An Isoform of the Eukaryotic Translation Elongation Factor 1A (eEF1a) Acts as a Pro-Viral Factor Required for Tomato Spotted Wilt Virus Disease in Nicotiana benthamiana.
The tripartite genome of the negative-stranded RNA virus Tomato spotted wilt orthotospovirus (TSWV) is assembled, together with two viral proteins, the nucleocapsid protein and the RNA-dependent RNA polymerase, into infectious ribonucleoprotein complexes (RNPs). These two viral proteins are, together, essential for viral replication and transcription, yet our knowledge on the host factors supporting these two processes remains limited. To fill this knowledge gap, the protein composition of viral RNPs collected from TSWV-infected Nicotiana benthamiana plants, and of those collected from a reconstituted TSWV replicon system in the yeast Saccharomyces cerevisiae, was analysed. RNPs obtained from infected plant material were enriched for plant proteins implicated in (i) sugar and phosphate transport and (ii) responses to cellular stress. In contrast, the yeast-derived viral RNPs primarily contained proteins implicated in RNA processing and ribosome biogenesis. The latter suggests that, in yeast, the translational machinery is recruited to these viral RNPs. To examine whether one of these cellular proteins is important for a TSWV infection, the corresponding N. benthamiana genes were targeted for virus-induced gene silencing, and these plants were subsequently challenged with TSWV. This approach revealed four host factors that are important for systemic spread of TSWV and disease symptom development.


IRAG working group 2. CAM-based assays. Interagency Regulatory Alternatives Group.
CAM-based assays, in which test material is applied to the chorion allantoic membrane (CAM) of embryonated chicken eggs, were assessed as alternatives to the Draize eye irritation test. Two general types of CAM-based assays are currently in use, the HET-CAM test and the CAMVA assay. Evaluations were made of five data sets produced with three different modifications of the HET-CAM test and two data sets obtained with the same CAMVA protocol. Data sets consisted of 9-133 test chemicals, usually from the sponsor's product line, and also from a validation trial. Each data set and assay protocol were analysed for quality of data, purpose and proposed use of the assay, range of responses covered, range of test materials amenable, current use in safety and risk assessment both in-house and for regulatory purposes. Since the MMAS Draize score was not available for all in vivo data sets, the sigma MMMIS, which correlates well with the MMAS, was used instead. In vitro/in vivo correlations calculated with Pearson's linear coefficient ranged from r = 0.6 to r = 0.9 for six of seven data sets. Corneal opacity and inflammation of the iris showed the best correlation to in vitro data. Prediction rates were significantly improved when partial linear regression was used, and the predictivity of three different HET-CAM protocols was almost the same. HET-CAM assays showed the best prediction with surfactants and surfactant-based formulations, whereas the CAMVA assay provided the best performance with alcohols.


Downregulation of miR-130a contributes to cisplatin resistance in ovarian cancer cells by targeting X-linked inhibitor of apoptosis (XIAP) directly.
MicroRNAs (miRNAs) are short, highly conserved small non-coding RNA molecules, which post-transcriptionally regulate genes expression and play crucial roles in diverse biological processes. Recent studies have shown that dysregulation of miRNAs might modulate the resistance of cancer cells to chemotherapeutic agents. To investigate the possible role of miR-130a in the development of cisplatin resistance in human ovarian cancer cell line A2780, we evaluated the expression of microRNA-130a (miR-130a) in the cells by the quantitative real-time reverse transcription-polymerase chain reaction. The results showed that miR-130a was significantly down-regulated in cisplatin-resistant ovarian cancer cells. MTT assay and flow cytometry (FCM) results showed that over-expression of miR-130a regulated apoptotic activity, and thereby cisplatin chemosensitivity, in ovarian cancer cells. Furthermore, we found that miR-130a can directly target XIAP, and participate in the regulation of apoptosis. The up-regulation of miR-130a led to a significant decrease in the XIAP mRNA levels and protein levels. XIAP plays an important role in cisplatin resistance in ovarian cancer cell line A2780. Our findings suggested that miR-130a could play a role in the development of cisplatin resistance in ovarian cancer cell line A2780, at least in part by modulation of apoptosis via targeting XIAP.


Acute Liver Infarct with a Superimposed Liver Abscess as a Consequence of Hypercoagulable State in a Patient with COVID-19 without Respiratory Manifestations.
COVID-19 infection has been associated, particularly in severely ill patients requiring hospitalization, with a hypercoagulable state. The case presented herein was a 66-year-old man with SARS-CoV-2 infection who did not have any respiratory symptoms. He presented with the following clinical manifestations: portal vein and hepatic artery thrombosis, liver infarction, and a superimposed abscess of the liver. In this case, early detection and the administration of anticoagulants and antibiotics led to a significant improvement within weeks of the diagnosis. We encourage physicians to be aware of COVID-19-associated hypercoagulable state and its potential complications, regardless of the acuity of the presentation or the absence of respiratory symptoms.


Automated walking aid detector based on indoor video recordings.
Due to the rapidly aging population, developing automated home care systems is a very important step in taking care of elderly people. This will enable us to automatically monitor the health of senior citizens in their own living environment and prevent problems before they happen. One of the challenging tasks is to actively monitor walking habits of elderlies, who alternate between the use of different walking aids, and to combine this with automated fall risk assessment systems. We propose a camera based system that uses object categorization techniques to robustly detect walking aids, like a walker, in order to improve the classification of the fall risk. By automatically integrating the application specific scenery knowledge like camera position and used walker type, we succeed in detecting walking aids within a single frame with an accuracy of 68% for trajectory A and 38% for trajectory B. Furthermore, compared to current state of the art detection systems, we use a rather limited set of training data to achieve this accuracy and thus create a system that is easily adaptable for other applications. Moreover, we applied spatial constraints between detections to optimize the object detection output and to limit the amount of false positive detections. Finally, we evaluate the output on a walking sequence base, leading up to a 92.3% correct classification rate of walking sequences. It can be noted that adapting this approach to other walking aids, like a walking cane, is quite straightforward and opens up the door for many future applications.


[Rhabdomyolysis and acute renal failure in human influenza A H1N1 mediated infection].
Rabdomiolysis and acute renal failure secondary to influenza infection are rare. Up to now, few cases have been reported and most of them are primarily among children. Myositis associated to influenza infection is caused by the toxic effect of the virus in the muscular fiber, dysregulation of inflammatory cytokines and a cross reaction between the muscle fiber and the viral particles. We present the case of a 57 year old male with a diagnosis of H1N1 influenza who developed polyuria, oligoanuria, elevation of lactic dehydrogenase, myoglobin, creatinin phosphokinase and an electromyography with a myopathic pattern. The diagnosis of rabdomyolisis and acute renal failure were made, hemodyalisis was started and the patient improved satisfactorily. This is the first report of a patient with radmoyolisis and acute renal failure secondary to A H1N1 influenza treated during the Mexico epidemic.


Intravaginal Chlamydia trachomatis Challenge Infection Elicits TH1 and TH17 Immune Responses in Mice That Promote Pathogen Clearance and Genital Tract Damage.
While ascension of Chlamydia trachomatis into the upper genital tract of women can cause pelvic inflammatory disease and Fallopian tube damage, most infections elicit no symptoms or overt upper genital tract pathology. Consistent with this asymptomatic clinical presentation, genital C. trachomatis infection of women generates robust TH2 immunity. As an animal model that modeled this response would be invaluable for delineating bacterial pathogenesis and human host defenses, herein we explored if pathogen-specific TH2 immunity is similarly elicited by intravaginal (ivag) infection of mice with oculogenital C. trachomatis serovars. Analogous to clinical infection, ascension of primary C. trachomatis infection into the mouse upper genital tract produced no obvious tissue damage. Clearance of ivag challenge infection was mediated by interferon (IFN)-γ-producing CD4+ T cells, while IFN-γ signaling blockade concomitant with a single ivag challenge promoted tissue damage by enhancing Chlamydia-specific TH17 immunity. Likewise, IFN-γ and IL-17 signaling blockade or CD4+ T cell depletion eliminated the genital pathology produced in untreated controls by multiple ivag challenge infections. Conversely, we were unable to detect formation of pathogen-specific TH2 immunity in C. trachomatis-infected mice. Together, our work revealed C. trachomatis infection of mice generates TH1 and TH17 immune responses that promote pathogen clearance and immunopathological tissue damage. Absence of Chlamydia-specific TH2 immunity in these mice newly highlights the need to identify experimental models of C. trachomatis genital infection that more closely recapitulate the human host response.


Greater unidirectional calcium efflux from bone during metabolic, compared with respiratory, acidosis.
There is a smaller net calcium efflux from bone in vitro during respiratory (increased PCO2) than metabolic (decreased [HCO3-] acidosis. This could be due to the elevated PCO2, which would lessen the driving force for mineral dissolution and increase the driving force for mineralization with respect to carbonated apatite in the bone mineral. To test this hypothesis, we injected neonatal mice with 45Ca and dissected the radiolabeled calvariae 24 h later. The live calvariae were then cultured for 24 h under conditions simulating respiratory acidosis (Resp, pH = 7.225 +/- 0.003, PCO2 = 87.5 +/- 0.1 mmHg), severe respiratory acidosis (SResp, pH = 7.072 +/- 0.004, PCO2 = 103.0 +/- 0.5 mmHg), metabolic acidosis (Met, pH = 7.212 +/- 0.003, HCO3- = 15.5 +/- 0.1 meq/l), or normal acid-base status (Ctl, pH = 7.452 +/- 0.003, PCO2 = 40.0 +/- 0.2 mmHg, HCO3- = 27.8 +/- 0.2 meq/l) and bidirectional net calcium flux (JCa) and unidirectional 45Ca release were determined. There was greater JCa from bone during Met than Resp, and JCa was not different from Met during SResp despite the latter having a significantly lower pH. There was greater unidirectional 45Ca release from bone during Met than Resp, SResp, or Ctl. There was a similar direct correlation between JCa and 45Ca efflux in the respiratory and metabolic groups. However, when calvarial osteoclast activity was inhibited with calcitonin,although there was again greater JCa and 45Ca release with a metabolic compared with respiratory acidosis, there was a greater proportion of 45Ca release than JCa from bone.(ABSTRACT TRUNCATED AT 250 WORDS)


[Papilla Vateri restenoses after papillosphincterotomy].
Biliary tract was investigated in 105 patients after endoscopic papillosphincterotomy for choledocholithiasis and papillostenosis. The follow-up revealed papillary restenosis in 8,6%, which occurred during first 2 years after the procedure. Short cut of the duodenal papilla and intramural part of the common bile duct and anamnestic papillostenosis and septic cholangitis proved to be the main reasons of the papillary restenosis.


Prognostic relevance of the revised R status definition in pancreatic cancer: meta-analysis.
The prognostic impact of margin status is reported with conflicting results after pancreatic cancer resection. While some studies validated an uninvolved resection margin (R0) 1 mm or more of tumour clearance, others have failed to show benefit. This systematic review and meta-analysis aimed to investigate the effects of margin definitions on median overall survival (OS). MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies reporting associations between resection margins and OS between 2010 and 2021. Data regarding margin status (R0 circumferential resection margin (CRM) negative (CRM-), R0 CRM positive (CRM+), R0 direct, and R1 and OS were extracted. Hazard ratios (HRs) were pooled with a random-effects model. The risk of bias was evaluated with the Quality in Prognosis Studies (QUIPS) tool. The full texts of 774 studies were screened. In total, 21 studies compromising 6056 patients were included in the final synthesis. In total, 188 (24 per cent) studies were excluded due to missing margin definitions. The R0 (CRM+) rate was 50 per cent (95 per cent confidence interval (c.i.) 0.40 to 0.61) and the R0 (CRM-) rate was 38 per cent (95 per cent c.i. 0.29 to 0.47). R0 (CRM-) resection was independently associated with improved OS compared to combined R1 and R0 (CRM+; HR 1.36, 95 per cent c.i. 1.23 to 1.56). The revised R status was confirmed as an independent prognosticator compared to combined R0 (CRM+) and R1. The limited number of studies, non-standardized pathology protocols, and the varying number of margins assessed hamper comparability.


Kv1.3 blockade by ShK186 modulates CD4+ effector memory T-cell activity of patients with Granulomatosis with polyangiitis.
Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory as it relies on strong immunosuppressive regimens, with either cyclophosphamide or rituximab, that reduce the immunogenicity of several vaccines and are risk factors of severe form of COVID-19. This emphasizes the need to identify new drug target and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186. Peripheral blood of 27 GPA-patients in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with PMA, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+TH cells were assessed using flow cytometry. ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17, and IL-21 in CD4+TH cells from GPA-patients in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs. Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.


Normal M mode values in healthy Turkish children.
Evaluation of cardiac structures requires a large study group for accurate data on normal values. The aim of the study was to obtain normal M mode echocardiographic values in a substantial sample of healthy term neonates and children to develop centile charts. Data were obtained over 2 years from a single center in Turkey, from 1200 healthy infants and children aged 1 day to 17 years. Using echocardiographic investigation, measurements were obtained of the following: left ventricular dimension at end diastole and end systole; thickness of interventricular septum and posterior wall of the left ventricle; aortic and pulmonary root diameter; and left atrial dimension. The influence of systematic errors as statistical noise in this large sample was decreased using third- degree polynomial curves. Measurements are presented graphically as curved lines of centiles with respect to body weight for healthy term neonates and children. The values showed a good correlation with body weight and allowed the construction of percentile curves (5%, 25%, 50%, 75%, and 95%). Higher values were observed in boys during adolescence. The presented charts and tables make it possible to judge the echocardiographic measurements of a particular patient as normal or abnormal.


Delineating clinical and developmental outcomes in STXBP1-related disorders.
STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental endpoints have not yet been described in detail, which is a critical prerequisite for clinical trial readiness. Here, we assessed 1,281 cumulative patient-years of seizure and developmental histories in 162 individuals with STXBP1-related disorders and established a natural history framework. STXBP1-related disorders are characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Epilepsy onset differed across seizure types, with 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of life. Epilepsy histories diverged between variant subgroups in the first 2 years of life, when individuals with protein-truncating variants and deletions in STXBP1 (n=39) were more likely to have infantile spasms between 5 and 6 months followed by seizure remission, while individuals with missense variants (n=30) had an increased risk for focal seizures and ongoing seizures after the first year. Developmental outcomes were mapped using milestone acquisition data in addition to standardized assessments including the Gross Motor Function Measure-66 Item Set and the Grasping and Visual-Motor Integration subsets of the Peabody Developmental Motor Scales. Quantification of endpoints revealed high variability during the first five years of life, with emerging stratification between clinical subgroups, most prominently between individuals with and without infantile spasms. We found that individuals with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of life had more predictable seizure trajectories in early to late childhood than compared to individuals with more severe seizure presentations, including individuals with refractory epilepsy throughout the first year. Characterization of anti-seizure medication response revealed age-dependent response over time, with phenobarbital, levetiracetam, topiramate, and adrenocorticotropic hormone effective in reducing seizures in the first year of life, while clobazam and the ketogenic diet were effective in long-term seizure management. Virtual clinical trials using seizure frequency as the primary outcome resulted in wide range of trial success probabilities across the age span, with the highest probability in early childhood between 1 year and 3.5 years. In summary, we delineated epilepsy and developmental trajectories in STXBP1-related disorders using standardized measures, providing a foundation to interpret future therapeutic strategies and inform rational trial design.


Bilirubin interference in a peroxidase-coupled procedure for creatinine eliminated by bilirubin oxidase.
A colorimetric peroxidase-coupled procedure for determination of creatinine in human serum and urine is described. A 30-s sample pre-treatment with bilirubin oxidase eliminates interference from endogenous bilirubin. The 4-aminoantipyrine-2-hydroxy-3,5-dichlorobenzenesulfonate chromogen system of this method is about fourfold more sensitive than current procedures that involve monitoring NAD(P)H and nearly fivefold more sensitive than the traditional picrate procedures. Incorporation of a sample blank eliminates positive interference from endogenous creatine. Results of the proposed procedure are somewhat lower than those of the common kinetic or equilibrium picrate techniques, as would be expected because of the effects of the well-known interferences in the latter methods.


Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study.
Anti-virulence agents are non-bacteriostatic and non-bactericidal emerging therapeutic options which hamper the production of virulence factors in pathogenic flora. In Staphylococcus aureus and Enterococcus faecalis, regulation of virulence genes' expression occurs through the cyclic peptide-mediated accessory gene regulator (agr) and its ortholog fsr quorum sensing systems, respectively. In the present study, we screened a set of 54 actinomycetales secondary metabolites as novel anti-virulence compounds targeting quorum sensing system of the Gram-positive bacteria. The results indicated that four compounds, Phenalinolactones A-D, BU-4664LMe, 4,5-dehydrogeldamycin, and Questinomycin A, potentially inhibit the agr quorum sensing system and hemolytic activity of S. aureus. On the other hand, Decatromicin A and B, Okilactomycin, Rishirilide A, Abyssomicin I, and Rebeccamycin selectively blocked the fsr quorum sensing system and the gelatinase production in E. faecalis at sub-lethal concentrations. Interestingly, Synerazol uniquely showed the capability to inhibit both fsr and agr quorum sensing systems. Further, in silico molecular docking studies were performed which provided closer insights into the mode of action of these compounds and proposed that the inhibitory activity of these compounds could be attributed to their potential ability to bind to the ATP-active site of S. aureus AgrA. Taken together, our study highlights the potential of actinomycetales secondary metabolites with diverse structures as anti-virulence quorum sensing inhibitors.


Motor learning principles for rehabilitation: a pilot randomized controlled study in poststroke patients.
Six months after a stroke, the hemiplegic arm often remains compromised. More innovative approaches to motor rehabilitation are needed. The authors compared a motor learning-based approach in a virtual environment with more conventional upper extremity therapy in a pilot trial. This prospective, single-blinded, randomized controlled trial compared reinforced feedback in a virtual environment (RFVE; n = 27) with a control intervention (n = 20) of progressive therapy for the affected upper extremity. Both treatments were provided for 4 weeks, 5 days per week, with 1-hour treatment sessions daily. The primary outcomes were the Fugl-Meyer Upper Extremity (F-M UE) and Functional Independence Measure (FIM) scores. Kinematic outcomes included mean duration (MD), mean linear velocity (MLV), and number of submovements to measure the motor performance. Analyses of the primary outcomes were performed per protocol and by intention to treat. F-M UE scores improved significantly in the RFVE group compared with the conventional therapy group ("intention to treat" = 5.10 points, P = .004; ANCOVA = 4.26 points, P < .01). Several of the kinematic parameters improved in the RFVE group (MD, P < .01; MLV, P < .01). FIM improvements did not differ. Both rehabilitation therapies improved arm motor performance and functional activity, but the RFVE therapy induced more robust results in patients exposed to late rehabilitation treatment.


Migration of retrievable expandable metallic stents inserted for malignant esophageal strictures: incidence, management, and prognostic factors in 332 patients.
The purpose of this study was to evaluate the incidence, prognostic factors, and secondary management of stent migration in patients with malignant esophageal strictures. A retrospective study was performed in a single tertiary referral university hospital to identify the incidence, management, and prognostic factors for stent migration in 332 consecutive patients with placement of a retrievable expandable metallic stent. Stent migration was classified into four patterns as locations of a migrated stent: pattern I, partially migrated in the proximal direction; pattern II, partially migrated in the distal direction; pattern III, completely migrated into the stomach; and pattern IV, completely migrated into the bowel. Stent migration occurred in 42 (12.6%) of 332 patients. Migration was partial (n = 21) or complete (n = 21), and nine (21%), 12 (29%), 11 (26%), and 10 (24%) patients had patterns I, II, III, and IV, respectively. Multivariate analysis identified the following prognostic factors: esophagogastric junction strictures caused by cancer of the gastric cardia (odds ratio 1.330; p = 0.004), patients who underwent anticancer treatment after stent placement (17.514; p < 0.001), and patients with a longer survival time (1.994; p < 0.001). Secondary management was needed for 33 of 42 patients. The strictures in the remaining nine patients improved throughout follow-up. Stent migration occurs most commonly in patients with cancer of the gastric cardia, patients with longer survival time, and those who underwent anticancer treatment after stent placement. Stent migration is successfully managed by further intervention. Accurate knowledge of the pattern of stent migration is important for successful management.


Curcumin as an inhibitor of cancer.
Curcumin I (Cur I) and curcumin III (Cur III) are the yellow coloring phenolic compounds isolated from the spice turmeric. The effect of curcumins on different stages of development of cancer was studied. Cur I inhibited benzopyrene- (BP) induced forestomach tumors in female Swiss mice, and Cur III inhibited dimethylbenzanthracene- (DMBA) induced skin tumors in Swiss bald mice. Cur I also inhibited DMBA-initiated, tetradeconyl phorbol acetate-promoted skin tumors in female Swiss mice. In vitro 3H-BP-DNA interaction studies, and in vivo carcinogen metabolizing enzyme studies revealed that curcumins exert anticarcinogenic activity by altering the activation and/or detoxification process of carcinogen metabolism. Cur I and Cur III also exhibit in vitro cytotoxicity against human chronic myeloid leukemia, which is dose dependent. This study shows that curcumins inhibit cancer at initiation, promotion and progression stages of development.


Hepatitis C virus associated arthritis in absence of clinical, biochemical and histological evidence of liver disease--responding to interferon therapy.
Extrahepatic manifestations associated with Hepatitis C virus (HCV) such as arthritis, vasculitis, cryoglobulinemia, are well known. However, HCV related arthritis in the absence of clinical, biochemical and histological evidence of liver disease is not common. This article deals with such a case and its response to interferon therapy. We present a case of a 32 year old Filipino male who presented with bilateral symmetrical painful swelling of multiple joints including, hands, elbows, shoulders, and knees. Serum rheumatoid factor, antinuclear antibodies and a comprehensive work-up for rheumatologic disorders were all negative. Both initially and subsequently, serological tests for hepatitis A, B, and autoimmune liver diseases, Wilson's disease, hemochromatosis, syphilis, human immunodeficiency virus (HIV) and cryoglobulinemia were negative, initially and subsequently. However, the hepatitis C antibody test was positive and hepatitis C viral RNA was detected in high titers. The joint symptoms did not improve despite therapy with nonsteroidal anti-inflammatory drugs and a short course of prednisone prescribed earlier by his primary care physician. The patient then requested and was subsequently treated with interferon alpha 2b. The patient responded rapidly to the interferon therapy with significant and sustained improvement in joint symptoms and disappearance of hepatitis C viral RNA from his serum. HCV arthritis should be considered in the differential diagnosis of seronegative arthritis of undetermined etiology even in the setting of normal liver chemistries.


Optimized In Silico Modeling of Drug Absorption after Gastric Bypass: The Case of Metformin.
Bariatric surgery is an effective treatment for severe obesity and related comorbidities, such as type II diabetes. Gastric bypass surgery shortens the length of the intestine, possibly leading to altered drug absorption. Metformin, a first-line treatment for type II diabetes, has permeability-dependent drug absorption, which may be sensitive to intestinal anatomic changes during bypass surgery, including Roux-en-Y gastric bypass (RYGB). Previous computer simulation data indicate increased metformin absorption after RYGB. In this study, we experimentally determined the region-dependent permeability of metformin, using the rat single-pass intestinal perfusion method (SPIP), which we then implemented into GastroPlusTM to assess the contribution of our SPIP data to post-RYGB metformin absorption modeling. Previous simulations allowed a good fit with in vivo literature data on healthy and obese control subjects. However, it was revealed that for post-RYGB drug absorption predictions, simply excluding the duodenum/jejunum is insufficient, as the software underestimates the observed plasma concentrations post-RYGB. By implementing experimentally determined segmental-dependent permeabilities for metformin in the remaining segments post-surgery, GastroPlusTM proved to fit the observed plasma concentration profile, making it a useful tool for predicting drug absorption after gastric bypass. Reliable evaluation of the parameters dictating drug absorption is required for the accurate prediction of overall absorption after bariatric surgery.


Activation of C-type virus during chemically induced leukemogenesis in mice.
Repeated percutaneous applications of 7,12-dimethylbenz(a)anthracene on weaning DBA/2 and ST/a mice induced 100% leukemias with short latency periods. Endogenous C-type viruses were activated during the treatment as evidenced by (a) increased expression of the murine leukemia virus major core protein, p30, in blood and spleens and (b) increased frequency of detection of ecotropic virus by cocultivation of the splenocytes with SC-1 cells. The treatment did not affect p30 expression in several nonlymphoid organs, and detection of xenotropic viruses in the splenocytes was decreased. Virus expression did not correlate with the progression of disease in that (a) high p30 levels were generally found in mice with relatively low spleen weights and (b) p30 levels had no obvious connection to survival of the individual. 7,12-Dimethylbenz(a)anthracene treatment had little influence on p30 expression in spleens and blood from C3H and BALB/c mice, which are less sensitive to 7,12-dimethylbenz(a)anthracene-induced leukemogenesis. The results indicate an association of C-type virus activation with chemical induction of leukemia but do not necessarily imply an etiological role of the virus in the disease.


Effect of aging differs for memory of object identity and object position within a spatial context.
There has been considerable focus on investigating age-related memory changes in cognitively healthy older adults, in the absence of neurodegenerative disorders. Previous studies have reported age-related domain-specific changes in older adults, showing increased difficulty encoding and processing object information but minimal to no impairment in processing spatial information compared with younger adults. However, few of these studies have examined age-related changes in the encoding of concurrently presented object and spatial stimuli, specifically the integration of both spatial and nonspatial (object) information. To more closely resemble real-life memory encoding and the integration of both spatial and nonspatial information, the current study developed a new experimental paradigm with novel environments that allowed for the placement of different objects in different positions within the environment. The results show that older adults have decreased performance in recognizing changes of the object position within the spatial context but no significant differences in recognizing changes in the identity of the object within the spatial context compared with younger adults. These findings suggest there may be potential age-related differences in the mechanisms underlying the representations of complex environments and furthermore, the integration of spatial and nonspatial information may be differentially processed relative to independent and isolated representations of object and spatial information.


Composition and Function of Spider Glues Maintained During the Evolution of Cobwebs.
Capture silks are an interesting class of biological glues that help spiders subdue their prey. Viscid capture silk produced by the orb web spiders is a combination of hygroscopic salts that aid in water uptake and interact with adhesive glycoproteins to make them soft and sticky. The orb was a stepping stone to the evolution of new web types, but little is known about the adhesives in these webs. For instance, cobweb spiders evolved from orb-weaving ancestors and utilize glue in specialized sticky gumfoot threads rather than an elastic spiral. Early investigation suggests that gumfoot adhesives are quite different viscid glues because they lack a visible glycoprotein core, act as viscoelastic fluids rather than solids, and are largely invariant to humidity. Here, we use spectroscopic and staining methods to show that the gumfoot silk produced by Latrodectus hesperus (western black widow) is composed of hygroscopic organic salts and water insoluble glycoproteins, similar to viscid silk, in addition to a low concentration of spider coating peptides reported before. Our adhesion studies reveal that the organic salts play an important role in adhesion, similar to that seen in orb web spiders, but modulating function at much lower humidity. Our work shows more similarities in the viscid silk produced by orb web and cobweb spiders than previously anticipated and provide guidelines for developing synthetic adhesives that can work in dry to humid environments.


Association of a central pattern of body fat with blood pressure and lipoproteins from adolescence into adulthood. The Amsterdam Growth and Health Study.
The association between the change in a central pattern of body fat and blood pressure and lipoprotein levels was investigated longitudinally in a healthy population of young males and females over 15 years. The subjects (males, n = 84; females, n = 98), participants in the Amsterdam Growth and Health Study, were measured six times between the mean ages of 13 and 27 years. As an indicator of a central pattern of body fat, subscapular/triceps skinfold ratio (S/T ratio) was used as an independent variable. Systolic blood pressure (SBP), diastolic blood pressure (DBP), total serum cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and TC/HDL-C ratio were used as dependent variables. Longitudinal associations were analyzed by generalized estimating equations (GEE) in which data of the six periods of measurement were included simultaneously. Between ages 13 and 27 years, and after adjustment for the sum of four skinfolds, physical activity, smoking, and alcohol intake, the increase of the S/T ratio was significantly associated with an increase in SBP in males and females and with a decrease in level of HDL-C in males only. The change in central pattern of body fat negatively affects the change in established risk factors for cardiovascular diseases early in life.


Lyme disease in transgenic mice expressing the Borrelia burgdorferi flagellin epitope implicated in human neuroborreliosis.
Because of an association of human neuroborreliosis with the development of an antibody response against an antigen in neural tissue that cross-reacts with an epitope on the flagellin protein of Borrelia burgdorferi, C3H transgenic mice were created that expressed the flagellin epitope (amino acids 213-224) as a fusion protein with myelin basic protein. The transgenic mice expressed the flagellin epitope selectively in myelinated regions of the nervous system. Both transgenic and non-transgenic mice developed an antibody response to the flagellin epitope during B. burgdorferi infection and both developed arthritis and carditis. However, no lesions were found in the central nervous system of either type of mouse for up to 8 weeks after infection. The data indicate that expression of the flagellin 213-24 epitope in mice does not result in neurologic disease, suggesting that B. burgdorferi flagellin antibodies may not be directly implicated in neuroborreliosis.


Immobilization of lipases in hydrophobic chitosan for selective hydrolysis of fish oil: The impact of support functionalization on lipase activity, selectivity and stability.
The objective of this paper was to carry out an integral study of the use of hydrophobic chitosan as a low-cost support for immobilizing lipases and their further application in the selective hydrolysis of fish oil. Chitosan functionalized with different alkyl chains (C4, C8, C12) were characterized by FTIR, TGA, SEM, and Rose Bengal adsorption. Lipase B from Candida antarctica (CalB) and lipase from Rhizomucor miehei (RML) were immobilized obtaining a higher expressed activity at a longer alkyl chain length of support. Biocatalyst thermal stability showed that the impact of the alkyl chain length on enzyme stabilization varied according to the lipase source. The biocatalysts were applied in menhaden oil hydrolysis. Total polyunsaturated fatty acids released after 30 h of reaction with lipases immobilized in butyl, octyl and dodecyl-chitosan was 60, 107, and 90 mM for CalB biocatalysts, and 560, 392, and 50 mM for RML biocatalysts, respectively. Selectivity of CalB was not affected by the alkyl chain, while in the case of RML, a higher selectivity to cis-4,7,10,13,16,19-docohexaenoic acid release was obtained with dodecyl-chitosan. In conclusion, the adequate functionalization of chitosan varied according to lipase source, affecting their activity, stability and performance in the hydrolysis of fish oil.


Short- and long-term dynamics of the toxic potential and genotypic structure in benthic populations of Microcystis.
Microcystis colonies are known to overwinter on the surface of the sediment of freshwater ecosystems. However, little is known about the genotypic and toxicological dynamics of Microcystis populations during this benthic life stage. In this study, we report a two-year-long survey of benthic populations of Microcystis, which had spent from a few days to more than six years in the sediment. In order to avoid any interaction with the planktonic proliferations, we chose two deeply buried benthic populations, which could be easily dated. Quantitative PCR on mcyB gene and protein phosphatase inhibition assays were performed to measure their toxic potential, and their genotypic structure was assessed by Capillary Electrophoresis-Single Strand Conformation Polymorphism (CE-SSCP), based on 16S-23S Intergenic Transcribed Spacer (ITS). The microcystin content of the cells seemed to change sharply during the first few months of benthic survival, whereas this content was low and decreased steadily after several years of benthic life. No genetic selection was observed in either the proportion of potentially toxic clones or the ITS sequences for any of the populations considered. From these results, the benthic life stage of Microcystis appears to preserve the structure and the composition of the population over a far larger time scale than classical overwintering period. Finally, some genotypes were common in both of the benthic populations, even though they originated from planktonic blooms that had developed five years apart, suggesting a major overlap of planktonic proliferations in successive years.


Testosterone, paternal behavior, and aggression in the monogamous California mouse (Peromyscus californicus).
Testosterone (T) mediates a trade-off, or negative correlation, between paternal behavior and aggression in several seasonally breeding avian species. However, the presence or absence of a T-mediated trade-off in mammals has received less attention. We examined the relationship between paternal behavior and territorial aggression in the biparental California mouse, Peromyscus californicus. In contrast to seasonally breeding birds, T maintains paternal behavior in this year-round territorial species. Castration reduced paternal behavior, whereas T replacement maintained high levels of paternal behavior. We hypothesize that T is aromatized in the brain to estradiol, which in turn stimulates paternal behavior. In contrast to paternal behavior, aggressive behavior was not reduced by castration. Interestingly, only sham males showed an increase in aggression across three aggression tests, while no change was detected in castrated or T-replacement males. Overall, trade-offs between aggression and paternal behavior do not appear to occur in this species. Measures of paternal behavior and aggression in a correlational experiment were actually positively correlated. Our data suggest that it may be worth reexamining the role that T plays in regulating mammalian paternal behavior.


[The readiness of women, after they have given birth to children, to participate in individualized counselling for smoking cessation ].
Smoking after pregnancy implies health risks for both the woman and the newborn. Smoking cessation interventions postpartum can prevent relapse in women who quit during pregnancy, protect the infant from environmental tobacco smoke (ETS), and motivate smokers to quit. The readiness of women postpartum to participate in smoking cessation counselling is described. In 6 maternity wards n = 2790 women were screened for smoking, n = 1128 smoked before pregnancy. Of these n = 869 gave informed consent. Information on sociodemographic status and smoking behaviour is available for n = 642 participating women and for n = 217 non-participating women. No differences between women participating and non-participating were found in age (p >.05) and having a partner (p >.05). Participants were slightly higher educated (p <.001) and were mainly in maintenance (44 %) or in precontemplation stage of change (38 %). The proportions were 44 % and 22 % in the group of the non-participating women. The readiness of women postpartum to participate in smoking cessation counselling was high. By reaching abstinent women and women not motivated to quit, a target group was addressed that barely benefits from currently existing preventive activities. Maternity wards are an effective location for addressing smoking behaviour of mothers.


A novel cognitive-motor exercise program delivered via a tablet to improve mobility in older people with cognitive impairment - StandingTall Cognition and Mobility.
Evidence-based interventions to improve mobility in older people include balance, strength and cognitive training. Digital technologies provide the opportunity to deliver tailored and progressive programs at home. However, it is unknown if they are effective in older people, especially in those with cognitive impairment. The aim of this study was to examine the efficacy of a novel tablet-delivered cognitive-motor program on mobility in older people with cognitive impairment. This was a 6-month single-blind randomised controlled trial of older people living in the community with subjective and/or objective cognitive impairment. Participants randomised to the intervention were asked to follow a 120 min per week balance, strength and cognitive training program delivered via an app on an iPad. Both the intervention and control group received monthly phone calls and health fact sheets. The primary outcome measure was gait speed. Secondary measures included dual-task gait speed, balance (step test, FISCIT-4), 5 sit to stand test, cognition (executive function, memory, attention), mood and balance confidence. Adherence, safety, usability and feedback were also measured. The planned sample size of 110 was not reached due to COVID-19 restrictions. A total of 93 (mean age 72.8 SD 7.0 years) participants were randomised to the two groups. Of these 77 participants returned to the follow-up clinic. In intention-to-treat analysis for gait speed, there was a non-significant improvement favouring the intervention group (β 0.04 m/s 95% CI -0.01, 0.08). There were no significant findings for secondary outcomes. Adherence was excellent (84.5%), usability of the app high (76.7% SD 15.3) and no serious adverse events were reported. Feedback on the app was positive and included suggestions for future updates. Due to COVID-19 the trial was under powered to detect significant results. Despite this, there was a trend towards improvement in the primary outcome measure. The excellent adherence and positive feedback about the app suggest a fully powered trial is warranted.


Assessing the impact of coverage gaps in the Medicare Part D drug benefit.
The new Medicare Part D drug benefit contains major coverage gaps for people who spend moderate to high amounts on prescription drugs who qualify only for the standard coverage. To help policymakers understand the impact such gaps will have on those affected, we studied a representative sample of Medicare beneficiaries with naturally occurring prescription benefit gaps between 1998 and 2000 using data from the Medicare Current Beneficiary Survey. Our findings suggest that discontinuities in drug benefits result in sizable reductions in medication use and spending, which is magnified in people with common chronic illnesses.


Interventions to improve health and the determinants of health among sex workers in high-income countries: a systematic review.
Many sex worker populations face high morbidity and mortality, but data are scarce on interventions to improve their health. We did a systematic review of health and social interventions to improve the health and wider determinants of health among adult sex workers in high-income countries. We searched MEDLINE, Embase, PsycINFO, CINAHL, the Cochrane Library, Web of Science, EthOS, OpenGrey, and Social Care Online, as well as the Global Network of Sex Work Projects and the Sex Work Research Hub for studies published between Jan 1, 2005 and Dec 16, 2021 (PROSPERO CRD42019158674). Quantitative studies reporting disaggregated data for sex workers were included and no comparators were specified. We assessed rigour using the Quality Assessment Tool for Quantitative Studies. We summarised studies using vote counting and a narrative synthesis. 20 studies were included. Most reported findings exclusively for female sex workers (n=17) and street-based sex workers (n=11). Intervention components were divided into education and empowerment (n=14), drug treatment (n=4), sexual and reproductive health care (n=7), other health care (n=5), and welfare (n=5). Interventions affected a range of mental health, physical health, and health behaviour outcomes. Multicomponent interventions and interventions that were focused on education and empowerment were of benefit. Interventions that used peer design and peer delivery were effective. An outreach or drop-in component might be beneficial in some contexts. Sex workers who were new to working in an area faced greater challenges accessing services. Data were scarce for male, transgender, and indoor-based sex workers. Co-designed and co-delivered interventions that are either multicomponent or focus on education and empowerment are likely to be effective. Policy makers and health-care providers should improve access to services for all genders of sex workers and those new to an area. Future research should develop interventions for a greater diversity of sex worker populations and for wider health and social needs.


Microcystin-leucine-arginine Modulates the Expression Patterns of Proinflammatory Cytokines and an Apoptotic Gene in Chicken Liver.
Microcystins (MCs) are included in drinking water and a family of cyclic heptapeptide hepatotoxins that have been implicated in the impairment of liver function in various animals. There is scarce information on the effect of MCs on cytokines and apoptotic gene expression and on whether MCs can induce inflammation and apoptosis in avian hepatic tissue. This study investigated the expression of genes related to proinflammatory interleukins, apoptosis, and antioxidant function in chicken liver tissues cultured in the presence of different doses of microcystin-leucine-arginine (MC-LR). Livers were collected from five hens and liver slices were placed in sterile tubes containing Dulbecco's medium supplemented with 0, 1, 10, or 100 ng/mL of MC-LR. After 6 h of cultivation, total RNA was extracted and quantitative PCR analysis was performed for interleukin genes (IL-1β, IL-6, and IL-8), TNF sf15, an apoptotic gene (caspase-3), and genes involved in antioxidant function ([catalase [CAT ], glutathione peroxidase [GSH-PX ], and superoxide dismutase [SOD]). Liver tissues in each group were fixed for histopathology. MC-LR downregulated the mRNA levels of IL-1β, IL-8, and TNF sf15 as compared to the control (0 ng/mL) in dose-dependent patterns; however, the differences were not significant. The expression of IL-6 in liver tissues exposed to 100 ng/mL of MC-LR was significantly (P<0.05) lower than that in tissues exposed to 1 ng/mL. In contrast, MC-LR upregulated the mRNA expression of caspase-3 and genes involved in antioxidant function in the liver tissues after 6 h, without the difference reaching statistical significance. Hepatocytes showed vacuolar degeneration and focal necrosis according to the dose of MC-LR. This study highlighted the risk of low doses of MC-LR in chicken liver. Moreover, MC-LR could modulate the transcriptional patterns of at least IL-6 in liver-tissue culture of chicken after 6 h of exposure.


Radioimmunotherapy of B-cell lymphoma with [131I]anti-B1 (anti-CD20) antibody.
Many patients with non-Hodgkin's lymphomas are not cured by current therapies, and new approaches to treatment are needed. As part of an ongoing phase 1 study, we examined the effect of radioimmunotherapy with 131I-labeled B-cell-specific anti-CD20 monoclonal antibody in 10 patients with CD20-positive B-cell lymphomas in whom primary chemotherapy had failed. Anti-B1 (anti-CD20) mouse monoclonal antibody trace-labeled with 131I (15 mg containing 5 mCi) was given intravenously at approximately one-week intervals: first, without pretreatment with unlabeled anti-B1 antibody, to all 10 patients; then, with pretreatment with 135 mg of unlabeled antibody, to 8 patients; and then, with pretreatment with 685 mg, to 2 patients. Serial quantitative gamma-camera images and measures of whole-body radioactivity were obtained after each tracer dose. All known disease sites larger than 2 cm could be imaged. The effect of a pretreatment dose of unlabeled anti-B1 antibody on targeting of the tumor with the radiolabeled antibody was variable. The pretreatment dose of unlabeled antibody that produced the highest ratio of the tumor dose to the whole-body dose in tracer studies was then used to deliver higher doses of radioactivity for radioimmunotherapy in nine patients. Three patients received doses designed to deliver 25 cGy to the whole body (two patients treated twice, six to eight weeks apart), four patients received 35 cGy (one patient treated twice), and two patients received 45 cGy (one patient treated twice); each dose contained 34 to 66 mCi of activity. Six of the nine treated patients had tumor responses, including patients with bulky or chemotherapy-resistant disease: four patients had complete remissions, and two had partial responses. Three patients had objective responses to tracer infusions before they received radioimmunotherapeutic doses. Of the four patients with complete remissions, one remained in remission for eight months and the other three continue to have no disease progression (for 11, 9, and 8 months). There was mild or no myelosuppression. Radioimmunotherapy with [131I]anti-B1 antibody is a promising new treatment for lymphoma.


High-fidelity deep functional photoacoustic tomography enhanced by virtual point sources.
Photoacoustic tomography (PAT), a hybrid imaging modality that acoustically detects the optical absorption contrast, is a promising technology for imaging hemodynamic functions in deep tissues far beyond the traditional optical microscopy. However, the most clinically compatible PAT often suffers from the poor image fidelity, mostly due to the limited detection view of the linear ultrasound transducer array. PAT can be improved by employing highly-absorbing contrast agents such as droplets and nanoparticles, which, however, have low clinical translation potential due to safety concerns and regulatory hurdles imposed by these agents. In this work, we have developed a new methodology that can fundamentally improve PAT's image fidelity without hampering any of its functional capability or clinical translation potential. By using clinically-approved microbubbles as virtual point sources that strongly and isotropically scatter the local pressure waves generated by surrounding hemoglobin, we can overcome the limited-detection-view problem and achieve high-fidelity functional PAT in deep tissues, a technology referred to as virtual-point-source PAT (VPS-PAT). We have thoroughly investigated the working principle of VPS-PAT by numerical simulations and in vitro phantom experiments, clearly showing the signal origin of VPSs and the resultant superior image fidelity over traditional PAT. We have also demonstrated in vivo applications of VPT-PAT for functional small-animal studies with physiological challenges. We expect that VPS-PAT can find broad applications in biomedical research and accelerated translation to clinical impact.


α-Hydroxylactams as Efficient Entries to Diversely Functionalized Ferrociphenols: Synthesis and Antiproliferative Activity Studies.
The [ferrocene-ene-phenol] motif has been identified as the pharmacophore responsible for the anticancer activity of the family of ferrocene-based molecules coined ferrocifens, owing to its unique redox properties. The addition of imide entities to the historical ferrociphenol scaffold tremendously enhanced the cytotoxic activity of a large panel of cancer cell cultures and preliminary studies showed that the reduction of one of the carbonyl groups of the imide groups to the corresponding α-hydroxylactams only slightly affected the antiproliferative activity. As a continuation to these studies, we took advantage of the facile conversion of α-hydroxylactams to highly electrophilic N-acyliminium ions to graft various substituents to the imide motif of phthalimido ferrocidiphenol. Cell viability studies showed that the newly synthesized compounds showed diverse cytotoxic activities on two breast cancer cell lines, while only one compound was significantly less active on the non-tumorigenic cell line hTERT-RPE1.


Extracorporeal membrane oxygenation as a bridge to lung transplantation: Practice patterns and patient outcomes.
Extracorporeal membrane oxygenation (ECMO) is increasingly relied on to bridge patients with respiratory failure to lung transplantation despite limited evidence for its use in this setting. This study evaluated longitudinal trends in practice patterns, patient characteristics, and outcomes in patients bridged with ECMO to lung transplant. A retrospective review of all adult isolated lung transplant patients in the United Network for Organ Sharing database between 2000 and 2019 was performed. Patients were classified as "ECMO" if supported with ECMO at the time of listing or transplantation and "non-ECMO" otherwise. Linear regression was used to evaluate trends in patient demographics during the study period. Trends in mortality were evaluated using Cox proportional hazards modeling, with time period as the primary covariate (2000-2004, 2005-2009, 2010-2014, or 2015-2019) and age, time on the waitlist, and underlying diagnosis as covariates. The number of patients included were 40,866, of whom 1,387 (3.4%) were classified as ECMO and 39,479 (96.6%) as no ECMO. Average age and initial Lung Allocation Score increased significantly during the study period in both cohorts, but occurred at a slower rate in the ECMO population. The hazard of death was significantly lower in more recent years (2015-2019) for both the ECMO and non-ECMO cohorts (aHR (adjusted hazards ratio) 0.59, 95% confidence interval (CI) 0.37-0.96 and aHR 0.74, 95% CI 0.70-0.79) when compared to the early years (2000-2004) of the study period. Post-transplantation survival for patients bridged to transplantation with ECMO demonstrates ongoing improvement despite cannulation of progressively older and sicker patients.


Layer-separated MoS2 bearing reduced graphene oxide formed by an in situ intercalation-cum-anchoring route mediated by Co(OH)2 as a Pt-free electrocatalyst for oxygen reduction.
A significant improvement in the electrochemical oxygen reduction reaction (ORR) activity of molybdenum sulphide (MoS2) could be accomplished by its layer separated dispersion on graphene mediated by cobalt hydroxide (Co(OH)2) through a hydrothermal process (Co(OH)2-MoS2/rGO). The activity makeover in this case is found to be originated from a controlled interplay of the favourable modulations achieved in terms of electrical conductivity, more exposure of the edge planes of MoS2 and a promotional role played by the coexistence of Co(OH)2 in the proximity of MoS2. Co(OH)2-MoS2/rGO displays an oxygen reduction onset potential of 0.855 V and a half wave potential (E1/2) of 0.731 V vs. RHE in 0.1 M KOH solution, which are much higher than those of the corresponding values (0.708 and 0.349 V, respectively) displayed by the as synthesized pristine MoS2 (P-MoS2) under identical experimental conditions. The Tafel slope corresponding to oxygen reduction for Co(OH)2-MoS2/rGO is estimated to be 63 mV dec(-1) compared to 68 mV dec(-1) displayed by the state-of-the-art Pt/C catalyst. The estimated number of electrons transferred during oxygen reduction for Co(OH)2-MoS2/rGO is in the range of 3.2-3.6 in the potential range of 0.77 V to 0.07 V, which again stands out as valid evidence on the much favourable mode of oxygen reduction accomplished by the system compared to its pristine counterpart. Overall, the present study, thus, demonstrates a viable strategy of tackling the inherent limitations, such as low electrical conductivity and limited access to the active sites, faced by the layered structures like MoS2 to position them among the group of potential Pt-free electrocatalysts for oxygen reduction.


Pregnancy prevention and unintended pregnancy across gender identity: a cross-sectional study of college students.
Using data from the Fall 2015 through Spring 2018 National College Health Assessment, we examined receipt of pregnancy prevention information and unintended pregnancy by gender identity among participants aged 18-25years who were assigned female at birth (n=185658). Non-binary students were more likely than cisgender students to report wanting (adjusted risk ratio [ARR]: 1.12; 95% CI: 1.08-1.16), receiving (ARR: 1.09; 95% CI: 1.04-1.13), and having an unmet need for (ARR: 1.10; 95% CI: 1.02-1.19) pregnancy prevention information from their school. Transmasculine students did not significantly differ from cisgender students for these outcomes. Non-binary and transmasculine students were as likely as cisgender students to have a past-year unintended pregnancy. Non-binary and transmasculine young people are at risk for unintended pregnancy and need access to comprehensive sexual education, reproductive health counseling, and care.


FTO deficiency induces UCP-1 expression and mitochondrial uncoupling in adipocytes.
Variants in the fat mass- and obesity-associated (FTO) gene are associated with obesity and body fat mass in genome-wide association studies. However, the mechanism by which FTO predisposes individuals to obesity is not clear so far. First mechanistic evidence was shown in Fto-negative mice. These mice are resistant to obesity due to enhanced energy expenditure, whereas the mass of brown adipose tissue remains unchanged. We hypothesize that FTO is involved in the induction of white adipose tissue browning, which leads to mitochondrial uncoupling and increases energy expenditure. Uncoupling protein 1 (Ucp-1) was significantly higher expressed in both gonadal and inguinal adipose depots of Fto(-/-) compared with Fto(+/+) littermates accompanied by the appearance of multivacuolar, Ucp-1-positive adipocytes in these tissues. By using lentiviral short hairpin RNA constructs, we established FTO-deficient human preadipocytes and adipocytes and analyzed key metabolic processes. FTO-deficient adipocytes showed an adipogenic differentiation rate comparable with control cells but exhibited a reduced de novo lipogenesis despite unchanged glucose uptake. In agreement with the mouse data, FTO-deficient adipocytes exhibited 4-fold higher expression of UCP-1 in mitochondria compared with control cells. The up-regulation of UCP-1 in FTO-deficient adipocytes resulted in enhanced mitochondrial uncoupling. We conclude that FTO deficiency leads to the induction of a brown adipocyte phenotype, thereby enhancing energy expenditure. Further understanding of the signaling pathway connecting FTO with UCP-1 expression might lead to new options for obesity and overweight treatment.


[Complete sub-His AV block caused by carotid sinus massage. Possible direct vagal effect on the His-Purkinje system].
A 64 year old male patient, with frequent syncopes, underwent an electro-physiologic study. A complete left bundle branch block and a first degree His-Purkinje system atrioventricular block (AH = 100 msec, HV = 60 msec) were present in basal condition. Left carotid sinus massage caused extreme sinus bradycardia (with PP intervals as long as 3000 msec), without AH and HV interval changes. Right carotid sinus massage caused a His-Purkinje atrioventricular block. Ventricular asystole of 4800 msec occurred while the sinus cycle varied between 1440 and 590 msec. Since His-Purkinje atrioventricular block is induced by the right carotid sinus massage with PP intervals even shorter than the basal cycles and since the block was not reproduced at PP intervals longer than 1440 msecs, a direct vagal effect on the His-Purkinje system may be suggested, rather than a bradycardia dependent phase 4 block.


Chromatin immunoprecipitation-promoter microarray identification of genes regulated by PRDM16 in murine embryonic palate mesenchymal cells.
The transcription factor PRDM16 regulates differentiation of brown adipocyte tissue in mice. Recently, however, it has been demonstrated that genetic knockout of Prdm16 in mice leads to a complete cleft of the secondary palate in offspring. To identify genes whose promoters bind PRDM16 in mouse embryonic palate/maxillary mesenchymal cells, we have conducted a chromatin immunoprecipitation-promoter microarray analysis (ChIP-Chip). One hundred and twenty-two gene promoters were identified as capable of binding PRDM16. These could be functionally grouped to include those on genes linked to muscle development, chondrogenesis and osteogenesis, in addition to many transcription factors. These results suggest that PRDM16 may play a role in differentiation of mesenchymal cells in the embryonic secondary palate that contribute to the anterior, bony palate and posterior, muscular palate.


The challenge of providing child health care in the indigenous population of New Zealand.
This paper defines who is Maori, and traditional Maori attitudes to health and children. It notes the differing levels of engagement of Maori with their culture and the reliance of most Maori on Non Maori practitioners for their medical services. Three relatively common paediatric problems are then used to illustrate the challenges of neither underplaying nor overplaying environmental factors in working with Maori families. The key role of the word respect in working towards positive encounters with Maori is emphasized.


Characterization of polygenic resistance to powdery mildew in tomato at cytological, biochemical and gene expression level.
Extensive research in the area of plant innate immunity has increased considerably our understanding of the molecular mechanisms associated with resistance controlled by a dominant resistance gene. In contrast, little is known about the molecular basis underlying the resistance conferred by quantitative trait loci (QTLs). In this study, using the interaction of tomato (Solanum lycopersicum) with Oidium neolycopersici, we compared the cytological, biochemical and molecular mechanisms involved in both monogenic and polygenic resistances conferred by a dominant gene (Ol-1) and three QTLs (Ol-qtls), respectively. Our results showed that the three Ol-qtls jointly confer a very high level of broad-spectrum resistance and that the resistance is associated with both the hypersensitive response and papillae formation, with the hypersensitive response being prevalent. Both H(2)O(2) and callose accumulation, which are coupled with Ol-1-mediated resistance, are also associated with the resistance conferred by Ol-qtls. Further, we analysed the pathogen-induced transcript profiles of near-isogenic lines carrying the three Ol-qtls and the Ol-1 gene. Transcript profiles obtained by cDNA-amplified fragment length polymorphism analysis showed that, on fungal challenge, about 70% of the transcript-derived fragments are up-regulated in both susceptible and resistant genotypes. Most of the sequenced transcript-derived fragments showed homology to genes with functions in defence responses, suggesting that defence-responsive genes responsible for basal defence are involved in both monogenic and polygenic resistances conferred by Ol-1 and Ol-qtls, respectively. Although about 18% of the identified transcript-derived fragments are specific for either monogenic or polygenic resistance, their expression patterns need to be further verified by quantitative reverse transcriptase-polymerase chain reaction.


A eukaryotic cytosolic chaperonin is associated with a high molecular weight intermediate in the assembly of hepatitis B virus capsid, a multimeric particle.
We have established a system for assembly of hepatitis B virus capsid, a homomultimer of the viral core polypeptide, using cell-free transcription-linked translation. The mature particles that are produced are indistinguishable from authentic viral capsids by four criteria: velocity sedimentation, buoyant density, protease resistance, and electron microscopic appearance. Production of unassembled core polypeptides can be uncoupled from production of capsid particles by decreasing core mRNA concentration. Addition of excess unlabeled core polypeptides allows the chase of the unassembled polypeptides into mature capsids. Using this cell-free system, we demonstrate that assembly of capsids proceeds by way of a novel high molecular weight intermediate. Upon isolation, the high molecular weight intermediate is productive of mature capsids when energy substrates are manipulated. A 60-kD protein related to the chaperonin t-complex polypeptide 1 (TCP-1) is found in association with core polypeptides in two different assembly intermediates, but is not associated with either the initial unassembled polypeptides or with the final mature capsid product. These findings implicate TCP-1 or a related chaperonin in viral assembly and raise the possibility that eukaryotic cytosolic chaperonins may play a distinctive role in multimer assembly apart from their involvement in assisting monomer folding.


Loop-mediated isothermal amplification assay for the rapid detection of Staphylococcus aureus.
Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), is an important human pathogen that produces a variety of toxins and causes a wide range of infections, including soft-tissue infections, bacteremia, and staphylococcal food poisoning. A loop-mediated isothermal amplification (LAMP) assay targeting the arcC gene of S. aureus was developed and evaluated with 119 S. aureus and 25 non-S. aureus strains. The usefulness of the assay was compared with the PCR method that targets spa and arcC genes. The optimal temperature for the LAMP assay was 58.5°C with a detection limit of 2.5 ng/μL and 10(2) CFU/mL when compared to 12.5 ng/μL and 10(3) CFU/mL for PCR (spa and arcC). Both LAMP and PCR assays were 100% specific, 100% sensitive, 100% positive predictive value (PPV), and 100% negative predictive value (NPV). When tested on 30 spiked blood specimens (21 MRSA, eight non-S. aureus and one negative control), the performance of LAMP and PCR was comparable: 100% specific, 100% sensitive, 100% PPV, and 100% NPV. In conclusion, the LAMP assay was equally specific with a shorter detection time when compared to PCR in the identification of S. aureus. The LAMP assay is a promising alternative method for the rapid identification of S. aureus and could be used in resource-limited laboratories and fields.


The influence of maternal treadmill running during pregnancy on short-term memory and hippocampal cell survival in rat pups.
Maternal exercise during pregnancy has been suggested to exert the beneficial effects on the brain functions of offspring. In the present study, we attempted to determine the effects of maternal treadmill running during pregnancy on short-term memory ability, hippocampal cell survival, and the expression of brain-derived neurotrophic factor (BDNF) mRNA in rat pups. After confirming pregnancy, the pregnant rats were divided into two groups: the control group and the running group (n = 6 in each group). Beginning on the 15th day of pregnancy, the pregnant rats in the running group were forced to run on a treadmill for 30 min at a mild-intensity, once a day until delivery. After all the pregnant rats had given birth, there were rat pups available for use in this study in each group (n = 15 in each group). The latency of the step-down avoidance task was used in order to evaluate the short-term memory ability of the rat pups on the 28 days after birth. Immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU) and reverse transcription-polymerase chain reaction (RT-PCR) for BDNF mRNA were performed to determine hippocampal neurogenesis and hippocampal BDNF mRNA expression of the rat pups on the 29 days after birth, respectively. Our results revealed that maternal running during pregnancy resulted in significant increase in the expression of BDNF mRNA, enhanced hippocampal cell survival, and improved the short-term memory capability of rat pups, as compared to those measured in the control group. The findings of our study provide evidence that maternal running during gestational period may enhance the brain functions of offspring.


Expression of the broad autism phenotype in simplex autism families from the Simons Simplex Collection.
The broad autism phenotype (BAP) refers to the phenotypic expression of an underlying genetic liability to autism, manifest in non-autistic relatives. This study examined the relationship among the Broad Autism Phenotype Questionnaire (BAPQ), Social Responsiveness Scale: Adult Research Version (SRS:ARV), and Family History Interview (FHI) in a large, multi-site study of 1,650 simplex families (Simons Simplex Collection). Correlations between the BAPQ and SRS:ARV Total scores were moderate, and correlations between FHI ratings and SRS:ARV and BAPQ were significant but weak. Overall, the results suggested that BAP traits occur at low rates in simplex families, and rates vary significantly depending upon the measure utilized. Implications include the need for multiple informants, and the assessment of distinct BAP traits in large-scale genetic studies of individuals with ASD.


Organic matter degradation in a greywater recycling system using a multistage moving bed biofilm reactor (MBBR).
Greywater is an important non-conventional water resource which can be treated and recycled in buildings. A decentralized greywater recycling system for 223 inhabitants started operating in 2006 in Berlin, Germany. High load greywater undergoes advanced treatment in a multistage moving bed biofilm reactor (MBBR) followed by sand filtration and UV disinfection. The treated water is used safely as service water for toilet flushing. Monitoring of the organic matter degradation was pursued to describe the degradation processes in each stage and optimize the system. Results showed that organic matter reduction was achieved for the most part in the first three reactors, whereas the highest reduction rate was observed in the third reactor in terms of COD (chemical oxygen demand), dissolved organic carbon and BOD7 (biological oxygen demand). The results also showed that the average loading rate entering the system was 3.7 kg COD/d, while the removal rate was 3.4 kg COD/d in a total bioreactor volume of 11.7 m³. In terms of BOD, the loading rate was 2.8 kg BOD/d and it was almost totally removed. This system requires little space (0.15 m²/person) and maintenance work of less than one hour per month and it shows operational stability under peak loads.


PSEUDO-VALUE APPROACH FOR CONDITIONAL QUANTILE RESIDUAL LIFETIME ANALYSIS FOR CLUSTERED SURVIVAL AND COMPETING RISKS DATA WITH APPLICATIONS TO BONE MARROW TRANSPLANT DATA.
Quantile residual lifetime analysis is conducted to compare remaining lifetimes among groups for survival data. Evaluating residual lifetimes among groups after adjustment for covariates is often of interest. The current literature is limited to comparing two groups for independent data. We propose a pseudo-value approach to compare quantile residual lifetimes given covariates between multiple groups for independent and clustered survival data. The proposed method considers clustered event times and clustered censoring times in addition to independent event times and censoring times. We show that the method can also be used to compare multiple groups on the cause specific residual life distribution in the competing risk setting, for which there are no current methods which account for clustering. The empirical Type I errors and statistical power of the proposed study are examined in a simulation study, which shows that the proposed method controls Type I errors very well and has higher power than an existing method. The proposed method is illustrated by a bone marrow transplant data set.


Comparison against 186 canid whole-genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor.
Canine transmissible venereal tumor (CTVT) is a parasitic cancer clone that has propagated for thousands of years via sexual transfer of malignant cells. Little is understood about the mechanisms that converted an ancient tumor into the world's oldest known continuously propagating somatic cell lineage. We created the largest existing catalog of canine genome-wide variation and compared it against two CTVT genome sequences, thereby separating alleles derived from the founder's genome from somatic mutations that must drive clonal transmissibility. We show that CTVT has undergone continuous adaptation to its transmissible allograft niche, with overlapping mutations at every step of immunosurveillance, particularly self-antigen presentation and apoptosis. We also identified chronologically early somatic mutations in oncogenesis- and immune-related genes that may represent key initiators of clonal transmissibility. Thus, we provide the first insights into the specific genomic aberrations that underlie CTVT's dogged perseverance in canids around the world.


Exacerbation of acute platelet thrombus formation in stenosed dog coronary arteries with smoke from a non-tobacco-burning cigarette.
The tobacco industry proposes to release a "new" cigarette with a burning charcoal tip, which heats the tobacco as air is drawn through it and into the lungs of the smoker. It is claimed to be safer because the tobacco does not burn. Using our established canine model of coronary artery stenosis with moderate intimal damage, we compared this new cigarette (0.4 mg nicotine) with a regular cigarette by ventilating dogs (n = 10) with room air and then either new or regular smoke (two cigarettes over about 10 minutes). In our dog model, periodic acute platelet thrombus formation followed by embolization produced cyclical flow reductions in coronary blood flow where the rate of flow decline was proportional to the degree of in vivo platelet-vessel wall interaction. The rate of flow decline increased from -4.81 +/- 1.29 ml/min2 to -9.60 +/- 2.29 ml/min2 after ventilation with the new-type smoke (p less than 0.01). Similarly, the rate of flow decline increased from -5.43 +/- 1.28 ml/min2 to -9.28 +/- 2.31 ml/min2 after ventilation with regular cigarette smoke (p less than 0.01). Despite the lack of a clear causal link between cigarette smoking and the acute manifestations of cardiovascular disease, the data presented here indicate that the new cigarette is just as potent as regular cigarettes at increasing in vivo platelet activity and exacerbating acute platelet thrombus formation in the dog. We conclude that the new proposed non-tobacco-burning cigarette has deleterious effects similar to those of conventional cigarettes, and thus does not eliminate smoking as a risk factor in cardiovascular disease in human beings.


The effects of sex steroid hormones on the pigment accumulation in the shell gland of Japanese quail.
Effects of sex steroid hormones on the accumulation of the superficial pigment of the eggshell in the quail shell gland were investigated. In Experiment 1, 10 or 20 mg/100 g BW of aminoglutethimide (AG) was injected s.c. into laying quail hens 10 h before the expected ovulation. Thirty percent of the hens that received 10 mg/100 g BW and 87% of the hens that received 20 mg/100 g BW failed to ovulate. They had significantly (P < .01) lower concentrations of preovulatory plasma progesterone (P) than the control hens and showed significantly (P < .05) low concentrations of plasma estradiol-17 beta (E) and small amounts of the pigment in their shell glands after oviposition of the preceding egg. In Experiment 2, AG (20 mg/100 g BW) was administered s.c. to quail hens 10 h before the expected ovulation, followed by the administration of P (.05, .1, or .2 mg/100 g BW), E (.1, .2, or 1.0 mg/100 g BW), or testosterone (T) (.5 mg/100 g BW). Significant increases in the accumulated pigment 18 h after oviposition of the preceding egg were found when P was injected. However, administration of E and T had no influence on pigment accumulation. These results suggested that P might affect the accumulation of pigment in the quail shell gland.


Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese Han.
Experimental and clinical data suggested that brain-derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) is characterized by declined cognitive function and has a high probability of evolving into AD. The aim of this study was to investigate serum BDNF concentrations in aMCI patients and determine whether there is an association of the BDNF gene Val66Met polymorphism with aMCI, cognitive function, and serum BDNF. Between April 2005 and January 2006, the present study recruited 99 aMCI patients who met diagnostic criteria for MCI proposed by the Mayo Clinic Alzheimer's Disease Research Center and 99 matched healthy controls from a population-based sample. All subjects underwent extensive assessment of cognitive function, measurement of serum BDNF by an enzyme-linked immunosorbent assay, and genotyping of the BDNF gene Val66Met polymorphism. The serum concentrations of BDNF in aMCI patients (median [interquartile range] = 4.37 [2.35-6.40] ng/mL) were significantly lower than those of healthy controls (4.98 [3.50-7.33] ng/mL) (z = -2.449, p = .014). There were significant positive correlations between serum BDNF and scores on delayed recall in the Auditory Verbal Learning Test, which reflects episodic memory (r = 0.264, p = .008). No significant differences were found for either the genotype or allele distribution of BDNF Val66Met polymorphism between aMCI patients and control subjects. The BDNF Val66Met polymorphism was not associated with serum BDNF or cognitive function in aMCI patients. This study suggests that reduced BDNF levels may play a role in the pathophysiology of aMCI, and the BDNF gene Val66Met polymorphism may not be an important factor in susceptibility to aMCI.


Accuracy of a commercial IgM ELISA for the diagnosis of human leptospirosis in Thailand.
The Leptospira immunoglobulin M enzyme-linked immunosorbent assay (IgM ELISA) has been recommended for the rapid diagnosis of leptospirosis in endemic areas. We conducted a retrospective case-control study of 218 patients (109 leptospirosis cases confirmed by Leptospira culture and/or microscopic agglutination test and 109 control patients with acute febrile illness) to evaluate the diagnostic accuracy of a commercial IgM ELISA (Panbio) in northeast Thailand. Paired serum samples taken on admission and at least 10 days after the onset of symptoms were tested. Using the cutoff value recommended by the manufacturer (11 Panbio units), sensitivity and specificity of IgM ELISA on paired sera were 90.8% and 55.1%. A receiver operating characteristic curve was used to determine the optimal cutoff value. This was 20 Panbio units, which gave a sensitivity and specificity of 76.1% and 82.6%, respectively, on paired sera. We conclude that using either cutoff value, the accuracy of IgM ELISA is limited in our setting.


Confidence Leak in Perceptual Decision Making.
People live in a continuous environment in which the visual scene changes on a slow timescale. It has been shown that to exploit such environmental stability, the brain creates a continuity field in which objects seen seconds ago influence the perception of current objects. What is unknown is whether a similar mechanism exists at the level of metacognitive representations. In three experiments, we demonstrated a robust intertask confidence leak-that is, confidence in one's response on a given task or trial influencing confidence on the following task or trial. This confidence leak could not be explained by response priming or attentional fluctuations. Better ability to modulate confidence leak predicted higher capacity for metacognition as well as greater gray matter volume in the prefrontal cortex. A model based on normative principles from Bayesian inference explained the results by postulating that observers subjectively estimate the perceptual signal strength in a stable environment. These results point to the existence of a novel metacognitive mechanism mediated by regions in the prefrontal cortex.


Identification of a gene regulating the tissue expression of a phosphoglucomutase locus in rainbow trout.
Nine percent of the rainbow trout (Salmo gairdneri) from a hatchery source have a greater than 100-fold increase in expression of a phosphoglucomutase (PGM) locus, Pgm1, in the liver but have normal expression of this locus in other tissues. The results of genetic crosses are consistent with a single regulatory gene with additive inheritance being responsible for the differences in the amount of PGM activity in the liver.--The allele responsible for the expression of Pgm1 in the liver is apparently a recent mutation. This is supported by its restricted distribution in rainbow trout and the absence of liver Pgm1 expression in closely related species. This genetic system is valuable for future analysis of the control of gene expression and in determining the relative evolutionary importance of genetic variation at structural and regulatory genes.


Machismo and anabolic steroid misuse among young Latino sexual minority men.
Latino sexual minority men (SMM) have elevated anabolic-androgenic steroid (AAS) misuse in comparison to their heterosexual and non-Latino peers. Within a gender role framework, desire to present as masculine through heightened muscularity may be related to increased AAS misuse. To assess the association between AAS misuse and a culturally-distinct masculinity, this study examined the relationship of two aspects of machismo, traditional machismo and caballerismo, with AAS misuse in the past month. Participants were 141 young adult Latino SMM recruited from the San Diego area. Participants completed a self-report questionnaire online in English or Spanish, which included measures of machismo and AAS misuse. Out of 141 participants, 27 reported AAS misuse (19.1%). Traditional machismo was positively associated with AAS misuse and caballerismo was negatively associated with AAS misuse. Traditional machismo, which emphasizes dominance, may be positively associated with AAS misuse due to its facilitation of muscle development, which could enable physical intimidation; greater musculature may also counteract assumptions about femininity and sexual orientation. Caballerismo may be negatively associated with AAS by providing a flexible masculinity model that emphasizes social cohesion over dominance. Future AAS misuse interventions could include values-based work and cognitive restructuring of masculinity schemas.


Natural selection at the MJD locus: phenotypic diversity, survival and fertility among Machado-Joseph Disease patients from the Azores.
Machado-Joseph Disease (MJD) is an autosomal dominant neurodegenerative disorder of adult onset, associated with the expansion of a (CAG)n tract in the coding region of the causative gene, localized on 14q32.1. Machado-Joseph Disease shows non-Mendelian features typical of other triplet repeat disorders, including clinical heterogeneity, variable age at onset and anticipation. Three phenotypes have been proposed (clinical types 1, 2 and 3). Type 1 is associated with early age at onset and a high repeat number of the CAG sequence, and Types 2 and 3 have later onset and lower numbers of CAG repeats. This paper investigates whether there is selection against the MJD gene, acting through differential survival. nuptiality and fertility associated with clinical type and age at onset. The study sample comprised 40 MJD patients from the Azores (Portugal) having fully documented reproductive histories and known dates of death. The proportion of married patients of each clinical type increased from 0.22 among Type 1 patients, to 0.40 in Type 2 and 0.95 in Type 3. Age at onset and length of survival were also associated with marital status, with the married cases having later mean age at onset and longer mean survival time. In the whole sample, clinical type was associated with fertility, with significantly fewer children born to Type 1 patients. Among married patients clinical type was not associated with age at marriage, reproductive span or number of children. No reduction of fertility was detected among married patients in whom the onset of MJD was below the age of 50. The authors' interpretation of these results is that the high-repeat CAG haplotypes associated with early age at onset and clinical Type 1 are selected against through reduced survival and fertility. The fertility component of selection is mediated by nuptiality rather than marital fertility.


Tissue Biomarkers Predicting Lymph Node Status in Cutaneous Melanoma.
Cutaneous melanoma is a severe neoplasm that shows early invasiveness of the lymph nodes draining the primary site, with increased risk of distant metastases and recurrence. The tissue biomarker identification could be a new frontier to predict the risk of early lymph node invasiveness, especially in cases considered by current guidelines to be at low risk of lymph node involvement and not requiring evaluation of the sentinel lymph node (SLN). For this reason, we present a narrative review of the literature, seeking to provide an overview of current tissue biomarkers, particularly vascular endothelium growth factors (VEGF), Tetraspanin CD9, lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), D2-40, and gene expression profile test (31-GEP). Among these, 31-GEP seems to be able to provide a distinction between low or high risk for positive SLN classes. VEGF receptor-3 and CD9 expression may be independent predictors of positive SLN. Lastly, LYVE-1 and D2-40 allow an easier assessment of lymph vascular invasion, which can be considered a good predictor of SLN status. In conclusion, biomarkers to assess the lymph node status of cutaneous melanoma patients may play an important role in those cases where the clinician is in doubt whether or not to perform SLN biopsy.


Serological Evidence for Influenza A Viruses Among Domestic Dogs and Cats in Kyiv, Ukraine.
Influenza A viruses (IAV) are zoonotic pathogens that can cause significant illness in wild and domestic animals, and humans. IAV can infect a broad range of avian and mammalian species, depending on subtype, and avian IAV can be moved over relatively long distances by migratory birds. Although spillover infections from wildlife or domestic animals to humans are an important part of the transmission cycle that can drive outbreaks, the relevance of companion animals, specifically dogs and cats, is not fully understood. A novel pandemic H1N1 reassortant (H1N1pdm09) emerged from swine in 2009, infecting humans, and wild and domestic animals worldwide. During a 2016 human influenza outbreak in Kyiv, subtype H1N1pdm09 predominated and was associated with severe disease and deaths; however, H3N2 and influenza B viruses were also detected. No case of avian influenza in humans was detected. To investigate potential involvement of companion animals, animals in a veterinary hospital (116 cats and 88 dogs) were randomly selected, and sera were tested using a commercially available IAV nucleoprotein enzyme-linked immunosorbent assay. Twelve of 203 serum samples were positive for influenza antibodies (5.7% of dogs and 6.08% cats). These are the first data to demonstrate influenza A infection of pets in Ukraine, highlighting the potential risk of infection of companion animals from close contact with humans.


[Caustic esophagitis in children].
Treatment of caustic ingestion in children is a difficult and controversial problem which has not yet to be resolved. Here we report the evolution of fourteen children with esophageal injury after caustic ingestion that were treated with steroids at high-doses, nasogastric intubation and antibiotics. An early esophagoscopy was performed in all patients. Four patients developed esophageal strictures, three of which were mild and subsequent dilatation was successful. Only one patient was referred to surgery. We think that although it cannot be established, the use of high-dose of steroids and nasogastric intubation may be helpful for children with caustic esophagitis. We conclude that early endoscopy is useful to evaluate the severity of the lesions and to establish the necessity for treatment.


Parental intention to vaccinate daughters with the human papillomavirus vaccine in Korea: a nationwide cross-sectional survey.
We aimed to identify and compare the characteristics and factors associated with parental intention to vaccinate daughters under 12 years old against human papillomavirus (HPV), examining data from 2016 and 2020. Data were obtained from the Korean National Cancer Screening Survey conducted in 2016 and 2020. The present study included 3,510 parents with daughters under 12 years old. Changes in parental intention-to-vaccinate rates were calculated. To identify factors associated with parental intention to vaccinate their daughters, the chi-square test and logistic regression analysis were used. The percentage of respondents intending to vaccinate their daughters increased from 33.4% in 2016 to 58.9% in 2020, constituting a 25.5 percentage point (%p) increase. Since 2016, the proportion of men expressing positive intention towards HPV vaccination increased by 31.5%p, while that of women demonstrated a 20.9%p increase. Logistic regression analysis indicated that parents with a strong intention to vaccinate their daughters tended to be younger, more educated, and aware of the free vaccination program available, as well as to have a history of HPV vaccination and to have undergone cervical cancer screening within 2 years, compared to those who did not intend to vaccinate. Being a mother with a history of HPV vaccination was the strongest predictor of positive intention to vaccinate a daughter. The intention among parents to vaccinate daughters remains relatively low, although it is rising. To increase the HPV vaccination rate, strong recommendations and education should be provided to parents and the younger generation.


Preparation and characterization of titanium-segmented polyurethane composites for bone tissue engineering.
Segmented polyurethanes were prepared with polycaprolactone diol as soft segment and 4,4-methylene-bis cyclohexyl diisocyanate and l-glutamine as the rigid segment. These polyurethanes were filled with 1 wt.% to 5 wt.% titanium particles (Ti), physicochemically characterized and their biocompatibility assessed using human dental pulp stem cells and mice osteoblasts. Physicochemical characterization showed that composites retained the properties of the semicrystalline polyurethane as they exhibited a glass transition temperature (Tg) between -35°C and -45°C, melting temperature (Tm) at 52°C and crystallinity close to 40% as determined by differential scanning calorimetry. In agreement with this, X-ray diffraction showed reflections at 21.3° and 23.6° for polycaprolactone diol and reflections at 35.1°, 38.4°, and 40.2° for Ti particles suggesting that these particles are not acting as nucleating sites. The addition of up to 5 wt.% of Ti reduced both, tensile strength and maximum strain from 1.9 MPa to 1.2 MPa, and from 670% to 172% for pristine and filled polyurethane, respectively. Although there were differences between composites at low strain rates, no significant differences in mechanical behavior were observed at higher strain rate where a tensile stress of 8.5 MPa and strain of 223% were observed for 5 wt.% composites. The addition to titanium particles had a beneficial effect on both human dental pulp stem cells and osteoblasts viability, as it increased with the amount of titanium in composites up to 10 days of incubation.


In-Hospital Bleeding and Mortality in Acute Coronary Syndrome Patients Treated with Tirofiban and Potent P2Y12 Inhibitors.
In this study, we aimed to determine whether potent agents affect in-hospital bleeding and mortality compared to clopidogrel in patients with the acute coronary syndrome in whom tirofiban and P2Y12 inhibitor are used together. Patients who were treated interventionally between 2015 and 2020 and were using tirofiban were retrospectively screened. Clinical, laboratory, and angiographic findings were obtained from the hospital database. Patients were analyzed by dividing them into clopidogrel and prasugrel/ticagrelor groups. Acute coronary syndrome patients (n = 227) who were treated interventionally were included in this retrospective study. Clopidogrel was given to 93 (41%), ticagrelor to 112 (49.3%), and prasugrel to 22 of the patients (9.7%). Compared to the ticagrelor/prasugrel group, the clopidogrel group was older and more were women, and the history of hypertension and previous coronary artery disease was higher (P, respectively: <.001; .001; .008; .0045). The creatinine value was higher, the basal hemoglobin was lower, and the GRACE (Global Registry of Acute Coronary Events) and CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) scores were higher (P, respectively: .026; .002; .002; <.001). The in-hospital bleeding rate was signifi- cantly higher in the clopidogrel group (P < .001). Although the in-hospital mortality rate was higher, it was not statistically significant (P = .07). Regression analysis showed that GRACE score and gender were associated with in-hospital mortality (P < .001; P=.031, respectively), and only age was associated with in-hospital bleeding (P < .001). No relationship was found with P2Y12 inhibitor. In our study, we found that the combined use of potent P2Y12 inhibitor with tiro- fiban in acute coronary syndrome patients treated interventionally was not different from the use of clopidogrel in terms of in-hospital bleeding and mortality.