Serial surveillance by circulating tumor DNA profiling after chimeric antigen receptor T therapy for the guidance of r/r diffuse large B cell lymphoma precise treatment.
Background: Circulating tumor DNA (ctDNA) released from tumor cells carries the tumor-associated genetic and epigenetic characteristics of cancer patients. Next-generation sequencing (NGS) facilitates the application of ctDNA profiling for identification and monitoring of minimal residual disease (MRD) in cancer, and can serve as the guidance for precise treatment. Methods: In this study, we profiled genomic alterations in the baseline, relapsed, and progressive tumor samples of eight diffuse large B cell lymphoma (DLBCL) patients (NCT03118180) after chimeric antigen receptor T (CAR-T) cell therapy. Results: The median follow-up was 41 months. 4 (50%) patients achieved complete remission (CR), 1 (12.5%) patient achieved partial remission (PR), and the other 3 (37.5%) patients showed no response. 3 of 5 patients who achieved remission relapsed within 4 months after CAR-T therapy, while the rest 2 patients remained CR for more than 3 years. Based on the positron emission tomography-computed tomography (PET-CT) scan, the current gold standard for evaluating response to therapy in lymphoma, the sensitivity and specificity of our ctDNA profiling in detecting tumor-related ctDNA mutations were 94.7% and 83.3%, respectively. The median numbers of baseline plasma ctDNA mutations in patients who remained long-term CR and patients who relapsed or became refractory to CAR-T therapy were 3 and 14.3, respectively. GNA13, SOCS1, TNFAIP3 and XPO1 mutations appeared to be associated with poor prognosis after CAR-T cell therapy. Our results also suggested that lenalidomide might relieve relapsed lymphoma with mutations in NFKBIA 202C>T (p.Q68*) and NFKBIE 433A>T (p.K145*) by targeting NF-Kappa B signaling. In addition, the inhibitor selinexor may be another choice for refractory or relapse (r/r) DLBCL patients after CAR-T cell treatment. Conclusion: Serial ctDNA monitoring is an emerging technology for the surveillance of disease status and prognosis prediction. In this work, we demonstrated the use of serial ctDNA monitoring in r/r DLBCL patients after CD19-targeted CAR-T cell therapy. Our longitudinal NGS profiling revealed the changes of ctDNA mutation in accordance with prognosis, and shed some light on exploring more targeted treatment options together with CAR-T cell therapy.


Substance abuse relapse in a ten-year prospective follow-up of clients with mental and substance use disorders.
This study addressed the rate and predictors of substance abuse relapse among clients with severe mental illness who had attained full remission from substance abuse. In a ten-year prospective follow-up study of clients with co-occurring severe mental and substance use disorders, 169 clients who had attained full remission, defined according to DSM-III-R as at least six months without evidence of abuse or dependence, were identified. The Kaplan-Meier survival curve was developed to show the pattern of relapse, and a discrete-time survival analysis was used to identify predictors of relapse. Approximately one-third of clients who were in full remission relapsed in the first year, and two-thirds relapsed over the full follow-up period. Predictors of relapse included male sex, less than a high school education, living independently, and lack of continued substance abuse treatment. After attaining full remission, clients with severe mental disorders continue to be at risk of substance abuse relapse for many years. Relapse prevention efforts should concentrate on helping clients to continue with substance abuse treatment as well as on developing housing programs that promote recovery.


The effect of high sugar intake on the esterification of dihydroxyacetone phosphate by rat liver microsomes.
Rat liver microsomes were used as an enzyme source to study dietary-induced changes in the rate of dihydroxyacetone phosphate esterification. Rats were fed (1) 75% glucose or fructose diets for various time intervals, or (2) fed a fractose diet for six days and then a chow diet. Both the glucose and fructose diets produced a 2--3-fold increase in total and neutral glycerolipid formation from dihydroxyacetone phosphate measured in the presence of ATP, palmitate, CoA, and NADH. The increased rate of dihydroxyacetone phosphate esterification and a simultaneous rise in serum triglyceride level in rats fed fructose was rapidly reversed when chow was substituted for the fructose. The results indicate that an increased rate of dihyroxyacetone phosphate esterification may contribute to the acceleration of endogenous glycerolipid biosynthesis noted under these dietary conditions.


Regional variation in end-stage renal disease.
Regional variations in end-stage renal disease have been found within a country, even within a race. Since diabetic nephropathy is the leading cause of end-stage renal disease in developed countries, first of all, regional differences in diabetic nephropathy must be considered. Although the incidence of end-stage renal disease due to diabetic nephropathy has been found to differ among different areas within a country, there are no data on regional variations in the incidence of type II diabetes or diabetic nephropathy without renal failure. Such regional variations could hardly be explained by local differences in gene pools alone, which suggests an important role of environmental factors. It is not clear at present how regional variations in the incidence of end-stage renal disease are generated. If we can identify the factors that contribute to the regional differences, we can take these into account in future treatment strategies for renal disease. Thus, much effort is required in further analysis of regional differences in end-stage renal disease dynamics.


Gradients of monoamine metabolites and cortisol in cerebrospinal fluid of psychiatric patients and healthy controls.
Amine metabolites and cortisol were measured in four consecutive 3 ml samples of lumbar cerebrospinal fluid (CSF). There were pronounced concentration gradients for both 5-hydroxyindoleacetic acid and homovanillic acid, and there was no difference in the gradients of 11 controls and 17 psychiatric patients (10 depressed). As there was a close correlation between the mean of the first two fractions and the mean of all four fractions, a concentration obtained in 6 ml can be used to calculate that in a 12 ml CSF sample. In psychiatric patients there was a slight, but statistically significant concentration gradient for 3-methoxy-4-hydroxyphenylglycol (unconjugated as well as conjugated). No gradient was found for cortisol in CSF.


A valuable string of PURLs.
To qualify as a PURL, a study had to meet 6 criteria. It had to be scientifically valid, relevant to family medicine, applicable in a medical care setting, immediately implementable, clinically meaningful, and practice changing. These criteria still stand today.


Knowledge, beliefs and practices of African-American nurses regarding genetics/genomics.
In an effort to increase the awareness of genetics among African-American nurses, a pilot study was conducted with members of the National Black Nurses Association (NBNA) in order to assess the interest, knowledge, and practice of African-American nurses regarding genetics and to identify program needs. Self-administered surveys were distributed to a convenience sample of 77 African-American nurses (N=77) attending the 2006 Annual Conference of the National Black Nurses Association (NBNA) in Hollywood, Florida. Measures of central tendency and frequencies were used to analyze the data. Over half the sample (56%) self-reported their knowledge of genetics as being only fair or poor; however, 56% were interested in genetic awareness training, and 93.5% were willing to participate in planned genomic education. An unexpected finding was that 77.9% believed that genetic tests could be used to discriminate against minorities. Although this sample reported limited genetics/genomic knowledge, their interest in genetics training and the incorporation of genetics into daily practice was high. These data can be used to support the development and implementation of culturally appropriate genetic awareness training. Challenges for the organization include identification of the type of venue to use for genetic/genomic awareness training and identification of resources and partnerships to support NBNA members in gaining genetic awareness training.


Isolated lower limb medium-vessel vasculitis: a new entity?
A 47-year-old female was referred with bilateral ischaemic lesions affecting her toes with associated gangrene. Systemic examination was normal and her medical history was unremarkable. Close examination of the hands revealed splinter haemorrhages. Her feet were dusky in colour and the toes were dark and weeping, each becoming gangrenous, with erythema around the metatarsal phalangeal joint. Dorsalis pedis and posterior tibial pulses were intact with strong Doppler signals. Investigations for surgical pathology and malignancy were all negative as were routine blood tests and tests for autoimmune and viral markers. Vasculitis was diagnosed when her toes showed improvement with steroids, however, attempts to reduce the steroid dose were unsuccessful and azathioprine was introduced. Despite immunosuppression and immunomodulators, her toes deteriorated and were amputated. Histology revealed findings consistent with a medium-vessel vasculitis which antineutrophil cytoplasmic antibody was negative. A similar vasculitis has not been formally reported in the literature.


Nonequilibrium model of short-range repression in gene transcription regulation.
Transcription factors are proteins that regulate gene activity by activating or repressing gene transcription. A special class of transcriptional repressors operates via a short-range mechanism, making local DNA regions inaccessible to binding by activators, and thus providing an indirect repressive action on the target gene. This mechanism is commonly modeled assuming that repressors interact with DNA under thermodynamic equilibrium and neglecting some configurations of the gene regulatory region. We elaborate on a more general nonequilibrium model of short-range repression using the graph formalism for transitions between gene states, and we apply analytical calculations to compare it with the equilibrium model in terms of the repression strength and expression noise. In contrast to the equilibrium approach, the new model allows us to separate two basic mechanisms of short-range repression. The first mechanism is associated with the recruiting of factors that mediate chromatin condensation, and the second one concerns the blocking of factors that mediate chromatin loosening. The nonequilibrium model demonstrates better performance on previously published gene expression data obtained for transcription factors controlling Drosophila development, and furthermore it predicts that the first repression mechanism is the most favorable in this system. The presented approach can be scaled to larger gene networks and can be used to infer specific modes and parameters of transcriptional regulation from gene expression data.


Clinical characteristics of hemodialysis patients with left brachiocephalic vein obstruction due to extrinsic compression or prior catheterization.
Left brachiocephalic vein (LBCV) stenosis is a common complication in hemodialysis patients and is a heterogenous disorder associated with either prior catheterization or extrinsic compression. This study aimed to characterize patients with LBCV stenosis or occlusion with and without a history of central venous catheterization. We performed a retrospective study in 84 hemodialysis patients with LBCV stenosis or occlusion with (n = 22) or without (n = 62) prior catheterization. We compared the clinical features, anatomical factors, restenosis after balloon venoplasty, and patency rates of patients in these two groups. In the cohort of 84 patients with LBCV stenosis or occlusion, 73.8% (62 patients) of them had no history of catheterization. Patients without prior catheterization had more stenotic lesions (p < 0.05) but less occlusive lesions (p < 0.05) than patients with prior catheterization. The space between the sternum and the aorta was narrower in patients without prior catheterization than that in patients with prior catheterization (p < 0.05). Percutaneous venography was performed in 81 patients, and the occurrence of recoil after venoplasty in patients without prior catheterization was significantly higher than that in patients with prior catheterization (p < 0.05). The rate of stent implantation was significantly higher in patients without prior catheterization than patients with prior catheterization (p < 0.05), whereas there was no significant difference in primary patency between the two groups. LBCV stenosis and occlusion are mainly due to extrinsic compression rather than prior central venous catheterization. Stent implantation is frequently required after venoplasty to treat LBCV obstructive lesions in patients without prior catheterization.


Proteomic characterization of plasma in Lemierre´s syndrome.
Background The underlying mechanisms of thrombosis in Lemierre's syndrome and other septic thrombophlebitis are incompletely understood. Therefore, in this case-control study we aimed to generate hypotheses on its pathogenesis by studying the plasma proteome in patients with these conditions. Methods All patients with Lemierre's syndrome in the Skåne Region, Sweden were enrolled prospectively during 2017-2021 as cases. Age-matched patients with other severe infections were enrolled as controls. Patient plasma samples were analyzed using label-free data-independent acquisition liquid chromatography tandem mass spectrometry. Differentially expressed proteins in Lemierre's syndrome vs. other severe infections were highlighted. Functions of differentially expressed proteins were defined based on a literature search focused on previous associations with thrombosis. Results Eight patients with Lemierre's syndrome and 15 with other severe infections were compared. Here, 20/449 identified proteins were differentially expressed between the groups. Of these, 14/20 had functions previously associated with thrombosis. 12/14 had a suggested prothrombotic effect in Lemierre's syndrome, whereas 2/14 had a suggested antithrombotic effect. Conclusion Proteins involved in several thrombogenic pathways were differentially expressed in Lemierre's syndrome compared to other severe infections. Among identified proteins, several were associated with endothelial damage, platelet activation and degranulation and warrant further targeted studies.


A chirality indicator for the surfaces of the silica nanotubes.
The chirality of the silicas attracted much attention, due to their potential applications in asymmetric catalysis and enantioseparation. However, their chirality has not been well understood. Herein, a chirality indicator for the surfaces of the silica nanotubes was developed. The helical silica nanotubes were prepared through a sol-gel transcription approach. The handedness was controlled by that of the self-assemblies of the low-molecular-weight amphiphiles. 4-Triethoxysilyl-1,1'-biphenyl (TSB) was modified on the surfaces of silica nanotubes through covalent bonds. The circular dichroism (CD) spectra of the TSB-modified silica nanotubes indicated that the chirality of silica surfaces could be transferred to the twist of the biphenyl rings. The origin of these CD signals was characterized using time-dependent density functional theory.


Comprehensive pan-cancer analysis of expression profiles and prognostic significance for NUMB and NUMBL in human tumors.
NUMB has been initially identified as a critical cell fate determinant that modulates cell differentiation via asymmetrical partitioning during mitosis, including tumor cells. However, it remains absent that a systematic assessment of the mechanisms underlying NUMB and its homologous protein NUMBLIKE (NUMBL) involvement in cancer. This study aimed to investigate the prognostic significance for NUMB and NUMBL in pan-cancer. In this study, using the online databases TIMER2.0, gene expression profiling interactive analysis, cBioPortal, the University of ALabama at Birmingham CANcer data analysis Portal, SearchTool for the Retrieval of Interacting Genes/Proteins, and R software, we focused on the relevance between NUMB/NUMBL and oncogenesis, progression, mutation, phosphorylation, function and prognosis. This study demonstrated that abnormal expression of NUMB and NUMBL were found to be significantly associated with clinicopathologic stages and the prognosis of survival. Besides, genetic alternations of NUMB and NUMBL focused on uterine corpus endometrial carcinoma, and higher genetic mutations of NUMBL were correlated with more prolonged overall survival and disease-free survival in different cancers. Moreover, S438 locus of NUMB peptide fragment was frequently phosphorylated in 4 cancer types and relevant to its phosphorylation sites. Furthermore, endocytosis processing and neurogenesis regulation were involved in the functional mechanisms of NUMB and NUMBL separately. Additionally, the pathway enrichment suggested that NUMB was implicated in Hippo, Neurotrophin, Thyroid hormone, and FoxO pathways, while MAPK, Hippo, Rap1, mTOR, and Notch pathways were related to the functions of NUMBL. This study highlights the predictive roles of NUMB and NUMBL in pan-cancer, suggesting NUMB and NUMBL might be served as potential biomarkers for diagnosis and prognosis in various malignant tumors.


Detection of ctDNA in the plasma of patients with papillary thyroid carcinoma.
A total of 15-30% of thyroid nodules that are evaluated by fine-needle aspiration are not clearly determined to be benign or malignant. Gene mutation analysis is recommended for the evaluation of thyroid nodules using clinical guidelines. The detection of circulating tumor DNA (ctDNA) has the potential to aid in the screening, diagnosis and prediction of thyroid cancer prognosis, and can be used when tissues are difficult to obtain. In the present study, whole-exome sequencing (WES) was performed on tumors and matched normal tissues from 10 patients with papillary thyroid carcinoma (PTC) in Quanzhou, China. Hotspot mutations in tumor DNA and cell-free DNA were identified in the validation cohort, which included 59 patients with PTC. BRAF V600E occurred in five samples, and was the most frequent mutation observed. Variation allele frequency (VAF) of BRAF V600E detected by WES was positively correlated with VAF determined using digital PCR (R2=0.9197; P=0.0099). A number of novel mutated genes were identified, including zinc finger protein 717, pleckstrin homology like domain family A member 1, RBMX like 3, lysine methyltransferase 5A and trichohyalin, along with the reported genes BRAF, NRAS and mucin 16, cell surface associated. Somatic mutated genes were enriched in the 'focal adhesion' pathway, as determined by Kyoto Encyclopedia of Genes and Genomes or Gene Ontology analysis. In the validation cohort, 44.07% of tumors were BRAF V600E-positive, and the sensitivity and specificity of BRAF V600E ctDNA were 61.54 and 90.91%, respectively. BRAF V600E was associated with aggressive tumor factors, including lymph node metastasis (P=0.001) and advanced disease stage (P=0.009). The present study investigated the accuracy of ctDNA detection in patients with PTC, and provided evidence that ctDNA can be used as an evaluation of tumor DNA in thyroid nodules.


The cytotoxic and mechanistic effects of aaptamine on hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the third most frequent cause of cancer-associated mortality worldwide. We isolated aaptamine from the marine sponge Aaptos, and synthesized derivatives of this compound. Aaptamine and synthetic derivatives displayed various biological activities. This represents the first account of studies on the effects of aaptamine and its derivatives in hepatocarcinogenesis. In this study, Cell Counting Kit (CCK8) was used to evaluate the anti-proliferative effect of aaptamine on HCC in vitro. Additionally, a subcutaneous xenograft model was used to determine if aaptamine could inhibit hepatocellular carcinoma in vivo. We also used RT-PCR and Western blot to analyze the mechanisms behind these effects. Our results showed that aaptamine has anti-proliferation effects on the cell lines LM3 and HepG2. Aaptamine also suppressed the colony-formation ability of HCC cells. We found that aaptamine treatment led to cell cycle arrest in HCC cells, reduced the expression of SOX9 and CDK2. Significant anti-tumor effects were observed in aaptamine-administered tumor-bearing mice as compared to controls. However, structural changes made to aaptamine yielded two derivatives for which all the effects listed above were considerably reduced as compared to the original compound aaptamine. In conclusion, aaptamine is demonstrated for the first time to inhibit liver cancer progression. The aaptamine-induced cell cycle arrest was associated with the increased binding of p21 to Cdk2-cyclin D/E complexes, inhibition of Cdk2 kinase activity in HCC cells. Furthermore, aaptamine appears to be a promising and efficient treatment of liver cancer HCC-LM3 in vivo. We have also uncovered structural changes that might affect the biological activity. The work provides a promising drug candidate for HCC treatment.


Regulation of triple-negative breast cancer cell metastasis by the tumor-suppressor liver kinase B1.
Liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11), has been identified as a tumor suppressor in many cancers including breast. Low LKB1 expression has been associated with poor prognosis of breast cancer patients, and we report here a significant association between loss of LKB1 expression and reduced patient survival specifically in the basal subtype of breast cancer. Owing to the aggressive nature of the basal subtype as evidenced by high incidences of metastasis, the purpose of this study was to determine if LKB1 expression could regulate the invasive and metastatic properties of this specific breast cancer subtype. Induction of LKB1 expression in basal-like breast cancer (BLBC)/triple-negative breast cancer cell lines, MDA-MB-231 and BT-549, inhibited invasiveness in vitro and lung metastatic burden in an orthotopic xenograft model. Further analysis of BLBC cells overexpressing LKB1 by unbiased whole transcriptomics (RNA-sequencing) revealed striking regulation of metastasis-associated pathways, including cell adhesion, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT). In addition, LKB1 overexpression inhibited EMT-associated genes (CDH2, Vimentin, Twist) and induced the epithelial cell marker CDH1, indicating reversal of the EMT phenotype in the MDA-MB-231 cells. We further demonstrated marked inhibition of matrix metalloproteinase 1 expression and activity via regulation of c-Jun through inhibition of p38 signaling in LKB1-expressing cells. Taken together, these data support future development of LKB1 inducing therapeutics for the suppression of invasion and metastasis of BLBC.


Cell wall anchoring of the Streptococcus pyogenes M6 protein in various lactic acid bacteria.
The M6 protein from Streptococcus pyogenes is the best-characterized member of a family of cell envelope-associated proteins. Based on the observation that the C-terminal sorting signals of these proteins can drive cell wall anchoring of heterologous unanchored proteins, we have cloned and expressed the emm6 structural gene for the M6 protein in various lactic acid bacteria (LAB). The emm6 gene was successfully expressed from lactococcal promoters in several Lactococcus lactis strains, an animal-colonizing Lactobacillus fermentum strain, Lactobacillus sake, and Streptococcus salivarius subsp. thermophilus. The M6 protein was efficiently anchored to the cell wall in all strains tested. In lactobacilli, essentially all detectable M6 protein was cell wall associated. These results suggest the feasibility of using the C-terminal anchor moiety of M6 for protein surface display in LAB.


Cultured growth cartilage cells.
Growth cartilage (GC) and resting cartilage (RC) cells from the ribs of young rats were separated and cultured. The cultured GC cells showed remarkable osteogenic potential only with the participation of certain host cells even after cultivation, while RC cells showed no osteogenic activity when transplanted as isografts loaded into Millipore chambers. The GC cells showed marked differences in glycosaminoglycan (GAG) synthesis and alkaline phosphatase activity as compared with RC cells in terms of the effects of various hormones, vitamins, and other agents. A linkage of parathyroid hormone (PTH) and polyamine metabolism was found, and it was suggested that PTH induces successive increase of ornithine decarboxylase activity, polyamine levels, and GAG synthesis in cultured chondrocytes obtained from growing rabbit costochondral junctions. A factor in a family of somatomedins was isolated from the cartilage of fetal calves and called "cartilage-derived factor" (CDF). CDF markedly increased GAG, protein, RNA, and DNA synthesis and cell division of the cultured cartilage cells. The GC cells formed matrix vesicles abundantly in vitro without mineral deposition. Co-culture of GC cells with bone marrow cells resulted in degradation of GAG and then formation of hydroxyapatite crystals in the extracellular matrix. Antirat GC mouse IgG was prepared to label and sort the osteogenic cells in bone marrow by fluorescence-activated cell-sorter II (FACS II). GC antigen-positive and -negative cells after FACS sorting were cultured and examined in terms of proteoglycan synthesis, alkaline phosphatase activity, and matrix vesicle production. The former cell group was found to be very similar to the cultured GC cells.


Multiple Free Flap Reconstructions of Head and Neck Defects Due to Oral Cancer.
We studied complications following multiple free flap reconstructions in the head and neck. In this cohort, 26 patients (14 men and 12 women) who underwent multiple microvascular free flap reconstructions were included in the study. The reasons for secondary reconstruction were recurrence of tumor (12 cases), necrosis of transferred skin and/or bone (6 cases), reconstruction plate fracture or exposure (4 cases), and others (4 cases). A third reconstruction in 4 cases and a fourth reconstruction in 1 case were performed. No flap necrosis occurred. Postsurgical infections occurred at only secondary reconstructions in 7 patients. Although 4 cases with a history of external radiation therapy were anastomosed at contralateral side, those 4 cases suffered from severe pre-and postsurgical infection of the ipsilateral side. Postsurgical infection occurred in 2 cases with anastomoses at the ipsilateral side of the neck and required drainage after secondary surgery. A history of external radiation therapy and the existence of severe preoperative infection affected complications after multiple reconstructions.


Metabolic engineering of Corynebacterium glutamicum for production of sunscreen shinorine.
Ultraviolet-absorbing chemicals are useful in cosmetics and skin care to prevent UV-induced skin damage. We demonstrate here that heterologous production of shinorine, which shows broad absorption maxima in the UV-A and UV-B region. A shinorine producing Corynebacterium glutamicum strain was constructed by expressing four genes from Actinosynnema mirum DSM 43827, which are responsible for the biosynthesis of shinorine from sedoheptulose-7-phosphate in the pentose phosphate pathway. Deletion of transaldolase encoding gene improved shinorine production by 5.2-fold. Among the other genes in pentose phosphate pathway, overexpression of 6-phosphogluconate dehydrogenase encoding gene further increased shinorine production by 60% (19.1 mg/L). The genetic engineering of the pentose phosphate pathway in C. glutamicum improved shinorine production by 8.3-fold in total, and could be applied to produce the other chemicals derived from sedoheptulose-7-phosphate.


Testing repeatability of forces when using neurosurgical spatulas.
Virtual reality systems seems to be useful for training the use of brain spatulas without damaging brain tissue but the success of such a system is dependant on the human ability to discriminate pressures applied with the spatula. This paper describes an experiment designed to explore some central issues related to this ability: are surgeons better than laypeople, are the abilities in Virtual Reality (VR) and real world (RW) comparable, and will visual feedback enhance the ability. A group of surgeons and a control group of laypeople were tested in VR and RW. The results showed that surgeons performed better than the control group in RW but worse in VR, and that visual feedback improved the surgeons' abilities more than the control group. The results indicated that visual feedback is important for the success of such a virtual training system.


Helicobacter pylori prevalence in northeastern Thailand.
Helicobacter pylori is distributed worldwide and has been demonstrated in Thailand. However, no study has been conducted so far in northeastern Thailand. The objective of this study was to find the prevalence of H. pylori in patients undergoing upper gastrointestinal endoscopy in northeastern part of Thailand. One hundred and twenty-six patients undergoing surgery between November 1992 and January 1993 were studied. Biopsies were done at antrum, corpus, and other positive lesions. Diagnostic tests of H. pylori by using CLO test, microbiological tests (Gram stain and culture), and histological examination (hematoxylin and eosin) were carried out. The prevalence of H. pylori by CLO test, Gram stain, culture, and histology were 49.2%, 61.9%, 22.2%, and 45.2% respectively. The overall prevalence of H. pylori by all diagnostic tests was 73.8% (95% confidence interval = 66.1-81.5%). This study revealed a high prevalence rate of H. pylori in patients which should alert clinicians who practice in this geographical area.


Problematic drinking and physiological responses among female college students.
Problematic drinking is a widespread problem among college students, and can contribute to alcohol dependence during later adulthood, particularly among females. The current study assessed vulnerability for alcohol-related consequences by comparing self-reported drinking with coping styles and physiological and behavioral stress responses during a challenging task. Cardiovascular measurements and saliva samples were taken from 88 female students at the beginning of the experiment and after the task. Hypothalamic-pituitary-adrenal (HPA) activity was measured by assessing cortisol and dehydroepiandrosterone (DHEA) salivary levels. The behavioral task consisted of a set of three anagrams of increasing difficulty, the last of which had no possible solution, to test the distress tolerance of the participants. Results showed that the majority of participants (70%) reported drinking in the six months prior to data collection, most of whom reported at least one incident of binge drinking. Excessive alcohol use was related to an impaired physiological response to stress during the impossible task. College students who drank to cope with stress had significantly higher basal levels of cortisol and DHEA, an indication of HPA axis over-regulation, while their stress response remained remarkably flat. Self-reported consequences of drinking were related to motives for drinking and lower DHEA levels. Regression analysis indicated that higher cortisol levels mediated the relationship between motives for drinking and problematic drinking.


Computerized-aid diagnosis of breast mass using ultrasound image.
This paper presents a comparative study of the diagnostic results of the ultrasologists with/without using a novel enhancement algorithm for breast ultrasonic images based on fuzzy entropy principle and textural information. Totally, 350 ultrasound images of 115 cases were analyzed including 59 benign and 56 malignant lesions. The original breast images were fuzzified, the edge and textural information were extracted, and the images were enhanced. The original and enhanced images were assessed and evaluated by ultrasologists using double blind method before and after enhancement. The diagnostic sensitivity and specificity were calculated by the areas (Az) under the receiver operating characteristic (ROC) curves. And the two diagnostic results before and after enhancement were compared by Chi-square test in a 2 x 2 table. The results demonstrated that the discrimination rate of breast masses had been highly improved after employing the novel enhancement algorithm. The result indicates the sensitivity could be raised from 74.3% to 89.3% with the false-positive rate 14.3%, and the area (Az) under the ROC curve of diagnosis also increased from 0.84 to 0.93. The novel enhancement algorithm can increase the classification accuracy and decrease the rate of missing and misdiagnosis, and it is useful for breast cancer control.


[Family planning among gipsy women].
Family is the major social unit of gipsy society. The basic value in ethno-culture of gypsies is children. As in almost all aspects of health, regarding the reproduction health and access to health care gipsy population do not have good enough indexes. The purpose of this research is to determine the information gipsy women have about family planning. The inquiry is conducted through 100 gipsy women in different ages in the village Bukovlak, Pleven municipality.


Rare predicted loss of function alleles in Bassoon (BSN) are associated with obesity.
Bassoon (BSN) is a component of a hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo (PCLO) from glutamatergic neurons throughout the brain. Heterozygous missense variants in BSN have previously been associated with neurodegenerative disorders in humans. We performed an exome-wide association analysis of ultra-rare variants in about 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. We found that rare heterozygous predicted loss of function (pLoF) variants in BSN are associated with higher BMI with p-value of 3.6e-12 in the UK biobank cohort. Additionally, we identified two individuals (one of whom has a de novo variant) with a heterozygous pLoF variant in a cohort of early onset or extreme obesity and report the clinical histories of these individuals with non-syndromic obesity with no history of neurobehavioral or cognitive disability. The BMI association was replicated in the All of Us whole genome sequencing data. Heterozygous pLoF BSN variants constitute a new etiology for obesity.


Mulberroside a possesses potent uricosuric and nephroprotective effects in hyperuricemic mice.
Mulberroside A is a major stilbene glycoside of MORUS ALBA L. (Moraceae), which is effectively used for the treatment of hyperuricemia and gout in traditional Chinese medicine. We examined whether mulberroside A had effects on renal urate underexcretion and dysfunction in oxonate-induced hyperuricemic mice and investigated the potential uricosuric and nephroprotective mechanisms involved. Mulberroside A at 10, 20, and 40 mg/kg decreased serum uric acid levels and increased urinary urate excretion and fractional excretion of uric acid in hyperuricemic mice. Simultaneously, it reduced serum levels of creatinine and urea nitrogen (10-40 mg/kg), urinary N-acetyl- β-D-glucosaminidase activity (10-40 mg/kg), β₂-microglobulin (10-40 mg/kg) and albumin (20-40 mg/kg), and increased creatinine clearance (10-40 mg/kg) in hyperuricemic mice. Furthermore, mulberroside A downregulated mRNA and protein levels of renal glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1), and upregulated mRNA and protein levels of renal organic anion transporter 1 (mOAT1) and organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1, and mOCTN2) in hyperuricemic mice. This is the first study demonstrating that mulberroside A exhibits uricosuric and nephroprotective effects mediated in part by cooperative attenuation of the expression alterations of renal organic ion transporters in hyperuricemic mice. These data suggest that mulberroside A may be a new drug candidate for the treatment of hyperuricemia with renal dysfunction.


Inorganic polyphosphate is essential for long-term survival and virulence factors in Shigella and Salmonella spp.
The importance of inorganic polyphosphate (poly P) and poly P kinase (PPK), the enzyme principally responsible for its synthesis, has been established previously for stationary-phase survival of Escherichia coli and virulence in Pseudomonas aeruginosa. The gene (ppk) that encodes PPK is highly conserved among many bacterial pathogens, including Shigella and Salmonella spp. In view of the phylogenetic similarity of the enteropathogens and the frequency with which virulence factors are expressed in stationary phase, the ppk gene of pathogenic Shigella flexneri, Salmonella enterica serovar Dublin, and Salmonella enterica serovar typhimurium have been cloned and deleted. In some of these mutants lacking ppk, the phenotypes included features indicative of decreased virulence such as: (i) growth defects, (ii) defective responses to stress and starvation, (iii) loss of viability, (iv) polymyxin sensitivity, (v) intolerance to acid and heat, and (vi) diminished invasiveness in epithelial cells. Thus PPK may prove, as it has with P. aeruginosa, to be an attractive target for antibiotics, with low toxicity because PPK is not found in higher eukaryotes.


Office-based Air-Fluid Exchange for Diabetic Post-Operative Vitreous Cavity Hemorrhage.
Post-operative vitreous cavity hemorrhage (POVCH) is observed in 6-75% of eyes undergoing pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR). We describe our technique for office-based Air fluid exchange (AFX) in the treatment of POVCH. Sixteen eyes (15 patients) with PDR and POVCH undergoing office-based AFX between January 2006 and November 2016 were retrospectively identified. The pre- and post- procedure visual acuity (VA) and complications were compared between eyes with and without traction retinal detachment (TRD). Medicare charges for office-based AFX versus PPV were also analyzed. Mean (± standard deviation [SD]) age at the time of AFX was 55.31 (± 8.02) years. Nine eyes (56.25%) had TRD prior to PPV and 11 eyes (68.75%) were pseudophakic. The improvements in mean (±SD) logMAR VA at the last postoperative visit (3 - 8 months) were 1.38 (± 0.99), 0.82 (± 0.91) and 2.09 (± 0.53) in all eyes, TRD eyes and non-TRD eyes, respectively. Complications included cataract progression, hypotony, and recurrence of TRD and ghost cell glaucoma. The total cost of outpatient AFX was $1,409.59 less than that of PPV. Office-based AFX is a cost-effective alternative treatment for non-clearing diabetic POVCH with an acceptable risk profile.


Project MotherCare: one hospital's response to the high perinatal death rate in New Haven, CT.
Starling national statistics indicate that New Haven, CT, is the seventh poorest city of its size, in terms of per capita income, in the United States. In 1989, it was reported to have the highest rate of infant mortality--18.5 infant deaths per 1,000 live birth--in the nation for a city with more than 100,000 people. Seventy-five percent of all perinatal deaths are attributed to low birth weight infants. Adequate prenatal care is a proven means of reducing this risk. To further compound the problem, substance abuse among pregnant women has increased dramatically. Census tract data revealed that many of the infant deaths were localized to several well-defined areas of the city. Forty-four percent of the infant deaths were ascribed to extreme immaturity or other causes related to low birth weight. Approximately 21 percent of the pregnant population had either no prenatal care or care was begun late--after the first trimester. The traditional avenues for prenatal care have been ineffective; an innovative approach, one that can be replicated, was initiated. The Hospital of Saint Raphael's "Project MotherCare" embarked on an initiative to address these problems by reducing the access barriers to prenatal care regardless of insurance status or ability to pay. The mission was twofold: (a) to bring prenatal care to underserved neighborhoods of New Haven and (b) to identify the substance-abusing pregnant woman and deliver a continuum of services including prenatal care, counseling, social services, and referral to a drug treatment program. Community need caused the program to expand beyond prenatal services and provide additional primary care services to other residents of these neighborhoods.


Generation and Functional Characterization of Anti-CD19 Chimeric Antigen Receptor-Natural Killer Cells from Human Induced Pluripotent Stem Cells.
Natural killer (NK) cells are a part of innate immunity that can be activated rapidly in response to malignant transformed cells without prior sensitization. Engineering NK cells to express chimeric antigen receptors (CARs) allows them to be directed against corresponding target tumor antigens. CAR-NK cells are regarded as a promising candidate for cellular immunotherapy alternatives to conventional CAR-T cells, due to the relatively low risk of graft-versus-host disease and safer clinical profile. Human induced pluripotent stem cells (iPSCs) are a promising renewable cell source of clinical NK cells. In the present study, we successfully introduced a third-generation CAR targeting CD19, which was validated to have effective signaling domains suitable for NK cells, into umbilical cord blood NK-derived iPSCs, followed by a single-cell clone selection and thorough iPSC characterization. The established single-cell clone of CAR19-NK/iPSCs, which is highly desirable for clinical application, can be differentiated using serum- and feeder-free protocols into functional CAR19-iNK-like cells with improved anti-tumor activity against CD19-positive hematologic cancer cells when compared with wild-type (WT)-iNK-like cells. With the feasibility of being an alternative source for off-the-shelf CAR-NK cells, a library of single-cell clones of CAR-engineered NK/iPSCs targeting different tumor antigens may be created for future clinical application.


c-Jun N-Terminal Phosphorylation: Biomarker for Cellular Stress Rather than Cell Death in the Injured Cochlea.
Prevention of auditory hair cell death offers therapeutic potential to rescue hearing. Pharmacological blockade of JNK/c-Jun signaling attenuates injury-induced hair cell loss, but with unsolved mechanisms. We have characterized the c-Jun stress response in the mouse cochlea challenged with acoustic overstimulation and ototoxins, by studying the dynamics of c-Jun N-terminal phosphorylation. It occurred acutely in glial-like supporting cells, inner hair cells, and the cells of the cochlear ion trafficking route, and was rapidly downregulated after exposures. Notably, death-prone outer hair cells lacked c-Jun phosphorylation. As phosphorylation was triggered also by nontraumatic noise levels and none of the cells showing this activation were lost, c-Jun phosphorylation is a biomarker for cochlear stress rather than an indicator of a death-prone fate of hair cells. Preconditioning with a mild noise exposure before a stronger traumatizing noise exposure attenuated the cochlear c-Jun stress response, suggesting that the known protective effect of sound preconditioning on hearing is linked to suppression of c-Jun activation. Finally, mice with mutations in the c-Jun N-terminal phosphoacceptor sites showed partial, but significant, hair cell protection. These data identify the c-Jun stress response as a paracrine mechanism that mediates outer hair cell death.


Expanding the phenotype of TTLL5-associated retinal dystrophy: a case series.
Inherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone-rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5. Examination of these patients included funduscopic evaluation, spectral-domain optical coherence tomography, short-wavelength autofluorescence, and full-field electroretinography (ffERG). Genetic diagnoses were confirmed using whole exome capture. Protein modeling of the identified variants was performed to explore potential genotype-phenotype correlations. Genetic testing revealed five novel variants in TTLL5 in three unrelated patients with retinal dystrophy. Clinical imaging demonstrated features of sectoral cone-rod dystrophy and cone dystrophy, with phenotypic variability seen across all three patients. One patient also developed high-frequency hearing loss during a similar time period as the onset of retinal disease, potentially suggestive of a syndromic disorder. Retinal structure findings were corroborated with functional measures including ffERG findings that supported these diagnoses. Modeling of the five variants suggest that they cause different effects on protein function, providing a potential reason for genotype-phenotype correlation in these patients. The authors report retinal phenotypic findings in three unrelated patients with novel mutations causing autosomal recessive TTLL5-mediated retinal dystrophy. These findings broaden the understanding of the phenotypes associated with TTLL5-mediated retinal disease and suggest that mutations in TTLL5 should be considered as a potential cause of sectoral retinal dystrophy in addition to cone-rod and cone dystrophies.


2005 American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Standards and Guidelines survey.
An online survey about the use and format of the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Standards and Guidelines documents was conducted. The survey was sent to A.S.P.E.N. members, and an acceptable number of responses were received (470, or 9% of those surveyed). Most respondents indicated an overall satisfaction with the standards and guidelines and suggested format changes, many of which will be incorporated into future guidelines and standards. The results of this survey are presented here for general interest. Changes in the process with which A.S.P.E.N. produces standards and guidelines are discussed.


Urinary Ascites and Transient Intestinal Obstruction in a Preterm Infant: An Interesting Case of Posterior Urethral Valve.
Posterior urethral valve (PUV) is the most common congenital cause of bladder outflow obstruction in male neonates. We report a preterm neonate with PUV who presented as nonimmune fetal hydrops with intestinal obstruction in the antenatal period. The mother of our patient is a 33-year-old woman who started her prenatal care at our hospital at 30 weeks' gestation. Her sonogram done at 32 weeks in our hospital revealed fetal hydrops. It showed polyhydramnios, mild pyelectasis of right kidney, normal left kidney, and fetal ascites. Amniocentesis revealed bile stained amniotic fluid. Ultrasound during the procedure showed dilated fetal bowel loops with increased echoes. Following delivery at 32 weeks postnatal exam showed ascites with absence of skin edema, pleural, or pericardial effusion. The abdominal sonogram showed distended urinary bladder and bilateral hydroureteronephrosis. Bladder catheterization was done which relieved the bladder outlet obstruction. Voiding cystourethrogram was done later which confirmed PUV and bilateral grade 5 vesicoureteral reflux. The formation of urinary ascites in PUV serves as a pop-off mechanism to relieve the intravesical and intrarenal pressure. When this happens by mechanisms other than bladder rupture, it can lead on to transient intestinal obstruction and hepatic synthetic defects.


Asymmetry alters immune-partner relationship.
Ambiguity in the mutual manipulation between the immune system, more appropriately termed integrated defense system, on the one hand and microbes and incipient tumors on the other, is to be taken into account. Such ambiguity may also apply to autoimmune infighting. Here we consider the association of its increased incidence with modern ways of living. Indifference about fate implies that longstanding, evolutionary regulated, immune/tissue relationships are no impediment for asymmetric estrangement promoted by ongoing globalization.


Dynamics of the nitroxide side chain in spin-labeled proteins.
The dynamics of the tether linking methanethiosulfonate (MTSSL) spin probes to alpha-helices has been investigated with the purpose of rationalizing its effects on ESR line shapes. Torsional profiles for the chain bonds have been calculated ab initio, and steric interactions with the alpha-helix and the neighboring residues have been introduced at the excluded-volume level. As a consequence of the restrictions deriving from chain geometry and local constraints, a limited number of allowed conformers has been identified that undergo torsional oscillations and conformational jumps. Torsional fluctuations are described as damped oscillations, while transition rates between conformers are calculated according to the Langer multidimensional extension of the Kramers theory. The time scale and amplitude of the different motions are compared; the major role played by rotations of the outermost bonds of the side chain emerges, along with the effects of substituents in the pyrroline ring on the conformer distribution and dynamics. The extent and symmetry of magnetic tensor averaging produced by the side chain motions are estimated, the implications for the ESR spectra of spin-labeled proteins are discussed, and suggestions for the introduction of realistic features of the spin probe dynamics into the line shape simulation are presented.


Understanding the role of the lysozyme-like domain of D29 mycobacteriophage-encoded endolysin in host cell lysis and phage propagation.
Mycobacteriophages are viruses that infect and kill mycobacteria. The peptidoglycan hydrolase, lysin A (LysA), coded by one of the most potent mycobacteriophages, D29, carries two catalytic domains at its N-terminus and a cell wall-binding domain at its C-terminus. Here, we have explored the importance of the centrally located lysozyme-like catalytic domain (LD) of LysA in phage physiology. We had previously identified an R198A substitution that causes inactivation of the LD when it is present alone on a polypeptide. Here, we show that upon incorporation of the same mutation (i.e. R350A) in full-length LysA, the protein demonstrates substantially reduced activity in vitro, even in the presence of the N-terminal catalytic domain, and has less efficient mycobacterial cell lysis ability when it is expressed in Mycobacterium smegmatis. These data suggest that an active LD is required for the full-length protein to function optimally. Moreover, a mutant D29 phage harbouring this substitution (D29R350A) in its LysA protein shows significantly delayed host M. smegmatis lysis. However, the mutant phage demonstrates an increase in burst size and plaque diameter. Taken together, our data show the importance of an intact LD region in D29 LysA PG hydrolase, and indicate an evolutionary advantage over other phages that lack such a domain in their endolysins.


Pathogenesis of trehalose dimycolate-induced interstitial pneumonitis. IV. Evidence against roles for immunoglobulins and the complement system.
We showed previously that trehalose dimycolate (TDM) in oil administered intraperitoneally into susceptible mice produced interstitial and hemorrhagic pneumonitis by the seventh day after injection and that mature T cells are necessary for the production of these lesions. TDM has been reported to activate complement and to be chemotactic for macrophages in vitro. Accordingly, we looked for involvement of humoral mechanisms in the pathogenesis of TDM-induced pneumonitis. Genetically C5-deficient B10D2/oSn mice developed pulmonary lesions just as well as C5-sufficient mice. No activation of C3 occurred in the plasma of TDM-treated mice as determined by crossed immunoelectrophoresis. Some splitting of C3 occurred in bronchoalveolar lavage fluids, but this was similar in control and experimental mice. By immunofluorescence microscopy, there was no deposition of C3 or immunoglobulins (Ig) along the alveolar membranes. These findings and our published data provide additional evidence that TDM-induced interstitial inflammation in mice is exclusively a T-lymphocyte-dependent process.


Brief Report: Six-Week Treatment of Axial Spondyloarthritis Patients With an Optimal Dose of Nonsteroidal Antiinflammatory Drugs: Early Response to Treatment in Signal Intensity on Magnetic Resonance Imaging of the Sacroiliac Joints.
To evaluate the early effect of full-dose nonsteroidal antiinflammatory drugs (NSAIDs) on the extent and intensity of bone marrow edema of the sacroiliac (SI) joints on magnetic resonance imaging (MRI) in axial spondyloarthritis (SpA). A single-center, 6-week study of a cohort of consecutive patients with clinically suspected axial SpA was conducted. A total of 117 patients were screened. Forty patients who were diagnosed as having axial SpA and had presented with a positive MRI of the SI joints as defined by the Assessment of SpondyloArthritis international Society (ASAS) criteria were considered for a followup MRI after 6 weeks of an optimal dose of NSAIDs. Twenty patients completed the study. Disease activity was monitored by determining the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score every 2 weeks and the Bath Ankylosing Spondylitis Functional Index score at baseline and week 6. NSAID intake was assessed by the ASAS NSAID index. Primary end points were improvement in bone marrow edema of the SI joints on MRI and BASDAI response at week 6. Approximately one-third of eligible patients newly diagnosed as having axial SpA were unable to continue the full-dose NSAID schedule. The median NSAID index was 97% in patients who completed the study. There was a reduction of 1.1 units (10.5%) in mean Spondyloarthritis Research Consortium of Canada (SPARCC) scores at week 6 in comparison to baseline (P = 0.032). Overall, only 30% of the patients (6 of 20) had a minimal clinically important difference of ≥2.5 in SPARCC score. However, 80% of the patients displayed high-intensity lesions on STIR images at baseline, which decreased significantly at week 6 (P = 0.011). There was a significant decrease in the relative intensity of the region of interest (P = 0.007) and a mean decrease of 0.6 in the BASDAI score per 2 weeks of therapy (P = 0.001). Only 29.4% of the patients met the BASDAI criteria for 50% improvement (BASDAI50) at week 6. Our findings indicate a high level of dropout among patients receiving full-dose NSAID therapy in daily practice. In those who tolerated NSAID therapy, there was no clinically relevant decrease in SPARCC scores and low BASDAI50 response. However, we found a decrease in signal intensity of bone marrow edema of the SI joints as an early response to 6 weeks of optimal NSAID therapy in patients newly presenting with axial SpA.


Trypanosoma cruzi (Chagas' disease agent) reduces HIV-1 replication in human placenta.
Several factors determine the risk of HIV mother-to-child transmission (MTCT), such as coinfections in placentas from HIV-1 positive mothers with other pathogens. Chagas' disease is one of the most endemic zoonoses in Latin America, caused by the protozoan Trypanosoma cruzi. The purpose of the study was to determine whether T. cruzi modifies HIV infection of the placenta at the tissue or cellular level. Simple and double infections were carried out on a placental histoculture system (chorionic villi isolated from term placentas from HIV and Chagas negative mothers) and on the choriocarcinoma BeWo cell line. Trypomastigotes of T. cruzi (VD lethal strain), either purified from mouse blood or from Vero cell cultures, 24 h-supernatants of blood and cellular trypomastigotes, and the VSV-G pseudotyped HIV-1 reporter virus were used for the coinfections. Viral transduction was evaluated by quantification of luciferase activity. Coinfection with whole trypomastigotes, either from mouse blood or from cell cultures, decreased viral pseudotype luciferase activity in placental histocultures. Similar results were obtained from BeWo cells. Supernatants of stimulated histocultures were used for the simultaneous determination of 29 cytokines and chemokines with the Luminex technology. In histocultures infected with trypomastigotes, as well as in coinfected tissues, IL-6, IL-8, IP-10 and MCP-1 production was significantly lower than in controls or HIV-1 transducted tissue. A similar decrease was observed in histocultures treated with 24 h-supernatants of blood trypomastigotes, but not in coinfected tissues. Our results demonstrated that the presence of an intracellular pathogen, such as T. cruzi, is able to impair HIV-1 transduction in an in vitro system of human placental histoculture. Direct effects of the parasite on cellular structures as well as on cellular/viral proteins essential for HIV-1 replication might influence viral transduction in this model. Nonetheless, additional mechanisms including modulation of cytokines/chemokines at placental level could not be excluded in the inhibition observed. Further experiments need to be conducted in order to elucidate the mechanism(s) involved in this phenomenon. Therefore, coinfection with T. cruzi may have a deleterious effect on HIV-1 transduction and thus could play an important role in viral outcome at the placental level.


Hepatitis C prevalence and risk behavior of injecting drug users in Sydney: a continuing concern.
This study examines patterns of injecting drug use and hepatitis C (HCV) risk behavior among injecting drug users. A survey of injecting drug users attending needle and syringe programs (NSPs) in the Sydney metropolitan area and members of NSW Users and AIDS Association (NUAA) yielded 336 responses. Demographic, behavioral and drug-use information was collected from injecting drug users aged from 14 to 64 years. The majority of respondents (66%) were HCV positive, 28% had tested negative and 5% did not know their status. Prevalence was higher among men than among women (54% vs 44%). Two thirds of respondents (72%) reported frequent heroin injection. Multivariate analysis identified the following significant risk factors for hepatitis C: being more than 30 years of age, an injecting history of five years or more, and having shared drug injecting equipment with a HCV positive user. The most significant factor associated with needle sharing was having unprotected sex with sexual partners and having a positive hepatitis C test result. Early identification of these factors should be a component of HCV prevention programs. Our data indicate that the promotion of safer injecting continues to be an important public health issue with regard to reducing HCV infections.


Accelerated stochastic simulation of the stiff enzyme-substrate reaction.
The enzyme-catalyzed conversion of a substrate into a product is a common reaction motif in cellular chemical systems. In the three reactions that comprise this process, the intermediate enzyme-substrate complex is usually much more likely to decay into its original constituents than to produce a product molecule. This condition makes the reaction set mathematically "stiff." We show here how the simulation of this stiff reaction set can be dramatically speeded up relative to the standard stochastic simulation algorithm (SSA) by using a recently introduced procedure called the slow-scale SSA. The speedup occurs because the slow-scale SSA explicitly simulates only the relatively rare conversion reactions, skipping over occurrences of the other two less interesting but much more frequent reactions. We describe, explain, and illustrate this simulation procedure for the isolated enzyme-substrate reaction set, and then we show how the procedure extends to the more typical case in which the enzyme-substrate reactions occur together with other reactions and species. Finally, we explain the connection between this slow-scale SSA approach and the Michaelis-Menten [Biochem. Z. 49, 333 (1913)] formula, which has long been used in deterministic chemical kinetics to describe the enzyme-substrate reaction.


HiCoDG: a hierarchical data-gathering scheme using cooperative multiple mobile elements.
In this paper, we study mobile element (ME)-based data-gathering schemes in wireless sensor networks. Due to the physical speed limits of mobile elements, the existing data-gathering schemes that use mobile elements can suffer from high data-gathering latency. In order to address this problem, this paper proposes a new hierarchical and cooperative data-gathering (HiCoDG) scheme that enables multiple mobile elements to cooperate with each other to collect and relay data. In HiCoDG, two types of mobile elements are used: the mobile collector (MC) and the mobile relay (MR). MCs collect data from sensors and forward them to the MR, which will deliver them to the sink. In this work, we also formulated an integer linear programming (ILP) optimization problem to find the optimal trajectories for MCs and the MR, such that the traveling distance of MEs is minimized. Two variants of HiCoDG, intermediate station (IS)-based and cooperative movement scheduling (CMS)-based, are proposed to facilitate cooperative data forwarding from MCs to the MR. An analytical model for estimating the average data-gathering latency in HiCoDG was also designed. Simulations were performed to compare the performance of the IS and CMS variants, as well as a multiple traveling salesman problem (mTSP)-based approach. The simulation results show that HiCoDG outperforms mTSP in terms of latency. The results also show that CMS can achieve the lowest latency with low energy consumption.


Impact of coronavirus disease 2019 on respiratory surveillance and explanation of high detection rate of human rhinovirus during the pandemic in the Republic of Korea.
After the detection of the first case of coronavirus disease 2019 (COVID-19) in South Korea on January 20, 2019, it has triggered three major outbreaks. To decrease the disease burden of COVID-19, social distancing and active mask wearing were encouraged, reducing the number of patients with influenza-like illness and altering the detection rate of influenza and respiratory viruses in the Korea Influenza and Respiratory Viruses Surveillance System (KINRESS). We examined the changes in respiratory viruses due to COVID-19 in South Korea and virological causes of the high detection rate of human rhinovirus (hRV) in 2020. We collected 52 684 oropharyngeal or nasopharyngeal swab samples from patients with influenza-like illness in cooperation with KINRESS from 2016 to 2020. Influenza virus and other respiratory viruses were confirmed using real-time RT-PCR. The weekly detection rate was used to compare virus detection patterns. Non-enveloped virus (hRV, human bocavirus, and human adenovirus) detection rates during the COVID-19 pandemic were maintained. The detection rate of hRV significantly increased in 2020 compared with that in 2019 and was negatively correlated with number of COVID-19-confirmed cases in 2020. The distribution of strains and genetic characteristics in hRV did not differ between 2019 and 2020. The COVID-19 pandemic impacted the respiratory virus detection rate. The extremely low detection rate of enveloped viruses resulted from efforts to prevent the spread of COVID-19 in South Korea. The high detection rate of hRV may be related to resistance against environmental conditions as a non-enveloped virus and the long period of viral shedding from patients.


Critical adsorption and critical Casimir forces for geometrically structured confinements.
We study the behavior of fluids, confined by geometrically structured substrates, upon approaching a critical point at T=T(c) in their bulk phase diagram. As generic substrate structures periodic arrays of wedges and ridges are considered. Based on general renormalization group arguments we calculate, within mean field approximation, the universal scaling functions for order parameter profiles of a fluid close to a single structured substrate and discuss the decay of its spatial variation into the bulk. We compare the excess adsorption at corrugated substrates to the one at planar walls. The confinement of a critical fluid by two walls generates effective critical Casimir forces between them. We calculate corresponding universal scaling functions for the normal critical Casimir force between a flat and a geometrically structured substrate as well as the lateral critical Casimir force between two identically patterned substrates.


Neighborhood Deprivation and Risks of Autoimmune Disorders: A National Cohort Study in Sweden.
Background: No study to date, as far as we know, has analyzed the potential effect of neighborhood-level deprivation on autoimmune disorders (ADs), when adjusted for individual-level characteristics. Methods: A total of 5.4 million individuals from 8363 neighborhoods, comprising the whole Swedish population (ages 25-74 years), were followed for the period 1 January 2000, until admission due to diagnosis of ADs during the period of the study, or the conclusion of the study (31 December 2010). We used a neighborhood deprivation index, constructed from variables such as low education, low income, unemployment, and social welfare assistance, to assess the level of neighborhood deprivation. Multilevel logistic regression was used in the analysis with individual level characteristics at the first level and level of neighborhood deprivation at the second level. Results: A significant association between level of neighborhood deprivation and ADs was found. The crude odds were 1.32 (95% confidence interval 1.27-1.36) for those residing in the high-deprived neighborhoods compared to those living in low-deprivation neighborhoods. In the full model, where individual level characteristics were taken into account, the odds of ADs were 1.18 (1.14-1.22) in the most deprived neighborhoods. Certain Ads-angiitis hypersensitive (5.14), ankylosing spondylitis (1.66), celiac disease (1.65), Crohn's disease (1.21), diabetes mellitus type 1 (1.45), Graves's disease (1.13), Hashimoto thyroiditis (1.51), psoriasis (1.15), rheumatoid arthritis (1.15), sarcoidosis (1.20), and systemic sclerosis (1.27)-remained significantly associated with high level of neighborhood deprivation after adjustment for the individual-level variables. Conclusion: This study is the largest to date analyzing the potential influence of neighborhood deprivation on ADs. Our results indicate that neighborhood deprivation may affect risk of ADs, independent of individual level sociodemographic characteristics. For health care policies, both individual and neighborhood level approaches seem to be of importance.


Hypertension, vascular headaches, and seizures after carotid endarterectomy. Case report and therapeutic considerations.
The following three unusual complications of carotid endarterectomy developed in a 64-year-old woman: vascular headaches, delayed hypertension, and seizures. beta-Blockade with propranolol hydrochloride had no beneficial effect on either the hypertension or the headaches. Peripheral alpha-blockade with prazosin hydrochloride resulted in prompt improvement in the patient's condition. Altered autonomic vascular control secondary to carotid sinus trauma is proposed as a possible causative mechanism for all three complications. The therapeutic implications are discussed. Based on this experience, we would caution against the use of unopposed beta-blockade in this setting and suggest that the role of prazosin in the initial management of postendarterectomy hypertension and vascular headache be explored.


Influenza vaccine effectiveness during the 2012 influenza season in Victoria, Australia: influences of waning immunity and vaccine match.
Vaccine effectiveness may wane with increasing time since vaccination. This analysis used the Victorian sentinel general practitioner (GP) network to estimate vaccine effectiveness for trivalent inactivated vaccines in the 2012 season. A test-negative design was used where patients presenting to GPs with influenza-like illness who tested positive for influenza were cases and noncases were those who tested negative. Vaccination status was recorded by GPs. Vaccine effectiveness was calculated as (1-odds ratio) × 100%. Estimates were compared early versus late in the season and by time since vaccination. Virus isolates were assessed antigenically by hemagglutination inhibition assay in a selection of positive samples and viruses from healthy adults who experienced a vaccine breakthrough were analyzed genetically. The adjusted vaccine effectiveness estimate for any type of influenza was 45% (95% CI: 8,66) and for influenza A(H3) was 35% (95% CI: -11,62). A non-significant effect of waning effectiveness by time since vaccination was observed for A(H3). For those vaccinated <93 days of presentation vaccine effectiveness was 37% (95% CI: -29,69), while for those vaccinated ≥93 days before presentation it was 18% (95% CI: -83,63). Comparison of early versus late in the season estimates was very sensitive to the cut off week chosen for analysis. Antigenic data suggested that low vaccine effectiveness was not associated with poor vaccine match among the A(H3) viruses. However, genetic analysis suggested nucleotide substitutions in antigenic sites. In 2012, the trivalent influenza vaccine provided moderate protection against influenza and showed limited evidence for waning effectiveness. Antigenic and genetic data can provide additional insight into understanding these estimates.


Antidiabetic, Antihyperlipidemic, and Antioxidant Activities of Mulberry Lees Fermented Products in Diabetic Mice.
Mulberry lees are the sediment in the bottom of the barrel, which can be obtained from the processing of mulberry wine, and they are considered as low-value byproducts. In this study, mulberry lees were extracted with ethanol, and then fermented with Monascus pilosus to obtain fermented products (M × M). Male ICR mice were diabetes induced by STZ, and then oral administration of fermented products. The results showed that fermented products could reduce 31.9% to 47.9% plasma glucose, 25.8% to 48.2% total cholesterol, and 16.7% to 25% triglyceride levels in diabetic mice, and it can greatly lower the malondialdehyde (MDA) content by 26.4% to 59.7% but raise antioxidant enzyme activity in the liver of the mice. Moreover, fermented products not only could reduce AST and ALT activity of the diabetic mice, thereby alleviating liver inflammation, but also lowered the urea nitrogen and creatinine levels, improved glomerulus volume, and reduced swelling and inflammation in the kidneys. It was concluded that mulberry lees fermented products could be served as a value-added resource for human health.


The Whole School, Whole Community, Whole Child model: a new approach for improving educational attainment and healthy development for students.
The Whole Child approach and the coordinated school health (CSH) approach both address the physical and emotional needs of students. However, a unified approach acceptable to both the health and education communities is needed to assure that students are healthy and ready to learn. During spring 2013, the ASCD (formerly known as the Association for Supervision and Curriculum Development) and the US Centers for Disease Control and Prevention (CDC) convened experts from the field of education and health to discuss lessons learned from implementation of the CSH and Whole Child approaches and to explore the development of a new model that would incorporate the knowledge gained through implementation to date. As a result of multiple discussions and review, the Whole School, Whole Community, Whole Child (WSCC) approach was developed. The WSCC approach builds upon the traditional CSH model and ASCD's Whole Child approach to learning and promotes greater alignment between health and educational outcomes. By focusing on children and youth as students, addressing critical education and health outcomes, organizing collaborative actions and initiatives that support students, and strongly engaging community resources, the WSCC approach offers important opportunities that will improve educational attainment and healthy development for students.


[Treatment of hypermetropia using the Holmium laser--laser thermokeratoplasty (LTK)].
The results of two year follow-up after Holmium LTK are presented. The choice of the technique was justified based on experimental, technical and anatomo-pathological data as well as on the property of the corneal collagen fibers to shrink at a temperature of 60-70 degrees C. Although the immediate results were encouraging, we found an important regression after two years follow-up, resulting in a final correction of maximally 1.5 D, independent on the degree of hypermetropia to be treated. These results were obtained with the "contact" method, which is in our experience slightly superior to the "non-contact" technique. The question is whether the regression will continue with time or will stabilize and remain at 1.5 D of hyperopic correction.


A National Collegiate Athletic Association Division I Athlete's Return to Play After Traumatic Knee Dislocation With Vascular and Nerve Injury.
Traumatic knee dislocations are thought to be relatively uncommon; however, they are a devastating injury that can be life altering. A concomitant vascular injury carries a particularly high morbidity rate, with some studies reporting as many as one in five patients losing a limb. Neurologic injury can pose problems as well, in particular for athlete populations that have structure and function as integral parts of their activities. This case study looks at the journey of an elite-level football player (NCAA Division I Pac-12 conference) who sustained a traumatic knee dislocation with vascular and neurologic injury and, eventually, his return to play. The study analyzes the treatment and management course, his ultimate performance after injury, and potential benefits in aiding the management of future knee dislocation with vascular and neurologic injuries.


Comparative proteomic and phosphoproteomic profiling of pancreatic adenocarcinoma cells treated with CB1 or CB2 agonists.
The pancreatic adenocarcinoma cell line Panc1 was treated with cannabinoid receptor ligands (arachidonylcyclopropylamide or GW405833) in order to elucidate the molecular mechanism of their anticancer effect. A proteomic approach was used to analyze the protein and phosphoprotein profiles. Western blot and functional data mining were also employed in order to validate results, classify proteins, and explore their potential relationships. We demonstrated that the two cannabinoids act through a widely common mechanism involving up- and down-regulation of proteins related to energetic metabolism and cell growth regulation. Overall, the results reported might contribute to the development of a therapy based on cannabinoids for pancreatic adenocarcinoma.


Anthropology and psychiatry--an alternative approach.
Whilst anthropology has employed an approach to society derived from Freud, the dominant perspective, as exemplified by Durkheim, has been to understand social processes without recourse to psychological theories. These two appraoches have offered opposing explanations of the genesis and significance of public symbols. The later developments of the Durkheimian position, notably symbolic classification and the structural anthropology of Lévi-Strauss, have however returned to a consideration of mental processes in bypassing the study of individual variation. The point of interaction of this approach with the reintroduced individual may offer a new point of definition for transcultural psychiatry. An illustration is offered by examining the experiences of a black West Indian in Britain.


Pulsatile flow filtration of yeast cell debris: influence of preincubation on performance.
The recovery of proteins from yeast cell debris suspension was investigated using a vortex mixing technique based on the combination of oscillatory flow and a baffled flat-sheet microfiltration system. For this system, increased protein transmission was obtained through the use of low transmembrane pressures and the preincubation of the yeast cell debris feed suspension at 30 degrees C. Furthermore, a plateau in the flux-time curve was observed. In the absence of baffles and pulsations, preincubation had a little effect.


Oxidation of Electron-Deficient Phenols Mediated by Hypervalent Iodine(V) Reagents: Fundamental Mechanistic Features Revealed by a Density Functional Theory-Based Investigation.
Hypervalent iodine (HVI) compounds are efficient reagents for the double oxidative dearomatization of electron-rich phenols to o-quinones. We recently reported that an underexplored class of iodine(V) reagents possessing bidentate bipyridine ligands, termed Bi(N)-HVIs, could dearomatize electron-poor phenols for the first time. To understand the fundamental mechanistic basis of this unique reactivity, density functional theory (DFT) was utilized. In this way, different pathways were explored to determine why Bi(N)-HVIs are capable of facilitating these challenging transformations while more traditional hypervalent species, such as 2-iodoxybenzoic acid (IBX), cannot. Our calculations reveal that the first redox process is the rate-determining step, the barrier of which hinges on the identity of the ligands bound to the iodine(V) center. This crucial process is composed of three steps: (a) ligand exchange, (b) hypervalent twist, and (c) reductive elimination. We found that strong coordinating ligands disfavor these elementary steps, and, for this reason, HVIs bearing such ligands cannot oxidize the electron-poor phenols. In contrast, the weakly coordinating triflate ligands in Bi(N)-HVIs allow for the kinetically favorable oxidation. It was identified that trapping in situ-generated triflic acid is a key role played by the bidentate bipyridine ligands in Bi(N)-HVIs as this serves to minimize the decomposition of the ortho-quinone product.


Rapamycin and Paclitaxel Affect Human Aortic Smooth Muscle Cells-Derived Foam Cells Viability and Proliferation.
Drug-eluting stents (DES) coated with rapamycin or paclitaxel as antiproliferative substances significantly reduced the incidence of clinical restenosis and had fewer side effects after percutaneous coronary intervention. However, DES coated with rapamycin or paclitaxel still cause restenosis due to abnormal tissue growth which remained a therapeutic problem, particularly in certain subgroups, possibly due to drug concentrations. This study examined the impact of different concentrations of rapamycin and paclitaxel on cytokine, cell viability and proliferation in human aortic smooth muscle cells (HASMC)-derived foam cells. The foam cell model was established in vitro by incubating HASMC with 20 µg/mL oxidized low-density lipoprotein (ox-LDL) for 48 hours. Subsequently, foam cells were treated with different concentrations (0.01 µg/mL, 0.1 µg/mL, 0.5 µg/mL, 1 µg/mL, 5 µg/mL and 10 µg/mL) of rapamycin or paclitaxel for 48 hours, to measure cytokine, cell viability and proliferation by ELISA and MTT, respectively. Finally, viability and proliferation were measured by MTT after the foam cells were treated with 1 µg/mL rapamycin or paclitaxel combined with cytokine antibody for 48 hours. After incubation of HASMC with ox-LDL, the ratios of cholesterol ester and total cholesterol increased significantly (55.29%) (P<0.01). Lipid staining with Oil Red O showed many lipid vacuoles and red dye particles in the cells. Meanwhile, cell viability and proliferation significantly increased compared with the control. This indicated that HASMC had been transformed into foam cells (P<0.01) while rapamycin or paclitaxel concentrations ≥0.1 µg/mL can significantly decrease the foam cell proliferation (P<0.05 or P<0.01), and 1 µg/mL of rapamycin or paclitaxel appeared the most effective concentration. As for cytokines, rapamycin or paclitaxel concentrations ≥1 ug/mL could significantly increase the level of inflammatory cytokines IL-6 (P<0.05 or P<0.01), which was enhanced with the increase of drug concentration. However, rapamycin or paclitaxel concentrations ≥1 µg/mL could significantly reduce the levels of anti-inflammatory cytokines IL-35 and transforming growth factor beta (TGF-β) (P<0.05 or P<0.01), which decreased with the increase of drug concentration. In addition, rapamycin or paclitaxel combined with anti-IL-1β, anti-IL-6, anti- TNF-α or anti-IL-35 had no significant effect on foam cell proliferation compared to the drug alone. However, rapamycin or paclitaxel combined with anti-IL-10 or anti-TGF-β can significantly enhance foam cell proliferation (P<0.01). In addition, there was no difference in the effects of the same concentrations of rapamycin and paclitaxel on foam cells. Although rapamycin or paclitaxel can reduce foam cell proliferation, too high or too low concentrations could decrease effectiveness. In particular, a high dose can induce foam cells to increase inflammatory cytokines secretion, reduce anti-inflammatory cytokines secretion, and thus affect the inhibiting proliferation. For rapamycin- and paclitaxel-eluting stents, this conclusion may explain the clinical observation of in-stent restenosis after percutaneous coronary intervention. DES coated with an appropriate concentration of rapamycin or paclitaxel may, at least to some extent, contribute significantly to reducing incidence of late in-stent restenosis.


Site of ovulation and ectopic pregnancy.
In a study of 130 tubal pregnancies the relationships as to location of the corpus luteum, the implantation site, and the gross findings of the non-pregnant fallopian tube were analyzed. A contralateral corpus luteum was found in 20% of the cases. Hydrosalpinx, peritubal adhesions and/or thickening of the tubal wall were observed in 33% of the non-pregnant tubes. Grouping by implantation site--ipsilateral or contralateral corpus luteum--showed no statistical differences. The incidence of chronic pelvic inflammatory diseases was no greater in the subjects above 30 years of age and those having had more than 2 pregnancies. The results suggest that "tube locking" of the ovum, sometimesa result of previous tubal inflammatory disease, sometimes a result of supposed insufficiency of tubal peristalsis. was the major cause of tubal gestation. External migration of the ovum alone may not be an important factor in the genesis of tubal pregnancy.


An analysis of cattle farmers' perceptions of drivers and barriers to on-farm control of Escherichia coli O157.
Structural equation modelling and survey data were used to test determinants' influence on farmers' intentions towards Escherichia coli O157 on-farm control. Results suggest that farmers more likely to show willingness to spend money/time or vaccinate to control Escherichia coli O157 are those: who think farmers are most responsible for control; whose income depends more on opening farms to the public; with stronger disease control attitudes; affected by outbreaks; with better knowledge and more informed; with stronger perceptions of biosecurity measures' practicality; using a health plan; who think farmers are the main beneficiaries of control; and whose farms are dairy rather than beef. The findings might suggest that farmers may implement on-farm controls for E. coli O157 if they identify a clear hazard and if there is greater knowledge of the safety and efficacy of the proposed controls.


Comparison of Epstein-Barr virus presence in Hodgkin lymphoma in pediatric versus adult Argentine patients.
In developed countries and high socioeconomic groups, Hodgkin lymphoma has an initial peak in young adulthood, whereas in undeveloped countries and low socioeconomic groups, it shows an early childhood peak. In developing countries, 90% of children are infected with the Epstein-Barr virus (EBV) by the age of 6 years, but in developed countries, only 30% to 40% are seropositive by that age. Early childhood EBV infection in 75% of Argentine patients was demonstrated. To explore the epidemiology of Hodgkin lymphoma and its relationship with EBV in Argentine patients. The presence of EBV was assessed by Epstein-Barr encoded RNA in situ hybridization and latent membrane protein 1 immunohistochemistry. We studied 92 pediatric and 42 adult Hodgkin lymphoma cases from a public center as well as 39 adult cases from a private center. The mixed cellularity Hodgkin lymphoma had a prevalence of 52% in the pediatric group, while similar frequencies of both nodular sclerosis Hodgkin lymphoma (47%) and mixed cellularity Hodgkin lymphoma (44%) were observed in adults. As for Epstein-Barr encoded RNAs, 55% of the pediatric cases and 31% of the adult cases were positive. Among adult EBV+ cases, 38% were from the public hospital, and 23% were from the private center. EBV was present in 77% of the pediatric mixed cellularity Hodgkin lymphoma cases when compared with the other histologic subtypes of Hodgkin lymphoma. EBV was mainly detected in mixed cellularity cases (39% in the adult group). Our findings strengthen the argument that EBV is involved in the pathogenesis of Hodgkin lymphoma in most children younger than 10 years. Our findings of EBV prevalence, along with both childhood and second-decade peaks as well as comparable frequencies for Hodgkin lymphomas of mixed cellularity and nodular sclerosis, distinguish our population from others in developing countries.


Severe infiltration of the kidneys with ultrasonic abnormalities in acute lymphoblastic leukemia.
A 3-year-old boy with acute lymphoblastic leukemia had enlarged kidneys with impairment of renal function and hypertension as the presenting features of relapse. Ultrasound demonstrated multiple nodular areas of echolucency within enlarged kidneys that reverted to normal when the patient was in remission but then recurred during relapse. This noninvasive procedure may be useful in patients with acute lymphoblastic leukemia to determine the incidence and prognostic significance of renal involvement at the time of diagnosis, and to follow the course of those who have demonstrable changes.


Migration Drives the Replacement of Xanthomonas perforans Races in the Absence of Widely Deployed Resistance.
Changes in Xanthomonas race and species composition causing bacterial spot of tomato have occurred throughout the world and are often associated with epidemics. Knowledge of bacterial population structure is key for resistance discovery and deployment. We surveyed Xanthomonas spp. composition from processing tomato fields in the Midwestern United States over a 4-year period between 2017 and 2020, compared these to strains collected previously, and found that X. perforans is currently the most prevalent species. We characterized 564 X. perforans isolates for sequence variation in avrXv3 to distinguish between race T3 and T4 and validated race designation using hypersensitive response (HR) assays for 106 isolates. Race T4 accounted for over 95% of X. perforans isolates collected in the Midwest between 2017 and 2020. Whole genome sequencing, Average Nucleotide Identity (ANI) analysis, core genome alignment and single nucleotide polymorphism (SNP) detection relative to a reference strain, and phylogenomic analysis suggest that the majority of Midwestern X. perforans strains collected between 2017 and 2020 were nearly identical, with greater than 99.99% ANI to X. perforans isolates collected from Collier County, Florida in 2012. These isolates shared a common SNP variant resulting an a premature stop codon in avrXv3. One sequenced isolate was identified with a deletion of avrXv3 and shared 99.99% ANI with a strain collected in Collier Co., Florida in 2006. A population shift to X. perforans T4 occurred in the absence of widely deployed resistance, with only 7% of tomato varieties tested having the resistant allele at the Xv3/Rx-4 locus. The persistence of nearly identical strains over multiple years suggests that migration led to the establishment of an endemic population. Our findings validate a genomics-based framework to track shifts in X. perforans populations due to migration, mutation, drift, or selection based on comparisons to 146 genomes.


Diabetic nephropathy in KK and KK-Ay mice.
KK mice and KK-Ay mice were examined for age related changes in blood and urinary biophysiological parameters. Blood hemoglobin A1c levels were significantly higher in KK-Ay and KK mice as compared to non-diabetic ddY mice. In both diabetic mice, especially KK-Ay mice, plasma insulin levels markedly increased at 2 to 4 months of age, and the urinary glucose and microalbumin levels and albumin-to-creatinine ratios increased dependent on age. Plasma thrombomodulin levels significantly increased at 2 to 4 months of age in both KK and KK-Ay mice. Mild enlargement of mesangial matrix and segmental proliferative glomerular nephritis were revealed in KK and KK-Ay mice, respectively, at 4 months of age. KK-Ay mice with insulin resistance and high urine mAlb level might be useful as models for the early stage of diabetic nephropathy.


The role of the mammalian branchpoint sequence in pre-mRNA splicing.
We show that base substitutions in the mammalian branchpoint sequence (BPS) YNCUGAC dramatically reduce the efficiency of pre-mRNA splicing in vitro and alter 3' splice-site selection in vivo. Contrary to current dogma that an adenine residue at the appropriate distance from the 3' splice site is the primary determinant of lariat formation, we find that many mutations in the BPS virtually abolish splicing even though the position of this adenine is unchanged. Comparison of the analogous single-base changes in the mammalian and yeast BPSs revealed similar relative effects on splicing efficiency. However, in contrast to yeast, mammalian branchpoint mutations that decrease splicing efficiency severely do not prevent spliceosome assembly. Thus, mutations in the mammalian BPS appear to uncouple spliceosome assembly from cleavage at the 5' splice site and lariat formation.


Comparability of total score performance on the Rey-Osterrieth Complex Figure and a modified Taylor Complex Figure.
One of the most commonly used neuropsychological measures of visuo-spatial abilities is the Rey-Osterrieth Complex Figure (ROCF) Test. Previous research has reliably shown that its companion figure, the Taylor Complex Figure, is not a comparable measure of visuo-spatial memory. The aims of the three studies presented here are to (a) introduce a modified version of the Taylor Figure (MTCF), and (b) examine the comparability of the ROCF and the MTCF using two different administration procedures. The first two studies used a between-subjects design in which half of the study participants received the ROCF and half received the MTCF. In Study 1, an incidental procedure was used in which participants were asked to first copy a figure and then reproduce it from memory without prior warning. In Study 2, an intentional procedure was used in which participants were first asked to observe the figures for the express purpose of reproducing them from memory followed by delay and copy trials. In Study 3, a within-subjects design using counterbalancing and an intentional procedure was used to examine the comparability of the two figures when administered to the same participants as in a true test-retest situation. Overall, the studies demonstrated that learning, memory, and copy score performance on the MTCF was comparable to that on the ROCF.


Identifying critical residues in protein folding: Insights from phi-value and P(fold) analysis.
We apply a simulational proxy of the phi-value analysis and perform extensive mutagenesis experiments to identify the nucleating residues in the folding "reactions" of two small lattice Go polymers with different native geometries. Our findings show that for the more complex native fold (i.e., the one that is rich in nonlocal, long-range bonds), mutation of the residues that form the folding nucleus leads to a considerably larger increase in the folding time than the corresponding mutations in the geometry that is predominantly local. These results are compared to data obtained from an accurate analysis based on the reaction coordinate folding probability P(fold) and on structural clustering methods. Our study reveals a complex picture of the transition state ensemble. For both protein models, the transition state ensemble is rather heterogeneous and splits up into structurally different populations. For the more complex geometry the identified subpopulations are actually structurally disjoint. For the less complex native geometry we found a broad transition state with microscopic heterogeneity. These findings suggest that the existence of multiple transition state structures may be linked to the geometric complexity of the native fold. For both geometries, the identification of the folding nucleus via the P(fold) analysis agrees with the identification of the folding nucleus carried out with the phi-value analysis. For the most complex geometry, however, the applied methodologies give more consistent results than for the more local geometry. The study of the transition state structure reveals that the nucleus residues are not necessarily fully native in the transition state. Indeed, it is only for the more complex geometry that two of the five critical residues show a considerably high probability of having all its native bonds formed in the transition state. Therefore, one concludes that, in general, the phi-value correlates with the acceleration/deceleration of folding induced by mutation, rather than with the degree of nativeness of the transition state, and that the "traditional" interpretation of phi-values may provide a more realistic picture of the structure of the transition state only for more complex native geometries.


A new incision for pyloromyotomy.
Over the past two years forty infants with hypertrophic pyloric stenosis have been operated on using a supraumbilical transverse midline skin incision with retraction of the two rectus muscles apart. This incision has given us good exposure, has improved the delivery of the pylorus, produced a strong closure, and given a good cosmetic result. We propose this incision as an alternative to be used in the operative approach to the pylorus in the treatment of hypertrophic pyloric stenosis.


Is concomitant radiotherapy necessary with gemcitabine-based chemotherapy in pancreatic cancer?
To evaluate the efficacy and safety of gemcitabine (GEM) plus radiotherapy compared with GEM alone for pancreatic cancer (PC). A systematic search for eligible studies comparing gemcitabine plus radiotherapy with gemcitabine alone for PC was performed using MEDLINE, EMBASE, and the Cochrane Library. A quality assessment was performed in each study. Meta-analyses were performed to study the pooled effects of relative risk with 95% confidence interval (CI). A total of 336 participants from four original studies were included. Gemcitabine plus radiotherapy resulted in comparable overall survival (HR = 0.84, 95%CI: 0.53-1.34, P = 0.48) and progress free survival (HR = 0.99, 95%CI: 0.97-1.01, P = 0.36) to gemcitabine alone. Moreover, concomitant radiotherapy was associated with a significantly higher incidence of severe (grade 3 or greater) toxicities, mainly anemia, leukocytopenia, thrombocytopenia, anorexia, nausea/vomiting, and asthenia/fatigue. Radiotherapy is not beneficial with gemcitabine-based chemotherapy for PC. Further exploration for better radiotherapy approaches and therapeutic regimens for the treatment of PC is warranted.


The role of acute and chronic respiratory colonization and infections in the pathogenesis of COPD.
COPD is a major global concern, increasingly so in the context of ageing populations. The role of infections in disease pathogenesis and progression is known to be important, yet the mechanisms involved remain to be fully elucidated. While COPD pathogens such as Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are strongly associated with acute exacerbations of COPD (AECOPD), the clinical relevance of these pathogens in stable COPD patients remains unclear. Immune responses in stable and colonized COPD patients are comparable to those detected in AECOPD, supporting a role for chronic colonization in COPD pathogenesis through perpetuation of deleterious immune responses. Advances in molecular diagnostics and metagenomics now allow the assessment of microbe-COPD interactions with unprecedented personalization and precision, revealing changes in microbiota associated with the COPD disease state. As microbial changes associated with AECOPD, disease severity and therapeutic intervention become apparent, a renewed focus has been placed on the microbiology of COPD and the characterization of the lung microbiome in both its acute and chronic states. Characterization of bacterial, viral and fungal microbiota as part of the lung microbiome has the potential to reveal previously unrecognized prognostic markers of COPD that predict disease outcome or infection susceptibility. Addressing such knowledge gaps will ultimately lead to a more complete understanding of the microbe-host interplay in COPD. This will permit clearer distinctions between acute and chronic infections and more granular patient stratification that will enable better management of these features and of COPD.