A randomized, blinded, controlled clinical study of particulate anorganic bovine bone mineral and calcium phosphosilicate putty bone substitutes for socket preservation.
The purpose of this study was to compare the clinical efficacy of an anorganic bovine bone graft particulate to that of a calcium phosphosilicate putty alloplast for socket preservation. Thirty teeth were extracted from 24 patients. The sockets were debrided and received anorganic bovine bone mineral (BOV, n=12), calcium phosphosilicate putty (PUT, n=12), or no graft (CTRL, n=6). The sockets were assessed clinically and radiographically 5 months later. Eight sockets in the BOV group and nine in the PUT group received implants 5 to 6 months postgrafting. The maximum implant insertion torque (MIT) was measured as an index of primary implant stability. The data were analyzed with the Mann-Whitney test. Both test groups had statistically significantly less reduction in mean ridge width (BOV: 1.39±0.57 mm; PUT: 1.26±0.41 mm) in comparison to the control group (2.53±0.59 mm). No statistically significant difference was identified between the test groups. MIT for PUT was ≤35 N/cm² (MIT grade 4) for seven of the nine implants. MIT values in the BOV group ranged from grade 1 (10 to 19 N/cm²) to grade 4, which was statistically significantly lower than for the PUT group. The overall implant success rate was 94.1% (16 of 17 implants were successful). No implants were lost in the PUT group; one implant failed in the BOV group. Both tested bone substitutes can be recommended for preservation of alveolar ridge width following extraction. PUT might be more suitable for achieving primary stability for implants placed at 5 to 6 months postextraction.


The gastritis connection: prevention and early detection of gastric neoplasms.
Most gastric polyps, adenocarcinomas, carcinoids, and B cell lymphomas arise on a gastric mucosa damaged by long-standing chronic gastritis. The most common form of chronic gastritis is caused by infection with Helicobacter pylori. All patients with H. pylori infection develop lymphoid aggregates with germinal centers that interact intimally with the gastric mucosa (mucosa-associated lymphoid tissue [MALT]); these follicles are the condition sine qua non for the development of primary B cell mantle lymphomas, also known as MALT lymphomas. As the infection progresses, atrophy of the gastric mucosa develops in a subset of patients, which is replaced by an intestinal-type epithelium (intestinal metaplasia). On this background, dysplasia and adenocarcinomas of the intestinal type may develop. When atrophy is sufficiently severe to impair acid production, the gastrin-producing cells of the antrum increase their secretion of gastrin and stimulate endocrine cells in the corpus, which may eventually proliferate, become dysplastic, and give raise to carcinoids. This development is more frequent in advanced cases of autoimmune gastritis associated with pernicious anemia. On this background, there is also extensive epithelial hyperplasia and the formation of hyperplastic or inflammatory polyps, a small percentage of which may become dysplastic and progress to adenocarcinoma. Chronic exposure of the corpus mucosa to pancreaticoduodenal secretions ("bile reflux") causes reactive mucosal changes that may predispose to neoplasia. Thus, the progression of inflammation to atrophy to metaplasia, and in some cases chronic chemical injury, may give rise, at different times and under the influence of other, unknown stimuli, to most types of gastric tumors. Other types of gastritis, including lymphocytic and granulomatous gastritis, are rare and have not been associated with gastric neoplasia. Awareness of these associations, appropriate treatment policies, and implementation of endoscopic surveillance programs would dramatically reduce the incidence of most types of gastric neoplasms and would allow the detection of many tumors at a stage when endoscopic resection or conservative treatment would still be possible.


Founder effect in spinal and bulbar muscular atrophy (SBMA).
We analyzed the polymorphic (CAG)n and (GGC)n repeats of the androgen receptor gene in 113 unrelated X-linked spinal and bulbar muscular atrophy (SBMA) X chromosomes and 173 control X chromosomes in Japanese males. The control chromosomes had an average CAG repeat number of 21 +/- 3 with a range from 14-32 repeat units, and SBMA chromosomes had a range from 40-55 with a median of 47 +/- 3 copies. The control chromosomes had seven different alleles of the (GGC)n repeat with the range of 11 to 17; the most frequent size of (GGC)n was 16 (79%), while (GGC)17 was very rare (1%). However, in SBMA chromosomes only two alleles were seen; the most frequent size of (GGC)n was 16 (61%) followed by 17 (39%). (GGC)n size distribution was significantly different between SBMA and control chromosomes (P < 0.0001), indicating the presence of linkage disequilibrium. There was no allelic association between the (CAG)n and (GGC)n microsatellites among control subjects as well as SBMA patients, which suggests that a founder effect makes a more significant contribution to generation of Japanese SBMA chromosomes than new mutations.


Antioxidants reduce cyclooxygenase-2 expression, prostaglandin production, and proliferation in colorectal cancer cells.
Increased expression of cyclooxygenase (COX) and overproduction of prostaglandins (PGs) have been implicated in the development and progression of colorectal cancer (CRC). Recent observations suggest that reactive oxygen intermediates play a role in tumor cell growth regulation and expression of the inducible COX, COX-2. We therefore evaluated the effects of various antioxidants on COX expression and cellular growth in the human CRC cell line HCA-7. The antioxidants pyrrolidinedithiocarbamate (PDTC), N-acetylcysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and U74006 decreased PG production, intracellular redox status, and cellular growth in a concentration-dependent manner. The decrease in cellular growth was associated with the induction of apoptosis. Unlike the selective COX inhibitors 1-[(4-methylsulfonyl)phenyl]-3-trifluoromethyl-5-[(4-fluoro)phenyl]pyraz ole (SC 58125) and (2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide (NS 398) that inhibit COX-2 catalytic activity, these antioxidants decreased COX-2 expression at the transcriptional level. Combined treatment of HCA-7 cells with PDTC and SC 58125 resulted in an additive decrease in PG levels and anchorage-dependent and -independent growth. Furthermore, whereas antioxidants or SC 58125 reduced tumor growth in vivo, coadministration of PDTC and SC 58125 resulted in actual tumor regression. These results suggest that combined therapy with NSAIDs and antioxidants might be useful in the prevention and/or treatment of CRC.


Effect of cigarette smoking on semen quality of infertile men.
Defective sperm quality is a significant cause of infertility. It is known that cigarette smoking affects semen quality. Our aim was to compare the semen of infertile cigarette smokers with infertile non-smokers to study the effect of smoking on semen quality. Semen samples of 100 cigarette smokers and 100 strictly non-smoking primary infertility patients were included in the study, following stringent exclusion criteria. Smokers were categorised as light, moderate and heavy smokers. Semen samples were examined for asthenozoospermia, oligozoospermia and teratozoospermia, according to World Health Organisation guidelines. 39 percent of non-smokers showed normozoospermia, while only three percent of smokers were normozoospermics. Light smokers predominantly showed asthenozoospermia. Heavy smokers showed asthenozoospermia, teratozoospermia and oligozoospermia. Statistical analysis using Fisher's exact test showed that the incidence of both isolated asthenozoospermia (p-value is 0.0015) and asthenozoospermia with teratozoospermia (p-value is 0.0106) among smokers was significant, in comparison to non-smokers. Overall impact of asthenozoospermia (p-value is less than 0.0001) and teratozoospermia (p-value is 0.0328) but not of oligozoospermia was observed on the semen quality in smokers, compared with non-smokers. Asthenozoospermia, the most common semen variable in our study, can be an early indicator of reduction in quality of semen, as seen in light smokers. In addition, heavy smoking produces teratozoospermia, which further reduces semen quality. Oligozoospermia may be due to factors other than smoking.


The contribution of active case detection to malaria elimination in Thailand.
Thailand's malaria surveillance system complements passive case detection with active case detection (ACD), comprising proactive ACD (PACD) methods and reactive ACD (RACD) methods that target community members near index cases. However, it is unclear if these resource-intensive surveillance strategies continue to provide useful yield. This study aimed to document the evolution of the ACD programme and to assess the potential to optimise PACD and RACD. This study used routine data from all 6 292 302 patients tested for malaria from fiscal year 2015 (FY15) to FY21. To assess trends over time and geography, ACD yield was defined as the proportion of cases detected among total screenings. To investigate geographical variation in yield from FY17 to FY21, we used intercept-only generalised linear regression models (binomial distribution), allowing random intercepts at different geographical levels. A costing analysis gathered the incremental financial costs for one instance of ACD per focus. Test positivity for ACD was low (0.08%) and declined over time (from 0.14% to 0.03%), compared with 3.81% for passive case detection (5.62%-1.93%). Whereas PACD and RACD contributed nearly equal proportions of confirmed cases in FY15, by FY21 PACD represented just 32.37% of ACD cases, with 0.01% test positivity. Each geography showed different yields. We provide a calculator for PACD costs, which vary widely. RACD costs an expected US$226 per case investigation survey (US$1.62 per person tested) or US$461 per mass blood survey (US$1.10 per person tested). ACD yield, particularly for PACD, is waning alongside incidence, offering an opportunity to optimise. PACD may remain useful only in specific microcontexts with sharper targeting and implementation. RACD could be narrowed by defining demographic-based screening criteria rather than geographical based. Ultimately, ACD can continue to contribute to Thailand's malaria elimination programme but with more deliberate targeting to balance operational costs.


RalA function in dermal fibroblasts is required for the progression of squamous cell carcinoma of the skin.
A large body of evidence has shown that stromal cells play a significant role in determining the fate of neighboring tumor cells through the secretion of various cytokines. How cytokine secretion by stromal cells is regulated in this context is poorly understood. In this study, we used a bioengineered human tissue model of skin squamous cell carcinoma progression to reveal that RalA function in dermal fibroblasts is required for tumor progression of neighboring neoplastic keratinocytes. This conclusion is based on the observations that suppression of RalA expression in dermal fibroblasts blocked tumorigenic keratinocytes from invading into the dermal compartment of engineered tissues and suppressed more advanced tumor progression after these tissues were transplanted onto the dorsum of mice. RalA executes this tumor-promoting function of dermal fibroblasts, at least in part, by mediating hepatocyte growth factor (HGF) secretion through its effector proteins, the Sec5 and Exo84 subunits of the exocyst complex. These findings reveal a new level of HGF regulation and highlight the RalA signaling cascade in dermal fibroblasts as a potential anticancer target.


Are postoperative activity restrictions necessary after posterior lumbar discectomy? A prospective study of outcomes in 50 consecutive cases.
A prospective clinical trial was conducted. To determine if removing activity restrictions after surgery and encouraging early return to work would affect clinical outcomes after lumbar discectomy. Current practice usually recommends several weeks to months of restricted activities after lumbar discectomy. No formal studies have been done to determine the optimal period of restriction, if any, after surgery. Fifty consecutive patients undergoing limited open discectomy for herniated lumbar intervertebral disc were prospectively treated with no restrictions at all after surgery and were urged to return to full activities as soon as possible. The patients were followed for a minimum of 2 years. At follow-up evaluation, an independent examiner evaluated each patient. The mean time from surgery to return to work was 1,7 weeks. Eleven of 44 (25%) patients returned to work on the next work day. Ninety-seven percent of patients who were working before surgery returned to their previous work. Forty-three of 44 (97%) patients had returned to full duty by 8 weeks after surgery. At follow-up evaluation (3.8 years), five patients had changed work; three patients increased their work level, and two decreased their work level. No patient changed employment because of back or leg pain. There were three reherniations at the operative level (6%), all occurring more than 1 year after surgery. One patient required reoperation. Back and leg pain scores at follow-up evaluation were very low. Lifting of postoperative restrictions after limited discectomy allowed shortened sick leave without increased complications. Postoperative precautions in these patients may not be necessary.


Evaluation of standardized ileal digestibility of amino acids and metabolic availability of methionine, using the indicator amino acid oxidation method, in black soldier fly larvae (Hermetia illucens) meal fed to growing pigs.
Standardized ileal digestibility (SID, %) of crude protein (CP) and amino acid (AA) and the metabolic availability (MA) of Met using the indicator amino acid oxidation (IAAO) method, in partially defatted black soldier fly larvae (PD-BSFL) meal were determined in growing pigs in 2 experiments. The Met SID value was then compared numerically with the Met MA to understand how different SID is compared with its MA value. In Exp. 1, 6 ileal-cannulated barrows (initial body weight [BW] = 18.03 ± 0.34 kg) were used in a 2-period switch back design and fed either a nitrogen-free diet (NFD) or test diet, with PD-BSFL meal as the sole source of AA, over two 11-d experimental periods, at a feeding level of 2.8 × estimated maintenance digestible energy requirement. Barrows were adapted for 9-d to the diet, followed by continuous 8-h ileal digesta collection on day 10 and 11. Digesta were pooled per pig within period. The SID of CP and Met of PD-BSFL meal were 76.1 ± 6.2% and 90.4 ± 3.9%, respectively. In Exp. 2, 7 barrows (initial BW = 18.77 ± 0.69 kg) were used in a 7 × 7 Latin square design with L-[1-13C]-Phe as the indicator AA. Each pig was randomly assigned to 1 of 7 dietary treatments over seven 3-d experimental periods. Two diet types were studied including reference (crystalline AA) and PD-BSFL test diets, each supplying graded intakes of Met at 55, 65, and 75% of the estimated SID requirement (NRC, 2012). The MA of Met was determined by comparing the IAAO response between the reference and PD-BSFL test diet using the slope-ratio method. Linear regression determined a negative slope of the best fit line for both the reference and test diets (P < 0.05). The MA of Met in PD-BSFL meal was 53.3%, which is as expected lower than the SID value. While it is generally appreciated that MA will be less than SID, the use of SID is more practical. In cases where SID cannot explain physiological outcomes of feeding a novel ingredient, IAAO may provide additional insight into whether MA should be explored.


Constrained nonlinear optimization approaches to color-signal separation.
Separating a color signal into illumination and surface reflectance components is a fundamental issue in color reproduction and constancy. This can be carried out by minimizing the error in the least squares (LS) fit of the product of the illumination and the surface spectral reflectance to the actual color signal. When taking in account the physical realizability constraints on the surface reflectance and illumination, the feasible solutions to the nonlinear LS problem should satisfy a number of linear inequalities. Four distinct novel optimization algorithms are presented to employ these constraints to minimize the nonlinear LS fitting error. The first approach, which is based on Ritter's superlinear convergent method (Luengerger, 1980), provides a computationally superior algorithm to find the minimum solution to the nonlinear LS error problem subject to linear inequality constraints. Unfortunately, this gradient-like algorithm may sometimes be trapped at a local minimum or become unstable when the parameters involved in the algorithm are not tuned properly. The remaining three methods are based on the stable and promising global minimizer called simulated annealing. The annealing algorithm can always find the global minimum solution with probability one, but its convergence is slow. To tackle this, a cost-effective variable-separable formulation based on the concept of Golub and Pereyra (1973) is adopted to reduce the nonlinear LS problem to be a small-scale nonlinear LS problem. The computational efficiency can be further improved when the original Boltzman generating distribution of the classical annealing is replaced by the Cauchy distribution.


Hepatitis C virus proteins inhibit C3 complement production.
The third component of human complement (C3) plays a central role in innate immune function as its activation is required to trigger classical as well as alternative complement pathways. In this study, we have observed that sera from patients chronically infected with hepatitis C virus (HCV) displayed significantly lower C3 levels than sera from healthy individuals. Liver biopsy specimens from the same patients also exhibited lower C3 mRNA expression than liver tissues from healthy donors. C3 mRNA level was reduced in hepatocytes upon infection with cell culture-grown HCV genotype 1a or 2a in vitro. Further analysis suggested that HCV core protein displayed a weak repression of C3 promoter activity by downregulating the transcription factor farnesoid X receptor (FXR). On the other hand, HCV NS5A protein strongly downregulated C3 promoter activity at the basal level or in the presence of interleukin-1β (IL-1β) as an inducer. In addition, the expression of the transcription factor CAAT/enhancer binding protein beta (C/EBP-β), which binds to the IL-1/IL-6 response element in the C3 promoter, was inhibited in liver biopsy specimens. Furthermore, expression of C/EBP-β was reduced in hepatocytes infected with cell culture-grown HCV, as well as in hepatocytes transfected with the NS5A genomic region of HCV. Together, these results underscore the role of HCV NS5A protein in impairing innate immune function.


Machine learning to improve the interpretation of intercalating dye-based quantitative PCR results.
This study aimed to evaluate the contribution of Machine Learning (ML) approach in the interpretation of intercalating dye-based quantitative PCR (IDqPCR) signals applied to the diagnosis of mucormycosis. The ML-based classification approach was applied to 734 results of IDqPCR categorized as positive (n = 74) or negative (n = 660) for mucormycosis after combining "visual reading" of the amplification and denaturation curves with clinical, radiological and microbiological criteria. Fourteen features were calculated to characterize the curves and injected in several pipelines including four ML-algorithms. An initial subset (n = 345) was used for the conception of classifiers. The classifier predictions were combined with majority voting to estimate performances of 48 meta-classifiers on an external dataset (n = 389). The visual reading returned 57 (7.7%), 568 (77.4%) and 109 (14.8%) positive, negative and doubtful results respectively. The Kappa coefficients of all the meta-classifiers were greater than 0.83 for the classification of IDqPCR results on the external dataset. Among these meta-classifiers, 6 exhibited Kappa coefficients at 1. The proposed ML-based approach allows a rigorous interpretation of IDqPCR curves, making the diagnosis of mucormycosis available for non-specialists in molecular diagnosis. A free online application was developed to classify IDqPCR from the raw data of the thermal cycler output ( http://gepamy-sat.asso.st/ ).


Treatment of intestinal parasitic disease.
Although improved sanitation in the United States has resulted in a general diminution in the prevalence of intestinal parasitic infections, some, such as enterobiasis, are not reduced by improved environmental or water sanitation and others, such as amebiasis and hookworm infection, persist in foci. Other infections, notably giardiasis, have increased due to the travels of American tourists in other countries where environmental sanitation is poor. North American physicians, therefore, may expect at some time to have to treat parasitic infections. Favored chemotherapeutic agents currently are: for amebiasis--metronidazole and diiodohydroxyquin; for giardiasis--metronidazole; for tapeworm infections--niclosamide; for enterobiasis--pyrantel pamoate, piperazine citrate, or pyrvinium pamoate; for ascariasis--piperazine citrate; for stronglyoidiasis--thiabendazole; for trichuriasis--mebendazole; for hookworm infection--pyrantel pamoate; for schistosomiasis japonica--tartar emetic; and for schistosomiasis mansoni--niridazole.


Extracellular matrix proteins (fibronectin, laminin, and type IV collagen) bind and aggregate bacteria.
The normal microbial colonization of sites in the body's tissues by certain bacteria requires that the bacteria first bind to extracellular secreted constituents, cell-surface membranes, or cell matrixes. This study examines two interactions of a variety of bacteria with the cell matrix noncollagenous proteins fibronectin and laminin and with basement membrane (Type IV) collagen. Adherence of bacteria to matrix proteins coated on tissue culture wells was examined with the use of radiolabeled bacteria. Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus sanguis bound well to fibronectin, laminin, and Type IV collagen, whereas a variety of gram-negative organisms did not bind. The interaction of soluble laminin, fibronectin, and Type IV collagen with bacteria was monitored by nephelometry with the use of a platelet aggregometer. S. aureus aggregated in response to fibronectin, laminin, or Type IV collagen. In contrast, gram-negative organisms did not aggregate with these proteins. It appears that fibronectin, laminin, and Type IV collagen can bind and aggregate certain gram-positive bacteria, and this binding is dependent on the surface characteristics of the organism. These adhesion molecules may play a role in the normal colonization of sites by microorganisms and in invasion during infections.


Quantitation of hemorrhagic enteritis virus antigen and antibody using enzyme-linked immunosorbent assays.
Enzyme-linked immunosorbent assays (ELISAs) were developed to quantitate hemorrhagic enteritis virus (HEV) antibodies in turkey sera and HEV antigens in tissue extracts. These assays were more sensitive than the commonly used agar-gel precipitin tests in detecting antigen and antibody. The antibody-ELISA was used to monitor the presence and decline of passive antibodies in turkey poults and the seroconversion of turkeys infected with HEV. The antigen-ELISA was carried out using a monoclonal antibody; this test was used to quantitate HEV antigen in experimentally infected turkeys in a time-sequence experiment. Both ELISAs measured a strong antigenic relationship between an avirulent strain (HEV-A) and a virulent strain (HEV-V).


Persistent pulmonary hypertension after maternal naproxen ingestion in a term newborn: a case report.
Constricting effect of indomethacin on the ductus arteriosus of the fetus is well known. The fetal effects of other nonsteroid anti-inflammatory drugs (NSAIDs) like naproxen are not well reported. We report here a case of a 3,790-g term neonate who developed persistent pulmonary hypertension after birth with a closed ductus arteriosus. The mother admitted to taking naproxen sodium immediately prior to the birth of the infant. The course of illness was progressively better on conservative management. Like indomethacin, other NSAIDs can also cause premature closure of fetal ductus arteriosus, pulmonary hypertension, and life-threatening problems to the neonate. Patient education regarding over-the-counter pain medication during pregnancy should be emphasized.


The relationship between out-of-school activities and positive youth development: an investigation of the influences of communities and family.
There is growing evidence that participation in constructive leisure activities facilitates positive youth development. Empirical evidence also supports the influence of families and communities on positive developmental outcomes for adolescents. This study examined the relationship among attitudes toward family and community, participation in structured out-of-school activities, and pro-social behavior. As predicted, community aspects such as opportunities available and the attitudes the youth held toward the community, as well as their attitude toward family were predictive of activity involvement. Activity involvement, in turn, was predictive of pro-social behavior. Attitude toward family was also predictive of attitude toward the community. Attitude toward community was a direct predictor of the positive developmental outcome of pro-social behavior, although contrary to the original hypothesis, family influences did not have a direct effect on pro-social behavior. Implications for continued practice and change for a variety of sectors in the positive youth development field such as educators and educational institutions, youth-serving organizations, families, and policy makers are discussed, along with recommendations for continued research in this field.


Time-dependent increase in nitric oxide formation concurrent with vasodilation induced by sodium nitroprusside, 3-morpholinosydnonimine, and S-nitroso-N-acetylpenicillamine but not by glyceryl trinitrate.
Nitrovasodilators is a term used to describe a diverse group of agents believed to exert their vasodilator effect by a common mechanism, namely formation of nitric oxide. The objective of the present study was to test this concept by comparing the magnitude of nitric oxide formation from four representative nitrovasodilators incubated in the presence of rabbit aortic strips (RAS) with the magnitude of nitrovasodilator-induced relaxation of RAS, over the time course of relaxation. The RAS were incubated in anaerobic condition with 100 microM either sodium nitroprusside, glyceryl trinitrate (GTN), 3-morpholinosydnonimine, or S-nitroso-N-acetylpenicillamine in Krebs' solution. Relaxation of RAS by each of the four drugs started at approximately 10 sec and increased with incubation time. Formation of nitric oxide was measurable using a chemiluminescence-headspace-gas method at 0.5 min with sodium nitroprusside, 3-morpholinosydnonimine, and S-nitroso-N-acetylpenicillamine, and formation increased concurrently with relaxation of RAS. In contrast, formation of nitric oxide from GTN was not measurable until 5 min, at which time GTN-induced relaxation of RAS was nearly complete. These data support the concept that sodium nitroprusside, 3-morpholinosydnonimine, and S-nitroso-N-acetylpenicillamine are nitrovasodilator drugs acting via formation of nitric oxide. However, the present study suggests that the mechanism of action for GTN-induced vasodilation may involve the formation of a nitric oxide-adduct, such as a nitrosothiol, rather than nitric oxide per se.


Right Ventricular Failure and Congenital Heart Disease.
Survivorship into adulthood of patients with congenital heart disease is due to improvements in prenatal detection, novel surgeries, and specialized adult congenital heart disease care. As patients survive further into adulthood, long-term complications of congenital and repaired physiology have been more clearly elucidated. The overall mortality of patients with adult congenital heart disease with heart failure is around 4%. Congenital malformations, palliations, residual defects, and resultant physiology impact the right ventricle. This relationship influences morbidity and mortality. For this discussion, focus on atrial septal defects, Ebstein anomaly, Tetralogy of Fallot, transposition of the great vessels, and single right ventricle physiology.


[Effect of thermal treatment of potato products on nutrient decomposition in the digestive tract of swine. 2. Nutrient content and bacterial activity in various parts of the intestine].
Dry matter (DM), starch, crude protein (CP), amino acids (AA) and diaminopimelic acid (DAPA) were estimated in the contents of the digestive tract of slaughtered pigs, which were fed a basal diet with raw (rKSt) or with cooked (QuSt) potato starch. When fed rKSt, there was larger quantities of starch and DAPA in the content of the distal small intestine and also of DM, CP, AA and DAPA in the contents of caecum and proximal colon, compared to QuSt. The bacterial breakdown of the raw potato starch granules in the proximal large intestine is shown by microscopic examinations. It is suggested, that the quantity of bacterial protein excreted in the faeces did not allow to quantify the extent of the bacterial activity in the different segments of the digestive tract.


Phenotypic differences in mephenytoin pharmacokinetics in normal subjects.
The urinary metabolic profile of mephenytoin and its oxidative metabolites indicates significant stereoselective metabolism of its two enantiomers. Also, polymorphic oxidation, which is present in about 2 to 5% of the Caucasian population, has been demonstrated by an impaired ability to 4-hydroxylate this anticonvulsant. In order to determine the consequences of such metabolism, the plasma concentration/time profiles of the enantiomers of mephenytoin and its N-demethylated metabolite, phenylethylhydantoin (PEH), were investigated after a single p.o. dose of racemic mephenytoin in normal subjects with different metabolizing ability for mephenytoin [extensive metabolizer (EM) vs. poor metabolizer (PM) phenotypes]. In the EM subjects, the disposition of S- and R-mephenytoin was markedly different with a 100- to 200-fold difference in mean oral clearance (4.7 vs. 0.027 liters/min) and a 30- to 40-fold difference in elimination half-life (2.1 vs. 76 hr). In these same subjects, R-PEH concentrations significantly accumulated over several days and then very slowly declined with an apparent half-life of about 200 hr. Plasma levels of S-PEH were essentially negligible. In contrast, the stereoselective elimination of mephenytoin was reduced markedly in subjects of the PM phenotype, with the disposition of the S-enantiomer being the same as that for R-mephenytoin, which in turn was similar to that observed for this enantiomer in EMs. Almost comparable plasma levels of S- and R-PEH were also present in PMs. Only a small amount (less than 5%) of unchanged mephenytoin was excreted in the urine regardless of phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)


[Treatment of supracondyloid fractures of the femur with Judet's bone plate and screws].
Severe fractures of the distal end of the femur, which have become increasingly numerous as a result of the multiplication of road accidents, frequently require surgical treatment. The Authors, updating to 1979 the cases of the "G. Pini" Orthopedic Institute in the field of Judet's screw-plate, document the validity of this means of synthesis as confirmed by the quality of the results.


An efficacy and safety evaluation of montelukast + fluticasone propionate vs. fluticasone propionate in the treatment of cough variant asthma in children: a meta-analysis.
This study aimed to evaluate the efficacy and safety of montelukast (Mon) + fluticasone propionate (Flu) versus Flu in the treatment of cough variant asthma (CVA) in children. Eligible documents were selected from various databases. Weighted mean difference (WMD) and 95% confidence interval (CI) were used to evaluate continuous variables, and categorical variables were evaluated using risk ratio (RR) and 95% CI. Heterogeneity analysis was performed using Cochran's Q test and I2 statistics, followed by sensitivity analysis and publication bias evaluation. Nine studies were included, and Flu + Mon was found to significantly improve the total effective rate and reduce cough recurrence compared to Flu. The cough remission and disappearance times in the Mon + Flu group were significantly lower than those in the Flu group. FEV1% recovery in the Mon + Flu group was significantly better than that in the Flu group. Mon + Flu is effective and safe for the treatment of CVA in children.


Ezrin is highly expressed in early thymocytes, but dispensable for T cell development in mice.
Ezrin/radixin/moesin (ERM) proteins are highly homologous proteins that function to link cargo molecules to the actin cytoskeleton. Ezrin and moesin are both expressed in mature lymphocytes, where they play overlapping roles in cell signaling and polarity, but their role in lymphoid development has not been explored. We characterized ERM protein expression in lymphoid tissues and analyzed the requirement for ezrin expression in lymphoid development. In wildtype mice, we found that most cells in the spleen and thymus express both ezrin and moesin, but little radixin. ERM protein expression in the thymus was differentially regulated, such that ezrin expression was highest in immature thymocytes and diminished during T cell development. In contrast, moesin expression was low in early thymocytes and upregulated during T cell development. Mice bearing a germline deletion of ezrin exhibited profound defects in the size and cellularity of the spleen and thymus, abnormal thymic architecture, diminished hematopoiesis, and increased proportions of granulocytic precursors. Further analysis using fetal liver chimeras and thymic transplants showed that ezrin expression is dispensable in hematopoietic and stromal lineages, and that most of the defects in lymphoid development in ezrin(-/-) mice likely arise as a consequence of nutritional stress. We conclude that despite high expression in lymphoid precursor cells, ezrin is dispensable for lymphoid development, most likely due to redundancy with moesin.


Comparison of pancreatic histology specimens obtained by EUS 19G versus 22G core biopsy needles: A prospective multicentre study among experienced pathologists.
Scanty data about inter-observer agreement (IOA) among pathologists in the evaluation of pancreatic samples acquired with EUS histology needle are available. The aim of this study was to determine IOA on adequacy of pancreatic histology specimens obtained with a 22G needle by a panel of experienced pathologist, in comparison with the 19G needle. This multicentre prospective study involved 73 pancreatic specimens prepared using histology needles of different calibres. Five pathologists independently reviewed all the samples, assessing the presence of a core, specimen adequacy and the possibility to perform additional analyses. IOA determined by Fleiss' Kappa statistic was used as the primary outcome measure. Secondary outcome was to compare 22G versus 19G needle results. A core was present in 57% of pancreatic specimens obtained by 22G needle. The specimens were considered adequate in 72% of cases, with poor agreement among pathologists (p = 0.02, Fleiss' κ = 0.26). The possibility to perform further analyses was rated as 'positive' in 66% of cases without significant difference among observers (p = 0.80). When comparing the results, the presence of a core and the adequacy of tissue slides were significantly better for the 19G needle (57% vs. 84% p = 0.002; 72% vs. 83% p = 0.004, respectively). Reproducibility in the assessment of pancreatic sample adequacy was significantly better with the 19G needle (κ = 0.26 for 22G samples vs. κ = 0.81 for 19G samples). Our results suggest that histology sampling of pancreatic masses should be performed with a 19G histology needle, since is able to provide a core in the majority of cases, with 83% of adequate specimens and excellent results in term of reproducibility among pathologists.


Snapchat elicits more jealousy than Facebook: a comparison of Snapchat and Facebook use.
Recent news in the media has suggested that younger people are using popular social media such as Facebook less and are quickly adopting newer media, such as the self-destructing app Snapchat. Snapchat is unique in that it erases messages several seconds after they have been sent, affording its users a higher level of privacy. Yet, little research exists on Snapchat use in general, let alone its broader psychological implications. This article offers a preliminary comparison of Snapchat and Facebook use and psychological effects on romantic jealousy. General motives for using Snapchat and Facebook are examined, as well as the nature of the content that Snapchat users most frequently share. Further, because of the differences in privacy and persistence of information, potential psychological effects in the domain of romantic jealousy are also examined, which has been widely studied on Facebook in the last few years. Findings show that the main difference in motives were that Snapchat was used more for flirting and finding new love interests, whereas Facebook was still the main social networking site used for keeping in touch with friends. Further, when presenting users with a series of potentially jealousy provoking scenarios, Snapchat elicited higher levels of jealousy than did Facebook. These findings are explained based on an affordance approach.


Acceptability of prolonged exposure therapy among U.S. Iraq war veterans with PTSD symptomology.
Despite efforts to increase the availability of prolonged exposure therapy (PE) within the Department of Veterans Affairs, little is known about the acceptability of PE among veteran populations. We queried a sample of 58 U.S. National Guard Iraq War veterans previously deployed to combat who screened positive for posttraumatic stress disorder (PTSD) as to whether they would prefer PE, treatment with an antidepressant, or no treatment. We also gathered open-ended responses regarding the veterans' reasons for their choice and potential barriers to engaging in that treatment. A majority (53.4%) of veterans who completed the interview said they would choose to participate in PE, 36.2% preferred antidepressant treatment, 8.6% chose no treatment, and 1.8% were unable to choose among the options. Credibility of the treatment rationale and beliefs about the treatment's efficacy were the most frequently given reasons for choosing PE (45.2%); past treatment experience was the most common reason for choosing antidepressant treatment (47.6%). The most commonly cited barrier for those who chose both antidepressant treatment and PE was time to participate (52.4% and 77.4%, respectively). The findings suggest that PE is a credible and acceptable treatment option for veterans with PTSD symptomology.


Newer Stents: Materials and Designs.
We aim to present here the experience with newer stents for coronary and peripheral interventions. Specifically, the design and technical considerations of the self-expanding nitinol coil stents for coronary and vascular indications, as well as the design and clinical experience with the tubular stainless steel balloon-expandable serpentine stents for coronary and peripheral interventions are discussed. The animal and clinical experience with both types of stent have shown that the mechanisms of deployment and expansion are different for these inherently different stents. The self-expanding coil stent, providing adequate scaffolding in various types of coronary lesions is deployed by self expansion, aided to a significant extent by balloon expansion. Long-term outside pressure on the wall may lead to further stent expansion as has been shown with this stent, which may be an important parameter in the restenosis process. The tubular balloon-expandable serpentine stent does not have the feature of long-term expansion, however, is characterized by superior scaffolding properties and unique features that allow its safe use in the most complex coronary diseases. Long-term clinical results are pending for these two families of stents.


Grading lung neuroendocrine tumors: Controversies in search of a solution.
Pathological grading of tumors is a way to measure biological aggressiveness. In lung neuroendocrine tumors (NET), grading is tautologically included into the current 2015 WHO histologic classification. Little is known, however, about alternative grading systems in lung NET. Through an extensive search of the English literature on lung NET (updated to April 2016), the following key questions were addressed: a) current concepts of grading; b) clinicians' requests for grading; c) functional parameters for grading; d) Ki-67 labeling index (LI) for grading; e) towards an effective pathology grading system. There is some room for inconsistency in the histologic classification of lung NET, likely due to the varying attribution of defining criteria. Innovative diffusion-weighted imaging upon magnetic resonance or molecular analysis could help separate indolent from aggressive lung NET, thus integrating a grading approach other than histology. Troubles in the clinical handling of metastatic or individual tumors when relying on morphology alone support the development of a lung-specific grading system for the more accurate prediction of prognosis and planning therapy in individual patients. To integrate the 2015 WHO classification using innovative grading based on Ki-67 LI, mitotic count and necrosis, a new proposal is emerging where three categories of lung NET are identified, namely Lu-NET G1, Lu-NET G2 and Lu-NET G3, which would allow tumors with similar behavior and therapy to be better handled according to their own biological potential. This new formulation of lung NET grading could have clinical relevance for the individual handling of patients.


Implementation of a hepatitis A prevention policy in haemophiliacs: results from the French cohort.
In the early nineties, the occurrence of hepatitis A outbreaks in some patients with haemophilia in some countries led French health authorities to recommend hepatitis A virus (HAV) vaccination in HAV-seronegative haemophiliacs. The French 'Suivi thérapeutique National des Hémophiles' cohort permitted to assess the implementation of this recommendation by the analysis of the vaccinal process, i.e. HAV seropositivity assessment and vaccination of HAV-seronegative patients, in a survival approach. In a subgroup of 812 patients diagnosed earlier than 1990 (prevalent cohort), the implementation of vaccinal process increased quickly from 0% in 1993 to 41.8% in 1994 and to 71.2% in 1996, suggesting a 'notification effect'. The vaccinal process was associated to three cofactors in a Cox model analysis (age, severity of haemophilia, centre of treatment). No infection was observed during the survey in this group. In another subgroup of 201 boys born since 1993 (incident cohort), 27.5% and 15.4% patients remained exposed to the risk at 3 and 5 years from diagnosis respectively, again with a 'centre effect', which might be linked to various factors such as regain in confidence for products or economic reasons. Only five infectious seroconversions were assessed over the 7-year survey, which represents 14.5 cases per 1000 person-year incidence without any relationship with products. Our data combined with the contemporary hepatitis A epidemiology and the current safety of anti-haemophilic concentrates, should lead to a new assessment of the risk of hepatitis A in haemophiliacs. We suggest that among patients with bleeding disorder, as well as in other populations, HAV prevention policy might be stressed on those who already suffer from chronic liver disease and/or travel in endemic countries.


Why do slim women consider themselves too heavy? A characterization of adult women considering their body weight as too heavy.
The purpose of this study was to characterize women who, in spite of a low body mass index (BMI), considered themselves too heavy. Of 11,905 women (27-38 years of age), we focused on 2,443 nonpregnant women with a low BMI (18.5-21.0 kg/m(2)), who considered their weight acceptable or too heavy. Participants completed a comprehensive questionnaire. By multiple logistic regression we examined associations between lifestyle and health variables and the risk of considering own body weight too heavy. Approximately 10 % considered their body weight too heavy. Risk factors included early severe life events, young age at start of risky lifestyle behaviors, weight fluctuation, self-reported lifetime history of eating disorders, perception of too heavy workload, and poor physical form and self-rated health. Body dissatisfaction decreased with increasing age. Our results indicate that body dissatisfaction is established in childhood and adolescence. It is unknown if this body dissatisfaction influences the life of the women, but it might influence the values they pass on to their children.


Nonspecific and cooperative binding of lectins to microorganisms.
Binding of lectins to microbial cell walls was investigated by fluorimetric titration and Scatchard plot. Data were correlated with agglutinability. Concanavalin A and lectins of wheat germ, soybean, pea, lentil, and peanut were tested against Escherichia coli. Micrococcus luteus, Lactobacillus plantarum, and Bacillus subtilis. In cases where binding occurred, it was either nonspecific or positively cooperative. Agglutination was observed only in those combinations of lectin and microorganism that showed positive cooperative binding, suggesting a definite relation between binding and agglutination. Lectins binding to the same carbohydrate did not necessarily bind to the same microorganism, confirming the complexity of the lectin-receptor bond.


[Clinical and economic aspects of laparoscopic surgery for acute cholecystitis in delayed presentation].
To study the clinical and economic features of laparoscopic surgery for acute cholecystitis in delayed presentation. A prospective non-randomized study (2020-2021) included 101 patients (73.2% (n=74) men and 26.8% (n=27) women, mean age 58±14.9 years) with acute cholecystitis who underwent laparoscopic cholecystectomy. Cost-effectiveness analysis of laparoscopic cholecystectomy at various periods after clinical manifestation was performed. Surgical treatment within 72 hours was performed in 15% (n=16) of cases (group 1), within 4-10 days - in 57.5% (n=58) (group 2), after 10 days - in 26.7% (n=27) of patients (group 3). Overall incidence of postoperative complications was 2.9%, postoperative mortality - 1.9% (two patients died from widespread peritonitis). Surgery time was 70 [65-83], 85 [69-110] and 115 [80-125] min (H=15.55, p<0.001), hospital-stay - 6 [5-7], 9 [7-10] and 11 [7-14] days, respectively (H=21.86, p<0.001). Cost of direct (medical and non-medical) treatment amounted to 29484 [27 509-33 885], 41265 [34 306-48 301] and 50591 [37 069-62 483] rubles, respectively (H=29.71, p<0.001)). Delayed hospitalization and surgical treatment of acute cholecystitis after 72 hours are accompanied by higher treatment costs by 29% in the period up to 10 days and by 58% after 10 days. These results require further validation and adjustment in large samples.


A mouse model for intellectual disability caused by mutations in the X-linked 2'‑O‑methyltransferase Ftsj1 gene.
Mutations in the X chromosomal tRNA 2'‑O‑methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143. Apart from an impaired learning capacity these mice presented with several statistically significantly altered features related to behaviour, pain sensing, bone and energy metabolism, the immune and the hormone system as well as gene expression. These findings show that Ftsj1 deficiency in mammals is not phenotypically restricted to the brain but affects various organ systems. Re-examination of ID patients with FTSJ1 mutations from two previously reported families showed that several features observed in the mouse model were recapitulated in some of the patients. Though the clinical spectrum related to Ftsj1 deficiency in mouse and man is variable, we suggest that an increased pain threshold may be more common in patients with FTSJ1 deficiency. Our findings demonstrate novel roles for Ftsj1 in maintaining proper cellular and tissue functions in a mammalian organism.


Monitoring HIV DNA and cellular activation markers in HIV-infected humanized mice under cART.
The major obstacle to cure of HIV type-1 infection is the presence of the HIV reservoir, hidden from the immune system and insensitive to combined antiretroviral therapy (cART). Eradication approaches have been hindered by the difficulty for accurately monitoring its size in vivo, especially in the lymphoid organs. Humanized mouse models are a valuable tool for systematically assess the efficacy of therapeutic interventions in reducing the HIV reservoir. Nonetheless, persistence of the HIV reservoir over time, in the presence of cART, has yet to be analyzed in this in vivo model. We found that the proviral DNA as well as the total DNA were very stable in the spleen and mesenteric lymph node irrespective of the length of cART. Notably, the amount of proviral DNA was very similar in the spleen and lymph node. Furthermore, we observed a correlation between the percentage of splenic human CD4+ T-cells with total HIV DNA, between the number of human CD38 + CD8+ T-cells in the spleen with the amount of integrated HIV DNA, and eventually between the hCD4/hCD8 ratio in the spleen with integrated as well as total HIV DNA implying that the CD8+ T cells influence the size of the HIV reservoir. Here, we demonstrated the stability of this reservoir in humanized mice irrespective of the length of cART, confirming the relevancy of this model for HIV latency eradication investigations. Notably, we also found correlates between the frequency of CD4+ T-cells, their activation status and viral parameters, which were analogous to the ones in HIV-infected patients. Thus, hu-mice represent a very valuable HIV latency model.


Effects of Climate Variability on Malaria Transmission in Southern Côte d'Ivoire, West Africa.
Malaria continues to be a major public health concern with a substantial burden in Africa. Even though it has been widely demonstrated that malaria transmission is climate-driven, there have been very few studies assessing the relationship between climate variables and malaria transmission in Côte d'Ivoire. We used the VECTRI model to predict malaria transmission in southern Côte d'Ivoire. First, we tested the suitability of VECTRI in modeling malaria transmission using ERA5 temperature data and ARC2 rainfall data. We then used the projected climatic data pertaining to 2030, 2050, and 2080 from a set of 14 simulations from the CORDEX-Africa database to compute VECTRI outputs. The entomological inoculation rate (EIR) from the VECTRI model was well correlated with the observed malaria cases from 2010 to 2019, including the peaks of malaria cases and the EIR. However, the correlation between the two parameters was not statistically significant. The VECTRI model predicted an increase in malaria transmissions in both scenarios (RCP8.5 and RCP4.5) for the time period 2030 to 2080. The monthly EIR for RCP8.5 was very high (1.74 to 1131.71 bites/person) compared to RCP4.5 (0.48 to 908 bites/person). These findings call for greater efforts to control malaria that take into account the impact of climatic factors.


Quality Assurance in Clinical Chemistry: A Touch of Statistics and A Lot of Common Sense.
Working in laboratories of clinical chemistry, we risk feeling that our personal contribution to quality is small and that statistical models and manufacturers play the major roles. It is seldom sufficiently acknowledged that personal knowledge, skills and common sense are crucial for quality assurance in the interest of patients. The employees, environment and procedures inherent to the laboratory including its interactions with the clients are crucial for the overall result of the total testing chain. As the measurement systems, reagents and procedures are gradually improved, work on the preanalytical, postanalytical and clinical phases is likely to pay the most substantial dividends in accomplishing further quality improvements. This means changing attitudes and behaviour, especially of the users of the laboratory. It requires understanding people and how to engage them in joint improvement processes. We need to use our knowledge and common sense expanded with new skills e.g. from the humanities, management, business and change sciences in order to bring this about together with the users of the laboratory.


Molecular diversity and selective sweeps in maize inbred lines adapted to African highlands.
Little is known on maize germplasm adapted to the African highland agro-ecologies. In this study, we analyzed high-density genotyping by sequencing (GBS) data of 298 African highland adapted maize inbred lines to (i) assess the extent of genetic purity, genetic relatedness, and population structure, and (ii) identify genomic regions that have undergone selection (selective sweeps) in response to adaptation to highland environments. Nearly 91% of the pairs of inbred lines differed by 30-36% of the scored alleles, but only 32% of the pairs of the inbred lines had relative kinship coefficient <0.050, which suggests the presence of substantial redundancy in allelic composition that may be due to repeated use of fewer genetic backgrounds (source germplasm) during line development. Results from different genetic relatedness and population structure analyses revealed three different groups, which generally agrees with pedigree information and breeding history, but less so by heterotic groups and endosperm modification. We identified 944 single nucleotide polymorphic (SNP) markers that fell within 22 selective sweeps that harbored 265 protein-coding candidate genes of which some of the candidate genes had known functions. Details of the candidate genes with known functions and differences in nucleotide diversity among groups predicted based on multivariate methods have been discussed.


Nitrate Radical Induced "Two in One" Interface Engineering toward High Reversibility of Zn Metal Anode.
Advanced interfacial engineering performs a forceful modulation effect on Zn2+ plating/stripping with simultaneous inhibition of hydrogen evolution reaction, chemical corrosion, and dendrite growth, which is responsible for high reversibility of Zn anode. Herein, a "two in one" interface engineering is developed to improve the reversibility of Zn anode, in which multi-functional Zn5 (NO3 )2 (OH)8 ·2H2 O layer and preferential Zn (002) texture are constructed simultaneously. Due to nucleophilicity to Zn2+ arising from electronegativity, the layer can accelerate the desolvation process of [Zn (H2 O)6 ]2+ and transfer kinetics of Zn2+ ions, leading to uniform nucleation and effective inhibition of water-induced side reactions. Meanwhile, the latter is beneficial to guiding Zn (002)-preferred orientation deposition with compact structure. Consequently, the Zn electrodes with such complementary interface modulation exhibit prominent reversibility. With an area capacity of 1 mAh cm-2 at 1 mA cm-2 , the symmetric cell operates steadily for 4000 h. Highly reversible Zn anode is maintained even at 50 mA cm-2 . For full cells coupled with MnO2 cathode, impressive rate capability and cycling stability with a high capacity beyond 100 mAh g-1 at 1 A g-1 after 2000 cycles are achieved. The results provide new insights into Zn anodes with high reversibility for next-generation aqueous zinc ion batteries.


Predictive factors for decreased baseline quality of life in patients with sinonasal malignancies.
The impact of sinonasal malignancies (SNMs) on quality of life (QOL) at presentation is poorly understood. The Sinonasal Outcome Test (SNOT-22) and University of Washington Quality of Life (UWQOL) are validated QOL instruments with distinctive subdomains. This study aims to identify factors impacting pretreatment QOL in SNM patients to personalize multidisciplinary management and counseling. Patients with previously untreated SNMs were prospectively enrolled (2015-2022) in a multicenter observational study. Baseline pretreatment QOL instruments (SNOT-22, UWQOL) were obtained along with demographics, comorbidities, histopathology/staging, tumor involvement, and symptoms. Multivariable regression models identified factors associated with reduced baseline QOL. Among 204 patients, presenting baseline QOL was significantly reduced. Multivariable regression showed worse total SNOT-22 QOL in patients with skull base erosion (p = 0.02). SNOT-rhinologic QOL was worse in women (p = 0.009), patients with epistaxis (p = 0.036), and industrial exposure (p = 0.005). SNOT extranasal QOL was worse in patients with industrial exposure (p = 0.016); worse SNOT ear/facial QOL if perineural invasion (PNI) (p = 0.027). Squamous cell carcinoma pathology (p = 0.037), palate involvement (p = 0.012), and pain (p = 0.017) were associated with worse SNOT sleep QOL scores. SNOT psychological subdomain scores were significantly worse in patients with palate lesions (p = 0.022), skull base erosion (p = 0.025), and T1 staging (p = 0.023). Low QOL was more likely in the presence of PNI on UW health (p = 0.019) and orbital erosion on UW overall (p = 0.03). UW social QOL was worse if palatal involvement (p = 0.023) or PNI (p = 0.005). Our findings demonstrate a negative impact on baseline QOL in patients with SNMs and suggest sex-specific and symptom-related lower QOL scores, with minimal histopathology association. Anatomical tumor involvement may be more reflective of QOL than T-staging, as orbital and skull base erosion, PNI, and palate lesions are significantly associated with reduced baseline QOL.


Single cell, super-resolution imaging reveals an acid pH-dependent conformational switch in SsrB regulates SPI-2.
After Salmonella is phagocytosed, it resides in an acidic vacuole. Its cytoplasm acidifies to pH 5.6; acidification activates pathogenicity island 2 (SPI-2). SPI-2 encodes a type three secretion system whose effectors modify the vacuole, driving endosomal tubulation. Using super-resolution imaging in single bacterial cells, we show that low pH induces expression of the SPI-2 SsrA/B signaling system. Single particle tracking, atomic force microscopy, and single molecule unzipping assays identified pH-dependent stimulation of DNA binding by SsrB. A so-called phosphomimetic form (D56E) was unable to bind to DNA in live cells. Acid-dependent DNA binding was not intrinsic to regulators, as PhoP and OmpR binding was not pH-sensitive. The low level of SPI-2 injectisomes observed in single cells is not due to fluctuating SsrB levels. This work highlights the surprising role that acid pH plays in virulence and intracellular lifestyles of Salmonella; modifying acid survival pathways represents a target for inhibiting Salmonella.


The psychological symptom burden in partners of pancreatic cancer patients: a population-based cohort study.
Pancreatic cancer (PC) has high morbidity and mortality and is stressful for patients and their partners. We investigated the psychological symptom burden in partners of PC patients. We followed 5774 partners of PC patients diagnosed from 2000 to 2016 up for first redeemed prescriptions of antidepressants or hospital admission, anxiolytics, and hypnotics as proxies for clinical depression, anxiety, and insomnia and compared them with 59,099 partners of cancer-free spouses. Data were analysed using Cox regression and multistate Markov models. The cumulative incidence proportion of first depression was higher in partners of PC patients compared to comparisons. The highest adjusted HR of first depression was seen the first year after diagnosis (HR 3.2 (95% CI: 2.9; 3.7)). Educational level, chronic morbidity, and bereavement status were associated with an increased risk of first depression. There was a significantly higher first acute use (1 prescription only) of both anxiolytics and hypnotics and chronic use (3+ prescriptions) of hypnotics in partners of PC patients than in comparisons. Being a partner to a PC patient carries a substantial psychological symptom burden and increases the risk for first depression and anxiolytic use and long-term use of hypnotics. Attention should be given to the psychological symptom burden of partners of PC patients, as this may pose a barrier for the optimal informal care and support of the PC patient, as well as a risk for non-optimal management of symptoms in the partner.


[Using nanotechnology and nanomaterials in ophthalmology].
Peculiarities of anatomy, histology and physiology of eyes, do not allow to create an effective concentration of a medication in damaged tissues by traditional methods. Therefore, effective remedy delivery to a pathological focus is an current issue for ophthalmologists, pharmacologists and pharmacists. One of the perspective ways to solve this problem is nanotechnology. The use of nanomaterials (nanoparticles, dendrimers, cyclodextrins, liposomes, niosomes, diskomes), medicine formulations (microemulsions, hydrogel systems, nanosuspenisons) and ways of medicine delivery and nanomaterials (contact lenses, microneedles, intraocular implants, iontophoresis), open new possibilities in the treatment of serious eye diseases, such as glaucoma, diabetic retinopathy, macular degeneration, uveitises of different etiology. It will establish new high level therapy standards in ophthalmology in future. Aspects of possible complications and long-term effects of application of these technologies are still poorly explored and need further development and improvement. Despite of it, this new direction of the treatment in ophthalmology is very important and perspective.


Characteristics of replication and pathogenicity of SARS-CoV-2 Alpha and Delta isolates.
The continuously arising of SARS-CoV-2 variants has been posting a great threat to public health safety globally, from B.1.17 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta) to B.1.1.529 (Omicron). The emerging or re-emerging of the SARS-CoV-2 variants of concern is calling for the constant monitoring of their epidemics, pathogenicity and immune escape. In this study, we aimed to characterize replication and pathogenicity of the Alpha and Delta variant strains isolated from patients infected in Laos. The amino acid mutations within the spike fragment of the isolates were determined via sequencing. The more efficient replication of the Alpha and Delta isolates was documented than the prototyped SARS-CoV-2 in Calu-3 and Caco-2 cells, while such features were not observed in Huh-7, Vero E6 and HPA-3 cells. We utilized both animal models of human ACE2 (hACE2) transgenic mice and hamsters to evaluate the pathogenesis of the isolates. The Alpha and Delta can replicate well in multiple organs and cause moderate to severe lung pathology in these animals. In conclusion, the spike protein of the isolated Alpha and Delta variant strains was characterized, and the replication and pathogenicity of the strains in the cells and animal models were also evaluated.


Cystitis: antibiotic prescribing, consultation, attitudes and opinions.
Despite stable overall antibiotic use between 2007 and 2011 in The Netherlands, use of nitrofurantoin and trimethoprim increased by 32%. The background of this increased antibiotic use against uropathogens is unknown. To determine whether increased use of urinary tract infection antibiotics is caused by changes in patients' consultation or physicians' prescribing behaviour and to investigate attitudes and opinions of women with respect to cystitis management and antibiotics. Consultation and prescribing for International Classification of Primary Care (ICPC) codes U01 (dysuria), U02 (frequency), U05 (other urination problems), U70 (pyelonephritis) and U71 (cystitis) were determined from 2007 to 2010, using routinely collected primary health care data. Separately, behaviour of women with respect to managing cystitis, consultation and opinions towards (delayed) antibiotic treatment were studied using questionnaires in 2012. Consultation for U02 and U71 significantly increased from 93 to 114/1000 patient-years from 2007 to 2010; proportion of episodes in which an antibiotic was prescribed remained constant. Questionnaires revealed that urination problems and pain were dominant complaints of cystitis; pain medication, however, was not adequately used. One-third of women directly consult upon first symptoms, whereas the majority awaits an average of 4 days. Sixty-six per cent of women report to be willing to postpone antibiotic use. Increased use of urinary tract infection antibiotics may be caused by increased consultation for cystitis in primary care. Future research should focus on the outcomes of adequate pain medication, enhanced diagnostic procedures and of delaying antibiotic use in cystitis management.


[Spindle-cell variant of thyroid medullary carcinoma with favourable prognosis].
A case of a favourable outcome of spindle-cell medullary carcinoma of the thyroid is reported. Electron-microscopically, there was no correlation between histological and ultrastructural differentiation. The tumor consisted mainly of ultrastructurally differentiated cells with endocrine granules which may be the cause of the favourable prognosis.


Combination medical and surgical therapy for infertile patients with endometriosis.
Endometriosis is a difficult problem for practicing gynecologists and is commonly associated with infertility. The diagnosis of endometriosis should only be made at the time of laparoscopy or laparotomy and should be confirmed with biopsy if possible. Once the diagnosis is made, it should be classified according to the revised AFS system. The treatment of infertility associated with endometriosis is controversial and usually consists of either medical therapy with hormonal manipulation designed to suppress the disease, surgical therapy designed to debulk the disease and repair anatomic distortion, or a combination of both. Despite an abundance of research on the treatment of endometriosis, the pregnancy rate for patients with endometriosis remains lower than that of the normal population. The reasons for this are obscure. Endometriosis does not respond to hormonal changes the same way that normal endometrium does and has been shown to persist despite extensive medical therapy. The recurrence rate of the disease is impressively high after either medical or surgical therapy. Interestingly, expectant management of minimal or mild disease is associated with pregnancy rates equal to those of any other type of therapy. Only when the disease is more extensive does aggressive treatment appear to show improvement in pregnancy rates. Whether combination therapy of endometriosis is better than single agent therapy remains open to debate. Some of the best-designed studies using combination therapy have shown no difference in pregnancy rates. Yet, when taken as a whole, it would appear that if combination medical and surgical therapy is chosen, the medical therapy should be given preoperatively. The literature abounds with a wide variety of classification systems, methods of calculating pregnancy rates, and inclusion of control groups. Because of this disparity between studies, reliable conclusions cannot be drawn.


Presentation of Gastrointestinal Stromal Tumor, Pancreatic Adenocarcinoma, and Gastric Adenocarcinoma in a Woman With No Identifiable Genetic Abnormalities.
This report details the first known case of co-occurrence of gastrointestinal stromal tumor (GIST), pancreatic adenocarcinoma, and gastric adenocarcinoma in an individual with no identifiable genetic abnormalities. The patient is a 57-year-old female who presented with abdominal pain. CT scan demonstrated a pancreatic mass, and endoscopic ultrasound demonstrated an additional gastric mass. Biopsy of both masses demonstrated adenocarcinoma; however, the masses were found to have different origins. The patient underwent neoadjuvant chemotherapy with excellent response. She then underwent surgical intervention, which demonstrated no ongoing adenocarcinoma in either location, and demonstrated a small focus of GIST. Genetic testing demonstrated no identifiable abnormalities. The presence of 3 primary neoplasms in an individual with no known genetic mutations represents a novel case study. These findings may suggest that screening for additional primary neoplasms may be indicated, even in patients for whom metastatic disease is initially suspected.


Eph signal inhibition potentiates the growth-inhibitory effects of PLK1 inhibition toward cancer cells.
Anti-mitotic drugs are clinically used as anti-cancer treatments. Polo-like kinase 1 (PLK1) is a promising target against cancer cell division due to its importance in the whole process of mitosis, and thus PLK1-targeting agents have been developed in the last few decades. Clinical trial studies show that several PLK1 inhibitors are generally well-tolerated. However, the response rates are limited; therefore, it is needed to improve the efficacy of those drugs. Here, we show that NVP-BHG712, an erythropoietin-producing human hepatocellular (Eph) signaling inhibitor, potentiates the growth-inhibitory effects of the PLK1 inhibitors BI2536 and BI6727 in cancer cells. This combination treatment strongly suppresses cancer spheroid formation. Moreover, the combination drastically arrests cells at mitosis by continuous activation of the spindle assembly checkpoint (SAC), thereby inducing apoptosis. SAC activation caused by the combination of NVP-BHG712 and BI2536 is due to the inhibition of centrosome maturation and separation. Although the inactivation level of the PLK1 kinase is comparable between BI2536 treatment alone and combination treatment, the combination treatment strongly inactivates MAPK signaling in mitosis. Since inhibition of MAPK signaling potentiates the efficacy of BI2536 treatment, inactivation of PLK1 kinase and MAPK signaling contributes to the strong inhibition of centrosome separation. These results suggest that Eph signal inhibition potentiates the effect of PLK1 inhibition, leading to strong mitotic arrest via SAC activation and the subsequent reduction of cancer cell survival. The combination of PLK1 inhibition and Eph signal inhibition will provide a new effective strategy for targeting cancer cell division.


Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells.
Wnt signaling controls early embryonic hematopoiesis and dysregulated β-catenin is implicated in leukemia. However, the role of Wnts and their source in adult hematopoiesis is still unclear, and is clinically important as upstream Wnt inhibitors enter clinical trials. We blocked Wnt secretion in hematopoietic lineages by targeting Porcn, a membrane-bound O-acyltransferase that is indispensable for the activity and secretion of all vertebrate Wnts. Surprisingly, deletion of Porcn in Rosa-CreER(T2)/Porcn(Del), MX1-Cre/Porcn(Del), and Vav-Cre/Porcn(Del) mice had no effects on proliferation, differentiation, or self-renewal of adult hematopoietic stem cells. Targeting Wnt secretion in the bone marrow niche by treatment with a PORCN inhibitor, C59, similarly had no effect on hematopoiesis. These results exclude a role for hematopoietic PORCN-dependent Wnts in adult hematopoiesis. Clinical use of upstream Wnt inhibitors is not likely to be limited by effects on hematopoiesis.


Iron deficiency is unacceptably high in refugee children from Burma.
Iron-deficiency anemia (IDA) in refugees is reported to be among the major medical problems worldwide. Because food rations are typically inadequate in iron, long-term reliance is a key predictor of anemia among displaced people. Comprehensive nutritional assessments of refugee children from Burma have not previously been completed. Refugee children aged 6-59 mo were studied to determine 1) the prevalences of anemia, iron deficiency (ID) and IDA and 2) the factors associated with anemia and ID. Cluster sampling in three camps and convenience sampling in two additional camps were used. Hemoglobin (Hb) levels were measured and micro mol zinc protoporphyrin/mol heme were determined in 975 children. Logistic regression analyses (95% CI) determined predictors of anemia and ID. The prevalences of IDA, anemia and ID in these refugee children were 64.9, 72.0 and 85.4%, respectively. Predictors of anemia included young age (P < 0.001), food ration lasting <1 mo (P = 0.001), daily consumption of dietary iron inhibitors (P < 0.05), weight-for-height Z-score of <-2 (P < 0.05), male gender (P < 0.05) and uneducated father (P < 0.001). Predictors of ID were young age (P < 0.001) and recently reported illness (P < 0.05). Laboratory tests confirmed that anemia and ID are major health problems among these refugee children and that ID is the leading cause of anemia. A comprehensive nutrition and public health-focused approach to combating anemia and ID is essential. Following the presentation of results to policy makers, the improvement of the micronutrient content of rations has been initiated.


Exercise-induced ischemic arrhythmias in patients with previous myocardial infarction: role of perfusion and tissue viability.
This study sought to investigate whether residual viability of infarcted myocardium may play a role in the pathogenesis of exercise-induced ventricular arrhythmias. We previously showed that transient ischemia within partially infarcted areas often precipitates ventricular arrhythmias during exercise that are consistently obliterated by intravenous nitrates. We studied 60 patients with chronic stable angina and a previous myocardial infarction. All underwent at least two consecutive exercise stress tests, coronary angiography and stress/rest myocardial perfusion tomography by Tc-99m 2-methoxy isobutyl isonitrile (MIBI). In the last 26 consecutive patients, residual viability was assessed by single-photon emission computed tomography (SPECT) using fluorine (F)-18 fluorodeoxyglucose. Perfusion and metabolic data were evaluated qualitatively by three independent observers in blinded manner. With exercise, 30 patients (group A) consistently developed ventricular arrhythmias (> 10 ventricular ectopic beats/min, couplets, nonsustained ventricular tachycardia); the remaining 30 patients (group B) did not. The severity of coronary artery disease (Gensini score) was similar in the two groups. Postexercise SPECT showed partial reperfusion of an infarcted area in 28 of 30 patients of group A but in only 9 of 30 of group B (p < 0.0001). Uptake of F-18 fluorodeoxyglucose was observed within the infarcted zone in 10 of 13 and 1 of 13 patients in groups A and B, respectively (p = 0.0003). In patients with myocardial infarction, exercise-induced ventricular arrhythmias appear to be triggered by transient ischemia occurring within a partially necrotic area containing large amounts of viable myocardium. Therefore, occurrence of arrhythmias during exercise may represent a clue to the presence of residual viability within a previously infarcted area.


Patellar Dislocation in Adolescent Patients: Influence on Cartilage Properties Based on T1ρ Relaxation Times.
Adolescents who experience a patellar dislocation have an elevated risk of patellofemoral posttraumatic osteoarthritis. Magnetic resonance imaging (MRI)-based T1ρ relaxation times were measured for adolescents to evaluate patellofemoral cartilage after patellar dislocation. Long T1ρ relaxation times are an indicator of cartilage degradation. The primary hypothesis is that patellofemoral cartilage T1ρ relaxation times will be elevated in the acute phase after patellar dislocation. The secondary hypothesis is that T1ρ relaxation times will be higher for knees with multiple rather than single dislocations due to repeated traumatic injury. Cross-sectional study; Level of evidence, 3. In total, 23 adolescents being treated for a recent patellar dislocation, 13 for a first-time dislocation (47 ± 38 days since most recent dislocation) and 10 for multiple dislocations (55 ± 24 days since most recent dislocation), and 10 healthy controls participated in MRI-based T1ρ relaxation time mapping. For multiple regions of the patellofemoral joint, mean T1ρ values were compared between the 3 groups with multiple group comparisons and post hoc tests. T1ρ relaxation times were also correlated against measures of patellofemoral anatomy and alignment for single and multiple dislocations. Statistical significance was set at P < .05. T1ρ relaxation times were significantly longer for injured knees (single and multiple dislocations) than controls at the medial and central patella and central trochlear groove. For the regions on the patella, significant differences between injured and control knees exceeded 15%. No significant differences were identified between single and multiple dislocations. For the initial dislocation group, T1ρ relaxation times within multiple regions of the patellofemoral joint were significantly correlated with lateral patellar alignment or patellar height. Elevated patellofemoral cartilage T1ρ relaxation times are consistent with a high risk of long-term patellofemoral osteoarthritis for adolescents who experience patellar dislocations. T1ρ relaxation times were elevated for multiple regions of patellofemoral cartilage. T1ρ relaxation times were expected to increase with additional dislocation episodes, but relaxation times after single and multiple dislocations were similar. After a first dislocation, parameters related to patellar maltracking were correlated with cartilage degradation.


De novo pyrimidine synthesis is necessary for intestinal colonization of Salmonella Typhimurium in chicks.
pyrE (STM3733) encodes orotate phosphoribosyltransferase (OPRTase; EC 126.96.36.199), the fifth enzyme of the de novo pyrimidine biosynthetic pathway. We identified a ΔpyrE mutant as under selection in screening of a Salmonella mutant library in 4-day old chicks. Here, we confirm that a ΔpyrE mutant colonizes 4-day old chicks poorly in competitive infection with isogenic wild type, and that the ability of this mutant to colonize chicks could be restored by providing a copy of pyrE in trans. We further show that our ΔpyrE mutant grows poorly in nutrient poor conditions in vitro, and that the ability of this mutant to grow is restored, both in vitro and in chicks, when precursors to the pyrimidine salvage pathway were provided. This finding suggests that the environment in the chick intestine during our infections lacks sufficient precursors of the pyrimidine salvage pathway to support Salmonella growth. Finally, we show that the colonization defect of a ΔpyrE mutant during infection occurs in to chicks, but not in CBA/J mice or ligated ileal loops in calves. Our data suggest that de novo pyrimidine synthesis is necessary for colonization of Salmonella Typhimurium in the chick, and that the salvage pathway is not used in this niche.


Ethanol-1-C14 metabolism in alcoholics and nonalcoholics.
Metabolism of ethanol-1-C(14) was assessed in a group of alcoholic and nonalcoholic male subjects. All subjects were screened for absence of physical derangement. Subjects were also carefully matched by dietary, social, and environmental criteria. No differences in rate of output of C(l4)CO(2) were detected after ingestion of alcohol which produced concentrations of 50 to 60 milligrams of alcohol per 100 milliliters of blood. These data do not support the hypothesis that alcoholics metabolize ethanol more rapidly than nonalcoholics do.


Decrease in the function of the gamma-aminobutyric acid-coupled chloride channel produced by the repeated administration of pentylenetetrazol to rats.
The acute administration of pentylenetetrazol (PTZ; 25-75 mg/kg i.p.) failed to modify the specific binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS) to membrane preparations from the cerebral cortex of the rat. In contrast, the repeated administration of PTZ (30 mg/kg i.p., three times a week for 12 weeks) reduced by 26% the density of [35S]TBPS binding sites without modifying the dissociation constant. This effect was observed 3 days after the last PTZ administration. A parallel reduction of gamma-aminobutyric acid (GABA)-stimulated 36Cl- uptake was measured in the cerebral cortex of PTZ-treated rats 3 days after the last injection. The repeated administration of PTZ produced sensitization to the drug, or chemical kindling. In fact, no convulsions were observed in the first week of treatment, but all the animals became sensitized to PTZ by the 12th week. The results are consistent with the hypothesis that chronic treatment with PTZ at a subconvulsant dose causes a decrease in GABA-coupled chloride channel activity that may be related to the chemical kindling produced by this compound.


Interventions targeting social isolation in older people: a systematic review.
Targeting social isolation in older people is a growing public health concern. The proportion of older people in society has increased in recent decades, and it is estimated that approximately 25% of the population will be aged 60 or above within the next 20 to 40 years. Social isolation is prevalent amongst older people and evidence indicates the detrimental effect that it can have on health and wellbeing. The aim of this review was to assess the effectiveness of interventions designed to alleviate social isolation and loneliness in older people. Relevant electronic databases (MEDLINE, EMBASE, ASSIA, IBSS, PsycINFO, PubMed, DARE, Social Care Online, the Cochrane Library and CINAHL) were systematically searched using an extensive search strategy, for randomised controlled trials and quasi-experimental studies published in English before May 2009. Additional articles were identified through citation tracking. Studies were included if they related to older people, if the intervention aimed to alleviate social isolation and loneliness, if intervention participants were compared against inactive controls and, if treatment effects were reported. Two independent reviewers extracted data using a standardised form. Narrative synthesis and vote-counting methods were used to summarise and interpret study data. Thirty two studies were included in the review. There was evidence of substantial heterogeneity in the interventions delivered and the overall quality of included studies indicated a medium to high risk of bias. Across the three domains of social, mental and physical health, 79% of group-based interventions and 55% of one-to-one interventions reported at least one improved participant outcome. Over 80% of participatory interventions produced beneficial effects across the same domains, compared with 44% of those categorised as non-participatory. Of interventions categorised as having a theoretical basis, 87% reported beneficial effects across the three domains compared with 59% of interventions with no evident theoretical foundation. Regarding intervention type, 86% of those providing activities and 80% of those providing support resulted in improved participant outcomes, compared with 60% of home visiting and 25% of internet training interventions. Fifty eight percent of interventions that explicitly targeted socially isolated or lonely older people reported positive outcomes, compared with 80% of studies with no explicit targeting. More, well-conducted studies of the effectiveness of social interventions for alleviating social isolation are needed to improve the evidence base. However, it appeared that common characteristics of effective interventions were those developed within the context of a theoretical basis, and those offering social activity and/or support within a group format. Interventions in which older people are active participants also appeared more likely to be effective. Future interventions incorporating all of these characteristics may therefore be more successful in targeting social isolation in older people.


Effect of the synaptic scaffolding protein Homer1a on chronic compression of dorsal root ganglion.
Activity-dependent plasticity in the spinal dorsal horn may underlie the development of neuropathic pain following peripheral nerve injury. A product of an immediate early gene (IEG), the synaptic scaffolding protein Homer1a, has received increasing attention because it appears to play a critical role in synaptic plasticity. In this study, we explored the early expression of Homer1 gene in the spinal dorsal horn by using the neuropathic pain model of chronic compression of dorsal root ganglion (CCD). The levels of Homer1a mRNA in the ipsilateral dorsal horn of CCD rats were markedly increased at 4 hr, remained elevated at 8 hr, and then returned to baseline values by 24 hr after CCD treatment. In contrast, there were no significant changes of Homer1a expression in the Sham-operated or Control groups. Significant thermal hyperalgesia appeared at 24 hr post-operation in the CCD rats, but not in the Sham-operated or Control groups. These data show that CCD induces a transient and rapid increase in Homer1a expression in the spinal dorsal horn. These data also suggest that the transient and rapid increase in Homer1a expression may play an important role in the thermal hyperalgesia elicited by neural injury.


Treatment approaches and adherence to urate-lowering therapy for patients with gout.
Gout is the most common inflammatory arthritis characterized by painful disabling acute attacks. It is caused by hyperuricemia and deposition of urate crystals in and around the joints. Long-standing untreated hyperuricemia can lead to chronic arthritis with joint damage, tophi formation and urate nephropathy. Gout is associated with significant morbidity and health care associated cost. The goal of long-term therapy is to lower the serum urate level to promote dissolution of urate crystals, reduce recurrent acute gout flares, resolve tophi and prevent joint damage. Despite the presence of established gout treatment guidelines and effective medications to manage gout, patient outcomes are often poor. Etiology for these shortcomings is multifactorial including both physician and patient characteristics. Poor adherence to urate-lowering therapy (ULT) is prevalent and is a significant contributor to poor patient outcomes. This article reviews the treatment strategies for the management of hyperuricemia in chronic gout, gaps in quality of care in gout management, factors contributing to poor adherence to ULT and discusses potential interventions to achieve improved gout-related outcomes. These interventions include initiation of prophylactic anti-inflammatory medication when starting ULT, frequent follow-ups, regular serum urate monitoring and improved patient education, which can be achieved through pharmacist- or nurse-assisted programs. Interventions such as these could improve adherence to ULT and, ultimately, result in optimal gout-related outcomes.


Postprandial Hyperglycemia Lowering Effect of the Isolated Compounds from Olive Mill Wastes - An Inhibitory Activity and Kinetics Studies on α-Glucosidase and α-Amylase Enzymes.
In the present study, we isolated seven compounds from olive mill wastes (OMW), one of them being novel, and investigated their antidiabetic potential through inhibition of α-glucosidase and α-amylase enzymes. To assist the possible characterization of the mechanisms involved, we analyzed the inhibitory kinetics of the active compounds. Oleanolic acid 1, maslinic acid 2, 1-acetoxypinoresinol 3, and luteolin-7-O-β-d-glucoside 6 exhibited stronger inhibitory activity against both enzymes, with IC50 values less than or close to that of acarbose. Other compounds pinoresinol and hydroxytyrosol-containing compounds (hydroxytyrosol acetate 4, hydroxytyrosol 7, and the novel one, 3,4-dihydroxyphenyl-2-methoxyethanol 5) showed weak activity against both enzymes (IC50 > 500 μM). Our findings show that, first, the esterification of C-1 of the furofuran ring is the key feature for the stronger activity of 1-acetoxypinoresinol 3 against both enzymes (IC50 = 13.9 and 313 μM for α-amylase and α-glucosidase, respectively), as compared to pinoresinol; second, the oleanane skeletons of the triterpenes (1 and 2) are optimum for the α-glucosidase and α-amylase inhibitory activities, while the hydroxytyrosol moiety may be responsible for the weak activities of 4, 5, and 7. Additionally, kinetics analysis of 1, 6, and 3 revealed that they inhibit α-glucosidase in mixed-type, noncompetitive, and uncompetitive mechanisms, respectively. We confirmed their mechanisms by measuring their affinity for the enzyme (K i), and they all (1, 6, and 3) had a higher affinity for the enzyme, K i > 1. This work adds more value to OMW for further studies as a potential source of lead antidiabetic compounds for the prevention and/or treatment of type 2 diabetes.


Serious adverse events in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD).
The study estimated serious adverse event (SAE) rates among entrants to pharmacotherapies for opioid dependence, during treatment and after leaving treatment. A longitudinal study based on data from 12 trials included in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD). A total of 1244 heroin users and methadone patients treated in hospital, community and GP settings. Intervention Six trials included detoxification; all included treatment with methadone, buprenorphine, levo-alpha-acetyl-methadol (LAAM) or naltrexone. During 394 person-years of observation, 79 SAEs of 28 types were recorded. Naltrexone participants experienced 39 overdoses per 100 person-years after leaving treatment (44% occurred within 2 weeks after stopping naltrexone). This was eight times the rate recorded among participants who left agonist treatment. Rates of all other SAEs were similar during treatment versus out of treatment, for both naltrexone-treated and agonist-treated participants. Five deaths occurred, all among participants who had left treatment, at a rate of six per 100 person-years. Total SAE rates during naltrexone and agonist treatments were similar (20, 14 per 100 person-years, respectively). Total SAE and death rates observed among participants who had left treatment were three and 19 times the corresponding rates during treatment. Individuals who leave pharmacotherapies for opioid dependence experience higher overdose and death rates compared with those in treatment. This may be due partly to a participant self-selection effect rather than entirely to pharmacotherapy being protective. Clinicians should alert naltrexone treatment patients in particular about heroin overdose risks. Duty of care may extend beyond cessation of dosing.


Apparent ploidy effects on silencing are post-transcriptional at HML and telomeres in Saccharomyces cerevisiae.
The repression of genes in regions of heterochromatin is known as transcriptional silencing. It occurs in a wide range of organisms and can have importance in adaptation to the environment, developmental changes and disease. The model organism Saccharomyces cerevisiae has been used for many years to study transcriptional silencing, but until recently no study has been made in relation to ploidy. The aim of this work was to compare transcriptional silencing in haploids and diploids at both telomeres and the hidden mating-type (HM) loci. Transcriptional silencing was assayed, by growth on 5-fluoroorotic acid (5-FOA) media or by flow cytometry, on strains where a telomere or HM locus was marked. RNA levels were measured by quantitative RT-PCR to confirm that effects were transcriptional. 5-FOA assays and flow cytometry were consistent with transcriptional silencing at telomeres and at HML being reduced as ploidy increases which agreed with conclusions in previous publications. However, QRT-PCR revealed that transcriptional silencing was unaffected by ploidy and thus protein levels were increasing independently of RNA levels. At telomere XI left (XI-L), changes in protein level were strongly influenced by mating-type, whereas at HML mating-type had much less influence. The post-transcriptional effects seen in this study, illustrate the often ignored need to measure RNA levels when assaying transcriptional silencing in Saccharomyces cerevisiae.


Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation.
Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T(FH) cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation.


Effects of membrane potential on the capacitance of skeletal muscle fibers.
A method for measuring muscle fiber capacitance using small test pulses applied with the three-microelectrode voltage clamp is presented. Using this method, three membrane potential-dependent changes in capacitance were observed: (a) Capacitance of polarized fibers increased by 5--15% with depolarization from V less then -100 mV to voltages slightly below the contraction threshold. (b) Capacitance of fibers depolarized to -30 mV by 100 mM Rb solution decreased by roughly 8% with further depolarization to about +50 mV and increased with repolarization, exhibiting a maximum increase of about 10% at -80 to -90 mV. (c) Capacitance of fibers depolarized to -15 mV by 100 mM K solution increased by about 19% with further depolarization to +43 mV and decreased by about 23% with repolarization to -62 mV. Effects a and b are attributed to changes in specific membrane capacitance due to voltage-dependent redistribution of mobile charged groups within surface of T-tubule membranes. Effect c is caused by changes in the T-system space constant lambdaT due to the voltage dependence of K conductance (inward rectification). Analysis of c showed that in 100 mM K solution lambdaT congruent to 30 mum when inward rectification was fully activated by hyperpolarization and that the density of inward rectifier channels is about the same in surface and tubular membranes. Fiber internal resistance was found to be independent of voltage, a necessary condition for the interpretation of the capacitance measurements.


Associations of parental age with health and social factors in adult offspring. Methodological pitfalls and possibilities.
Parental age is increasing rapidly in many countries. Analysis of this potentially important influence on offspring well-being is hampered by strong secular trends and socioeconomic patterning and by a shortage of follow-up data for adult offspring. We used Swedish national data on up to 3,653,938 offspring to consider the associations of parental age with a suite of outcomes in adult offspring, comparing the results from an array of statistical methods for optimal causal inference. The offspring of older mothers had higher BMI, blood pressure, height, intelligence, non-cognitive ability and socioeconomic position. They were less likely to smoke or to be left-handed. Associations with paternal age were strongly, but not completely, attenuated by adjustment for maternal age. Estimates from the commonly-used sibling comparison method were driven primarily by a pathway mediated by offspring date of birth when outcomes showed strong secular trends. These results suggest that the intra-uterine and early life environments provided by older mothers may be detrimental to offspring cardiovascular health, but that their greater life experience and social position may bring intellectual and social advantages to their offspring. The analysis of parental age presents particular challenges, and further methodological developments are needed.