Normal human B cells display ordered light chain gene rearrangements and deletions.
Human kappa-producing B cell lines and leukemias retain their excluded lambda light chain genes in the germ line configuration, whereas transformed lambda-producing B cells uniformly rearrange or delete their kappa genes (12). Whether the unexpected lambda gene recombinations within malignant lambda-producing B cells reflect a normal developmental process or are secondary to transformation and specific chromosomal translocations was uncertain. To resolve this issue, we purified circulating lambda-bearing B cells from a normal individual to 97% purity by using a series of negative selection steps and a final positive selection on a cell sorter. Over 95% of the collective kappa genes in these lambda B cells were no longer in their germ line form, with the majority (60%) deleted and the remainder present but in a rearranged state. The chromosomal loss of the germ line kappa genes included the joining (J kappa) segments as well as the constant (C kappa) region, yet the particular variable (V kappa) gene family studied was spared. In addition, the incidence of kappa gene deletions was higher in long-term than in freshly transformed lambda B cell lines. This implies that the deletion of aberrantly rearranged kappa genes may occur as a second event. Such a mechanism would serve to eliminate aberrant transcripts and light chain fragments that might interfere with the synthesis and assembly of effective immunoglobulin molecules. Thus, despite the nearly equal usage of kappa and lambda light chain genes in man, there appears to be a sequential order to their expression during normal B cell ontogeny in which kappa gene rearrangements precede those of lambda.


Structural evidence for MADS-box type I family expansion seen in new assemblies of Arabidopsis arenosa and A. lyrata.
Arabidopsis thaliana diverged from A. arenosa and A. lyrata at least 6 million years ago. The three species differ by genome-wide polymorphisms and morphological traits. The species are to a high degree reproductively isolated, but hybridization barriers are incomplete. A special type of hybridization barrier is based on the triploid endosperm of the seed, where embryo lethality is caused by endosperm failure to support the developing embryo. The MADS-box type I family of transcription factors is specifically expressed in the endosperm and has been proposed to play a role in endosperm-based hybridization barriers. The gene family is well known for its high evolutionary duplication rate, as well as being regulated by genomic imprinting. Here we address MADS-box type I gene family evolution and the role of type I genes in the context of hybridization. Using two de-novo assembled and annotated chromosome-level genomes of A. arenosa and A. lyrata ssp. petraea we analyzed the MADS-box type I gene family in Arabidopsis to predict orthologs, copy number, and structural genomic variation related to the type I loci. Our findings were compared to gene expression profiles sampled before and after the transition to endosperm cellularization in order to investigate the involvement of MADS-box type I loci in endosperm-based hybridization barriers. We observed substantial differences in type-I expression in the endosperm of A. arenosa and A. lyrata ssp. petraea, suggesting a genetic cause for the endosperm-based hybridization barrier between A. arenosa and A. lyrata ssp. petraea.


Gene therapy-mediated modulation of immune processes in the central nervous system.
Selective interference with immune processes in the central nervous system (CNS) is a very difficult task because of the limitations associated with the delivery of immuno modulatory molecules across the blood brain barrier. Systemic administration of immune-mediators, either by conventional routes or by intramuscularly or intravenous gene therapy, is hampered by severe side effects and alters immune-system functions also in peripheral organs. To overcome these problems, different gene therapy strategies have been developed to deliver immuno modulatory molecules directly within the central nervous system. The use of engineered CNS antigen-specific circulating cells as selective delivery vehicles, the direct injection of gene vectors into the brain parenchyma, or also the ependymal route, have been proposed as possible alternative gene therapy protocols to selectively interfere with immuno-pathological processes in the CNS. We will review the use of these CNS-targeted gene therapy protocols for the treatment of experimental autoimmune encephalomyelitis (EAE), the prototypical experimental immune-mediated disease of the CNS, and therefore discuss the relevance of these results for the therapy of multiple sclerosis (MS) the most common, immune-mediated, demyelinating disease of the CNS in humans.


Comparisons of Culturally Targeted Food and Beverage Advertisements in Caribbean-American Neighborhood and Non-Latinx White Neighborhood in New York City.
This descriptive study aimed to (1) compare the number of food and beverage advertisements (ads) located in a Caribbean-American neighborhood and non-Latinx white neighborhood in New York City (NYC), and (2) qualitatively assess and compare the culturally targeted marketing themes of the food and beverage advertisements in both neighborhoods. Three research assistants photographed all outdoor food and beverage advertisements (n=361) across a 1.6 kilometer distance on a high-retail street in a Caribbean-American neighborhood and a non-Latinx white neighborhood. We used content analysis to evaluate advertising themes, and sorted food into nutritional categories (e.g., fast food and alcohol). We identified two neighborhoods with similar income levels in Queens, NYC, USA-South Ozone Park residents are predominantly non-white Caribbean Americans based on data from the NYC Department of City Planning, whereas residents of Steinway are predominantly non-Latinx white. We identified a significantly higher proportion of fast-food advertisements in the Caribbean-American neighborhood (19.78%, n=36) compared with the non-Latinx white neighborhood (5.03%, n=9; p<0.001). Among beverage advertisements, 30.77% (n=56) featured alcohol brands in the Caribbean-American neighborhood, whereas 22.91% (n=41) featured alcohol brands in the non-Latinx white neighborhood. In the Caribbean-American neighborhood, 24.18% (n=44) of food and beverage advertisements referenced Caribbean culture. The Caribbean-American neighborhood in this study had more fast-food advertisements relative to non-Latinx white neighborhoods. More research is needed to understand the effects of culturally targeted ads on Caribbean-American communities.


[Chronic pancreatitis in India (author's transl)].
The etiology, clinical features and course of chronic pancreatitis as reported from developing countries of Africa and Asia ("Afro-asian type") differ significantly from that described in Europe and America ("Euro-american type"). The paper presents the natural history of chronic pancreatitis in India, a country in which both types of the disease have been reported. The incidence is lowest in north and increases as one descends to the south. In the north the euro-american type is more common whereas in the south afro-asian type predominates. The exact etiology of afro-asian type is not known; however, suggestive evidence indicates that protein malnutrition is in some way responsible.


A novel class of GABAA receptor subunit in tissues of the reproductive system.
A novel subunit of the gamma-aminobutyrate, type A (GABAA) receptor family has been identified in human and rat tissues. The subunit displays 30-40% amino acid identity with known family members and represents a distinct subunit class (termed pi). Transcripts of the pi subunit were detected in several human tissues and were particularly abundant in the uterus. The pi subunit protein can assemble with known GABAA receptor subunits and confer unique ligand binding properties to the recombinant receptors in which it combines. Most notably, the presence of the pi subunit alters the sensitivity of recombinant receptors to the endogenous steroid, pregnanolone. Identification of the pi subunit indicates a new target for pharmacological manipulation of GABAA receptors that are located outside of the central nervous system.


Selective coronary angiography in pediatric patients.
Selective coronary angiography (SCA) is an important diagnostic tool in pediatric cardiology; however, there are few reports on its feasibility and safety in young patients. We reviewed our experience with SCA from July 1, 1993 to December 31, 1997. There were 158 cardiac catheterizations that included SCA in patients whose ages ranged from 2 days to 46 years (median, 5.3 years). The most common indication was surveillance for coronary vasculopathy after heart transplantation. A retrograde approach was used in all patients through the femoral artery (n = 157) or umbilical artery (n = 1). Preformed coronary catheters were used and the Judkins left (JL) and Judkins right (JR) were the most common catheters, with the catheter curve size correlating with patient height (R(2) =.76 for JL, R(2) =. 673 for JR). Complications during SCA included brief ST-T wave changes (11%), bradycardia (2.5%), and ventricular fibrillation (0. 6%). Complications of vascular access were transient pulse loss (6%), hematoma (5%), and rebleeding (0.6%). Only one case of femoral artery occlusion was encountered on subsequent cath. In conclusion, complications of SCA were infrequent and serious complications were rare. SCA can be safely performed in pediatric patients at any age including neonates.


Exotic mice as models for aging research: polemic and prospectus.
Most gerontological research using rodent models employs inbred strains, or F1 hybrids derived from them, rather than populations of genetically heterogeneous individuals. This study presents the argument that reliance on genetically homogeneous rodents, though sanctioned by tradition, may not be ideal for many sorts of investigations, and that use of heterogeneous mice and rats would allow researchers to reach robust conclusions that were less likely to reflect strain-specific idiosyncrasies. Segregating stocks, bred by backcross, F2 cross, or four-way cross procedures, would be an improvement over inbred and F1 stocks, providing inexpensive, arbitrarily large, and reproducible populations of genetically diverse test subjects. These stocks would not, however, recapture allelic variations that are likely to have been lost when wild-trapped mice and rats are selected inadvertently over dozens of generations for breeding success in laboratory conditions. Development of specific pathogen free stocks from wild-trapped progenitors particularly from populations selected for relevant evolutionary history and physiological characteristics, may be of great value for analysis of aging and late-life pathophysiology.


Phosphotriesterase: an enzyme in search of its natural substrate.
The bacterial PTE is able to catalyze the hydrolysis of a wide range of organophosphate nerve agents. The active site has been shown to consist of a unique binuclear metal center that has evolved to deliver hydroxide to the site of bond cleavage. The reaction rate for the hydrolysis of activated substrates such as paraoxon is limited by product release or an associated protein conformational change.


Micafungin is more active against Candida albicans biofilms with high metabolic activity.
The ability to form biofilm enables Candida spp. to cause catheter-related candidaemia. The use of agents with in vitro activity against Candida albicans biofilms, such as micafungin, could obviate catheter removal. The metabolic activity of C. albicans biofilms is strain-dependent, and cell wall formation is thought to be more prominent in biofilms showing high metabolic activity. We studied the antifungal activity of micafungin against 265 C. albicans isolates with different degrees of metabolic activity causing fungaemia in 246 patients admitted to Gregorio Marañón Hospital (January 2007 to June 2013). All strains were classified according to the metabolic activity of their biofilm, which was classified as low, moderate and high using XTT. Micafungin MICs for planktonic and sessile cells were assessed using the EUCAST E.Def 7.2 procedure and XTT reduction assay, respectively. The MIC was defined as a 50% and 80% reduction in metabolic activity compared with the control well. Micafungin was uniformly more active against planktonic cells than against sessile cells (MIC50 ≤ 0.015 versus 8 mg/L), although it was not consistently active against all C. albicans biofilms. Isolates with low metabolic activity biofilms showed the lowest susceptibility to micafungin, followed by moderate and high metabolic activity biofilms (P < 0.001). Our study suggests that the metabolic activity of biofilm may have a role in future evaluations of micafungin for the eradication of C. albicans biofilms (e.g. the lock therapy approach).


Frodo interacts with Dishevelled to transduce Wnt signals.
Dishevelled (Dsh) is required for the specification of cell fate and polarity by secreted Wnt proteins. Frodo, a novel conserved Dsh-binding protein, synergized with Xenopus Dsh (XDsh) in secondary axis induction in Xenopus laevis embryos. A dominant inhibitory construct and antisense oligonucleotide-mediated depletion of Frodo inhibited axial development in response to XDsh and XWnt8, and suppressed transcriptional activation of a reporter construct. At later embryonic stages, both dominant negative Frodo and antisense oligonucleotides interfered with the expression of regional neural markers and caused eye deficiencies, indicating that Frodo is required for normal eye and neural tissue development. Full-length Frodo RNA suppressed these loss-of-function phenotypes, attesting to their specificity. These findings establish a function for Frodo as an essential positive regulator of Wnt signalling.


Automorphosis and auxin polar transport of etiolated pea seedlings under microgravity conditions.
On STS-95 space experiment, etiolated pea (Pisum sativum L. cv. Alaska) seedlings showed automorphosis and activities of auxin polar transport in epicotyls were substantially suppressed. These results together with the fact that inhibitors of auxin polar transport induced automorphosis-like growth and development strongly suggested that there are close relationships between automorphosis and auxin polar transport in etiolated pea seedlings. In order to know how gravistimuli control auxin polar transport at molecular levels, we isolated novel cDNAs of PsPIN2 and PsAUX1 encoding putative auxin efflux and influx carriers from etiolated pea seedlings. Significantly high levels in homology were found on nucleotide and deduced amino acid sequences among PsPIN2, PsPIN1 (accession no. AY222857) and AtPINs, and between PsAUX1 and AtAUX1. Exogenously applied auxin substantially enhanced the expression of PsAUX1 and PsPIN2 as well as PsPIN1. Simulated microgravity conditions on a 3-dimensional clinostat remarkably increased gene expression of PsPIN1 and PsAUX1 in the hook and the 1st internode of pea epicotyls, while the increase of expression of PsPIN2 in both organs was not so much. These results suggest that PsPINs and PsAUX1 are auxin-inducible genes, and the expression of PsPINs and PsAUX1 is under the control of gravistimulation. A possible role of these genes in regulating auxin transport relevant to automorphosis of etiolated pea seedlings is also discussed.


[Placenta chorioangioma. Case report at Hospital Español].
Placenta chorioangioma is the most frequent non-trophoblastic tumor of the placenta. Its real incidence is unknown. This incidence is reported as 1% in microscopically examined placentas and counts with clinical evidence in approximately 1: 3,500 to 9,000 births. This tumor is not generally associated to maternal fetal complications, unless the tumor size surpasses a diameter of 5 cm or is near the place of umbilical cord insertion. When the tumor is big, it can complicate the pregnancy with hydramnios, postpartum bleeding, delay in the intrauterine growth, or congestive heart failure in the newborn. The clinic case belongs to a Korean female patient, aged 32, without important antecedents. A placental tumouration, 50.2 x 44.1 mm, was detected by ultrasound to this patient in her 37 1/7 week of pregnancy. She has a normoevolutive pregnancy whose was a term, she had an a eutocic delivery, getting a male whose weight was 2,850 g. The baby is still alive. The placenta histopathological study reported placental chorioangioma, which infracted partially, with multifocal calcification areas.


Halfway encounters: meeting points of colonization routes among the southern beeches Nothofagus pumilio and N. antarctica.
The Patagonian region is characterized by a complex biogeographic history, with evidence of deep phylogeographic breaks shared among species. Of particular interest to conservation is the nature of colonization and settlement patterns after the last glacial period, including the detection of secondary contact between different lineages and/or hybridization among related species around phylogeographic breaks. Here we studied population demography and past hybridization of two widespread tree species endemic to South America, Nothofagus pumilio and N. antarctica. Using 8 nuclear microsatellites we genotyped 41 populations of both species. Genetic variation and structure across the geographic region were evaluated within and among species and the past demographic history of hybridization between the two species was inferred using Approximate Bayesian Computation (ABC). Northern and southern lineages were identified in each species, and Bayesian clustering revealed their convergence at mid latitudes (42°S). Spatial genetic structure (SGS) also indicated the existence of a genetic discontinuity at these latitudes, which is in agreement with previous data from maternal DNA markers. Several populations around 42-44°S presented high levels of genetic diversity with a decrease toward southern populations. Even though the species are clearly differentiated (G'ST=0.335), admixed gene pools were observed in both species. Two independent runs of ABC suggested that inter species admixture-like patterns occurred within the timescale of the Last Glacial Maximum (around 20,000 BP). We also provide evidences of recent and bi-directional hybridization/introgression between the two Nothofagus species and describe features of the populationś demography in the past. The settlement of a secondary contact zone in Nothofagus species around 42-44°S coincides with the phylogeographic breaks and hotspots of genetic diversity found in other plant and animal species in Patagonia, highlighting its importance as reservoir of diversity. The characterization of the population history of native species can contribute substantially to long-term conservation and management policies.


Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation. Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease. The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN. A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM.


Bodies out of control: Relapse and worsening of eating disorders in pregnancy.
Being pregnant is a vulnerable period for women with a history of eating disorders. A central issue in eating disorders is searching control of one's body and food preferences. Pregnancy implies being increasingly out of control of this. Treatment and targeted prevention start with the patient's experience. Little is known about how women with a history of eating disorder experience being pregnant. We interviewed 24 women with a history of eating disorder at the time of pregnancy, recruited from five public pregnancy controls at local family health centers in Norway. Interviews were analyzed by means of ideal type analysis, with a particular focus on how the participants experienced pregnancy and perceived triggers in possible experiences of relapse or worsening during pregnancy. All participants completed the Eating Disorder Examination Questionnaire (EDE-Q) and were diagnosed (DSM-5) by using the Eating Disorder Examination (EDE). On becoming pregnant, 23 of the 24 participants experienced worsening or relapse of their disorder. This occurred both at first time and after several pregnancies, and either interviewed early or late in pregnancy. Ideal type analyses indicated seven different personal features associated with worsening or relapse: the "chaotic" "rigid" "perfect" "worried" "shameful" "motherhood fearing" and "the mother with lost identity" Perceived triggers of worsening or relapse were: "loss of control" "unpredictability" "competition" "change of appearance" "shame and nausea" and "loss of identity." Pregnancy is a vulnerable period for women with a history of eating disorders. A great variation in personal psychological dynamics seems to interact with perceived triggers in worsening or relapse of eating disorder. Our findings have important implications in understanding mechanisms of relapse in pregnancy, preventing relapse and help tailoring adequate intervention.


Care Need Index, a useful tool for the distribution of primary health care resources.
To demonstrate how Care Need Index (CNI), a social deprivation index, may be used to allocate total primary health care resources. Cross sectional survey and register data. The CNI was based on sociodemographic factors: elderly persons living alone, children under age 5, unemployed people, people with low educational status, single parents, high mobility, and foreign born people. The CNI weights were calculated from the ratings of Swedish GPs of the impact of these factors on their workload. The CNI scale was transformed into a positive scale to avoid negative values. CNI weights were calculated for each decile of the study population. The risk of poor self reported health in the CNI deciles was estimated by means of a hierarchical logistic regression in the age range 25-74 (n=27 346). The MigMed database comprising all people living in Sweden was used to calculate the CNI for Stockholm. The Swedish population and the population in Stockholm County. The means of the CNI for deciles ranged from 61 (most affluent neighbourhoods) to 140 (most deprived) in Stockholm County. The ratio between the tenth and the first decile was 1.66. There was an approximately 150% increased risk of poor self reported health for people living in the most disadvantaged neighbourhoods (OR=2.50) compared with those living in the most affluent ones (OR=1). CNI ratios for the deciles corresponded approximately to the odds ratios of poor self reported health status. The CNI can be used to allocate total primary health care resources.


Looming motion primes the visuomotor system.
A wealth of evidence now shows that human and animal observers display greater sensitivity to objects that move toward them than to objects that remain static or move away. Increased sensitivity in humans is often evidenced by reaction times that increase in rank order from looming, to receding, to static targets. However, it is not clear whether the processing advantage enjoyed by looming motion is mediated by the attention system or the motor system. The present study investigated this by first examining whether sensitivity is to looming motion per se or to certain monocular or binocular cues that constitute stereoscopic motion in depth. None of the cues accounted for the looming advantage. A perceptual measure was then used to examine performance with minimal involvement of the motor system. Results showed that looming and receding motion were equivalent in attracting attention, suggesting that the looming advantage is indeed mediated by the motor system. These findings suggest that although motion itself is sufficient for attentional capture, motion direction can prime motor responses.


Glucokinase and glucokinase regulatory protein: mutual dependence for nuclear localization.
Conditional expression of the glucokinase regulatory protein in insulinoma cells, under control of the reverse tetracycline-dependent transactivator, was used to investigate whether expression of this protein de novo would alter the intracellular distribution of glucokinase. The regulatory protein, which was undetectable in the basal state, could be induced by doxycycline to levels comparable to those of liver and was detected mostly in the nucleus. Concomitantly, glucokinase accumulated in the nucleus. Human embryonic kidney cells were transiently transfected to express glucokinase and the regulatory protein, either separately or together. Each protein localized predominantly to the cytoplasm when expressed alone. On co-expression, however, both proteins localized virtually entirely to the nucleus. The enzymic activity of glucokinase was not required for promoting nuclear import of the two proteins, as shown with a glucose-phosphorylation-deficient mutant. Finally, in embryonic kidney cells expressing the regulatory protein alone, treatment with leptomycin B resulted in a partial redistribution of the protein from the cytoplasm to the nucleus, suggesting that this protein can shuttle between the two compartments.


Deciphering Determinants in Ribosomal Methyltransferases That Confer Antimicrobial Resistance.
Post-translational methylation of rRNA at select positions is a prevalent resistance mechanism adopted by pathogens. In this work, KsgA, a housekeeping ribosomal methyltransferase (rMtase) involved in ribosome biogenesis, was exploited as a model system to delineate the specific targeting determinants that impart substrate specificity to rMtases. With a combination of evolutionary and structure-guided approaches, a set of chimeras were created that altered the targeting specificity of KsgA such that it acted similarly to erythromycin-resistant methyltransferases (Erms), rMtases found in multidrug-resistant pathogens. The results revealed that specific loop embellishments on the basic Rossmann fold are key determinants in the selection of the cognate RNA. Moreover, in vivo studies confirmed that chimeric constructs are competent in imparting macrolide resistance. This work explores the factors that govern the emergence of resistance and paves the way for the design of specific inhibitors useful in reversing antibiotic resistance.


Human immunodeficiency virus positive status disclosure to a sexual partner and its determinant factors in Ethiopia: a systematic review and meta-analysis.
Disclosure of Human Immunodeficiency Virus positive status significantly reduced the transmission of HIV; yet, it remains a challenge for many HIV patients. Disclosure serves plays a crucial role to raise awareness and to reduce risky behaviors. Hence, this study aimed to determine the pooled prevalence and effect sizes of determinant factors of HIV positive status disclosure through a systematic review and meta-analysis of the results of the existing primary studies in Ethiopia. This systematic review and meta-analysis was aimed to determine prevalence of HIV positive status disclosure and associated factors by considering and searching published primary articles from different sources. A sensitivity test was conducted to evaluate the presence of influential studies. Besides, the heterogeneity test has been conducted; and publication bias was examined through observing the funnel plot as well as objectively by interpreting the Egger's regression test. Following the Egger's regression test, P-value < 0.05 was considered as statistically significant at 95% Confidence Interval. A total of 18 primary studies were searched from different data sources. The overall pooled prevalence of HIV positive status disclosure among adult PLWHA in Ethiopia was indicated to be 75.95% (95% CI:69.93-81.98); the highest and lowest pooled estimated HIV status disclosure was in Amhara (82.78%) and Tigray (54.31%) regions respectively. Furthermore, Knowing the HIV positive status of sexual partner, AOR = 19.66(95% CI: 10.19-37.91), having prior discussion about HIV testing with their partner, AOR = 9.18(95% CI: 5.53-15.24), got Human Immunodeficiency Virus pretest counseling service AOR = 4.29(95% CI: 2.56-7.21) and being a member of HIV/AIDS associations, AOR = 3.34(95% CI: 2.17-5.12), were significantly associated with HIV positive status disclosure among People living With HIV/AIDS in Ethiopia. The pooled national estimate of HIV/AIDS positive status disclosure is low as compared to the WHO disclosure rate of developing countries and the findings of other national and international studies. Ministry of health and other stakeholders shall design new approaches and strategies to encourage disclosure of HIV status, educate the public about the negative impact of nondisclosure within family members. Health care providers working at Human HIV test centers shall emphasis extensive counseling on disclosure of status to a partner. Moreover, different stakeholders, health workers and community members shall establish, organize, and support HIV/AIDS Associations and motivate HIV positive people to be engaged and participated.


U.S. Selected Practice Recommendations for Contraceptive Use, 2013: adapted from the World Health Organization selected practice recommendations for contraceptive use, 2nd edition.
The U. S. Selected Practice Recommendations for Contraceptive Use 2013 (U.S. SPR), comprises recommendations that address a select group of common, yet sometimes controversial or complex, issues regarding initiation and use of specific contraceptive methods. These recommendations are a companion document to the previously published CDC recommendations U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 (U.S. MEC). U.S. MEC describes who can use various methods of contraception, whereas this report describes how contraceptive methods can be used. CDC based these U.S. SPR guidelines on the global family planning guidance provided by the World Health Organization (WHO). Although many of the recommendations are the same as those provided by WHO, they have been adapted to be more specific to U.S. practices or have been modified because of new evidence. In addition, four new topics are addressed, including the effectiveness of female sterilization, extended use of combined hormonal methods and bleeding problems, starting regular contraception after use of emergency contraception, and determining when contraception is no longer needed. The recommendations in this report are intended to serve as a source of clinical guidance for health-care providers; health-care providers should always consider the individual clinical circumstances of each person seeking family planning services. This report is not intended to be a substitute for professional medical advice for individual patients. Persons should seek advice from their health-care providers when considering family planning options.


Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer.
Recent studies showed that transcription of the MYC gene is driven by the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. JQ1, a potent inhibitor that effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription. The role of MYC in human ATC and whether JQ1 can effectively target MYC as a treatment modality have not been elucidated. To understand the underlying molecular mechanisms of JQ1, we evaluated its efficacy in human ATC cell lines and xenograft models. We determined the effects of JQ1 on proliferation and invasion in cell lines and xenograft tumors. We identified key regulators critical for JQ1-affected proliferation and invasion of tumor cells. JQ1 markedly inhibited proliferation of four ATC cell lines by suppression of MYC and elevation of p21and p27 to decrease phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial-mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in which the size and rate of tumor growth were inhibited by JQ1 via inhibition of p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling. These results suggest targeting of the MYC protein could be a potential treatment modality for human ATC for which effective treatment options are limited.


Solitary sclerotic fibroma.
A 63-year-old Chinese man with a solitary sclerotic fibroma on the abdomen is described. Skin biopsy showed a well-demarcated dermal nodule composed of hypocellular, eosinophilic collagen bundles separated by prominent clefts. Retrospective electron microscopic study revealed wide collagen bundles containing tightly packed collagen fibrils, only 50 nm in diameter. There were no signs of Cowden's disease. To our knowledge, this is the first report of electron microscopic study of sclerotic fibroma. A brief review of the literature is included.


The safety and efficacy of tislelizumab, alone or in combination with chemotherapy, for the treatment of non-small cell lung cancer: a systematic review of clinical trials.
Tislelizumab is an anti-programmed death-1 (PD-1) monoclonal antibody with a construction that enables it to have a higher affinity to its target. We aimed to evaluate tislelizumab's safety and efficacy for treating non-small cell lung cancer (NSCLC). Embase, Scopus, PubMed, Web of Science, and Google Scholar were searched up to December 20, 2022. The review only included randomized controlled trials (RCTs) that evaluated the safety or efficacy of tislelizumab for treating patients with lung cancer. The revised Cochrane risk-of-bias tool (RoB2) was utilized to evaluate study quality. There were four RCTs identified, which included 1565 patients with confirmed locally advanced or metastatic squamous and/or non-squamous types of NSCLC. Treatment with tislelizumab was associated with better progression-free survival (PFS) and objective response rate (ORR), particularly when used in combination with chemotherapy. Almost all patients in both arms reported at least one treatment-emergent adverse event (TEAE). Decreased hematologic indexes accounted for more than 20% of the grade ≥ 3 TEAEs in the tislelizumab plus chemotherapy group. The proportion of TEAE that led to death in the tislelizumab plus chemotherapy arms ranged from 3.2 to 4.2%. Hypothyroidism, pneumonitis, and hyperglycemia were the most frequently noted immune-mediated adverse events in the tislelizumab group. Tislelizumab, whether used alone or in combination with chemotherapy, seems to demonstrate both a safety and efficacy as a treatment for NSCLC.


Major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin: a "real-world" observational study in the United States.
Limited data are available about the real-world safety of non-vitamin K antagonist oral anticoagulants (NOACs). To compare the major bleeding risk among newly anticoagulated non-valvular atrial fibrillation (NVAF) patients initiating apixaban, warfarin, dabigatran or rivaroxaban in the United States. A retrospective cohort study was conducted to compare the major bleeding risk among newly anticoagulated NVAF patients initiating warfarin, apixaban, dabigatran or rivaroxaban. The study used the Truven MarketScan(®) Commercial & Medicare supplemental US database from 1 January 2013 through 31 December 2013. Major bleeding was defined as bleeding requiring hospitalisation. Cox model estimated hazard ratios (HRs) of major bleeding were adjusted for age, gender, baseline comorbidities and co-medications. Among 29 338 newly anticoagulated NVAF patients, 2402 (8.19%) were on apixaban; 4173 (14.22%) on dabigatran; 10 050 (34.26%) on rivaroxaban; and 12 713 (43.33%) on warfarin. After adjusting for baseline characteristics, initiation on warfarin [adjusted HR (aHR): 1.93, 95% confidence interval (CI): 1.12-3.33, P=.018] or rivaroxaban (aHR: 2.19, 95% CI: 1.26-3.79, P=.005) had significantly greater risk of major bleeding vs apixaban. Dabigatran initiation (aHR: 1.71, 95% CI: 0.94-3.10, P=.079) had a non-significant major bleeding risk vs apixaban. When compared with warfarin, apixaban (aHR: 0.52, 95% CI: 0.30-0.89, P=.018) had significantly lower major bleeding risk. Patients initiating rivaroxaban (aHR: 1.13, 95% CI: 0.91-1.41, P=.262) or dabigatran (aHR: 0.88, 95% CI: 0.64-1.21, P=.446) had a non-significant major bleeding risk vs warfarin. Among newly anticoagulated NVAF patients in the real-world setting, initiation with rivaroxaban or warfarin was associated with a significantly greater risk of major bleeding compared with initiation on apixaban. When compared with warfarin, initiation with apixaban was associated with significantly lower risk of major bleeding. Additional observational studies are required to confirm these findings.


Increased clearance of 1,25(OH)2D3 and tissue-specific responsiveness to 1,25(OH)2D3 in diabetic rats.
The kinetics of 1,25-dihydroxyvitamin D3 [1,25(OH)2-D3] and the in vivo response to 1,25(OH)2D3 (7.5, 15, and 30 ng/100 g body wt), infused or injected subcutaneously for 12-14 days, were studied in male spontaneously diabetic and control BB rats. In control rats, increasing doses of 1,25(OH)2D3 produced parallel increases in plasma 1,25(OH)2D3 and calcium, urinary calcium, duodenal CaBP9K, and renal CaBP28K. 1,25-(OH)2D3 at 30 ng/100 g markedly raised plasma osteocalcin and osteoblast/osteoid surfaces in the tibial metaphysis, but inhibited bone mineralization rate. In diabetic rats, plasma 1,25-(OH)2D3 concentrations were decreased, and the rise of plasma 1,25(OH)2D3 during 1,25(OH)2D3 infusion was blunted, but the free 1,25(OH)2D3 index remained normal or above normal. Diabetic rats had an increased metabolic clearance rate of 1,25-(OH)2D3 (0.38 +/- 0.015 vs. 0.24 +/- 0.007 ml.min-1.kg-1), with no further increase in 1,25(OH)2D3-infused diabetic rats; their relative production rate of 1,25(OH)2D3 was unchanged. The responses of plasma and urinary calcium, duodenal CaBP9K, and renal CaBP28K to infused 1,25(OH)2D3 were normal, as was duodenal calcium absorption in 1,25(OH)2D3-injected diabetic rats. However, the virtual absence of osteoblasts/osteoid in trabecular bone was unaltered in diabetic rats infused with 30 ng/100 g 1,25(OH)2D3, with only minimal increase of their low plasma osteocalcin levels. 1,25(OH)2D3 treatment therefore cannot be expected to reverse diabetic osteopenia.


VIDAS test for avidity of Toxoplasma-specific immunoglobulin G for confirmatory testing of pregnant women.
Because congenital toxoplasmosis is almost solely the result of maternal infection acquired during gestation, it is critical to determine whether infection during pregnancy has occurred. In the United States, definitive diagnosis of the acute infection and the time of its occurrence have been compromised by a lack of systematic screening and the fact that only a single serum sample is submitted for testing. In studies in Europe, and depending on the method used, the demonstration of high-avidity immunoglobulin G (IgG) toxoplasma antibodies has been shown to exclude infection having occurred in the first 3 to 5 months of pregnancy. We investigated the usefulness of determining the avidity of IgG toxoplasma antibodies with a VIDAS kit (herein referred to as the VIDAS Toxo-IgG avidity kit, the VIDAS kit essentially rules out acute infection having occurred within the 4 prior months) in the setting of a reference serology laboratory in the United States. Sera (132 samples) from 132 women in the first 16 weeks of pregnancy were chosen because at least one test in the toxoplasma serological profile (TSP) suggested or was equivocal for a recently acquired infection. High-avidity antibodies were demonstrated in 75% of 99 sera positive with the IgM enzyme-linked immunosorbent assay (ELISA) and 31.3% of 16 sera with acute TSP results. A significant percentage of sera with equivocal results wtih the IgM ELISA or TSP also had high-avidity test results. Of 39 women for whom treatment with spiramycin had been suggested to attempt to prevent congenital transmission, 19 (48.7%) had high-avidity antibodies. These findings highlight the value of the VIDAS IgG avidity kit when used in combination with the TSP to exclude recent infection, especially when only a single serum sample is available.


[Platonic conception of a man as an element of the universe on the base of dialogue "Timajos"].
Dialogue "Timajos" states Plato's lecture on a nature of the universe with special regard for position of a man. Presented in it ideas are based in a considerable degree on the knowledge of earlier thinkers, first of all Phytagoreans. They concern problems of primeval matter properties and world creation based on the rules of geometry. Afterwords the question of soul bestowal on the world and creation of living beings, connected directly with a problem of metempsychosis, are discussed. In the final part of the dialogue Plato focuses his attention on a corporal dimension of human structure. On the basis of triangle theory he describes creation of internal organs, skeleton, blood vessels and organs of senses, their function and the processes of growing old and death of the body. In the whole lecture an attention is brought to disclosure the effect of mind in the universe and purposefulness of creator activity.


Tissue-specific and ubiquitous expression patterns from alternative promoters of human genes.
Transcriptome diversity provides the key to cellular identity. One important contribution to expression diversity is the use of alternative promoters, which creates mRNA isoforms by expanding the choice of transcription initiation sites of a gene. The proximity of the basal promoter to the transcription initiation site enables prediction of a promoter's location based on the gene annotations. We show that annotation of alternative promoters regulating expression of transcripts with distinct first exons enables a novel methodology to quantify expression levels and tissue specificity of mRNA isoforms. The use of distinct alternative first exons in 3,296 genes was examined using exon-microarray data from 11 human tissues. Comparing two transcripts from each gene we found that the activity of alternative promoters (i.e., P1 and P2) was not correlated through tissue specificity or level of expression. Furthermore neither P1 nor P2 conferred any bias for tissue-specific or ubiquitous expression. Genes associated with specific diseases produced transcripts whose limited expression patterns were consistent with the tissue affected in disease. Notably, genes that were historically designated as tissue-specific or housekeeping had alternative isoforms that showed differential expression. Furthermore, only a small number of alternative promoters showed expression exclusive to a single tissue indicating that "tissue preference" provides a better description of promoter activity than tissue specificity. When compared to gene expression data in public databases, as few as 22% of the genes had detailed information for more than one isoform, whereas the remainder collapsed the expression patterns from individual transcripts into one profile. We describe a computational pipeline that uses microarray data to assess the level of expression and breadth of tissue profiles for transcripts with distinct first exons regulated by alternative promoters. We conclude that alternative promoters provide individualized regulation that is confirmed through expression levels, tissue preference and chromatin modifications. Although the selective use of alternative promoters often goes uncharacterized in gene expression analyses, transcripts produced in this manner make unique contributions to the cell that requires further exploration.


Digital breast tomosynthesis (3D mammography) for breast cancer screening and for assessment of screen-recalled findings: review of the evidence.
Digital breast tomosynthesis (DBT) addresses some of the limitations of digital mammography (DM) by reducing the effect of overlapping tissue. Emerging data have shown that DBT increases breast cancer (BC) detection and reduces recall in BC screening programs. Studies have also suggested that DBT improves assessment of screen-recalled findings. Areas covered: Studies of DBT for population BC screening and those for assessment of screen-detected findings were reviewed to provide an up-to-date summary of the evidence on DBT in the screening setting. A systematic literature search was conducted for each of the topics; study-specific information and/or quantitative data on detection or accuracy were extracted and collated in tables. Expert commentary: The evidence on DBT for BC screening reinforces that DBT integrated with DM increases cancer detection rates compared to DM alone, although the extent of improved detection varied between studies. The effect of DBT on recall rates was heterogeneous with substantial reductions evident noticeably in retrospective comparative studies. The evidence on DBT for workup was sparse and those studies had limitations related to design and methods. Even though the majority showed improved specificity using DBT compared with conventional imaging, there was little evidence on how DBT impacts assessment outcomes.


The secreted peptidyl prolyl cis,trans-isomerase HP0175 of Helicobacter pylori induces apoptosis of gastric epithelial cells in a TLR4- and apoptosis signal-regulating kinase 1-dependent manner.
Apoptosis contributes to the pathology of gastric epithelial cell damage that characterizes Helicobacter pylori infection. The secreted peptidyl prolyl cis, trans-isomerase of H. pylori, HP0175 executed apoptosis of the gastric epithelial cell line AGS in a dose- and time-dependent manner. The effect of HP0175 was confirmed by generating an isogenic mutant of H. pylori disrupted in the HP0175 gene. The apoptosis-inducing ability of this mutant was impaired compared with that of the wild type. The effect of HP0175 was mediated through TLR4. Preincubation of the gastric epithelial cell line AGS with anti-TLR4 mAb inhibited apoptosis induced by HP0175. Downstream of TLR4, apoptosis signal-regulating kinase 1 activated MAPK p38, leading to the caspase 8-dependent cleavage of Bid, its translocation to the mitochondria, mitochondrial pore formation, cytochrome c release, and activation of caspases 9 and 3. We show for the first time that a secreted bacterial Ag with peptidyl prolyl cis,trans-isomerase activity signals through TLR4, and that this Ag executes gastric epithelial cell apoptosis through a signaling pathway in which TLR4 and apoptosis signal-regulating kinase 1 are central players.


Development of a colorless Centella asiatica (L.) Urb. extract using a natural deep eutectic solvent (NADES) and microwave-assisted extraction (MAE) optimized by response surface methodology.
This study outlines a green process for Centella asiatica (L.) Urb. (CA) extraction. Natural deep eutectic solvents (NADESs) and microwave-assisted extraction (MAE) were combined to provide a high bioactive compound yield and high antioxidant activity. Among the NADESs evaluated, the combination of acetylcholine chloride : malic acid : water (1 : 2 : 2): water (40 : 60) was the best for extraction. These conditions provide high madecassoside (MS) (21.7 mg g-1 dry weight) and asiaticoside (AS) (12.7 mg g-1 dry weight) yields, with greater than 80% (v/v) EtOH (13.3 mg g-1 MS and 7.80 mg g-1 AS). In addition, the extracts from this process showed higher antioxidant activity (IC50 = 0.26 mg mL-1) than the CA aqueous EtOH and water extracts. Moreover, the color of the extract products was less green than that of the extracts prepared using EtOH and aqueous EtOH as solvents, which are suitable for cosmeceutical products. Response surface methodology (RSM) was used for MAE optimization. The ANOVA data from the central composition design (CCD) of RSM were fitted with quadratic models yielding acceptable R 2 (>0.93), adjusted R 2 (>0.87), predicted R 2 (>0.81), and nonsignificant lack of fit (p > 0.05) values. The quadratic model was validated using optimal conditions (30 s, power 300 W, and a liquid to solid ratio 20 mL g-1), and the model validation showed more than 80% accuracy in both MS and AS yields. This research presented an effective green process for CA extraction, which resulted in an environmentally friendly CA extract requiring little energy consumption and no organic solvents.


Clinicopathological characteristics and prognostic analysis of Lauren classification in gastric adenocarcinoma in China.
According to the Lauren classification, gastric adenocarcinomas are divided into diffuse and intestinal types. The causative attribution explaining the dismal prognosis of diffuse-type remains unknown. We examined the archive of 1000 patients with gastric adenocarcinomas who received radical gastrectomy in our center and assessed the effect of the Lauren classification on survival in a multivariate approach. Moreover we compared the variation of clinical features between the diffuse-type and intestinal-type and explored the contributing factors for the prognostic difference. There were 805 resectable patients for the final analysis. Diffuse-type comprised of 48.7% in the gastric carcinoma in our group and showed poorer prognosis than intestinal-type (P=0.013). Multivariate analysis revealed that independent prognostic factors for gastric carcinoma patients were T stage (P<0.001), N stage (P<0.001) tumor size (P<0.001) and Lauren classification (P=0.003). For the clinical features, diffuse-type was significantly associated with younger age (p<0.001), female preponderance (p <0.001), distal location (P<0.001), advanced pT (p < 0.001), advanced pN (p < 0.001) and advanced TNM stage (p = 0.027). Diffuse type adenocarcinoma carries a worse prognosis that may be partially explained by the tendency of this subtype to present at more advanced T and N stage. However, Lauren classification has prognostic significance that is independent of T and N stage as well as other prognostic variables based on the multivariate cox analysis.


Thyroid hormones as molecular determinants of thermogenesis.
Thyroid hormones (TH) are major modulators of energy metabolism and thermogenesis. It is generally believed that 3,5,3'-triiodo-l-thyronine (T3) is the only active form of TH, and that most of its effects are mediated by nuclear T3 receptors, which chiefly affect the transcription of target genes. Some of these genes encode for the proteins involved in energy metabolism. However, a growing volume of evidence now indicates that other iodothyronines may be biologically active. Several mechanisms have been proposed to explain the calorigenic effect of TH, but none has received universal acceptance. Cold acclimation/exposure and altered nutritional status are physiological conditions in which a modulation of energy expenditure is particularly important. TH seem to be deeply involved in this modulation, and this article will review some aspects of their possible influence in these conditions.


Experimental and Theoretical Determination of the pH inside the Confinement of a Virus-Like Particle.
In biology, a variety of highly ordered nanometer-size protein cages is found. Such structures find increasing application in, for example, vaccination, drug delivery, and catalysis. Understanding the physiochemical properties, particularly inside the confinement of a protein cage, helps to predict the behavior and properties of new materials based on such particles. Here, the relation between the bulk solution pH and the local pH inside a model protein cage, based on virus-like particles (VLPs) built from the coat proteins of the cowpea chlorotic mottle virus, is investigated. The pH is a crucial parameter in a variety of processes and is potentially significantly influenced by the high concentration of charges residing on the interior of the VLPs. The data show a systematic more acidic pH of 0.5 unit inside the VLP compared to that of the bulk solution for pH values above pH 6, which is explained using a theoretical model based on a Donnan equilibrium. The model agrees with the experimental data over almost two orders of magnitude, while below pH 6 the experimental data point to a buffering capacity of the VLP. These results are a first step in a better understanding of the physiochemical conditions inside a protein cage.


Survival after spinal cord injury: a systematic review.
Spinal cord injury (SCI) leading to neurological deficits produces long-term effects that persist over a lifetime. Survival analysis of patients with SCI, at individual and population level, is important for public health management and the assessment of treatment achievements. The current study evaluated survival following traumatic and non-traumatic SCI worldwide. A systematic review was conducted, and all included papers were assessed for quality using a purposely designed assessment form. Survival data were presented in Kaplan-Meier curves and compared using the log-rank test. Sixteen studies were included of which 11 concerned traumatic SCI, four non-traumatic SCI, and one both. Crude standard mortality rates (SMRs) revealed that overall mortality in SCI is up to three times higher than in the general population. Survival rates were statistically significantly lower in non-traumatic SCI than in traumatic SCI (log-rank p = 0.000). Age at injury, neurological level, extent of lesion, and year of injury have been described as predictors of survival. Causes of death stem from secondary complications, with failure of the respiratory system being the leading cause. This is the first systematic literature review on survival analysis following SCI worldwide. An increase in survival over time was found. However, the SMRs of individuals with SCI still exceed those of an age-matched non-disabled population, mainly due to secondary complications. Lower survival rates were observed in non-traumatic SCI compared with traumatic SCI.


[Clinical and epidemiological aspects of neurocysticercosis in Brazil: a critical approach].
With the objective to show the characteristics of neurocysticercosis (NCC) in Brazil, was performed a critical analysis of national literature which showed a frequency of 1.5% in autopsies and 3.0% in clinical studies, corresponding to 0.3% of all admissions in general hospitals. In seroepidemiological studies the positivity of specific reactions was 2.3%. Brazilian patient with NCC presents a general clinical-epidemilogical profile (31-50 years old man, rural origin, complex partial epileptic crisis, increased protein levels or normal CSF, CT showing calcifications, constituting the inactive form of NCC), and a profile of severity (21-40 years old woman, urban origin, vascular headache and intracranial hypertension, typical CSF syndrome of NCC or alteration of two or more CSF parameters, CT showing vesicles and/or calcifications, constituting the active form of NCC). Although two localities from the state of S o Paulo have 72:100000 and 96:100000/habitants as prevalence coefficients, regional and national prevalences are very underestimated. Some aspects related to underestimation of NCC prevalence in Brazil are discussed.


Preliminary Efficacy of a Brief Cognitive Restructuring Intervention to Reduce Sexual Coercion Intentions: Roles of Alcohol and Emotion Regulation.
Sexual coercion (SC), the use of nonphysical tactics to obtain sexual contact with a nonconsenting partner, is a prevalent form of sexual misconduct that is associated with several physical and psychological health concerns. Therefore, effective preventative interventions to reduce SC prevalence are needed. Alcohol consumption and difficulties in emotion regulation (ER) are two risk factors that contribute to SC. Cognitive restructuring (CR) has the potential to reduce SC intentions by improving ER through actively challenging one's thoughts to modify emotions. This study represents a secondary data analysis to examine the effectiveness of a brief, web-based CR intervention in reducing SC intentions. To test whether the intervention would remain beneficial in the presence of alcohol, we tested effects among intoxicated versus sober participants. Young, male, heavy episodic drinkers with a history of sexual aggression (N = 137) were randomized into a CR intervention versus control condition as well as alcohol consumption versus no alcohol condition. Then, participants completed a sexual aggression analog scenario. General linear regression analyses showed that intoxicated men reported stronger SC intentions than sober men. Additionally, relative to controls, men in the CR condition who had better preexisting ER cognitive reappraisal skills had significantly lower SC intentions. Our findings provide preliminary support for CR as an effective strategy to reduce SC intentions among sexually aggressive, heavy episodic drinking men with better cognitive reappraisal skills. If findings are replicated, this brief, web-based CR intervention could overcome potential challenges in dissemination and be easily applied in clinical settings.


Arthroscopy of the elbow. Diagnostic and therapeutic benefits and hazards.
We analyzed the results of seventy-one arthroscopies of the elbow in seventy patients who had been followed for an average of thirty-four months, in order to evaluate the risks and benefits of the procedure. Thirty-four arthroscopies were done for diagnostic purposes, fifteen were done for treatment, and twenty-two were done for both diagnosis and treatment. Overall, fifty-one (73 per cent) of the seventy patients benefited in some way. There were diagnostic benefits in thirty-six (64 per cent) of the fifty-six elbows in which diagnosis was an indication for the procedure, and there were therapeutic benefits in thirty (70 per cent) of the forty-three elbows in which treatment was intended or was performed although not planned. The procedure was of benefit in only eighteen (75 per cent) of the twenty-four elbows that had loose bodies, but it was successful in all elbows in which the loose bodies were not secondary to some other condition, including arthrosis. The procedure was also successful in all four elbows in which the loose bodies had been due to osteochondritis dissecans. In twelve (80 per cent) of the fifteen patients who had débridement (removal of flaps or loose fragments of articular cartilage) and in one of the two in whom a synovectomy had been performed, the treatment was successful. Seven (10 per cent) of the seventy patients had complications, none of which were major. Three patients (4 per cent) had a transient radial-nerve palsy after intra-articular injection of local anesthetic; four others had persistent drainage and negative cultures, but the drainage resolved with antibiotic therapy. In one of the four patients, a permanent flexion contracture of 15 degrees developed, and 10 degrees of flexion was lost.


Peroral endoscopic myotomy for the treatment of esophageal achalasia: systematic review and pooled analysis.
Peroral endoscopic myotomy (POEM) is a novel approach to performing esophageal myotomy for the treatment of achalasia. This review aims to assess subjective and objective metrics of achalasia treatment efficacy, perioperative adverse events and the incidence of postoperative gastroesophageal reflux disease in patients treated with POEM. Secondary aims include a pooled analysis comparison of the clinical outcomes and procedural safety of POEM versus laparoscopic Heller's myotomy (LHM). A systematic review of the literature, up to and including January 15, 2015, was conducted for studies reporting POEM outcomes. Studies comparing POEM to LHM were also included for the purpose of pooled analysis. Outcomes from 1122 POEM patients, from 22 studies, are reported in this systematic review. Minor operative adverse events included capno/pneumo-peritoneum (30.6%), capno/pneumo-thorax (11.0%) and subcutaneous emphysema (31.6%). Major operative adverse events included mediastinal leak (0.3%), postoperative bleeding (1.1%) and a single mortality (0.09%). There was an improvement in lower esophageal sphincter pressure and timed barium esophagram column height of 66% and 80% post-POEM, respectively. Symptom improvement was demonstrated with a pre- and post-POEM Eckardt score ± standard deviation of 6.8 ± 1.0 and 1.2 ± 0.6, respectively. Pre- and post-POEM endoscopy showed esophagitis in 0% and 19% of patients, respectively. The median (interquartile range) points scored for study quality was 15 (14-16) out of total of 32. Pooled analysis of three comparative studies between LHM and POEM showed similar results for adverse events, perforation rate, operative time and a nonsignificant trend toward a reduced length of hospital stay in the POEM group. In conclusion, POEM is a safe and effective treatment for achalasia, showing significant improvements in objective metrics and achalasia-related symptoms. Randomized comparative studies of LHM and POEM are required to determine the most effective treatment modality for achalasia.


Effect of hypoxia on respiratory system impedance in dogs.
The effects of hypoxia on lung and airway mechanics remain controversial, possibly because of the confounding effects of competing reflexes caused by systemic hypoxemia. We compared the effects of systemic hypoxemia with those of unilateral alveolar hypoxia (with systemic normoxemia) on unilateral respiratory system impedance (Z) in intact, anesthetized dogs. Independent lung ventilation was obtained with a Kottmeier endobronchial tube. Individual left and right respiratory system Z was measured during sinusoidal forcing with 45 ml of volume at frequencies of 0.2-2.1 Hz during control [100% inspired O2 fraction (FIO2)], systemic hypoxemia (10% FIO2), and unilateral alveolar hypoxia (0% FIO2 to left lung, 100% FIO2 to right lung). During systemic hypoxemia, there was a mean Z magnitude increase of 18%. This change was entirely attributable to a decrease in the imaginary component of Z; there was no change in the real component of Z. Administration of atropine (0.2 mg/kg) did not block the increase in Z with systemic hypoxemia. In contrast, there was no change in Z in the lung subjected to unilateral alveolar hypoxia. We conclude that alveolar hypoxia has no direct effect on lung mechanical properties in intact dogs. In contrast, systemic hypoxemia does increase lung impedance, apparently through a noncholinergic mechanism.


A soluble transforming growth factor beta type III receptor suppresses tumorigenicity and metastasis of human breast cancer MDA-MB-231 cells.
Transforming growth factor beta (TGF-beta) can promote late stage tumor progression in a number of model systems. In the present study, we have examined whether expression of a truncated soluble extracellular domain of TGF-beta type III receptor (sRIII) in human breast cancer MDA-MB-231 cells can antagonize the tumor-promoting activity of TGF-beta by sequestering active TGF-beta isoforms that are produced by the cancer cells. The secretion of sRIII reduced the amount of active TGF-beta1 and TGF-beta2 in the conditioned medium. This led to a significant reduction of the growth-inhibitory activity of the medium conditioned by sRIII-expressing cells on the growth of mink lung epithelial CCL64 cells in comparison with the medium conditioned by the control cells. The tumor incidence and growth rate of all of the three sRIII-expressing clones studied were significantly lower than those of the control cells in athymic nude mice. Four of five control cell-inoculated mice showed spontaneous metastasis in the lung, whereas none of the sRIII-expressing cell-inoculated mice had any lung metastasis. Thus, our results suggest that the sRIII may be used to antagonize the tumor-promoting activity of TGF-beta.


Evidence for both sequential mutations and recombination in the evolution of kdr alleles in Aedes aegypti.
Aedes aegypti is a globally distributed vector of human diseases including dengue, yellow fever, chikungunya, and Zika. Pyrethroid insecticides are the primary means of controlling adult A. aegypti populations to suppress arbovirus outbreaks, but resistance to pyrethroid insecticides has become a global problem. Mutations in the voltage-sensitive sodium channel (Vssc) gene are a major mechanism of pyrethroid resistance in A. aegypti. Vssc resistance alleles in A. aegypti commonly have more than one mutation. However, our understanding of the evolutionary dynamics of how alleles with multiple mutations arose is poorly understood. We examined the geographic distribution and association between the common Vssc mutations (V410L, S989P, V1016G/I and F1534C) in A. aegypti by analyzing the relevant Vssc fragments in 25 collections, mainly from Asia and the Americas. Our results showed all 11 Asian populations had two types of resistance alleles: 1534C and 989P+1016G. The 1534C allele was more common with frequencies ranging from 0.31 to 0.88, while the 989P+1016G frequency ranged from 0.13 to 0.50. Four distinct alleles (410L, 1534C, 410L+1534C and 410L+1016I+1534C) were detected in populations from the Americas. The most common was 410L+1016I+1534C with frequencies ranging from 0.50 to 1.00, followed by 1534C with frequencies ranging from 0.13 to 0.50. Our phylogenetic analysis of Vssc supported multiple independent origins of the F1534C mutation. Our results indicated the 410L+1534C allele may have arisen by addition of the V410L mutation to the 1534C allele, or by a crossover event. The 410L+1016I+1534C allele was the result of one or two mutational steps from a 1534C background. Our data corroborated previous geographic distributions of resistance mutations and provided evidence for both recombination and sequential accumulation of mutations contributing to the molecular evolution of resistance alleles in A. aegypti.


Functional Crypto-Adenylate Cyclases Operate in Complex Plant Proteins.
Adenylyl cyclases (ACs) and their catalytic product cAMP are regulatory components of many plant responses. Here, we show that an amino acid search motif based on annotated adenylate cyclases (ACs) identifies 12 unique Arabidopsis thaliana candidate ACs, four of which have a role in the biosynthesis of the stress hormone abscisic acid (ABA). One of these, the 9-cis-epoxycarotenoid dioxygenase (NCED3 and At3g14440), was identified by sequence and structural analysis as a putative AC and then tested experimentally with two different methods. Given that the in vitro activity is low (fmoles cAMP pmol-1 protein min-1), but highly reproducible, we term the enzyme a crypto-AC. Our results are consistent with a role for ACs with low activities in multi-domain moonlighting proteins that have at least one other distinct molecular function, such as catalysis or ion channel activation. We propose that crypto-ACs be examined from the perspective that considers their low activities as an innate feature of regulatory ACs embedded within multi-domain moonlighting proteins. It is therefore conceivable that crypto-ACs form integral components of complex plant proteins participating in intra-molecular regulatory mechanisms, and in this case, potentially linking cAMP to ABA synthesis.


Quality of life of breast cancer patients medicated with anti-estrogens, 2 years after acupuncture treatment: a qualitative study.
The aim of this study was to examine the quality of life of breast cancer patients medicated with estrogen antagonists, 2 years after having acupuncture treatment for hot flashes. Our sample was taken from women who had recently participated in a randomized controlled trial investigating the effects of acupuncture on hot flashes, a side effect of estrogen-antagonist treatment. Forty-one women from the true acupuncture treatment group and 41 women from the control group (sham acupuncture), who had 2 years previously received a course of 15 acupuncture treatments over a period of 10 weeks, were asked to answer an open question. The question, "Would you like to share your thoughts and experiences related to your breast cancer diagnosis, treatments or anything else?" was by being open, broad, and nonspecific, intended to stimulate subjective information, which was not included in the original, or future quantitative studies. Qualitative data were analyzed using systematic text condensation. Most women were troubled by two or more side effects due to anti-estrogen medication, negatively affecting their life quality. Symptoms included hot flashes, sleep problems, muscle and joint pain, arm edema, fatigue, weight gain, depression, and lack of sexual desire. Women previously treated with sham acupuncture complained that hot flashes were still problematic, whilst those previously treated with traditional Chinese acupuncture found them less of a problem and generally had a more positive outlook on life. These results compare favorably with the findings from our original study that measured quantitatively health related quality of life. Side effects due to anti-estrogen treatment seriously affect the quality of life of breast cancer operated patients. Patients who had previously been treated with traditional Chinese acupuncture complained less of hot flashes, and had a more positive outlook on life, than women who had previously been treated with sham acupuncture.


A Diverse Tetrapod Fauna at the Base of 'Romer's Gap'.
The lack of fossil tetrapod bearing deposits in the earliest Carboniferous ('Romer's Gap') has provoked some recent discussions regarding the proximal cause, with three explanations being offered: environmental, taphonomic, and collection failure. One of the few, and earliest, windows into this time is the locality of Blue Beach exposed in the Tournaisian deposits at Horton Bluff lying along the Avon River near Hantsport, Nova Scotia, Canada. This locality has long been known but, because the fossils were deposited in high energy settings they are almost always disarticulated, so the fauna has not been described in detail. Recent intensive collection has revealed a diverse assemblage of material, including for the first time associated elements, which permits an evaluation of the faunal constituents at the locality. Although not diagnosable to a fine taxonomic level, sufficient apomorphies are present to identify representatives from numerous clades known from more complete specimens elsewhere. The evidence suggests a diverse fauna was present, including whatcheeriids and embolomeres. A single humerus previously had been attributed to a colosteid, but there is some uncertainty with this identification. Additional elements suggest the presence of taxa otherwise only known from the late Devonian. Depositional biases at the locality favor tetrapod fossils from larger individuals, but indirect evidence from trackways and tantalizing isolated bones evidences the presence of small taxa that remain to be discovered. The fossils from Blue Beach demonstrate that when windows into the fauna of 'Romer's Gap' are found a rich diversity of tetrapods will be shown to be present, contra arguments that suggested this hiatus in the fossil record was due to extrinsic factors such as atmospheric oxygen levels. They also show that the early tetrapod fauna is not easily divisible into Devonian and Carboniferous faunas, suggesting that some tetrapods passed through the end Devonian extinction event unaffected.


Root canal hydrophobization by dentinal silanization: improvement of silicon-based endodontic treatment tightness.
A new strategy to improve silicon-based endodontic treatment tightness by dentine hydrophobization is presented in this work: root dentine was silanized to obtain a hydrophobic dentine-sealer interface that limits fluid penetration. This strategy was based on the grafting of aliphatic carbon chains on the dentine through a silanization with the silane end groups [octadecyltrichlorosilane (OTS) and octadecyltriethoxysilane]. Dentine surface was previously pretreated, applying ethylenediaminetetraacetic acid and sodium hypochlorite, to expose hydroxyl groups of collagen for the silane grafting. Collagen fibers exposure after pretreatment was visible with scanning electron microscopy, and Fourier transform infrared (FTIR) spectroscopy showed their correct exposition for the silanization (amide I and II, with 1630, 1580, and 1538 cm⁻¹ peaks corresponding to the vibration of C=O and C--N bonds). The grafting of aliphatic carbon chains was confirmed by FTIR (peaks at 2952 and 2923 cm⁻¹ corresponding to the stretching of C--H bonds) and by the increasing of the water contact angle. The most efficient hydrophobization was obtained with OTS in ethyl acetate, with a water contact angle turning from 51° to 109°. Gas and liquid permeability tests showed an increased seal tightness after silanization: the mean gas and water flows dropped from 2.02 × 10⁻⁸ to 1.62 × 10⁻⁸ mol s⁻¹ and from 10.8 × 10⁻³ to 5.4 × 10⁻³ µL min⁻¹, respectively. These results show clear evidences to turn hydrophilic dentine surface into a hydrophobic surface that may improve endodontic sealing.


The role of vicinal tyrosine residues in the function of Haemophilus influenzae ferric-binding protein A.
The periplasmic FbpA (ferric-binding protein A) from Haemophilus influenzae plays a critical role in acquiring iron from host transferrin, shuttling iron from the outer-membrane receptor complex to the inner-membrane transport complex responsible for transporting iron into the cytoplasm. In the present study, we report on the properties of a series of site-directed mutants of two adjacent tyrosine residues involved in iron co-ordination, and demonstrate that, in contrast with mutation of equivalent residues in the N-lobe of human transferrin, the mutant FbpAs retain significant iron-binding affinity regardless of the nature of the replacement amino acid. The Y195A and Y196A FbpAs are not only capable of binding iron, but are proficient in mediating periplasm-to-cytoplasm iron transport in a reconstituted FbpABC pathway in a specialized Escherichia coli reporter strain. This indicates that their inability to mediate iron acquisition from transferrin is due to their inability to compete for iron with receptor-bound transferrin. Wild-type iron-loaded FbpA could be crystalized in a closed or open state depending upon the crystallization conditions. The synergistic phosphate anion was not present in the iron-loaded open form, suggesting that initial anchoring of iron was mediated by the adjacent tyrosine residues and that alternate pathways for iron and anion binding and release may be considered. Collectively, these results demonstrate that the presence of a twin-tyrosine motif common to many periplasmic iron-binding proteins is critical for initially capturing the ferric ion released by the outer-membrane receptor complex.


Electrophoretically distinct forms of uridine kinase in the rat. Tissue distribution and age-dependence.
By the use of polyacrylamide-gel electrophoresis, uridine kinase from foetal rat liver was separated into four types designated I, II, III and IV in decreasing order of mobility towards the anode. The most anodic (type I) was found only in rapidly growing tissues, such as foetal liver and brain, postnatal spleen and tumour cells. In adult tissues, types II, III and IV were found in the kidney, and types III and IV in the spleen and the liver, whereas type IV was the sole form of uridine kinase present in the brain.


Combining varenicline preloading with Acceptance and Commitment Therapy (ACT) in persons with serious mental illness who smoke: The randomized ACTSLow pilot feasibility trial.
People with serious mental illness (SMI; bipolar [BD] or schizophrenia spectrum disorders [SSD]) who smoke have 30-60% lower odds of quitting and are more prone to experience neuropsychiatric adverse events (NPSAEs) when quitting than smokers without SMI. We pilot-tested the feasibility of combining two different dosing strategies of varenicline preloading with Acceptance and Commitment Therapy (ACT) in persons with SMI in an attempt to bolster quit rates without increasing NPSAEs. Twelve-week, single center, randomized, double-blind, pilot feasibility trial of low (0.5mg twice daily, slower titration) versus standard dose (1.0mg twice daily, standard titration) varenicline in persons with BD or SSD with a 12-week follow-up. All participants received up to 10 sessions of ACT for smoking cessation. Participants were asked to preload with varenicline while still smoking and set a flexible target quit day (TQD) by day 35. Recruitment was hampered by shutdowns related to COVID-19 and the worldwide varenicline recall, respectively. Retention goals were met. Treatment satisfaction was high across both dosing and diagnostic groups. Most participants (92.9%) adhered to preloading instructions and the flexible TQD. Seven-day point prevalence abstinence at week 12 was highest in BD participants (37.5%) but lowest in SSD participants (16.7%) who received the standard dose. Medication was well tolerated. Although recruitment was hindered by unanticipated world events, feasibility was demonstrated. Participants adhered to and were highly satisfied with the combination of pre-cessation varenicline plus ACT. Findings support testing this combined treatment approach in a fully powered trial of persons with BD who smoke.


Cloxacillin concentrations in serum, subcutaneous fat, and muscle in patients with chronic critical limb ischemia.
Patients suffering from critical limb ischemia (CLI) have poor wound healing in the ankle and foot areas. Secondary wound infections are frequent and often treated with prolonged courses of antibiotics. This study set out to investigate to what extent the unbound fraction of 4 g of cloxacillin i.v. reaches its target organ in poorly vascularized tissues, i.e., the calf and foot of patients suffering from CLI. Cloxacillin concentrations were measured by HPLC in serum and in microdialysis samples from skin and muscle of the lower part of the calf and as reference subcutaneously at the pectoral level in eight patients suffering from CLI (four males, four females, mean age 78 years, range 66-85 years) and in three healthy controls (two females, one male, mean age 67, range 66-68 years). In patients suffering from CLI, the tissue penetration of cloxacillin after a single 4 g dose was comparable to that of healthy controls, despite impaired blood circulation. The reduced blood flow in the peripheral vessels of the CLI patients presented here apparently is not the rate-limiting factor for delivery or tissue penetration of cloxacillin.


Radiolucent rim as a possible diagnostic aid for differentiating jaw lesions.
In this study, we formulate a new proposal that complements previous classifications in order to assist dental practitioners in performing a differential diagnosis based on patients' radiographs. We used general search engines and specialized databases such as Google Scholar, PubMed, PubMed Central, MedLine Plus, Science Direct, Scopus, and well-recognized textbooks to find relevant studies by using keywords such as "jaw disease," "jaw lesions," "radiolucent rim," "radiolucent border," and "radiolucent halo." More than 200 articles were found, of which 70 were broadly relevant to the topic. We ultimately included 50 articles that were closely related to the topic of interest. When the relevant data were compiled, the following eight lesions were identified as having a radiolucent rim: periapical cemento-osseous dysplasia, focal cemento-osseous dysplasia, florid cemento-osseous dysplasia, cemento-ossifying fibroma, osteoid osteoma, osteoblastoma, odontoma, and cementoblastoma. We propose a novel subcategory, jaw lesions with a radiolucent rim, which includes eight entities. The implementation of this new category can help improve the diagnoses that dental practitioners make based on patients' radiographs.


DNA immunization with HIV early genes in HIV type 1-infected patients on highly active antiretroviral therapy.
The aim of this study was to evaluate the immunological responses induced by DNA plasmids containing HIV regulatory genes administered in combination in HIV-1-infected patients with pretreatment with highly active antiretroviral treatment (HAART). The study is a double-blind, randomized, and placebo-controlled study, including 15 asymptomatic HIV-1-infected patients on stable HAART for at least 6 months and with plasma HIV RNA levels below 50 copies/ml. Ten patients received a combination of rev, tat, and nef intramuscularly (im) at weeks 0, 4, and 16 at increasing doses giving totals of 300 (100 x 3), 900 (300 x 3), and 1800 (600 x 3) micrograms DNA. Five patients received saline in the same amounts im. Antigen-specific cytotoxic T lymphocyte (CTL) levels were preserved or increased and new T lymphocyte proliferative responses were induced in the group immunized with the HIV DNA genes. No increase in antibody levels was noted. Despite a 10-fold higher vaccine dose, patients on HAART did not respond better to vaccination compared to non-HAART patients included in a previous study where the genes were administered separately. Combining the regulatory genes rev, tat, and nef in increasing doses may reduce the anticipated augmentation of HIV-specific T cell proliferative and CTL responses. Viral suppression did not seem to further improve the initial vaccine responses of patients with comparable CD4 levels.


Amplifiers in Tinnitus Patients.
High tinnitus loudness can be provoked by peripheral disorders of the somatosensory and/or auditory system. The object of our study was to compare high tinnitus loudness patients with low tinnitus loudness patients and to find specific factors associated with high tinnitus loudness. A retrospective cohort analysis of 234 patients with tinnitus as main complaint who visited our clinic in a four-year period. Data obtained from the subjects were age, sex, the loudness of tinnitus estimated by the VAS, and the outcomes of the audiogram and the cervical spine radiograph. High tinnitus loudness was associated with a higher prevalence of females, more dizziness, less self-perceived hearing loss, more cervical disc degeneration at C3 to C6, and a larger anterior spur of cervical vertebrae C3 to C6. Females had a lower prevalence of tinnitus but a higher chance on high tinnitus loudness. Gender, the size of the largest anterior spur from C3 to C6, and the ratio of hearing loss at 8 kHz and hearing loss at 2 kHz are involved in the amplification of tinnitus loudness. High tinnitus loudness can be provoked by peripheral disorders of the somatosensory and/or auditory system. A steep audiometric edge between hearing at 2 kHz and hearing at 8 kHz and/or cervical spine pathology with sympathetic nervous system irritation can amplify tinnitus loudness causing high tinnitus loudness.


The orientation of mycobacteriophage Bxb1 integration is solely dependent on the central dinucleotide of attP and attB.
Integration of the mycobacteriophage Bxb1 genome into its host chromosome is catalyzed by a serine-integrase, a member of the transposon-resolvase family of site-specific recombinases. These enzymes use a concerted mechanism of strand exchange involving double-stranded cleavages with two-base extensions, and covalent protein-DNA linkages via phosphoserine bonds. In contrast to the resolvase/invertase recombination systems--where there are strict requirements for a specific synaptic complex within which the catalytic potential of the enzyme is activated--synapsis of attP and attB by Bxb1 integrase is completely promiscuous, aligning the sites with equal proclivity in parallel and antiparallel alignments. Moreover, the catalytic potential of Bxb1 integrase is fully active in either alignment. As a consequence, the nonpalindromic central dinucleotide (5'-GT) at the center of attP and attB is the sole determinant of Bxb1 prophage orientation, and a single base pair substitution in the two sites is sufficient to eliminate orientation control.


At the Intersection of Faith, Culture, and Family Dynamics: A Complex Case of Refusal of Treatment for Childhood Cancer.
Refusing treatment for potentially curable childhood cancers engenders much discussion and debate. I present a case in which the competent parents of a young Amish child with acute myeloid leukemia deferred authority for decision making to the child's maternal grandfather, who was vocal in his opposition to treatment. I analyze three related concerns that distinguish this case from other accounts of refused treatment. First, I place deference to grandparents as decision makers in the context of surrogate decision making more generally. Second, the maternal grandfather's ardent refusal of treatment and his rationale appeared to be inconsistent with the beliefs expressed by other family members and by members of the same Amish community, leading members of the medical team to question whether refusal of treatment should be treated differently when it appears to be based on the idiosyncratic beliefs of an individual rather than on community-wide values. Third, the medical team perceived tension and dissension between the nonverbal behavior of some family members and the verbal statements made by the maternal grandfather, leading the team to question the parents' true wishes and debate how to weigh nonverbal and indirect forms of communication. Finally, building upon the conclusions of these queries, I explore whether, if the child's prognosis was less favorable or if he were to relapse later, the maternal grandfather should have been permitted to drive a decision to refuse further treatment.


Percutaneous Endoscopic Surgery for Lumbar Discal Cyst: Two Case Reports.
Discal cyst is a rare disease, the pathogenesis is not yet clear and its symptoms are very similar to lumbar disc herniation. Although some cases may regress spontaneously, most cases of lumbar discal cysts are treated surgically. At present, there is no consensus on the treatment of this disease. The authors report the clinical usefulness of the percutaneous endoscopic transforaminal surgery technique in two patients with the lumbar 4-5 discal cyst. The clinical symptoms of both patients were unilateral lower extremity pain and lower back pain. Magnetic resonance imaging of the lumbar spine revealed lumbar discal cysts, causing compression to the spinal dura and roots. Both patients received conservative treatment for more than 6 months, but the clinical symptoms persisted so surgical treatment by percutaneous endoscopic transforaminal surgery without additional discectomy was performed under local anesthesia. The symptoms were relieved immediately after removal of the discal cysts. Postoperative magnetic resonance imaging showed that both patients had complete excision of discal cysts and complete decompression of the treated segmental. There were no recurrent lesions and complications during the follow-up period. We believe that percutaneous transforaminal endoscopic surgery could be a safe, mini-invasive and appropriate method for the treatment of discal cysts.


Rapid Assessment of Microbiota Changes in Individuals with Autism Spectrum Disorder Using Bacteria-derived Membrane Vesicles in Urine.
Individuals with autism spectrum disorder (ASD) have altered gut microbiota, which appears to regulate ASD symptoms via gut microbiota-brain interactions. Rapid assessment of gut microbiota profiles in ASD individuals in varying physiological contexts is important to understanding the role of the microbiota in regulating ASD symptoms. Microbiomes secrete extracellular membrane vesicles (EVs) to communicate with host cells and secreted EVs are widely distributed throughout the body including the blood and urine. In the present study, we investigated whether bacteria-derived EVs in urine are useful for the metagenome analysis of microbiota in ASD individuals. To address this, bacterial DNA was isolated from bacteria-derived EVs in the urine of ASD individuals. Subsequent metagenome analysis indicated markedly altered microbiota profiles at the levels of the phylum, class, order, family, and genus in ASD individuals relative to control subjects. Microbiota identified from urine EVs included gut microbiota reported in previous studies and their up- and down-regulation in ASD individuals were partially consistent with microbiota profiles previously assessed from ASD fecal samples. However, overall microbiota profiles identified in the present study represented a distinctive microbiota landscape for ASD. Particularly, the occupancy of g_Pseudomonas, g_Sphingomonas, g_Agrobacterium, g_Achromobacter, and g_Roseateles decreased in ASD, whereas g_Streptococcus, g_Akkermansia, g_Rhodococcus, and g_Halomonas increased. These results demonstrate distinctively altered gut microbiota profiles in ASD, and validate the utilization of urine EVs for the rapid assessment of microbiota in ASD.


Quantitative thresholds for mitotic counts in histologic grading: confirmation in nonfrozen samples of invasive ductal breast cancer.
Increasing evidence in the medical literature suggests that freezing a sample before fixation causes changes in the histologically observed mitotic activity. In a recent study we determined quantitative thresholds for mitotic counts in invasive ductal breast cancer in both nonfrozen and frozen formalin-fixed specimens. Survival- and recurrence-based analyses of this study material indicated grading thresholds of 17 and 32 mitoses/mm(2) for standardized mitotic index (SMI) and 13 and 35 mitoses/10 high-power fields for mitotic activity index (MAI). The purpose of the present study is to confirm and adjust the introduced thresholds in only nonfrozen formalin-fixed samples. The SMI and MAI in 202 cases of nonfrozen formalin-fixed samples were analyzed to determine optimal cutpoints for prognostication of invasive breast cancer on the basis of mitotic activity. The SMI thresholds were identical in both the present nonfrozen specimens and the previous combined specimens. The optimal MAI thresholds in the nonfrozen material changed to 11 and 37 mitoses/10 high-power field. The confirmation and adjustment of the mitotic thresholds improved the prognostic significance of the method in the nonfrozen material, which will contribute to the clinical applicability of a morphometric grading system.


Average out-of-pocket healthcare and work-loss costs of traffic injuries in Karachi, Pakistan.
The objective of this study was to assess the average out-of-pocket healthcare and work-loss costs of road traffic injuries (RTI) in Karachi. In this cross-sectional study, RTI patients presenting to the five trauma centres in Karachi were contacted using stratified sampling to report their inpatient and outpatient expenses, the time spent in hospital and their average monthly income. These costs were compared among different categories of patient-related variables using analysis of variance test. Out of 341 RTI victims, two wheelers accounted for the majority of injuries (77.2%, N = 256) followed by pedestrians (14.2%, N = 48). Almost half of the sample patients were breadwinners (N = 135, 45.2%), with 87.4% (N = 118) earning less than US$ 248. Average out-of-pocket healthcare costs were US$ 271 (SD = 440.9), which were significantly higher (P ≤ 0.026) for pedestrians (US$ 442), moderate (US$ 341.7) or severe (US$ 553.8) injury, and treatment in private hospitals (US$ 451.7). Similarly, average work loss was US$ 67.1 (SD = 132.1), which were significantly higher (P = 0.001) for breadwinners (US$ 99.1), moderate (US$ 130.0) or severe (US$ 157.1) injury, and treatment in private hospitals (US$ 150.0). Study results clearly showed the need to advocate RTI prevention measures in Pakistan as any such event could lead to a difficult economic situation for those involved and their family.


Evolutionary and genomic insights into meningococcal biology.
Epidemic disease caused by Neisseria meningitidis, the meningococcus, has been recognized for two centuries, but remains incompletely controlled and understood. There have been dramatic reductions in serogroup A and C meningococcal disease following the introduction of protein-polysaccharide conjugate vaccines, but there is currently no comprehensive vaccine against serogroup B meningococci. Genetic analyses of meningococcal populations have provided many insights into the biology, evolution and pathogenesis of this important pathogen. The meningococcus, and its close relative the gonococcus, are the only pathogenic members of the genus Neisseria, and the invasive propensity of meningococci varies widely, with approximately a dozen 'hyperinvasive lineages' responsible for most disease. Despite this, attempts to identify a 'pathogenome', a subset of genes associated with the invasive phenotypes, have failed; however, genome-wide studies of representative meningococcal isolates using high-throughput sequencing are beginning to provide details on the relationship of invasive phenotype and genotype in this fascinating organism and how this relationship has evolved.


Low-range, mid-range and high-range speeding: The association with speeding habits, perceived legitimacy and deterrence.
Speeding is a global road safety concern contributing to an excessive number of fatal crashes and serious debilitating injuries. Research identifying amendable factors associated with speeding to inform interventions is critical. This study examined the association of habit, perceived legitimacy of enforcement, and deterrence elements with three levels of speeding behavior; low- (<10 km/hr over the posted speed limit), mid- (10-20 km/hr), and high-range (>20 km/hr) speeding. An online survey of 870 participants aged over 17 years (M = 37 years) was administered. Approximately 80% of participants reported low-range speeding, 40% mid-range speeding, and 20% high-range speeding. Differences were found between speeding on urban and open roads with the proportion of participants greater for mid- and high-range speeding on open roads. Multiple linear regressions were run finding habit and deterrence variables to be significant predictors of all three levels of speeding. Perceived legitimacy of enforcement was a significant predictor of high-range speeding only. These findings suggest countermeasures that encourage good speed-related habits would be promising. It is also concluded that additional deterrence measures that reduce punishment avoidance experiences (e.g., better detection of speeding behaviors) are needed to further curb speeding behaviors. Nevertheless, the current punishment for all levels of speeding is perceived to be an effective deterrent. These recommendations inform policy, training and education, and campaigns that target engagement in speeding.


MOCRA: a Monte Carlo code for the simulation of radiative transfer in the atmosphere.
This paper describes the radiative transfer model (RTM) MOCRA (MOnte Carlo Radiance Analysis), developed in the frame of DOAS (Differential Optical Absorption Spectroscopy) to correctly interpret remote sensing measurements of trace gas amounts in the atmosphere through the calculation of the Air Mass Factor. Besides the DOAS-related quantities, the MOCRA code yields: 1- the atmospheric transmittance in the vertical and sun directions, 2- the direct and global irradiance, 3- the single- and multiple- scattered radiance for a detector with assigned position, line of sight and field of view. Sample calculations of the main radiometric quantities calculated with MOCRA are presented and compared with the output of another RTM (MODTRAN4). A further comparison is presented between the NO2 slant column densities (SCDs) measured with DOAS at Evora (Portugal) and the ones simulated with MOCRA. Both comparisons (MOCRA-MODTRAN4 and MOCRA-observations) gave more than satisfactory results, and overall make MOCRA a versatile tool for atmospheric radiative transfer simulations and interpretation of remote sensing measurements.