conducted to evaluate the accuracy of the PAWPER tape, a new two-step weight-estimation tape device which employs a length-based habitus-modified weight estimation system. This was a prospective study in the Emergency Departments of two hospitals in Johannesburg, South Africa on a population of children aged from 1 month to 12 years. Each child had their weight estimated by both the Broselow tape and the PAWPER tape. These weight estimates were then compared against measured weight to determine the bias and precision of the estimation techniques. The PAWPER tape performed well, and better than the Broselow tape in every analysis performed. The mean percentage error was -3.8% vs. 0% and the root mean squared percentage error was 9.1% vs. 4.5% for the Broselow tape and PAWPER tape, respectively (p<0.0001). The Broselow tape predicted weight to within 10% of actual weight in 63.6% of children and the PAWPER tape in 89.2% (p<0.0001). The difference between the performances of the Broselow tape and PAWPER tape was most pronounced in children >20 kg, and in children above or below average weight-for-length. The PAWPER tape has been shown to be a simple and reliable method of weight estimation in children and infants. The inclusion of an appraisal of body habitus in the methodology considerably improved the accuracy of weight estimation.


The defective seed5 (des5) mutant: effects on barley seed development and HvDek1, HvCr4, and HvSal1 gene regulation.
Barley, one of the major small grain crops, is especially important in climatically demanding agricultural areas of the world, with multiple uses within food, feed, and beverage. The barley endosperm is further of special scientific interest due to its three aleurone cell layers, with the potential of bringing forward the molecular understanding of seed development and cell specification from Arabidopsis and maize. Work done in Arabidopsis and maize indicate the presence of conserved seed developmental pathways where Crinkly4 (Cr4), Defective kernel1 (Dek1), and Supernumerary aleurone layer1 (Sal1) are key players. With the use of microscopy, a comprehensive phenotypic characterization of the barley defective seed5 (des5) mutant is presented here. The analysis further extends to molecular quantification of gene expression changes in the des5 mutant by qRT-PCR. Moreover, full-length genomic sequences of the barley orthologues were generated and these were annotated as HvDek1, HvCr4, and HvSal1. The most striking results in this study are the patchy reduction in number of aleurone cells, rudimentary anticlinal aleurone cell walls, and the specific change of HvCr4 expression compared to HvDek1 and HvSal1. The data presented support the involvement of Hvdes5 in establishing aleurone cells. Finally, how these results might affect the current model of aleurone and epidermal cell identity and development is discussed with a speculation regarding a possible role of Des5 in regulating cell division/ secondary cell wall building.


Viable Options for Fertility Preservation in Breast Cancer Patients: A Focus on Latin America.
Thanks to the improved survival outcomes observed in recent years, a growing attention has been given to the quality of life issues faced by young women with breast cancer such as fertility preservation and concerns related to future pregnancies. However, several challenges remain for young women with breast cancer considering undergoing fertility preservation strategies. Further specific issues on this regard should be taken into account in Latin America, where patients and physicians face particular barriers that hinder the routine adoption of this practice. Hence, further efforts are needed to overcome these deficiencies and improve the correct referral of breast cancer patients to fertility preservation strategies. The aim of the present review is to focus on the risk of anticancer treatment-related premature ovarian failure and infertility in young breast cancer patients, to summarize the current knowledge on the available options for fertility preservation, and to discuss the safety issues of pregnancy in breast cancer survivors. Furthermore, this review aims to highlight the specific clinical challenges in this field encountered by healthcare providers and young breast cancer patients from Latin American countries.


Is Arthrodesis a Reliable Salvage Option following Two-Stage Revision for Suspected Infection in Proximal Tibial Replacements? A Multi-Institutional Study.
The aim of this multicentric retrospective study was to verify whether knee arthrodesis (KA) is a viable reconstructive option after two-stage revision for infection of proximal tibia (PT) endoprosthetic reconstruction (EPR). Sixty patients who underwent a two-stage revision were included. Definitive EPR or a KA with a modular system was performed following consideration of soft tissue and extensor mechanism conditions. Patients were evaluated with Musculoskeletal Tumor Society Score and Oxford Knee Score. Implant survival was assessed on the basis of recurrence of infection. Five patients did not receive any reconstruction after the first stage. In 14 cases, a KA was performed, and in 41, an EPR was implanted. At 5 years follow-up, reinfection rate in the KA group was lower (10 vs. 17.5% in KA and EPR groups, respectively). In reinfected patients, the KA group had a reduced rate of amputation when compared with those with EPR (50 vs. 88%). Functional evaluation did not show any significant differences between the two groups. A successful KA using a modular implant can eradicate infection and allow preservation of the limb with good function and good pain relief in after two-stage revision for an infected PT EPR.


Evolving neural networks to play checkers without relying on expert knowledge.
An experiment was conducted where neural networks compete for survival in an evolving population based on their ability to play checkers. More specifically, multilayer feedforward neural networks were used to evaluate alternative board positions and games were played using a minimax search strategy. At each generation, the extant neural networks were paired in competitions and selection was used to eliminate those that performed poorly relative to other networks. Offspring neural networks were created from the survivors using random variation of all weights and bias terms. After a series of 250 generations, the best-evolved neural network was played against human opponents in a series of 90 games on an internet website. The neural network was able to defeat two expert-level players and played to a draw against a master. The final rating of the neural network placed it in the "Class A" category using a standard rating system. Of particular importance in the design of the experiment was the fact that no features beyond the piece differential were given to the neural networks as a priori knowledge. The process of evolution was able to extract all of the additional information required to play at this level of competency. It accomplished this based almost solely on the feedback offered in the final aggregated outcome of each game played (i.e., win, lose, or draw). This procedure stands in marked contrast to the typical artifice of explicitly injecting expert knowledge into a game-playing program.


Genetic influences on asthma susceptibility in the developing lung.
Asthma is the leading serious pediatric chronic illness in the United States, affecting 7.1 million children. The prevalence of asthma in children under 4 years of age has increased dramatically in the last 2 decades. Existing evidence suggests that this increase in prevalence derives from early environmental exposures acting on a pre-existing asthma-susceptible genotype. We studied the origins of asthma susceptibility in developing lung in rat strains that model the distinct phenotypes of airway hyperresponsiveness (Fisher rats) and atopy (brown Norway [BN] rats). Postnatal BN rat lungs showed increased epithelial proliferation and tracheal goblet cell hyperplasia. Fisher pups showed increased lung resistance at age 2 weeks, with elevated neutrophils throughout the postnatal period. Diverse transcriptomic signatures characterized the distinct respiratory phenotypes of developing lung in both rat models. Linear regression across age and strain identified developmental variation in expression of 1,376 genes, and confirmed both strain and temporal regulation of lung gene expression. Biological processes that were heavily represented included growth and development (including the T Box 1 transcription factor [Tbx5], the epidermal growth factor receptor [Egfr], the transforming growth factor beta-1-induced transcript 1 [Tgfbr1i1]), extracellular matrix and cell adhesion (including collagen and integrin genes), and immune function (including lymphocyte antigen 6 (Ly6) subunits, IL-17b, Toll-interacting protein, and Ficolin B). Genes validated by quantitative RT-PCR and protein analysis included collagen III alpha 1 Col3a1, Ly6b, glucocorticoid receptor and Importin-13 (specific to the BN rat lung), and Serpina1 and Ficolin B (specific to the Fisher lung). Innate differences in patterns of gene expression in developing lung that contribute to individual variation in respiratory phenotype are likely to contribute to the pathogenesis of asthma.


Thiazide diuretics and the risk of gallbladder disease requiring surgery in women.
Previous studies have suggested that thiazide diuretic use increases the risk of cholecystitis. We prospectively examined the association between thiazide use and cholecystectomy, a surrogate for symptomatic cholelithiasis, in a cohort of 81 351 US women who were aged 30 to 55 years in 1980 and followed up to 2000. Regular use of thiazide diuretics was assessed at baseline by asking the participants to report whether they currently took "any of the following medications in most weeks" and listing "thiazide diuretics (eg, Diuril and Hydrodiuril)" among other drugs. Respondents were also requested to report the duration of thiazide diuretic use. Assessment of thiazide diuretic use was updated in 1982, 1988, 1994, 1996, and 1998. Cox regression was used to adjust simultaneously for other potential risk factors for cholecystectomy. During follow-up, 8607 women reported undergoing a cholecystectomy. A modest positive relation between the use of thiazide diuretics and cholecystectomy was observed. Compared with never users of thiazide diuretics, the multivariate relative risk of cholecystectomy for past users was 1.16 (95% confidence interval,1.08-1.24) and the multivariate relative risk for current users was 1.39 (95% confidence interval, 1.29-1.50). These findings are compatible with the hypothesis that the use of thiazide diuretics increases the risk of symptomatic cholecystitis. However, we cannot rule out the possibility that our results are in part explained by unconsidered factors related to the indication for antihypertensive therapy or by differences in medical surveillance between users and nonusers of thiazide diuretics.


[State of the peripheral catecholaminergic systems during pharmacologic correction of immobilization stress using sodium oxybutyrate].
Fluorescent microscopy and spectrofluorometry of biogenic amines were employed to study the peripheral catecholaminergic systems in immobilized rats which received sodium hydroxybutyrate. The content of catecholamines was measured in the adrenergic nerves of dura mater, vas deferens and chromaffin tissue of the adrenals. It was established that sodium hydroxybutyrate in a dose of 40 mg/kg intraperitoneally promoted returning to normal of the adrenergic mediator activity during alarm and resistance stages. The role of the peripheral catecholaminergic systems in the mechanism of the stress-protective effect of sodium hydroxybutyrate is discussed.


Cell volume regulation in the proximal convoluted tubule.
To evaluate the effect of hyper- and hypotonicity on proximal convoluted tubule (PCT) cell volume, nonperfused PCT were studied in vitro with hypertonic solutions containing sodium chloride, urea, or mannitol (450 mosmol/kg H2O) and with hypotonic low sodium chloride solutions (160 mosmol/kg H2O). When the tubules were subjected to hypertonic peritubular solutions containing NaCl, cell volume immediately decreased by 15.5% and remained constant throughout the experimental period (60 min). With mannitol, the initial decrease was identical to that with NaCl (17.7%), but the PCT volume increased slightly during the experimental period. With urea, the decrease in cell volume was smaller (7%) and transient. In hypotonicity, the PCT swelled rapidly, but this swelling was followed by a rapid regulatory phase in which PCT volume nearly returned to control values after less than 10 min. With a potassium-free peritubular medium or 10(-3) M ouabain, the regulatory phase of hypotonicity completely disappeared, whereas the cells did not maintain their reduced volume in NaCl-induced hypertonicity. These results suggest that Na-K-ATPase plays an important role in the maintenance of a reduced cellular volume in hypertonicity and in the regulatory phase of hypotonicity, probably by an active extrusion of sodium and water from the cell.


Low-dose radiation-induced enhancement of thymic lymphomagenesis in Lck-Bax mice is dependent on LET and gender.
The hypothesis that mitochondrial dysfunction and increased superoxide levels in thymocytes over expressing Bax (Lck-Bax1 and Lck-Bax38&1) contributes to lymphomagenesis after low-dose radiation was tested. Lck-Bax1 single-transgenic and Lck-Bax38&1 double-transgenic mice were exposed to single whole-body doses of 10 or 100 cGy of (137)Cs or iron ions (1,000 MeV/n, 150 keV/μm) or silicon ions (300 MeV/n, 67 keV/μm). A 10 cGy dose of (137)Cs significantly increased the incidence and onset of thymic lymphomas in female Lck-Bax1 mice. In Lck-Bax38&1 mice, a 100 cGy dose of high-LET iron ions caused a significant dose dependent acceleration of lymphomagenesis in both males and females that was not seen with silicon ions. To determine the contribution of mitochondrial oxidative metabolism, Lck-Bax38&1 over expressing mice were crossed with knockouts of the mitochondrial protein deacetylase, Sirtuin 3 (Sirt3), which regulates superoxide metabolism. Sirt3(-/-)/Lck-Bax38&1 mice demonstrated significant increases in thymocyte superoxide levels and acceleration of lymphomagenesis (P < 0.001). These results show that lymphomagenesis in Bax over expressing animals is enhanced by radiation exposure in both an LET and gender dependent fashion. These findings support the hypothesis that mitochondrial dysfunction leads to increased superoxide levels and accelerates lymphomagenesis in Lck-Bax transgenic mice.


Genotype and phenotype in cystic fibrosis.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene which encodes a protein expressed in the apical membrane of exocrine epithelial cells. CFTR functions principally as a cAMP-induced chloride channel and appears capable of regulating other ion channels. Besides the most common mutation, DeltaF508, accounting for about 70% of CF chromosomes worldwide, more than 850 mutant alleles have been reported to the CF Genetic Analysis Consortium. These mutations affect CFTR through a variety of molecular mechanisms which can produce little or no functional CFTR at the apical membrane. This genotypic variation provides a rationale for phenotypic effects of the specific mutations. The extent to which various CFTR alleles contribute to clinical variation in CF is evaluated by genotype-phenotype studies. These demonstrated that the degree of correlation between CFTR genotype and CF phenotype varies between its clinical components and is highest for the pancreatic status and lowest for pulmonary disease. The poor correlation between CFTR genotype and severity of lung disease strongly suggests an influence of environmental and secondary genetic factors (CF modifiers). Several candidate genes related to innate and adaptive immune response have been implicated as pulmonary CF modifiers. In addition, the presence of a genetic CF modifier for meconium ileus has been demonstrated on human chromosome 19q13.2. The phenotypic spectrum associated with mutations in the CFTR gene extends beyond the classically defined CF. Besides patients with atypical CF, there are large numbers of so-called monosymptomatic diseases such as various forms of obstructive azoospermia, idiopathic pancreatitis or disseminated bronchiectasis associated with CFTR mutations uncharacteristic for CF. The composition, frequency and type of CFTR mutations/variants parallel the spectrum of CFTR-associated phenotypes, from classic CF to mild monosymptomatic presentations. Expansion of the spectrum of disease associated with the CFTR mutant genes creates a need for revision of the diagnostic criteria for CF and a dilemma for setting nosologic boundaries between CF and other diseases with CFTR etiology.


Disease-causing dysfunctions of barttin in Bartter syndrome type IV.
Bartter syndrome type IV is an inherited human condition characterized by severe renal salt wasting and sensorineural deafness. The causal gene, BSND, encodes barttin, an accessory subunit of chloride channels located in the kidney and inner ear. Barttin modulates the stability, cell surface localization, and function of ClC-K channels; distinct mutations cause phenotypes of varying severity. For definition of the molecular basis of this diversity, the functional consequences of six disease-causing mutations (R8L, R8W, G10S, Q32X, G47R, and E88X) on ClC-K channel properties were studied by heterologous expression in renal cell lines, electrophysiology, confocal imaging, and biochemical analysis. Three missense mutations (R8L, R8W, and G10S) eliminated the function of ClC-K/barttin channels but did not prevent the insertion of the channels into the surface membrane. Another mutant that produces a mild renal phenotype (G47R) was capable of performing all functions of wild-type barttin but bound to ClC-K channels less effectively. The nonsense mutation E88X affected epithelial sorting, leading to equal amounts of barttin inserting into the basolateral and apical membranes, contrasting with the preferential apical insertion of wild-type barttin. Last, the nonsense mutation Q32X allowed barttin to associate with ClC-K channels but prevented surface membrane insertion and channel activation. These results demonstrate that Bartter syndrome type IV can be caused by various derangements in the function of barttin, likely contributing to the diversity of observed phenotypes.


Synaptonemal Complex Central Region Proteins Promote Localization of Pro-crossover Factors to Recombination Events During Caenorhabditis elegans Meiosis.
Crossovers (COs) between homologous chromosomes are critical for meiotic chromosome segregation and form in the context of the synaptonemal complex (SC), a meiosis-specific structure that assembles between aligned homologs. During Caenorhabditis elegans meiosis, central region components of the SC (SYP proteins) are essential to repair double-strand DNA breaks (DSBs) as COs. Here, we investigate the relationships between the SYP proteins and conserved pro-CO factors by examining the immunolocalization of these proteins in meiotic mutants where SYP proteins are absent, reduced, or mislocalized. Although COs do not form in syp null mutants, pro-CO factors COSA-1, MSH-5, and ZHP-3 nevertheless colocalize at DSB-dependent sites during late prophase, reflecting an inherent affinity of these factors for DSB repair sites. In contrast, in mutants where SYP proteins are present but form aggregates or display abnormal synapsis, pro-CO factors consistently track with SYP-1 localization. Further, pro-CO factors usually localize to a single site per SYP-1 structure, even in SYP aggregates or in mutants where the SC forms between sister chromatids, suggesting that CO regulation occurs within these aberrant SC structures. Moreover, we find that the meiotic cohesin REC-8 is required to ensure that SC formation occurs between homologs and not sister chromatids. Taken together, our findings support a model in which SYP proteins promote CO formation by promoting the localization of pro-CO factors to recombination events within an SC compartment, thereby ensuring that pro-CO factors identify a recombination event within an SC structure and that CO maturation occurs only between properly aligned homologous chromosomes.


Inflammation biomarkers in acute ischemic stroke according to different etiologies.
High throughput technologies provide new opportunities to further investigate the pathophysiology of ischemic strokes. The present cross-sectional study aimed to evaluate potential associations between the etiologic subtypes of ischemic stroke and blood-based proteins. We investigated the associations between ischemic stroke subtypes and a panel of circulating inflammation biomarkers in 364 patients included in the Stroke Cohort Augsburg (SCHANA). Stroke etiologies were categorized according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Serum concentrations of 52 biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel, ICAM-1 set and VCAM-1 set, plus the Pro™ Human TH17 cytokine sCD40L set and IL31 set (all Bio-Rad, USA). Multivariable linear regression models were used to examine associations. Point estimates were calculated as the mean difference in σ -standardized cytokine levels on the log2 -scale. Stromal-cell-derived-factor 1 alpha (SDF-1a) showed significantly higher serum levels in cardioembolic compared with large vessel atherosclerotic stroke (β = 0.48; 95% CI 0.22; 0.75; Padj = 0.036). Significantly lower levels of interleukin-6 (IL-6) (β = -0.53; 95% CI -0.84; -0.23; Padj = 0.036) and macrophage migration inhibitory factor (MIF) (β = -0.52; 95% CI -0.84; -0.21; Padj = 0.043) were found in the small vessel versus large vessel stroke subtype. Immune dysregulations observed in different stroke subtypes might help uncover pathophysiological mechanisms of the disease. Further studies are needed to validate identified biomarkers in diverse study populations before they can potentially be used in clinical practice to further improve stroke management and patient outcomes.


The mechanisms of action of conventional chrysotherapy.
The discovery of chrysotherapy occurred 90 years ago. Gold salts (GS) as an antibacterial agent were used initially for tuberculosis (TB), but an infectious etiology was also suspected for rheumatoid arthritis (RA). Patients who received GS for TB and who also had RA noted improvement of their arthritis. The injectable GS regimen now commonly used evolved from the empirical use of GS for RA from 1920-1960. Originally, clinical experience perpetuated the use of injectable GS to modify RA and its progression. However, scientific data obtained in the last 2 decades have supported the efficacy of chrysotherapy. Studies of protein binding, blood and serum concentrations, tissue distribution, and the toxicity of GS all provided suggestions for its mode of action. As chemical and cellular mediators of inflammation were uncovered, the possible actions of gold have been refined. Because the immune system seems to perpetuate rheumatoid inflammation, the interactions with GS continue to be studied. The in vitro and in vivo actions of GS with the immune system so far have provided conflicting data for its immunological effect. Studies by models of mucosal immunity may lead to new insights in the mode of action for gold.


Comparative biochemistry of entomocidal parasporal crystals of selected Bacillus thuringiensis strains.
Parasporal crystals of Bacillus thuringiensis subspp. kurstaki, tolworthi, alesti, berliner, and israelensis were compared by electron microscopy, polyacrylamide gel electrophoresis, amino acid analysis, tryptic peptide mapping, immunological analysis, and insecticidal activity. Spore coats also were compared by polyacrylamide gel electrophoresis. B. thuringiensis subsp. israelensis crystals were lethally toxic to mosquito larvae and nontoxic to tobacco hornworm larvae. Conversely, crystals from the other subspecies killed tobacco hornworm larvae but were ineffective against mosquitoes. Crystalline inclusion bodies of all subspecies contained a protoxic subunit that had an apparent molecular weight of approximately 1.34 X 10(5). However, polyacrylamide gel electrophoretic patterns of solubilized crystals revealed a small-molecular-weight component (apparent molecular weight, 26,000) in B. thuringiensis subsp. israelensis that was absent in the other subspecies. Also, differences were noted in amino acid composition and tryptic peptide fingerprints. Crystal proteins were found in spore coats of all subspecies. The results suggest that insecticidal specificity is due to unique polypeptide toxins.


Alternaria Leaf Spot Caused by Alternaria Species: An Emerging Problem on Ornamental Plants in Italy.
Serious outbreaks of Alternaria leaf spot and plant decay have recently been recorded on several ornamental plants in the Biella Province (Northern Italy). Twenty-two fungal isolates were obtained from Alternaria infected plant tissues from 13 ornamental hosts. All the isolates were identified morphologically as small-spored Alternaria species. Multilocus sequence typing, carried out by means of ITS, rpb2, tef1, endoPG, Alt a 1, and OPA10-2, assigned 19 isolates as Alternaria alternata, two isolates as belonging to the Alternaria arborescens species complex, and one isolate as an unknown Alternaria sp. Haplotype analyses of ornamental and reference A. alternata isolates from 12 countries identified 14 OPA10-2 and 11 endoPG haplotypes showing a relatively high haplotype diversity. A lack of host specialization or geographic distribution was observed. The host range of the studied A. alternata isolates expanded in cross-pathogenicity assays, and more aggressiveness was frequently observed on the experimental plants than on the host plants from which the fungal isolates were originally isolated. High disease severity, population expansion, intraspecies diversity, and increased range of experimental hosts were seen in the emergence of Alternaria disease on ornamentals. More epidemiological and molecular studies should be performed to better understand these diseases, taking into consideration factors such as seed transmission and ongoing climate changes.


Refining genotype-phenotype correlation in Alström syndrome through study of primary human fibroblasts.
Alström syndrome (AS), featuring retinal dystrophy, neuronal deafness, cardiomyopathy, metabolic syndrome, and diffuse fibrosis, is caused by biallelic mutations in the centrosomal protein ALMS1. Genotype-phenotype correlation has been suggested without assessment of ALMS1 expression. ALMS1 expression (real-time PCR and immunocytochemistry) and cilia formation (immunocytochemistry) were assessed in fibroblasts from deeply phenotyped volunteers diagnosed with AS recruited from a dedicated AS Service. Exome sequencing was used in two participants without convincing biallelic ALMS1 mutations, and BBS2 (Bardet-Biedl syndrome 2) protein expression was assessed in one patient with biallelic BBS2 mutations. Hedgehog-induced GLI1 expression and PDGFA signaling was assessed using quantitative real-time PCR, immunoblotting, or immunostaining of fixed cells after stimulation. In 16 of the patient cell lines examined, ALMS1 protein was undetectable (14 with biallelic loss-of-function (LoF) mutations), and in two, ALMS1 staining was equivocal (one with biallelic LoF mutations). In five lines, ALMS1 expression was normal using at least one fixation method (one with biallelic LoF mutations). These differences were not accounted for by major differences in ALMS1 mRNA expression. Exome sequencing of two participants with normal ALMS1 expression identified biallelic LoF BBS2 mutations in one. No second, known ciliopathy mutation was found in the other patient, who had one LoF ALMS1 mutation. Phenotypes were milder or atypical in participants with preserved ALMS1 immunostaining, even when two with likely alternative genetic diagnoses were excluded. All cells studied developed normal cilia, ALMS1 and BBS2 mutant cells showed normal Hedgehog-induced upregulation of GLI1 expression, and PDGFA signaling was normal in ALMS1-deficient cells. Milder or atypical presentations of AS should prompt genetic evaluation for alternative, clinically overlapping ciliopathies. A subgroup of patients with bona fide ALMS1 defects have milder phenotypes due to residual ALMS1 expression, which may be more important than mutation site.


Simultaneous detection of all four alkaline phosphatase isoenzymes in human germ cell tumors using reverse transcription-PCR.
We have developed a reverse transcription-PCR method that clearly distinguishes between the RNA transcripts of all four alkaline phosphatase (AP) genes. If compared to the methods used up to the present, the main advantages of the reverse transcription-PCR method presented are its specificity and high sensitivity. The germ cell AP and the placental AP, which are the two most closely related AP isoenzymes (98% homology), can clearly be distinguished without any interference by other AP isoenzymes. An enhanced expression of AP isoenzymes has been reported for various tumors. The examination of the pattern of AP isoenzyme expression in a specific tumor and the corresponding tissue of origin enables discrimination between eutopically and ectopically expressed isoenzymes and thus represents an important tool in the elucidation of AP isoenzymes as potential tumor markers. The pattern of AP expression in 15 germ cell tumors, 2 germinal epithelia adjacent to seminoma, 2 cell lines of germ cell tumor origin (Tera-1 and BeWo), and 5 normal testes was studied. In comparison to normal testes, in all seminomatous germ cell tumors eutopic expression of germ cell AP and ectopic expression of tissue-nonspecific AP were demonstrated. In both samples of pure embryonal carcinoma and in the embryonal carcinoma cell line, the transcription of all four mRNAs was shown. These results indicate that the expression of the isoenzymes depends on the degree of differentiation of a tumor and that a simultaneous up-regulation of all AP isoenzymes in all types of germ cell tumors does not exist.


Addressing vaccine hesitancy: experimental evidence from nine high-income countries during the COVID-19 pandemic.
We study the impact of public health messages on intentions to vaccinate and vaccination uptakes, especially among hesitant groups. We performed an experiment comparing the effects of egoistic and altruistic messages on COVID-19 vaccine intentions and behaviour. We administered different messages at random in a survey of 6379 adults in December 2020, following up with participants in the nationally representative survey Citizens' Attitudes Under COVID-19 Project covering nine high-income countries (Australia, Austria, France, Germany, Italy, New Zealand, Sweden, the UK and the USA). Four alternative interventions were tested, based on narratives of (1) self-protection, (2) protecting others, (3) reducing health risks and (4) economic protection. We measure vaccination intentions in the December 2020 survey and elicit actual vaccination behaviour by respondents in the June/July 2021 survey. Messages conveying self-protection had no effect on vaccine intentions but altruistic messages, emphasising protecting other individuals (0.022, 95% CI -0.004 to 0.048), population health (0.030, 95% CI 0.003 to 0.056) and the economy (0.038, 95% CI 0.013 to 0.064) had substantially stronger effects. These effects were stronger in countries experiencing high COVID-19 mortality (Austria, France, Italy, Sweden, the UK and the USA), where health risks may have been more salient, but weaker and, in several cases, not significant where mortality was low (Australia, Germany and New Zealand). On follow-up at 6 months, these brief communication interventions corresponded to substantially higher vaccination uptake. Our experiments found that commonly employed narratives around self-protection had no effect. However, altruistic messages about protecting individuals, population health and the economy had substantially positive and enduring effects on increasing vaccination intentions. Our results can help structure communication campaigns during pandemics and are likely to generalise to other vaccine-preventable epidemics.


[Subdural effusions in children. Pathophysiology and treatment].
Nine children harboring subdural effusions were treated by subduro peritoneal shunt. These patients were followed-up by CT scans. The area of the subdural effusions was measured by quantitative morphology with a planimeter. With the surgical treatment, the subdural effusion disappeared completely or near completely in 8 patients. The patient's functional state were excellent in 4, good in 3 and bad in 2 in the postoperative follow-up. We aldo reviewed the literature as far as the pathophysiology and the treatment of the subdural effusions are concerned.


Spontaneous Deletion of an "ORFanage" Region Facilitates Host Adaptation in a "Photosynthetic" Cyanophage.
Viruses have been suggested to be the largest source of genetic diversity on Earth. Genome sequencing and metagenomic surveys reveal that novel genes with unknown functions are abundant in viral genomes. Yet few observations exist for the processes and frequency by which these genes are gained and lost. The surface waters of marine environments are dominated by marine picocyanobacteria and their co-existing viruses (cyanophages). Recent genome sequencing of cyanophages has revealed a vast array of genes that have been acquired from their cyanobacterial hosts. Here, we re-sequenced the cyanophage S-PM2 genome after 10 years of near continuous passage through its marine Synechococcus host. During this time a spontaneous mutant (S-PM2d) lacking 13% of the S-PM2 ORFs became dominant in the cyanophage population. These ORFs are found at one loci and are not homologous to any proteins in any other sequenced organism (ORFans). We demonstrate a fitness cost to S-PM2WT associated with possession of these ORFs under standard laboratory growth. Metagenomic surveys reveal these ORFs are present in various aquatic environments, are likely of cyanophage origin and appear to be enriched in environments from the extremes of salinity (freshwater and hypersaline). We posit that these ORFs contribute to the flexible gene content of cyanophages and offer a distinct fitness advantage in freshwater and hypersaline environments.


Reorienting the HIV response in Niger toward sex work interventions: from better evidence to targeted and expanded practice.
Niger's low-burden, sex-work-driven HIV epidemic is situated in a context of high economic and demographic growth. Resource availability of HIV/AIDS has been decreasing recently. In 2007-2012, only 1% of HIV expenditure was for sex work interventions, but an estimated 37% of HIV incidence was directly linked to sex work in 2012. The Government of Niger requested assistance to determine an efficient allocation of its HIV resources and to strengthen HIV programming for sex workers. Optima, an integrated epidemiologic and optimization tool, was applied using local HIV epidemic, demographic, programmatic, expenditure, and cost data. A mathematical optimization algorithm was used to determine the best resource allocation for minimizing HIV incidence and disability-adjusted life years (DALYs) over 10 years. Efficient allocation of the available HIV resources, to minimize incidence and DALYs, would increase expenditure for sex work interventions from 1% to 4%-5%, almost double expenditure for antiretroviral treatment and for the prevention of mother-to-child transmission, and reduce expenditure for HIV programs focusing on the general population. Such an investment could prevent an additional 12% of new infections despite a budget of less than half of the 2012 reference year. Most averted infections would arise from increased funding for sex work interventions. This allocative efficiency analysis makes the case for increased investment in sex work interventions to minimize future HIV incidence and DALYs. Optimal HIV resource allocation combined with improved program implementation could have even greater HIV impact. Technical assistance is being provided to make the money invested in sex work programs work better and help Niger to achieve a cost-effective and sustainable HIV response.


Gold nanoparticles located at the interface of anatase/rutile TiO2 particles as active plasmonic photocatalysts for aerobic oxidation.
Visible-light irradiation (λ > 450 nm) of gold nanoparticles loaded on a mixture of anatase/rutile TiO(2) particles (Degussa, P25) promotes efficient aerobic oxidation at room temperature. The photocatalytic activity critically depends on the catalyst architecture: Au particles with <5 nm diameter located at the interface of anatase/rutile TiO(2) particles behave as the active sites for reaction. This photocatalysis is promoted via plasmon activation of the Au particles by visible light followed by consecutive electron transfer in the Au/rutile/anatase contact site. The activated Au particles transfer their conduction electrons to rutile and then to adjacent anatase TiO(2). This catalyzes the oxidation of substrates by the positively charged Au particles along with reduction of O(2) by the conduction band electrons on the surface of anatase TiO(2). This plasmonic photocatalysis is successfully promoted by sunlight exposure and enables efficient and selective aerobic oxidation of alcohols at ambient temperature.


The prefrontal cortex in a pandemic: Restoring functions with system-, family-, and individual-focused interventions.
The COVID-19 pandemic is an unanticipated and uncontrollable chronic stressor that is detrimental to the mental and behavioral health of children and families, particularly those from disadvantaged and marginalized backgrounds. Chronic stress impairs a myriad of prefrontal cortical functions, important for coping with the COVID-19 pandemic, and has consequences on dyadic parent-child functioning. Informed by neuroscience and clinical evidence, sensitive parenting is a vital avenue of intervention that buffers against the toxic effects of COVID-19 on parent-child mental health. In the context of the COVID-19 pandemic, we first discuss the neurobiological, psychological, and behavioral mechanisms behind exacerbated mental health risks in families. We then highlight the role of sensitive parenting as a buffer against stress-related mental health problems, and conclude with recommendations for systemic-, family-, and individual-interventions to most effectively address stress-related mental health problems and their impact on children and families during the COVID-19 pandemic. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Reconstruction of the anterior cruciate ligament with human allograft. Comparison of early and later results.
Sixty-eight patients who had had reconstruction of an acute rupture of the anterior cruciate ligament with either a fascia lata or a bone-patellar ligament-bone allograft returned for two follow-up evaluations, at two to four years and at five to nine years (mean, seven years) postoperatively. The early (two to four-year) results in these patients have been reported previously. The mean time between the early and the later evaluation was fifty-six months (range, twenty to ninety-six months). At the early evaluation, fifty-two (78 per cent) of the sixty-seven patients who were tested with an arthrometer at eighty-nine newtons had less than three millimeters of increased anterior-posterior displacement compared with that of the contralateral limb; at the later evaluation, fifty-four (79 per cent) of the sixty-eight patients had this finding (p=0/97). With use of arthrometric and pivot-shift-test data, forty-eight (75 per cent) of sixty-four grafts were classified as functional at the early evaluation and fourteen (22 per cent), as partially functional; two (3 per cent) had failed. (Four grafts could not be classified because of incomplete data.) At the later examination, fifty (74 per cent) of the sixty-eight grafts were functional, thirteen (19 per cent) were partially functional, and five (7 per cent) had failed. At the early evaluation, sixty-two (93 percent) of sixty-seven patients had no palpable patellofemoral crepitus and five (7 per cent) had moderate crepitus. At the later evaluation, fifty-one (75 per cent) of the sixty-eight patients continued to have no crepitus, sixteen (24 per cent) had moderate crepitus, and on (1 per cent) had severe crepitus. An increase in crepitus between the early and the later evaluation was found in twelve (19 per cent) of the sixty-two patients who had normal crepitus at the early evaluation. With the numbers available, no factor, such as the type of graft, associated ligamentous injury, or meniscal repair, correlated significantly with the amount of patellofemoral crepitus at either follow-up evaluation. At the early evaluation, the result was rated excellent or good for thirty-eight (60 per cent) of sixty-three patients, fair for twenty-one (33 per cent), and poor for four (6 per cent). (The result could not be rated for four patients because of incomplete data.) At the later evaluation, the result was rated excellent or good for forty-five (66 per cent) of the sixty-eight patients, fair for eighteen (26 per cent), and poor for five (7 per cent). For nine patients (13 per cent), the over-all rating deteriorated from excellent or good at the early evaluation to fair or poor at the later examination. For six patients (9 per cent), the rating improved from fair at the early evaluation to excellent or good at the later evaluation. With the numbers available, we could detect no significant decrease in anterior-posterior displacement of the knee, patellofemoral crepitus, the pain or the jumping score, or the over-all knee rating over the time-period studied. While we currently recommend arthroscopically assisted reconstruction with a bone-patellar ligament-bone autogenous graft as the first choice for an acute rupture of the anterior cruciate ligament, our study shows that favorable results can be obtained with allografts and justifies their use when the surgeon and patient choose this approach.


Comparison of inflammatory markers in COVID-19 patients- a study based on disease severity groups.
To compare different inflammatory markers in various coronavirus disease 2019 severity groups. The cross-sectional, retrospective, comparative study was conducted at the Central Park Teaching Hospital, Lahore, Pakistan, and comprised data from April to June 2021 of coronavirus disease 2019 inpatients. The data was divided into mild, moderate and severe/critical category using the World Health Organisation interim guidelines. Data was analysed using SPSS 22. Of the 50 patients, 29(58%) were males and 21(42%) were females. The overall mean age was 54.12±21.23 years. The mean age was 62±17.1years in critical group compared to 50±19.7 years in mild and 52±15.9 years in moderate groups. There were 8(16%) patients in the mild group, 16(32%) in the moderate group and 26(52%) in the critical severity group. Mortality was the outcome in overall 19(38%) cases, and 14(73.7%) of them were in the critical group (p=0.03). C reactive protein, interleukin-6, serum ferritin and D-dimer levels were significantly different among the groups (p<0.05). Older people were found to have experienced coronavirus disease 2019 in more severe forms. The inflammatory markers were significantly high in patients with severe disease and were associated with high mortality.


[Experience of the surgical management of the esophageal achalasia in a tertiary care hospital].
Achalasia is a primary esophageal motor disorder. The most common symptoms are: dysphagia, chest pain, reflux and weight loss. The esophageal manometry is the standard for diagnosis. The aim of this paper is to determine the effectiveness of the surgical management in patients with achalasia in a tertiary care hospital. A case series consisting of achalasia patients, treated surgically between January and December of 2011. Clinical charts were reviewed to obtain data and registries of the type of surgical procedure, morbidity and mortality. Fourteen patients were identified, with an average age of 49.1 years. The most common symptoms were: dysphagia, vomiting, weight loss and pyrosis. Eight open approaches were performed and six by laparoscopy, with an average length of cardiomyotomy of 9.4 cm. Eleven patients received an antireflux procedure. The effectiveness of procedures performed was 85.7 %. Surgical management offered at this tertiary care hospital does not differ from that reported in other case series, giving effectiveness and safety for patients with achalasia.


Anti-Suicide Function of Nonsuicidal Self-Injury in Female Inpatient Adolescents.
There have been numerous studies investigating the relationship between nonsuicidal self-injury (NSSI) and suicidality. On the one side, NSSI is an important risk factor for suicidality, including suicidal thoughts and behaviors. On the other side, it has been suggested that one function of NSSI might be as a coping mechanism that can help individuals in the short term avoid suicide. The present study investigated the relationship between suicidality and NSSI in female inpatient adolescents, focusing on NSSI as an anti-suicide strategy. Subjects were 56 female adolescents, aged 12-18 years (M = 15.95 years, SD = 1.27), recruited from different inpatient child and adolescent psychiatric units. All participants fulfilled the DSM-5 research criteria for nonsuicidal self-injury disorder (NSSI-D). To assess suicidality, NSSI-D, and current and past diagnoses, a structured clinical interview was conducted. NSSI as a short-term coping strategy for avoiding suicide was indicated by one third (32.1%) of the participants. Before participants engaged in NSSI, the anti-suicide function was reported more frequently than reducing interpersonal problems (d = -.59). Getting relief from negative emotions and inducing positive feelings were reported at the same frequency as avoiding suicide before NSSI. Participants engaging in NSSI to avoid suicide and those reporting other functions did not significantly differ regarding other NSSI characteristics, suicidality, or psychopathology. Results indicate that the anti-suicide function significantly predicts the duration of current suicidal ideation (β = .557). This study provides preliminary support for the idea that NSSI is frequently used by female adolescents with NSSI-D to avoid suicide. Given the high co-occurrence of NSSI and suicidality, our results underline the importance of clinical assessment of suicidality and several NSSI functions, including the anti-suicide function, in adolescents with NSSI.


Non melanoma skin cancer and subsequent cancer risk.
Several studies have shown an increased risk of cancer after non melanoma skin cancers (NMSC) but the individual risk factors underlying this risk have not been elucidated, especially in relation to sun exposure and skin sensitivity to sunlight. The aim of this study was to examine the individual risk factors associated with the development of subsequent cancers after non melanoma skin cancer. Participants in the population-based New Hampshire Skin Cancer Study provided detailed risk factor data, and subsequent cancers were identified via linkage with the state cancer registry. Deaths were identified via state and national death records. A Cox proportional hazard model was used to estimate risk of subsequent malignancies in NMSC patients versus controls and to assess the potential confounding effects of multiple risk factors on this risk. Among 3584 participants, risk of a subsequent cancer (other than NMSC) was higher after basal cell carcinoma (BCC) (adjusted HR 1.40 [95% CI 1.15, 1.71]) than squamous cell carcinoma (SCC) (adjusted HR 1.18 [95% CI 0.95, 1.46]) compared to controls (adjusted for age, sex and current cigarette smoking). After SCC, risk was higher among those diagnosed before age 60 (HR 1.96 [95% CI 1.24, 3.12]). An over 3-fold risk of melanoma after SCC (HR 3.62; 95% CI 1.85, 7.11) and BCC (HR 3.28; 95% CI 1.66, 6.51) was observed, even after further adjustment for sun exposure-related factors and family history of skin cancer. In men, prostate cancer incidence was higher after BCC compared to controls (HR 1.64; 95% CI 1.10, 2.46). Our population-based study indicates an increased cancer risk after NMSC that cannot be fully explained by known cancer risk factors.


Efficacy of 4 Years of Octreotide Long-Acting Release Therapy in Patients With Severe Polycystic Liver Disease.
To observe the effect on total liver volume (TLV) on and off therapy in selected symptomatic patients with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PLD) who received octreotide long-acting release (OctLAR) for up to 4 years. Twenty-eight of 42 participants in a prospective 2-year clinical trial of OctLAR (40 mg monthly) consisting of double-blind, randomized (year 1) and open-label treatment (year 2) phases reenrolled in a 2-year open-label extension (OLE) study after being off OctLAR a mean of 8.3 months (original study: July 1, 2007, through June 30, 2013). Participants underwent magnetic resonance imaging at baseline, years 1 and 2, reenrollment, and study completion. Primary end point: change in TLV; secondary end points: changes in total kidney volume, glomerular filtration rate, quality of life (QoL), safety, vital signs, and laboratory parameters. Twenty-five participants (59.5%) completed the OLE. Off therapy, TLVs increased a mean ± SD of 3.4%±8.2% per year; after resuming therapy, TLVs decreased a mean ± SD of -4.7%±6.1% per year. Despite regrowth off treatment, overall reductions were observed, with a median (interquartile range) TLV of 4047 mL (3107-7402 mL) at baseline and 3477 (2653-7131 mL) at study completion (-13.2%; P<.001) and with improved health-related QoL. Total kidney volumes increased, and glomerular filtration rates declined from 58.2 mL/min to 54.5 mL/min (n=16) in patients with ADPKD on therapy from baseline to study completion. Therapy with OctLAR over 4 years in selected patients with symptomatic PLD arrested PLD progression, alleviating symptoms and improving health-related QoL. Discontinuation led to organ regrowth. clinicaltrials.gov Identifier: NCT00426153.


Trainee's Perceptions and Practices on Social Media at One Internal Medicine Program and Its Potential Uses in Graduate Medical Education.
This article was migrated. The article was marked as recommended. Introduction: Social media is a potential tool in Graduate Medical Education (GME). However, the perceptions that trainees themselves hold about the usefulness of social media in education has not yet been examined. Methods: A 34-item questionnaire was conducted at LAC+USC Medical Center in Los Angeles, CA and distributed to all Internal Medicine (IM) and Medicine-Pediatric residents and IM subspecialty fellows September through December 2017 with a 31% response rate. Most questions utilized 5-point or 6-point Likert-type scales. Results: We found that IM GME trainees were familiar with, and used social media regularly, with Messaging apps and social networks used most frequently. Video content/sharing and podcasts were identified as having the most potential for education. Trainees were in strong agreement about openness to social media use in GME. However, the majority of respondents answered "maybe" when asked whether it would be a positive addition. The majority of trainees did not see social media as unprofessional, and were mixed about whether or not it would be an invasion of privacy. Conclusions: Our analysis of the data reveals that social media may be a potential tool, but ambiguity remains as to whether or not social media tools would be fully embraced by trainees.


Selecting informative genes for discriminant analysis using multigene expression profiles.
Gene expression data extracted from microarray experiments have been used to study the difference between mRNA abundance of genes under different conditions. In one of such experiments, thousands of genes are measured simultaneously, which provides a high-dimensional feature space for discriminating between different sample classes. However, most of these dimensions are not informative about the between-class difference, and add noises to the discriminant analysis. In this paper we propose and study feature selection methods that evaluate the "informativeness" of a set of genes. Two measures of information based on multigene expression profiles are considered for a backward information-driven screening approach for selecting important gene features. By considering multigene expression profiles, we are able to utilize interaction information among these genes. Using a breast cancer data, we illustrate our methods and compare them to the performance of existing methods. We illustrate in this paper that methods considering gene-gene interactions have better classification power in gene expression analysis. In our results, we identify important genes with relative large p-values from single gene tests. This indicates that these are genes with weak marginal information but strong interaction information, which will be overlooked by strategies that only examine individual genes.


Suggestions for improvement of school screening for idiopathic scoliosis.
There is skepticism and the worth of school screening for the purposes of health care has been challenged. Numerous reasons are raised by the negativists to abandon these programs, even though the value of school screening is well documented in the literature. The aim of the present study is to update the evidence based recommendations for the improvement of school screening effectiveness, in order to support its continuation. All the relative research papers which originated from our scoliosis school screening program were analyzed. Specific suggestions for a) the organization, b) the optimal age of screening according to the geographical latitude, c) the best examined position, d) the standardization of referrals, e) the follow up of younger referrals with trunk asymmetry and f) the reduction of the financial cost are made. Today there is evidence that the incidence of surgery can significantly be reduced in areas where idiopathic scoliosis can be detected at an early stage through these programs. The introduction of these recommendations to all the existing school screening programs is strongly suggested, to reduce the negative impact they may have on families and on the health system and to improve their effectiveness.


The role of PET-CT in patients with incidental gallbladder cancer.
After a cholecystectomy, incidental gallbladder cancer (IGC) requires accurate imaging studies to determine the actual extent of the disease to properly tailor subsequent treatment. The aim of this study was to evaluate the utility of (18)F-fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET-CT) to provide optimal pre-treatment staging in patients with IGC. Between January 2006 and August 2008, all patients with IGC and at least muscular layer invasion were studied with (18)FDG PET-CT. The examination was considered positive when the standardized uptake values (SUV) were >/=2.5. In all instances patients were offered to undergo definitive exploration and possible radical resection. The series included 32 patients, 26 women and 6 men, with a median age of 57 years (range 30-81 years). The examination was performed at a median time of 6 weeks after cholecystectomy (range 2-52 weeks). (18)FDG PET-CT was negative in 13 patients and positive in 19 patients: 9 with localized potentially resectable disease (PRD) and in 10 with disseminated disease. Of the 13 patients with negative PET-CT, 9 refused surgery and 4 underwent formal exploration: 3 patients were resected with no disease identified in the final pathology report (FPR) and 1 was not resected as a result of peritoneal carcinomatosis. Of the 9 with PRD, 4 patients refused reoperation and 5 underwent exploration: 3 were resected with residual disease noted in the FPR and 2 did not undergo resection because of dissemination. Two patients with disseminated disease were reoperated and in both instances disseminated disease was confirmed. The median survival for the entire group was 20.3 months (range 1.6-32.9 months). The median survival for those patients with negative PET-CT was 13.5 months (range 5.6-32.9 months), 6.2 months (range 1.6-18.7 months) for localized potentially resectable disease and 4.9 months (range 2-14.1 months) for disseminated disease (P < 0.003). For patients presenting with stage T1b or greater IGC, the use of (18)FDG PET-CT will help reduce the number of patients undergoing non-therapeutic re-exploration and may help to determine the likely prognosis. (18)FDG PET-CT might be a useful tool for the selection of patients for potentially curative treatment.


Fgf-9 is required for angiogenesis and osteogenesis in long bone repair.
Bone healing requires a complex interaction of growth factors that establishes an environment for efficient bone regeneration. Among these, FGFs have been considered important for intrinsic bone-healing capacity. In this study, we analyzed the role of Fgf-9 in long bone repair. One-millimeter unicortical defects were created in tibias of Fgf-9(+/-) and wild-type mice. Histomorphometry revealed that half-dose gene of Fgf-9 markedly reduced bone regeneration as compared with wild-type. Both immunohistochemistry and RT-PCR analysis revealed markedly decreased levels of proliferating cell nuclear antigen (PCNA), Runt-related transcription factor 2 (Runx2), osteocalcin, Vega-a, and platelet endothelial cell adhesion molecule 1 (PECAM-1) in Fgf-9(+/-) defects. muCT angiography indicated dramatic impairment of neovascularization in Fgf-9(+/-) mice as compared with controls. Treatment with FGF-9 protein promoted angiogenesis and successfully rescued the healing capacity of Fgf-9(+/-) mice. Importantly, although other pro-osteogenic factors [Fgf-2, Fgf-18, and bone morphogenic protein 2 (Bmp-2)] still were present in Fgf-9(+/-) mice, they could not compensate for the haploinsufficiency of the Fgf-9 gene. Therefore, endogenous Fgf-9 seems to play an important role in long bone repair. Taken together our data suggest a unique role for Fgf-9 in bone healing, presumably by initiating angiogenesis through Vegf-a. Moreover, this study further supports the embryonic phenotype previously observed in the developing limb, thus promoting the concept that healing processes in adult organisms may recapitulate embryonic skeletal development.


Fibroblast growth factor 10 alters the balance between goblet and Paneth cells in the adult mouse small intestine.
Intestinal epithelial cell renewal relies on the right balance of epithelial cell migration, proliferation, differentiation, and apoptosis. Intestinal epithelial cells consist of absorptive and secretory lineage. The latter is comprised of goblet, Paneth, and enteroendocrine cells. Fibroblast growth factor 10 (FGF10) plays a central role in epithelial cell proliferation, survival, and differentiation in several organs. The expression pattern of FGF10 and its receptors in both human and mouse intestine and their role in small intestine have yet to be investigated. First, we analyzed the expression of FGF10, FGFR1, and FGFR2, in the human ileum and throughout the adult mouse small intestine. We found that FGF10, FGFR1b, and FGFR2b are expressed in the human ileum as well as in the mouse small intestine. We then used transgenic mouse models to overexpress Fgf10 and a soluble form of Fgfr2b, to study the impact of gain or loss of Fgf signaling in the adult small intestine. We demonstrated that overexpression of Fgf10 in vivo and in vitro induces goblet cell differentiation while decreasing Paneth cells. Moreover, FGF10 decreases stem cell markers such as Lgr5, Lrig1, Hopx, Ascl2, and Sox9. FGF10 inhibited Hes1 expression in vitro, suggesting that FGF10 induces goblet cell differentiation likely through the inhibition of Notch signaling. Interestingly, Fgf10 overexpression for 3 days in vivo and in vitro increased the number of Mmp7/Muc2 double-positive cells, suggesting that goblet cells replace Paneth cells. Further studies are needed to determine the mechanism by which Fgf10 alters cell differentiation in the small intestine.


Oxidative Stress and Low-Grade Inflammation in Polycystic Ovary Syndrome: Controversies and New Insights.
The pathophysiology of Polycystic Ovary Syndrome (PCOS) is quite complex and different mechanisms could contribute to hyperandrogenism and anovulation, which are the main features of the syndrome. Obesity and insulin-resistance are claimed as the principal factors contributing to the clinical presentation; in normal weight PCOS either, increased visceral adipose tissue has been described. However, their role is still debated, as debated are the biochemical markers linked to obesity per se. Oxidative stress (OS) and low-grade inflammation (LGI) have recently been a matter of researcher attention; they can influence each other in a reciprocal vicious cycle. In this review, we summarize the main mechanism of radical generation and the link with LGI. Furthermore, we discuss papers in favor or against the role of obesity as the first pathogenetic factor, and show how OS itself, on the contrary, can induce obesity and insulin resistance; in particular, the role of GH-IGF-1 axis is highlighted. Finally, the possible consequences on vitamin D synthesis and activation on the immune system are briefly discussed. This review intends to underline the key role of oxidative stress and low-grade inflammation in the physiopathology of PCOS, they can cause or worsen obesity, insulin-resistance, vitamin D deficiency, and immune dyscrasia, suggesting an inverse interaction to what is usually considered.


Rainfall increases the abundance of antibiotic resistance genes within a riverine microbial community.
Infections with antibiotic resistant bacteria are among the major threats for human health. Studies elucidating the role of the environment in their spread are still in their infancy, it, however, seems that different environments might function as a long-term reservoir of antibiotic resistance genes (ARGs) that reside within their microbial communities. An increasing number of studies target the presence and the persistence of ARGs in waters and soils that are exposed to human activities; they, however, rarely consider the spatial/temporal variability that predominate in these environments. Here we evaluated the effect of a moderate rain event (4 mm rain h-1) on the abundance and distribution of ARGs (tetA, ermB, blaCTXM, sulII, and qnrS), by comparing measurements of gene abundances during the rainfall to the yearly average, in the waters of a large subalpine river. ARG abundances, which all increased during the rain event, were then correlated to several microbiological, physical and chemical variables, in order to establish their potential origin. Increments in ARG abundances during rainfall (total ARGs: 24 fold) was concomitant to an increase in total phosphorous, N-NH4, and microbial aggregates. Our results show a strong influence of a moderate rainfall on the abundances of ARGs, and suggest the catchment as their source. The impact of moderate rainfalls in areas exposed to anthropic activities should then be considered in modelling and management of ARG dynamics.


Fertility among a cohort of male sawmill workers exposed to chlorophenate fungicides.
The purpose of this study was to determine whether exposure to chlorophenate fungicides and their dioxin contaminants is associated with male infertility among sawmill workers. The study was conducted using fertility data compiled from 26,487 sawmill workers in 14 British Columbian sawmills. Our analysis was restricted to workers who had been employed for at least 1 continuous year between 1950 and 1985 and to live-births born at least 1 year after the initiation of employment in the period 1955-1988. We assessed fertility trends by internal comparison using Mantel-Haenszel rate ratios and by calculating standardized fertility ratios using an external and an internal reference population. We identified 19,684 births in the study period. Initially, both external and internal analyses showed that sawmill workers from mills using chlorophenates had lower fertility than workers employed in mills not using chlorophenates. After controlling for time since first hire, however, we found no inverse relation between cumulative exposure to chlorophenate fungicides and fertility. Based on the results of our study, there is little evidence for a reduction in fertility among chlorophenate-exposed sawmill workers in British Columbia. The analyses indicate the importance of time since hire as a potentially strong confounder in this type of investigation.


Electrical measurement of sweat activity.
A multichannel logger for long-term measurements of sweat activity is presented. The logger uses skin surface electrodes for unipolar admittance measurements in the stratum corneum. The logger is developed with emphasis on clinical use. The portability of the logger enables recording of sweat activity under circumstances such as daily errands, exercise and sleep. Measurements have been done on 24 healthy volunteers during relaxation and exercise with heart rate monitoring. Recordings of sweat activity during sleep have been done on two healthy subjects. Early results show good agreement with the literature on sweating physiology and electrodermal activity. Results are presented showing measurements related to physical exercise, dermatomes, distribution of sweat glands and sympathetic activity. This study examines the normal sweating patterns for the healthy population, and we present results with the first 24 healthy volunteers. Comparing these results with similar measurements on hyperhidrosis patients will make it possible to find the most useful parameters for diagnosis and treatment evaluation.


Effect of guar, pectin, psyllium, soy polysaccharide, and cellulose on breath hydrogen and methane in healthy subjects.
Different types of dietary fiber are fermented to various extents in vitro, but little is known about the effects of fiber on breath hydrogen and methane levels in vivo. Therefore, we studied the effects on breath hydrogen and methane of 15 g of guar, pectin, psyllium, soy polysaccharide, or cellulose in eight healthy subjects over a 12-h period. None of the fibers had a significant effect on breath hydrogen or methane concentrations, compared with the control (fasting). The four methane producers had lower breath hydrogen levels than the nonproducers 1 h after 15 g of lactulose (3 +/- 1 vs. 42 +/- 9, p less than 0.005) and 5-12 h after the different fibers (3.3 vs. 4.8 ppm; pooled SEM = 0.8; p less than 0.025). When the methane responses of the methane producers were expressed as increments relative to the control, there were small differences between treatments, with guar producing a larger response, 8.2 +/- 3.3 ppm, than cellulose, -2.9 +/- 2.3 ppm (p less than 0.05). The incremental methane responses of the different fibers in vivo were related to the previously reported production of propionic acid (r = 0.94, n = 5, p less than 0.02) and methane (r = 0.93, n = 4, NS) from in vitro fermentation of the same fibers. We conclude that methane producers have lower breath hydrogen levels than nonproducers. Purified fermentable and nonfermentable dietary fibers have no effect on breath hydrogen levels over 12 h in subjects previously consuming a normal diet. However, fermentable fibers may produce small increases in breath methane in methane-producing subjects.


The uptake and stability of simian-virus-40 DNA after calcium phosphate transfection of CV-1 cells.
The uptake and fate of purified SV40 (Simian virus 40) DNA, transfected into permissive CV-1 cells by calcium phosphate precipitates, was examined. By using a viral plaque assay, optimum conditions for transfection were established and transfection efficiencies of up to 10(6) plaque-forming units/micrograms of SV40 DNA were obtained. After a 2h exposure to 3H-labelled SV40 DNA-calcium phosphate co-precipitates under basal conditions, up to 7% of the input DNA became cell-associated, with approx. 4% reaching the nuclear fraction. This value was never exceeded, even under conditions known to enhance significantly the ultimate transfection efficiency, such as increased exposure time, addition of carrier DNA or treatment with DMSO (dimethyl sulphoxide) or glycerol. Substantial degradation of this SV40 DNA occurred within a further 4h, apparently in both nucleus and cytoplasm. Degradation of form-II and form-III SV40 DNA, which have lower transfection efficiencies than form-I DNA, was no more rapid than degradation of form-I DNA. The results indicate that less than 0.5% of the transfected DNA which reached the nucleus is protected from nuclease attack. The mechanism of action of agents such as glycerol, DMSO or carrier DNA remains obscure, but they may be involved in conferring greater stability to the intracellular SV40 DNA rather than merely affecting its rate of entry into the cell.


[A case of liver angiosarcoma arising in a pre-existing cavernous hemangioma].
A 36-year-old woman presented with a solitary hepatic tumor. Macroscopically, the tumor measured 9 cm in greatest diameter, and was well encapsulated; it was reddish, and showed multiple foci of hemorrhage. Microscopic examination revealed two different patterns: a peripheral angiosarcoma surrounding a centrally located cavernous haemangioma. To our knowledge, such an entity has not been reported up to now. Possible pathomechanisms, radiological and pathological findings of this angiosarcoma of liver arising within a cavernous haemangioma are commented.


Suppression of UV-B stress responses by flg22 is regulated at the chromatin level via histone modification.
Genes of the flavonol pathway are activated by UV-B, but suppressed by concomitant flg22 application in Arabidopsis. Analysis at the metabolite level suggested that this regulation allows the plant to focus its secondary metabolism on the plant defence towards pathogen attack. We now demonstrate by chromatin immunoprecipitation followed by quantitative PCR, that this antagonistic gene regulation is mediated at the chromatin level by differential regulation of histone 3 lysine 9 acetylation (H3K9ac), which is a hallmark for gene activation. Since H3K9ac levels were altered at least at four independent gene loci, namely, chalcone synthase, chalcone-flavone isomerase, flavanone 3-hydroxylase and the positive regulator MYB12, which correlates with the observed gene activation/suppression reported previously, it appears that this process is mediated by chromatin remodelling. Since suppression of H3K9ac prevents gene expression, we conclude H3K9ac is rather cause than consequence of gene activation. This finding allows us also to extend our working model, involving the two opposing MYB transcription factors of the flavonol pathway, MYB12 (being UV-B-activated and flg22-suppressed) and MYB4 (a negative regulator, which is activated by both flg22 and UV-B stress).


[The prevalence of the arterial hypertension and associated risk factors among population of various gender and age].
To study the pubescent characteristics of the prevalence of the arterial hypertension, the hyperglycemia, the hypercholesterolemia, the overweight and their combination the comprehensive examination of 4837 citizen of the City of Veliki Novgorod and Novgorod oblast aged from 20 to 87 years was organized. The analysis revealed in the examined territory the higher prevalence of hypertension and other studied risk factors and their combination are strongly related to the gender and the age of population. The prevalence of the obesity and the hyperglycemia, the combination of the overweight with the arterial hypertension and the hyperglycemia and the combination of the arterial hypertension with the hyperglycemia as well are significantly higher in the female subpopulation and in the elder population. It is established that the arterial hypertension affects about 46.80% of the adult population. The hyperglycemia is detected in 6.039% of cases. The prevalence of the fore-obesity and the obesity itself among male population consists of 50.4% and among female population--63.1%. The I degree obesity occurs among the females twice time more often than among the males; the II degree obesity--fourth times more often and the III degree obesity--sixth times more often. Among the females, as compared with the males, the prevalence of the combination of the arterial hypertension with the overweight is 1.5 times higher, the combination of the arterial hypertension with the hyperglycemia--1.7 times higher and the combination of the overweight with the hyperglycemia--1.7 times higher.


Atraumatic restorative treatment with resin-modified glass ionomer material: short-term results of a pilot study.
The aim of this study was to assess the feasibility of the resin-modified glass ionomer (RMGI) material in atraumatic restorative treatment (ART) approach and compare RMGI with the high-strength traditional glass ionomer cement (GIC) in permanent teeth with one or more surface-carious cavities. This study was conducted in a village school in rural southeastern Anatolia, Turkey. The RMGI and GIC restorations with the ART technique were placed randomly employing a split mouth design. In addition, the ART approach was used when necessary for both primary and/or permanent teeth with no pulpal involvement and no perceived pain before treatment. Ninety-one fillings were placed on contralateral molar pairs of 37 children. Baseline and 6-month evaluation of the fillings were made with the classic ART, modified Ryge and USPHS criteria. Based on the ART criteria, 100% of RMGI and 92.4% of GIC restorations were classified as successful after 6 months, and the difference between the 2 groups was statistically significant (p=0.009). While marginal discoloration was the commonest failure in the RMGI group according to both the modified Ryge and USPHS criteria, unsatisfactory surface texture and low anatomic form were the commonly seen failures in the ART technique. Generally, for each rating system, RMGI exhibited better clinical performance than GIC in all categories, except for marginal discoloration. Results based on the 6-month evaluation show that RMGI can be an alternative material to the GIC.


Induction and expression of abnormal involuntary movements is related to the duration of dopaminergic stimulation in 6-OHDA-lesioned rats.
Dyskinesia induction in Parkinson's disease (PD) appears less marked with long-acting dopamine agonists than with short-acting L-Dopa, but the relationship to duration of drug action is unknown. It is also unclear whether the duration of drug action affects the expression of established dyskinesia. This study compared the ability of L-Dopa and four dopamine agonists of different duration of action to induce abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats, and their ability to express established AIMs following prior exposure to L-Dopa. 6-OHDA-lesioned rats were treated with saline, L-Dopa/benserazide, apomorphine, ropinirole, pramipexole or pergolide once daily for 15 days. Repeated administration of the short-acting dopamine agonists, apomorphine (duration 80 min) and ropinirole (duration 90 min) induced marked axial, limb and orolingual AIMs at peak effect. L-Dopa (duration 100 min) produced moderate AIMs at peak effect, while administration of the long-acting dopamine agonists, pramipexole (duration 150 min) and pergolide (duration 240 min) resulted in mild AIMs. In rats primed to exhibit severe AIMs following repeated L-Dopa administration, acute administration of apomorphine, ropinirole and L-Dopa induced severe AIMs. By contrast, pramipexole and pergolide evoked only mild-moderate AIMs. Again, there was a negative correlation between duration of effect and the severity of AIMs expressed. These studies show that both the induction and expression of AIMs in 6-OHDA-lesioned rats are related to the duration of action of dopaminergic drugs. These findings suggest that continuous dopaminergic stimulation could be used both to avoid dyskinesia induction and to improve motor function in late-stage PD when troublesome dyskinesia is evident.


Conformational sampling and large amplitude motion of methyl valerate.
The microwave spectrum of the fruit ester methyl valerate was recorded using two molecular jet Fourier transform spectrometers covering the frequency range from 2 to 40 GHz. Quantum chemical calculations yielded 11 minima for the anti ester configuration, among them two were identified in the experimental spectrum. The methyl group in the methoxy moiety undergoes internal rotation, leading to torsional splittings of all rotational transitions into doublets. The barrier to internal rotation of the methoxy methyl group was deduced to be 417.724(70) cm-1 and 418.059(27) cm-1 for the C1 and the Cs conformer, respectively, essentially the same values as those in methyl alkanoates with shorter alkyl chains, which are methyl acetate, methyl propionate and methyl butyrate. Geometry parameters such as the rotational and centrifugal distortion constants could be determined with very high accuracy. Optimisations at different levels of theory were performed for a comparison with the experimental results. The MP2/6-311++G(d,p) level of theory failed to calculate reliable rotational constants to guide the assigment of the C1 conformer, while the MP2/cc-pVDZ level fully succeeded.


Comparative genomics analysis of Stenotrophomonas maltophilia strains from a community.
Stenotrophomonas maltophilia is a multidrug-resistant (MDR) opportunistic pathogen with high resistance to most clinically used antimicrobials. The dissemination of MDR S. maltophilia and difficult treatment of its infection in clinical settings are global issues. To provide more genetic information on S. maltophilia and find a better treatment strategy, we isolated five S. maltophilia, SMYN41-SMYN45, from a Chinese community that were subjected to antibiotic susceptibility testing, biofilm formation assay, and whole-genome sequencing. Whole-genome sequences were compared with other thirty-seven S. maltophilia sequences. The five S. maltophilia strains had similar antibiotic resistance profiles and were resistant to β-lactams, aminoglycosides, and macrolides. They showed similar antimicrobial resistance (AMR) genes, including various efflux pumps, β-lactamase resistance genes (blaL1/2), aminoglycoside resistance genes [aac(6'), aph(3'/6)], and macrolide-resistant gene (MacB). Genome sequencing analysis revealed that SMYN41-SMYN45 belonged to sequence type 925 (ST925), ST926, ST926, ST31, and ST928, respectively, and three new STs were identified (ST925, ST926, and ST928). This study provides genetic information by comparing genome sequences of several S. maltophilia isolates from a community of various origins, with the aim of optimizing empirical antibiotic medication and contributing to worldwide efforts to tackle antibiotic resistance.


Grab a Cup, Fill It Up! An Intervention to Promote the Convenience of Drinking Water and Increase Student Water Consumption During School Lunch.
We evaluated a low-cost strategy for schools to improve the convenience and appeal of drinking water. We conducted a group-randomized, controlled trial in 10 Boston, Massachusetts, schools in April through June 2013 to test a cafeteria-based intervention. Signage promoting water and disposable cups were installed near water sources. Mixed linear regression models adjusting for clustering evaluated the intervention impact on average student water consumption over 359 lunch periods. The percentage of students in intervention schools observed drinking water during lunch nearly doubled from baseline to follow-up compared with controls (+ 9.4%; P < .001). The intervention was associated with a 0.58-ounce increase in water intake across all students (P < .001). Without cups, children were observed drinking 2.4 (SE = 0.08) ounces of water from fountains; with cups, 5.2 (SE = 0.2) ounces. The percentage of intervention students observed with sugar-sweetened beverages declined (-3.3%; P < .005). The current default of providing water through drinking fountains in cafeterias results in low water consumption. This study shows that an inexpensive intervention to improve drinking water's convenience by providing cups can increase student water consumption.


Antisense therapy of hematologic malignancies.
Many tumor cells are inherently resistant to curative treatment due to an altered pattern of gene expression. It is an attractive and logical proposition to use this difference within the lymphoma cell to eradicate the malignant process. One such new therapeutic approach based on the "silencing" of genes involved in the prevention of apoptosis is Bcl-2 antisense oligonucleotide (AO) therapy. In the field of lymphoma, obvious targets included follicular lymphoma with the t(15;18) translocation, which results in deregulated expression of the Bcl-2 gene, chemoresistance, and subsequent protection against lymphoma cell death. Targeting the initiating codon of the Bcl-2 gene decreases both cell viability and Bcl-2 protein expression in lymphoma and leukemia cell lines that overexpress Bcl-2. Preclinical toxicity studies using a Bcl-2 AO G3139 (Genta, San Diego, CA) show good tolerance at a dose of 10 mg/kg, which is considerably higher than the dose required for good antilymphoma efficacy. In a phase I clinical study, G3139 was well tolerated with minimal toxicity in a dose escalation up to 147.2 mg/m2/d. Evidence of efficacy includes a responder with stage IVB follicular lymphoma who achieved complete clinical and radiologic response that has lasted more than 2 years. The main dose-limiting toxicity has been reversible thrombocytopenia related to the thioate backbone. Other antisense reagents are also in development to combat non-Hodgkin's lymphoma (NHL). These include oligonucleotides that target the messages of the Bcl-X(L) and protein kinase-Calpha (PKCalpha) genes. AOs may also have an application in tumors expressing mutant p53. AOs against MDM2 genes have shown the ability to restore wild-type p53 expression, suggesting that as oncogenic pathways are unraveled, normal cell growth and death patterns may be restored by molecular manipulation. Downregulation of antiapoptosis by AOs in the human setting has low toxicity and antilymphoma activity in cases in which conventional chemotherapy has failed. In the future, antisense therapy followed by chemotherapy may overcome chemoresistance to provide effective therapy for a range of malignancies.


Anti-Inflammatory Activity of Sanjie Zhentong Capsule Assessed By Network Pharmacology Analysis of Adenomyosis Treatment.
Sanjie Zhentong capsule (SZC) offers excellent effect in treating adenomyosis (AM), which is a common and difficult gynecological disease in the clinic. However, the systematic analysis of its mechanism has not been carried out yet and further studies are needed to reveal the role of SZC. A systematic network pharmacology analysis was conducted by integrating construction of SZC compound database and AM target database, prediction of potential active compounds and targets by molecular docking combined with compound-target prediction graph (CTPG), protein-protein interaction (PPI) analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Then, the anti-inflammation experiments in vitro were performed by investigating SZC and the representative compounds regulating nitric oxide (NO), interleukin-6 (IL-6), and interleukin-10 (IL-10). Our findings show that SZC mainly treated AM by stimulating 28 core targets through 30 key potential active compounds, and affecting 4 crucial pathways. The treatment was associated with inflammation reaction, hormone regulation, cell adhesion, proliferation, and angiogenesis. Additionally, SZC achieved the anti-inflammatory activity by the cooperation of the compounds through inhibiting NO and IL-6, both promoting and inhibiting IL-10. This study investigated the anti-inflammatory activity of SZC based on a systematic analysis of SZC remedying AM, which was revealed to be one of the essential mechanisms. These findings will provide valuable guidance for further research of the SZC treatment of AM, and help improve the comprehension of SZC pharmacological basis as well as AM pathogenesis.