Bio-organic soil amendment promotes the suppression of Ralstonia solanacearum by inducing changes in the functionality and composition of rhizosphere bacterial communities.
Stimulating the development of soil suppressiveness against certain pathogens represents a sustainable solution toward reducing pesticide use in agriculture. However, understanding the dynamics of suppressiveness and the mechanisms leading to pathogen control remain largely elusive. Here, we investigated the mechanisms used by the rhizosphere microbiome induces bacterial wilt disease suppression in a long-term field experiment where continuous application of bio-organic fertilizers (BFs) triggered disease suppressiveness when compared to chemical fertilizer application. We further demonstrated in a glasshouse experiment that the suppressiveness of the rhizosphere bacterial communities was triggered mainly by changes in community composition rather than only by the abundance of the introduced biocontrol strain. Metagenomics approaches revealed that members of the families Sphingomonadaceae and Xanthomonadaceae with the ability to produce secondary metabolites were enriched in the BF plant rhizosphere but only upon pathogen invasion. We experimentally validated this observation by inoculating bacterial isolates belonging to the families Sphingomonadaceae and Xanthomonadaceae into conducive soil, which led to a significant reduction in pathogen abundance and increase in nonribosomal peptide synthetase gene abundance. We conclude that priming of the soil microbiome with BF amendment fostered reactive bacterial communities in the rhizosphere of tomato plants in response to biotic disturbance.


Genetic transformation of Centaurium erythraea Rafn by Agrobacterium rhizogenes and the production of secoiridoids.
Hairy roots of Centaurium erythraea were obtained by infection with Agrobacterium rhizogenes strain LBA 9402. They spontaneously regenerated adventitious shoots in Woody Plant liquid medium without growth regulators. The shoots were grown continuously in Murashige and Skoog (MS) liquid or agar solidified media supplemented with 0.1 mg l(-1) indole-3-acetic acid and 1.0 mg l(-1) 6-benzylaminopurine. These shoots produced roots 4 weeks after transfer into agar-solidified MS medium without phytohormones. Regenerated plants grown and flowered under greenhouse conditions. The transgenic value of the regenerated plants was confirmed by the polymerase chain reaction amplification. Transformation by Agrobacterium rhizogenes alters plant morphology and production of secoiridoid glucosides. The level of secoiridoids was also modified by development stage of transformed plants. The total content of the compounds (expressed as the sum of gentiopicroside, sweroside and swertiamarin) in 10-week old pRi-transformed regenerants was 280 mg g(-1) dry weight and was 8-times the content in the sample of commercially available C. erythraea herb.


Evaluation of autofluorescence colonoscopy for the detection and diagnosis of colonic polyps.
Colorectal cancer is the second most common cause of death in the United Kingdom. Most cancers are believed to arise within preexisting adenomas. Although colorectal adenomas have a clear neoplastic potential, hyperplastic polyps do not. It, therefore, would be helpful to be able to differentiate between different polyps at a colonoscopy. Autofluorescence (AF) endoscopy has been developed to enhance conventional white light (WL) endoscopy in the diagnosis of GI lesions. The aim of the present study was to evaluate whether AF colonoscopy can facilitate endoscopic detection and differentiation of colorectal polyps. Patients were invited to attend for colonic assessment with both AF and WL endoscopy. AF readings, pictures, and biopsy specimens were taken of any visible pathology and of any high AF areas. Gartnavel General Hospital, Glasgow, U.K. A total of 107 patients were assessed. Each patient was assessed with AF and WL colonoscopy. An AF intensity ratio (AIR) was calculated for each polyp (ratio of direct polyp AF reading/background rectal AF activity). A total of 75 polyps were detected: 54 adenomatous and 21 hyperplastic polyps. Colorectal adenomas had a significantly higher AIR compared with hyperplastic polyps (median, interquartile range): adenoma (3.54, 2.54-5.00] versus hyperplastic (1.60, 1.30-2.24); P = .0001). When using an AIR with the empirically cutoff value of 2.3, AF endoscopy had a sensitivity of 85% and a specificity of 81% at distinguishing adenomatous polyps from hyperplastic polyps. AF colonoscopy may be a valuable tool for the visual distinction between adenomatous and hyperplastic polyps.


[Flow mediated vasodilation in overweight children].
Present knowledge suggests that cardiovascular disease originates and progresses from childhood and adolescence. Endothelial dysfunction is an early and crucial event in atherosclerosis. Prospective study that compares Flow Mediated Vasodilation (FMV) in children with overweight (OWC) and normal weight children. An ultrasound transducer a standard method were used to measure FMD. The study included 82 children, of whom 49 were cases (OWC) and 33 controls. FMV values ranged from -6 to 56% (x=11.1%) in OW, and from 0 to 29.6% (x=16.6%) in control children (P<.005). Paradoxical vasoconstriction was found in 34.7% in OWC as compared to nil in controls (P<.005). A significant association was found between vasoconstriction and central obesity and hypertension. The results of this study show that FMV is lower in obese compared to normal children; thus they are more likely to have endothelial dysfunction.


In vivo imaging and histochemistry are combined in the cryosection labelling and intravital microscopy technique.
Intravital microscopy has been used extensively to study dynamic processes in the context of a living animal; however, only a limited number of fluorescent probes and mouse models are available. By contrast, many dyes and antibodies exist for the immuno-labelling of fixed tissue. Here we report a method that combines the advantages of histochemistry and in vivo imaging by correlating cryosection labelling with corresponding intravital microscopy images (CLIM). Using CLIM, we find that the presence of CD3(+) T cells correlates with mammary tumour cell migration. When CD4(+) and CD8(+) T-cell subsets are depleted, reduced tumour cell migration is observed. From these data we conclude that CLIM is a powerful tool to correlate intravital microscopy data with cryosection labelling data.


Variability of Basal Rate Profiles in Insulin Pump Therapy and Association with Complications in Type 1 Diabetes Mellitus.
Traditionally, basal rate profiles in continuous subcutaneous insulin infusion therapy are individually adapted to cover expected insulin requirements. However, whether this approach is indeed superior to a more constant BR profile has not been assessed so far. This study analysed the associations between variability of BR profiles and acute and chronic complications in adult type 1 diabetes mellitus. BR profiles of 3118 female and 2427 male patients from the "Diabetes-Patienten-Verlaufsdokumentation" registry from Germany and Austria were analysed. Acute and chronic complications were recorded 6 months prior and after the most recently documented basal rate. The "variability index" was calculated as variation of basal rate intervals in percent and describes the excursions of the basal rate intervals from the median basal rate. The variability Index correlated positively with severe hypoglycemia (r = .06; p<0.001), hypoglycemic coma (r = .05; p = 0.002), and microalbuminuria (r = 0.05; p = 0.006). In addition, a higher variability index was associated with higher frequency of diabetic ketoacidosis (r = .04; p = 0.029) in male adult patients. Logistic regression analysis adjusted for age, gender, duration of disease and total basal insulin confirmed significant correlations of the variability index with severe hypoglycemia (β = 0.013; p<0.001) and diabetic ketoacidosis (β = 0.012; p = 0.017). Basal rate profiles with higher variability are associated with an increased frequency of acute complications in adults with type 1 diabetes.


Edaphic adaptation maintains the coexistence of two cryptic species on serpentine soils.
Divergent edaphic adaptation can contribute to reproductive isolation and coexistence between closely related species, yet we know little about how small-scale continuous edaphic gradients contribute to this phenomenon. We investigated edaphic adaptation between two cryptic species of California wildflower, Lasthenia californica and L. gracilis (Asteraceae), which grow in close parapatry on serpentine soil. We reciprocally transplanted both species into the center of each species' habitat and the transition zone between species. We quantified multiple components of fitness and used aster models to predict fitness based on environmental variables. We sampled soil across the ridge throughout the growing season to document edaphic changes through time. We sampled naturally germinating seedlings to determine whether there was dispersal into the adjacent habitat and to help pinpoint the timing of any selection against migrants. We documented within-serpentine adaptation contributing to habitat isolation between close relatives. Both species were adapted to the edaphic conditions in their native region and suffered fitness trade-offs when moved outside that region. However, observed fitness values did not perfectly match those predicted by edaphic variables alone, indicating that other factors, such as competition, also contributed to plant fitness. Soil water content and concentrations of calcium, magnesium, sodium, and potassium were likely drivers of differential fitness. Plants either had limited dispersal ability or migrants experienced early-season mortality outside their native region. Demonstrating that continuous habitats can support differently adapted, yet closely related, taxa is important to a broader understanding of how species are generated and maintained in nature.


Quality assessment of Rheum species cultivated in Japan by focusing on M2 polarization of microglia.
In traditional Japanese medicine, Rhei Rhizoma is used as a purgative, blood stasis-resolving and antipsychotic drug. The latter two properties are possibly related to anti-inflammatory effects. Microglia regulate inflammation in the central nervous system. M1 microglia induce inflammation, while M2 microglia inhibit inflammation and show neurotrophic effects. This study investigated the effects from water extracts of roots of cultivated Rheum species in Nagano Prefecture, Japan (strain C, a related strain to a Japanese cultivar, 'Shinshu-Daio'; and strain 29, a Chinese strain) and 3 kinds of Rhei Rhizoma available in the Japanese market, and also examined their constituents on the polarization of cultured microglia. All extracts significantly decreased M1 microglia, and strains C and 29 significantly increased M2 microglia. Furthermore, the extracts of both strains significantly increased the M2/M1 ratio. Among the constituents of Rhei Rhizoma, ( +)-catechin (2), resveratrol 4'-O-β-D-(6″-O-galloyl) glucopyranoside (5), isolindleyin (8), and physcion (15) significantly increased the M2/M1 ratio. The contents of the constituents in water extract of each strain were quantified using HPLC. The extracts of strains C and 29 contained relatively large amounts of 2 and 5; and 2, 8, and 15, respectively. This study showed the water extracts of roots of cultivated Rheum strains in Japan had the effects of M2 polarization of microglia, suggesting that these strains become the candidate to develop anti-inflammatory Rhei Rhizoma. Moreover, the suitable chemical composition to possess anti-inflammatory activity in the brain was clarified for the future development of new type of Rhei Rhizoma.


Novel Gemini vitamin D(3) analogs have potent antitumor activity.
The active form of vitamin D(3), 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], modulates proliferation and induces differentiation of many cancer cells. A new class of analogs of vitamin D(3) has been synthesized, having two side-chains attached to carbon-20 (Gemini) and deuterium substituted on one side-chain. We have examined six of these analogs for their ability to inhibit growth of myeloid leukemia (HL-60), prostate (LNCaP, PC-3, DU145), lung (H520), colon (HT-29), and breast (MCF-7) cancer cell lines. Dose-response clonogenic studies showed that all six analogs had greater antiproliferative activities against cancer cells than 1,25(OH)(2)D(3). Although they had similar potency, the most active of these analogs was BXL-01-0120. BXL-01-0120 was 529-fold more potent than 1,25(OH)(2)D(3) in causing 50% clonal growth inhibition (ED(50)) of HL-60 cells. Pulse-exposure studies demonstrated that exposure to BXL-01-120 (10(-9)M, 48h) resulted in 85% clonal inhibition of HL-60 growth. BXL-01-0120 (10(-11)M, 4 days) induced the differentiation marker, CD11b. Also, morphologically differentiation was more prominent compared to 1,25(OH)(2)D(3). Annexin V assay showed that BXL-01-0120 (10(-10)M, 4 days) induced significantly (p<0.05) more apoptosis than 1,25(OH)(2)D(3). In summary, these analogs have a unique structure resulting in extremely potent inhibition of clonal proliferation of various types of cancer cells, especially HL-60 cells.


Metabolism of (24R and 24S)-27-nor-24-methyl-3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acids and 27-nor-3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acid in guinea pigs.
[7beta-3H]-(24R and 24S)-27-nor-24-methyl-3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acids and [7beta-3H]-27-nor-3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acid (C27 and C26 bile acids having the same nuclear configuration as cheno-deoxycholic acid and its precursor, 3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic-acid) were synthesized and administered intraperitoneally to bile fistula guinea pigs. The biliary bile acids formed were hydrolyzed and analyzed by thin layer chromatography, and the metabolites were identified by the inverse isotope dilution method. The results showed that both (24R and 24S)-27-nor-24-methyl-3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acids were not metabolized by the liver and were excreted unchanged as their taurine and glycine conjugates whereas 27-nor-3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acid was converted to chenodeoxycholic acid.


The relationship between emotional labour and job satisfaction in nursing.
To investigate the relationship between emotional labour strategies and job satisfaction among nurses in Turkey. Nursing is one of the professions in which emotional labour is heavily used. The relationship between emotional labour strategies and job satisfaction has many different consequences in nursing. Although studies have focused on the relationship between emotional labour and job satisfaction among nurses abroad, no studies on the subject have been found in Turkey. A cross-sectional descriptive design was employed. The study was conducted with 281 nurses working in a university hospital and three public hospitals in Manisa, Turkey. Research data were collected using the Personal Information Form, Emotional Labour Scale and Minnesota Satisfaction Questionnaire. Descriptive statistics and Pearson correlation analysis were used in data evaluation. Analyses showed that the type of emotional labour strategy most frequently exhibited by nurses was surface acting. In surface acting, behaviours do not reflect employees' true feelings. Job satisfaction of nurses was higher than the medium level. A negative correlation was found between deep acting and job satisfaction. In deep acting, employees try to feel the emotions appropriate to the behaviour expected of them. Nurses' emotional labour may cause some undesirable consequences. Nurses' emotional labour strategies are related to their job satisfaction levels. Managers should be aware of the emotional labour of nurses and its possible negative consequences. Management strategies that target the negative consequences of emotional labour are important not only for the well-being of nurses but also for the quality of patient care.


A low-volume surgeon is an independent risk factor for leg length discrepancy after primary total hip arthroplasty: a case-control study.
Leg length discrepancy (LLD) is one of the bothersome complications that reduce patient satisfaction after total hip arthroplasty (THA). This study aimed to investigate the independent risk factors of LLD after primary THA. This is a case-control study of 163 THAs for 163 patients at our institution between April 2015 and March 2018. The relevant data about the general characteristics of the patients (age, sex, body mass index, and diagnosis), surgery (surgical approach, type of femoral stem fixation, and surgeon volume), and radiological findings (Dorr classification and pre-operative LLD) were reviewed to identify the risk factors of ≥ 5 mm post-operative LLD according to radiological measurement and to calculate odds ratios (OR) via logistic regression analysis. The median (interquartile) absolute value of post-operative LLD was 3.9 (2.3-7.4) mm, and 57 (35.0%) patients had LLD of ≥ 5 mm. After controlling for possible confounders, a low-volume surgeon was considered the only independent risk factor of post-operative LLD (adjusted OR: 8.26; 95% confidence interval: 3.48, 19.60; P < 0.001). Among the 103 patients performed by high-volume surgeons, 82 (79.6%) had LLD of < 5 mm, whereas among the 60 patients performed by low-volume surgeons, only 24 (40.0%) achieved LLD of < 5 mm (P < 0.001). A low-volume surgeon is associated with an increased risk of a post-operative LLD after primary THA, and the importance of measurements should be recognized to prevent post-operative LLD and achieve optimal outcomes. Moreover, surgeons must inform patients about the risk of developing LLD pre-operatively.


Encysted peritoneal hydatidosis in a child -- the effectiveness of pre-operative therapy with a combination of praziquantel and albendazole.
A child with encysted peritoneal hydatidosis was found to be completely cured after 3 months of combined therapy with praziquantel and albendazole followed by resection of a huge peritoneal cyst and the removal of numerous, dead, daughter cysts.


The key role of the sea urchin Diadema aff. antillarum in controlling macroalgae assemblages throughout the Canary Islands (eastern subtropical Atlantic): an spatio-temporal approach.
Diadema aff. antillarum performs a key role in organizing and structuring rocky macroalgae assemblages in the Canary Islands. Densities of D. aff. antillarum higher than 2 individuals m(-2) are found to drastically reduce non-crustose macroalgal cover to below 30% and wave exposure appears as a major factor determining sea urchin density, which decreases with exposure level. Substrates containing >20% sand limit urchin to under 1 individual m(-2) but high relief rocky habitats show higher density. Moreover, several anthropogenic factors (number of islanders and tourists per coastal perimeter, and number of operational fishing boats) were positively correlated with urchin abundance. A trend of increasing urchin density through time was found, although well structured marine systems found at Mar de Las Calmas Marine Protected Area and at the no-take area of La Graciosa Marine Protected Area do not seem to follow this general trend.


Formation of cartilage in cardiac semilunar valves of chick and quail.
The development of cartilage in the aortic and pulmonary valves of chick and quail was studied using histological, histochemical and immunohistochemical techniques. In both species, the earliest evidence of chondrogenesis is the formation of smooth muscle alpha-actin-negative prechondrogenic (type II collagen-negative) cellular condensations in the tunica media of the proximal aorta and pulmonary trunk, in front of or slightly distal to the valvular commissures. Such condensations are present as early as stage 37 of Hamburger-Hamilton in the aortic and pulmonary valves of the chick. In quail embryos, they form somewhat later, namely, at stage 38 in the aortic valves and stage 39 in the pulmonary valves. In the chick, synthesis of type II collagen starts in the central core of the aortic cellular condensations at stage 38. In the pulmonary valves of chick and aortic and pulmonary valves of quail, production of type II collagen does not begin until stage 40. This production then gradually increases toward the periphery of the condensations, which remain devoid of perichondrium prior to hatching. After birth, the condensations become transformed into hyaline cartilaginous foci. In the aortic valves of some chickens and quails, more or less extensive deposits of hyaline cartilage or fibrocartilage form along the attachments of the leaflets to their supporting sinuses. They develop later than the commissural cartilages. The present findings, together with previous data from the literature, suggest that the aortic and pulmonary valve cartilages differentiate from neural crest-derived nonmuscular cells.


Serologic markers of viral hepatitis A, B, C, and D in patients with hemophilia.
Forty-one patients with hemophilia A were studied for the prevalence of serological markers for hepatitis A, hepatitis B, hepatitis C (non-A and non-B hepatitis), and delta hepatitis (hepatitis D). Ten of 41 (24.4%) patients demonstrated hepatitis A antibody and 31 of 41 (75.6%) patients had a serologic marker for previous hepatitis B infection; four of these 31 patients (13%) also demonstrated antibody to delta agent (hepatitis D). Thirty-seven of 41 (90.2%) patients demonstrated antibody for hepatitis C. Nine of 31 (29%) patients with a hepatitis B marker (no hepatitis B vaccinees) were negative for anti-HBc but positive for anti-HBs; all of these nine patients were HIV antibody positive, although they had no overt immunodeficiency. Twenty-six of 41 (63.5%) patients were HIV antibody positive. Of HIV antibody positive patients, 27%, 88%, and 100% demonstrated evidence of a previous hepatitis A, hepatitis B, or hepatitis C, respectively. Of HIV antibody negative patients; 20%, 53%, and 73% of the patients demonstrated evidence of a previous hepatitis A, hepatitis B, or hepatitis C infections, respectively. The difference between HIV antibody positive and HIV antibody negative groups was not significant for hepatitis A but was significant for hepatitis B (P < 0.001) and hepatitis C (P < .001). Of the 31 patients with a hepatitis B serologic marker, all had antibody to hepatitis C. Of 10 patients, without a hepatitis B serologic marker, only 6 (60%) had antibody to hepatitis C.(ABSTRACT TRUNCATED AT 250 WORDS)


Maternal stress and vulnerability to depression: coping and maternal care strategies and its consequences on adolescent offspring.
Depressive mothers often find mother-child interaction to be challenging. Maternal stress may further impair mother-child attachment, which may increase the risk of negative developmental consequences. We used rats with different vulnerability to depressive-like behavior (Wistar and Kyoto) to investigate the impact of stress (maternal separation-MS) on maternal behavior and adolescent offspring cognition. MS in Kyoto dams increased pup-contact, resulting in higher oxytocin levels and lower anxiety-like behavior after weaning, while worsening their adolescent offspring cognitive behavior. Whereas MS in Wistar dams elicited higher quality of pup-directed behavior, increasing brain-derived neurotrophic factor (BDNF) in the offspring, which seems to have prevented a negative impact on cognition. Hypothalamic oxytocin seems to affect the salience of the social environment cues (negatively for Kyoto) leading to different coping strategies. Our findings highlight the importance of contextual and individual factors in the understanding of the oxytocin role in modulating maternal behavior and stress regulatory processes.


Effect of Maillard reaction on the quality of clarified butter, ghee.
In Ayurveda, a traditional Indian medicine system, clarified butter is called ghee and is used for food and medicinal purposes. Since butter is subjected to heat to prepare ghee, the heating process affects the ghee quality, such as oxidation, flavor, nutritional value, and biological activity. Therefore, this study focused on the Maillard reaction progress and free-radical scavenging activity with temperature and time during ghee preparation. First, ghee was prepared at low to high temperatures, and its quality (milk fat content, retinol, α-tocopherol, peroxide value, Maillard reaction progress, and free radical scavenging activity) was evaluated. Maillard reaction progress was enhanced at medium and high temperatures (120-160 ℃), and the free radical-scavenging activity of ghee corresponded to the Maillard reaction progress. Since ghee is often reheated during use, we further evaluated the effect of the reheating process. The reheating process did not alter the Maillard reaction progress or the free radical scavenging activity. Our findings serve as good quality control measures for ghee preparation.


Overlap lamivudine treatment in patients with chronic hepatitis B receiving adefovir for lamivudine-resistant viral mutants.
Adefovir dipivoxil is effective against lamivudine-resistant hepatitis B virus (HBV) strains. Whether short-term overlap lamivudine is beneficial remains unknown, particularly in patients with decompensated chronic hepatitis B. We enrolled 30 patients who underwent 48-week adefovir treatment (10 mg daily) for exacerbation of hepatitis B, associated with lamivudine-resistant mutants. Nineteen (63.3%) patients had baseline evidence of hepatic decompensation. Lamivudine was combined for <or=1 month in eight (group I), 2-5 months in 10 (group II) and >or=6 months in 12 (group III). We analysed their serial alanine aninotransferase (ALT) levels, Child-Pugh (CP) score, serum viral load and lamivudine-resistant strains. We found that serum ALT became normalized in 20 (66.7%) and HBV-DNA decreased to <or=100 copies/mL in eight (26.7%) at the end of the 48-week treatment. The log(10) reduction of serum HBV-DNA was significantly smaller in group I patients compared with group II and III patients at week 24 and 48 of treatment [median (range): 3.0 (1.5-5.6) vs 4.5 (1.5-7.4), P = 0.032; and 3.4 (0.9-4.7) vs 5.2 (2.2-7.7), P = 0.008 respectively]. In contrast, the virologic responses at the end of the 48-week therapy were similar between group II and III patients. The improvement in serum ALT and CP score at week 48 was similar irrespective of baseline decompensation, liver cirrhosis and the duration of overlap lamivudine therapy. Our findings suggested that an overlap of lamivudine for >or=2 months might lead to better virological but not biochemical outcomes in patients receiving adefovir for lamivudine-resistance HBV. As our sample size was small and the study was not randomly controlled, further studies are needed.


Targeting endothelial CD146 attenuates neuroinflammation by limiting lymphocyte extravasation to the CNS.
The ability to selectively block the entry of leukocytes into the central nervous system (CNS) without compromising the immune system is an attractive therapeutic approach for treating multiple sclerosis (MS). Using endothelial CD146-deficienct mice as a MS model, we found that endothelial CD146 plays an active role in the CNS-directed extravasation of encephalitogenic T cells, including CD146(+) TH1 and TH17 lymphocytes. Moreover, treating both active and passive MS models with the anti-CD146 antibody AA98 significantly decreased the infiltrated lymphocytes in the CNS and decreased neuroinflammation. Interestingly, the ability of AA98 to inhibit the migration of CD146(+) lymphocytes was dependent on targeting endothelial CD146, but not lymphocytic CD146. These results suggest a key molecular target located on the blood-brain barrier endothelium that mediates the extravasation of inflammatory cells into the CNS. In addition, our data suggest that the AA98 is a promising candidate for treating MS and other CNS autoimmune diseases.


Wide excision without radiation for desmoplastic melanoma.
Adjuvant radiation has been proposed for the treatment of patients with desmoplastic melanoma, who reportedly have local recurrence rates as high as 40-60%. The authors investigated local recurrence rates at a tertiary referral center to determine the success of wide excision alone for patients with desmoplastic melanoma. A review of a prospectively maintained melanoma clinical data base identified 65 patients between March 1997 and March 2004 with pure cutaneous desmoplastic melanoma. Complete surgical, histopathologic, and staging information was collected along with data on outcome, including local, regional, and distant recurrence and survival. Similar to previous reports, patients with desmoplastic melanoma had a male-to-female ratio of 2 to 1, a mean age of 65.0 years (range, 31-92 yrs), and the majority of their tumors (55%) were located on the head and neck. The mean Breslow depth at diagnosis was 4.21 mm, with 38% of tumors thicker than 4.0 mm. All patients in this series underwent wide excision without radiation therapy. Surgical margins < or = 2 cm were obtained for all trunk and extremity lesions and for 63% of head and neck lesions that measured > 1 mm in depth (63%). Margins of 1-2 cm were obtained for the remaining patients. Among 49 patients who had a minimum of 2 years of follow-up (mean, 3.7 yrs), the local recurrence rate was 4% (2 of 49 patients). Seventy-eight percent of the patients studied remained alive with no evidence of disease. Local recurrence rates in the current series were considerably lower than the historically reported rates. This finding suggests that, for patients with desmoplastic melanoma, wide local excision with careful attention to appropriate margins produces excellent local control rates without the need for adjuvant radiation.


Does the medical college admission test predict clinical reasoning skills? A longitudinal study employing the Medical Council of Canada clinical reasoning examination.
To investigate the predictive validity of the Medical College Admission Test (MCAT) for clinical reasoning skills upon completion of medical school. A total of 597 students (295 males, 49.4%; 302 females, 50.6%) participated from 1991 to 1999. Stepwise multiple regressions of the MCAT and premedical school GPA (independent variables) on the Part 1(declarative knowledge) and Part 2 (clinical reasoning) of the Medical Council of Canada Examinations (dependent variables) were employed. For Part 1, the multiple regression revealed that three predictors (verbal reasoning, biological sciences, GPA) accounted for 23.3% of the variance, and for Part 2, two predictors (verbal reasoning, GPA) accounted for 11.2%. There is both convergent and divergent evidence for the predictive validity of the MCAT for clinical reasoning.


Effect of mouthguards on the transmission of force across the human jaw.
To determine if impact responses (stiffness and damping values) of the jaw and neck are significantly different between mouthguards of varying material and manufacturing properties, in controlled conditions involving specified upper limb orientation and applied loading. Quasi-experimental design. Simon Fraser University biomechanical laboratory. Twelve male subjects between the ages of 19 to 28 participated in this study. All subjects were healthy, had no missing teeth, and had no mechanical (orthodontic) appliances. For each condition, the system stiffness and damping values were estimated using the free vibration technique. Stiffness and damping values are relevant because they are the major determinants of impact force and, potentially, injury risk. It is the first study to show experimentally the quantitative effects of mouthguard in situ. All the mouthguards lowered the system stiffness as compared with the no mouthguard condition (P < 0.001). There was no observed effect on stiffness between the 2 limb orientation positions. Excitation weight had an unexpected effect on system stiffness (P = 0.041), with increasing weight leading to increased stiffness. The findings suggest that wearing any mouthguard is better than wearing none at all due to their ability to reduce system stiffness and damping values after a blow to the chin.


Ti3C2(OH)x-assisted LDI-TOF-MS for the rapid analysis of natural small molecules.
The inhomogeneous distribution of co-crystallized analytes and the traditional organic matrices as well as the intensive background interference in the low molecular weight range hinder the application of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in the analysis of small-molecular compounds. New two-dimensional material MXene (e.g., Ti3C2) exerts better hydrophilicity, homogeneity and repeatability, and higher laser desorption efficiency, as well as less background interference than traditional organic matrices and other nanomaterial matrices such as titanium oxide, graphene, and gold nanostructures. This study was aimed to design Ti3C2 matrix with abundant hydroxyls on its surface, enhance the stability of this hydroxyl-rich Ti3C2 (Ti3C2(OH)x), and evaluate the analytical performances of Ti3C2(OH)x-assisted laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF-MS) for small-molecular natural compounds in complex samples. The developed Ti3C2(OH)x showed the distinct advantages such as minimum background interference, high peak intensity (~105), high salt (0.6 M) and protein (0.5 mg/mL) tolerance, good repeatability (relative standard deviation<20%), and good stability after eight months of storage. Ti3C2(OH)x-assisted LDI-TOF-MS analysis could be used to rapidly identify Artemisia annua (a world-famous traditional Chinese medicine) and quantify the contents of the main chemical ingredients (oxymatrine (OXY) and matrine) of Compound Kushen Injection (CKI). Interestingly, the content of OXY in CKI could be accurately quantified by Ti3C2(OH)x-assisted LDI-TOF-MS, and there was a good linear relationship (R2 -0.9929), a low limit of detection (400 pg), and a low limit of quantification (600 pg) of OXY. Taken together, the rapid and accurate analysis of small-molecular natural compounds in complicated samples could be achieved by the Ti3C2(OH)x-assisted LDI-TOF-MS analysis.


The practical understanding and treatment of asthma.
Asthma is a syndrome which is seen by physicians in nearly every specialty and affects millions of people throughout the world. Although the geoepidemiology with respect to prevalence and incidence of asthma does vary, even under the most mild of circumstance, asthma is among the leading causes of school absenteeism, work loss, and physician visits. In the past, it was considered primarily a disorder of childhood. Hence, the adage that children outgrow their asthma. We now realize that children really only outgrow their pediatrician and the genetic predisposition to asthma and bronchial hyperactivity persists throughout life. This issue is devoted to key papers that focus on important clinical problems in allergies and asthma. This issue is dedicated to helping the many sufferers of asthma with the hope that this topic will eventually become a medical anachronism.


Conversion to sirolimus in a population of kidney and kidney-pancreas transplant recipients.
Calcineurin inhibitors (CI) are associated with nephrotoxicity that might reduce long-term graft survival. We report our experience with sirolimus (SRL) conversion among a population of kidney and kidney pancreas transplant recipients. Thirty transplant recipients (6 women, 24 men; age 41 +/- 10.5 years old) were converted to SRL therapy at 25.97 +/- 32.5 months after transplantation. Indications for conversion were: intolerance to mycophenolate mofetil (n = 13), diabetes mellitus (n = 3), CI nephrotoxicity (n = 11), CI nephrotoxicity with chronic allograft rejection (n = 2), and side effects of azathioprine (n = 1). Follow-up after conversion is 3 to 45 months. No significant changes were observed in the 3 months postconversion in renal function, hematological profile, and mean arterial blood pressure. In contrast there was a significant increase in cholesterol values (pre: 198.7 +/- 49.4, versus post 221.2 +/- 60.8, P = .018). At a follow-up of 15.2 +/- 9.9 months after conversion two patients (6.7%) died with functioning allograft (one because of infection and one to myocardial infarct) three kidney allografts (10.7%) have been lost: two chronic rejection; one infection. In two patients SRL therapy was discontinued (one infection, one refractory edema). Neither significant change in renal function nor episodes of acute rejection were observed. Conversion to SRL was safe. There was no deterioration in renal function nor episodes of acute rejection. There was a significant increase in cholesterol values after conversion. The size of the sample and the time of follow-up may have determined our results.


Cloning and expression of Clostridium thermocellum genes coding for thermostable exoglucanases (cellobiohydrolases) in Escherichia coli cells.
By special screening approach two independent Cl. thermocellum genes directing the synthesis of thermostable glucanases with an exo-mode of action have been isolated from pUC19-based gene bank in E. coli TG1. The genes are located on 3.4 and 11.3 kb DNA fragments showing no homology. E. coli-derived exoglucanases, presumably, cellobiohydrolases, are able to cleave lichenan, carboxymethyl cellulose, xylan and p-nitrophenyl derivatives of cellobioside and lactoside. Cellobiose is the main degradation product of carboxymethyl cellulose, treated with the identified exoglucanases. With p-nitrophenil-beta-D-cellobioside as substrate the enzymes had a pH optimum around 6.5 and a temperature optimum at 65 degrees C. The identified and expressed enzymes differ from all other Cl. thermocellum proteins known to date.


New pathway to prepare gold nanoparticles and their applications in catalysis and surface-enhanced Raman scattering.
As shown in the literature, additional energies are necessary for the reduction of positively charged noble metal ions to prepare metal nanoparticles (NPs). In this work, we report a new green pathway to prepare Au NPs in neutral 0.1M NaCl aqueous solutions from bulk Au substrates without addition of any stabilizer and reductant just via aid of natural chitosan (Ch) at room temperature. Au- and Ch-containing complexes in aqueous solution were electrochemically prepared. The role of Ch is just an intermediate to perform electron transfer with Au NPs. The stability of these prepared Au NPs is well maintained by Au NPs themselves with slightly positively charged Au remained on the surface of Au NPs. The particle size of prepared spherical Au (111) NPs is ca. 15 nm in diameter. Moreover, increasing the pH of preparation solutions can be contributive to preparing concentrated Au NPs in solutions. The prepared Au NPs are surface-enhanced Raman scattering (SERS)-active for probe molecules of Rhodamine 6G. They also demonstrate significantly catalytic activity for decomposition of acetaldehyde in rice wine.


The hypothalamic paraventricular nucleus mediates the photoperiodic control of reproduction but not the effects of light on the circadian rhythm of activity.
Photoperiods of less than 12.5 h of light/24 h induce gonadal regression in the golden hamster. Photic information is relayed from the retina to the hypothalamic suprachiasmatic nucleus (SCN), a structure responsible for the generation of many circadian rhythms including the circadian rhythms in locomotor activity and pineal melatonin synthesis and release. Although pineal melatonin mediates the photoperiodic-neuroendocrine response, the complete neural circuit from the SCN to the pineal gland is unknown. Complete destruction of the hypothalamic paraventricular nucleus (PVN) prevented short-day-induced testicular regression without affecting the circadian rhythm of locomotor activity. The results indicate that the PVN plays an important role in the photoperiodic-neuroendocrine circuit and is responsible for relaying information from the SCN to the pineal. A different efferent pathway connects the SCN to structures in the brain responsible for locomotor activity.


Assessing behavioral economic biases among young adults who have increased likelihood of acquiring HIV: a mixed methods study in Baltimore, Maryland.
Behavioral economic (BE) biases have been studied in the context of numerous health conditions, yet are understudied in the field of HIV prevention. This aim of this study was to quantify the prevalence of four common BE biases-present bias, information salience, overoptimism, and loss aversion-relating to condom use and HIV testing in economically-vulnerable young adults who had increased likelihood of acquiring HIV. We also qualitatively examined participants' perceptions of these biases. 43 participants were enrolled in the study. Data were collected via interviews using a quantitative survey instrument embedded with qualitative questions to characterize responses. Interviews were transcribed and analyzed using descriptive statistics and deductive-inductive content analyses. 56% of participants were present-biased, disproportionately discounting future rewards for smaller immediate rewards. 51% stated they were more likely to spend than save given financial need. Present-bias relating to condom use was lower with 28% reporting they would engage in condomless sex rather than wait one day to access condoms. Most participants (72%) were willing to wait for condom-supported sex given the risk. Only 35% knew someone living with HIV, but 67% knew someone who had taken an HIV test, and 74% said they often think about preventing HIV (e.g., high salience). Yet, 47% reported optimistically planning for condom use, HIV discussions with partners, or testing but failing to stick to their decision. Most (98%) were also averse (b = 9.4, SD ±.9) to losing their HIV-negative status. Qualitative reasons for sub-optimal condom or testing choices were having already waited to find a sex partner, feeling awkward, having fear, or not remembering one's plan in the moment. Optimal decisions were attributed qualitatively to self-protective thoughts, establishing routine care, standing on one's own, and thinking of someone adversely impacted by HIV. 44% of participants preferred delayed monetary awards (e.g., future-biased), attributed qualitatively to fears of spending immediate money unwisely or needing time to plan. Mixed methods BE assessments may be a valuable tool in understanding factors contributing to optimal and sub-optimal HIV prevention decisions. Future HIV prevention interventions may benefit from integrating savings products, loss framing, commitment contracts, cues, or incentives.


Organization of the exons coding for pro alpha 1(II) collagen N-propeptide confirms a distinct evolutionary history of this domain of the fibrillar collagen genes.
The organization of the exons coding for the N-terminal portion of human type II procollagen has been determined. Aside from inferring the previously unknown primary structure of type II N-propeptide, this study has revealed that this coding domain of the gene exhibits an organization uniquely distinct from those of type I and type III collagens. This finding substantiates the notion that the N-propeptide coding domains of the fibrillar collagen genes evolved under less stringent selection than those encoding the C-propeptide and triple helical regions.


Influence of furan and lead co-exposure at environmentally relevant concentrations on neurobehavioral performance, redox-regulatory system and apoptotic responses in rats.
Furan and lead are contaminants of global concern due to the potential public health threat associated with their exposure. Herein, the neurobehavioral performance, biochemical effects and histological alterations associated with co-exposure to furan (8 mg/kg) and lead acetate at low, environmentally realistic concentrations (1, 10 and 100 µg PbAc/L) for 28 uninterrupted days were investigated in rats. The results demonstrated that locomotor, motor and exploratory deficits associated with separate exposure to furan and lead was exacerbated in the co-exposed rats. Furan and lead co-exposure aggravated the marked decrease in acetylcholinesterase activity and antioxidant status, elevation in oxido-inflammatory stress indices and caspases activation in the cerebrum and cerebellum of exposed rats compared with control. Furan and lead co-exposure worsened neuronal degeneration as verified by histomorphometry and histochemical staining. Collectively, furan and lead acts together to exacerbate neurotoxicity via inhibition of cholinergic system, induction of oxido-inflammatory stress and caspases activation in rats.


Stroke related to cerebral amyloid angiopathy: the significance of systemic vascular disease.
A retrospective postmortem analysis of 25 cases of cerebral amyloid angiopathy (CAA) in the setting of Alzheimer's disease or senile dementia of the Alzheimer type (AD/SDAT) is reported. Seven patients experienced clinically significant cerebral infarcts or hemorrhages or both. There was no statistically significant difference in the incidence of infarcts or hemorrhages in hypertensive and nonhypertensive patients. Hypertension does not appear to be an additional risk factor in the causation of cerebral infarct or hemorrhage associated with CAA in the setting of AD/SDAT. Just over half of patients with CAA and significant ischemic and/or hemorrhagic brain lesions showed atherosclerosis of the circle of Willis, sometimes in the context of severe disseminated atheromatous disease.


Enhanced breakdown in vitro of bovine articular cartilage proteoglycans by conditional synovial medium. The effect of superoxide dismutase and catalase.
We have previously reported that addition of conditioned medium derived from fragment cultures of synovial tissue dissected from bovine knee-joints (SM) to cultures of articular cartilage derived from the same knee-joint resulted in enhanced breakdown of cartilage proteoglycans, measured as the release of [35S]sulphate from pieces of prelabelled cartilage. It has also been reported that oxygen-centered free radicals can degrade cartilage proteoglycans and that superoxide dismutase and catalase can reduce such degradation. Here we report that superoxide dismutase and catalase do not significantly affect the degradation of articular cartilage proteoglycans enhanced by conditioned synovial medium. It therefore appears that oxygen-centered free radicals are of at most minor importance for the degradation of cartilage enhanced by conditioned synovial medium.


[Efficacy of pulmonary resection for primary hepatocellular carcinoma patients with pulmonary metastasis].
Pulmonary resection is considered as an active therapy for malignant tumor patients with pulmonary metastasis. This study was to evaluate the efficacy of pulmonary resection for primary hepatocellular carcinoma (HCC) patients with pulmonary metastasis. Clinicpathologic data and outcomes of 12 HCC patients underwent pulmonary resection due to pulmonary metastasis were analyzed. Among the 12 patients, 9 had 1 or 2 pulmonary metastases, 1 of which had relapsed pulmonary metastasis after the first pulmonary resection; the other 3 patients who had 3 or more pulmonary metastases all recurred with pulmonary metastasis after the first pulmonary resection. The median survival time was 52 months after the first hepatectomy and 24 months after the first pulmonary resection. The overall 1-, 3-and 5-year survival rates were 100.0%,75.0% and 47.3% after the first hepatectomy, and 83.3%, 46.7% and 21.0% after the first pulmonary resection, respectively. When intrahepatic recurrence is effectively controlled, HCC patients with 1 or 2 pulmonary metastases might benefit from pulmonary resection and achieve prolonged survival.


Fibre in enteral formulae: effects of sugar-beet versus soy fibre on zinc and folic acid absorption in human subjects.
The present study was conducted to compare the effect of soypolysaccharide (Fibrem) and sugar-beet (Fibrex) on zinc and folic acid absorption when incorporated into enteral formulae. Following an overnight fast, 15 adults were challenged with an oral dose of zinc (60 mg) and folic acid (600 mug) given with enteral formula without fibre, or with 15g of dietary fibre from Fibrem or Fibrex. Serum concentrations of zinc and folic acid were measured at zero-time and at hourly intervals for up to 5h. Results showed that Fibrem caused a significant decrease in the concentrations of zinc and folic acid. However, Fibrex caused a slight increase in serum zinc concentration and a less pronounced decrease in serum folic acid concentration as compared to Fibrem. We conclude that for patients who are at risk of zinc or folic acid deficiency, the fibre source in enteral formulae should be selected carefully.


Ellagic acid increases implantation rates with its antifibrotic effect in the rat model of intrauterine adhesion.
Intrauterine adhesions (IUA) are defined as the adhesion of opposing endometrial tissue with dense fibrous adhesive bands within the uterine cavity. With the increase in cesarean sections and endometrial surgical procedures, intrauterine adhesions have become a problem with increasing incidence and decreasing implantation. The purpose of the study was to investigate the effect of ellagic acid (EA), a phenolic compound, on fibrosis in IUA model rats. Another goal of the study was to increase endometrial receptivity with EA. The groups in the study were planned as control, DMSO, EA, IUA, IUA+DMSO, and IUA+EA, with 8 Sprague Dawley rats in each group. EA was administered at a dose of 100 mg/kg/day for 35 days. At the end of the experiment, the uterine tissues of the rats were removed. Histochemical staining was used to validate the IUA model and determine the degree of fibrosis. The levels of some fibrosis-related genes and proteins in the obtained uterine tissues were evaluated. In addition, implantation rates were determined. In our findings, it was observed that the fibrotic structure was decreased in the treated IUA+EA group compared to the IUA group, while fibrotic improvement was supported by down-regulation of TGFβ1 activity and up-regulation of BMP7 activity. The increase in the expression of the endometrial marker LIF with EA treatment was consistent with the increase in implantation rates with treatment. As a result of the study, it can be said that EA applied as a treatment against IUA causes healing in uterine tissue by reducing fibrosis and increases implantation rates by increasing endometrial receptivity.


Structural and compositional diversity in the kainate receptor family.
The kainate receptors (KARs) are members of the ionotropic glutamate receptor family and assemble into tetramers from a pool of five subunit types (GluK1-5). Each subunit confers distinct functional properties to a receptor, but the compositional and stoichiometric diversity of KAR tetramers is not well understood. To address this, we first solve the structure of the GluK1 homomer, which enables a systematic assessment of structural compatibility among KAR subunits. Next, we analyze single-cell RNA sequencing data, which reveal extreme diversity in the combinations of two or more KAR subunits co-expressed within the same cell. We then investigate the composition of individual receptor complexes using single-molecule fluorescence techniques and find that di-heteromers assembled from GluK1, GluK2, or GluK3 can form with all possible stoichiometries, while GluK1/K5, GluK2/K5, and GluK3/K5 can form 3:1 or 2:2 complexes. Finally, using three-color single-molecule imaging, we discover that KARs can form tri- and tetra-heteromers.


Aprotinin preserves cellular junctions and reduces myocardial edema after regional ischemia and cardioplegic arrest.
Cardiac surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest has been associated with myocardial edema attributable to vascular permeability, which is regulated in part by thrombin-induced alterations in cellular junctions. Aprotinin has been demonstrated to prevent activation of the thrombin protease-activated receptor, and we hypothesized that aprotinin preserves myocardial cellular junctions and prevents myocardial edema in a porcine model of regional ischemia and cardioplegic arrest. Fourteen pigs were subjected to 30 minutes of regional ischemia, followed by 60 minutes of CPB, with 45 minutes of crystalloid cardioplegia, then 90 minutes of post-CPB reperfusion. The treatment group (n=7) was administered aprotinin (40,000 kallikrein inhibitor units [KIU]/kg loading dose, 40,000 KIU/kg pump prime, and 10,000 KIU/kg per hour continuous infusion). Control animals (n=7) received normal saline. Myocardial vascular endothelial (VE)-cadherin, beta-catenin and gamma-catenin, and associated mitogen-activated protein kinase (MAPK) pathways were assessed by immunoblot and immunoprecipitation. Histologic analysis of the cellular junctions was done by immunofluorescence. Myocardial tissue water content was measured. VE-cadherin, beta-catenin, and gamma-catenin levels were significantly greater in the aprotinin group (all P<0.05). Immunfluorescence confirmed that aprotinin prevented loss of coronary endothelial adherens junction continuity. Aprotinin reduced tyrosine phosphorylation in myocardial tissue sections. Phospho-p38 activity was approximately 30% lower in the aprotinin group (P=0.007). The aprotinin group demonstrated decreased myocardial tissue water content (81.2+/-0.5% versus 83.5+/-0.3%; P=0.01) and reduced intravenous fluid requirements (2.9+/-0.2 L versus 4.0+/-0.4 L; P=0.03). Aprotinin preserves adherens junctions after regional ischemia and cardioplegic arrest through a mechanism potentially involving the p38 MAPK pathway, resulting in preservation of the VE barrier and reduced myocardial tissue edema.


Prospects for molecular farming in the green alga Chlamydomonas.
Protein-based therapeutics have enjoyed great success over the past decade. Unfortunately, this clinical success has come with a heavy price tag that is due to the inherently high costs of the capitalization and production of these complex molecules using current mammalian-based fermentation systems. Recent progress has been made in the production of recombinant proteins, including antibodies, in the eukaryotic unicellular green alga Chlamydomonas reinhardtii. C. reinhardtii offers an attractive alternative to traditional mammalian-based expression systems for several reasons, including its ability to provide stable plastid and nuclear transformants rapidly and its inherently low costs for capitalization and production.


Relationships of C-reactive protein, uric acid, and glomerular filtration rate to arterial stiffness in Japanese subjects.
The relationships between C-reactive protein (CRP), uric acid (UA), glomerular filtration rate (GFR), and arterial stiffness have not been fully investigated. The aim of this study was to clarify whether CRP, UA, and estimated GFR are related to arterial stiffness estimated using brachial-ankle pulse wave velocity (baPWV). The subjects were local government employees (3412 men and 854 women). baPWV, CRP, UA, GFR, and conventional risk factors were evaluated. Multiple linear regression analyses revealed that CRP and UA were significantly related to an elevation of PWV in male and female subjects, and that the estimated GFR was significantly related to an elevation of PWV in male subjects. Significant progressive increases in baPWV were observed across the quartiles of CRP in male subjects and for UA in male and female subjects. In female subjects, the relationship of quartile CRP to baPWV had marginal significance (P = 0.055). But, in male and female subjects, quartile of estimated GFR had no significant association with PWV. These results suggest that CRP and UA are associated with an increase of arterial stiffness in male and female subjects, and that estimated GFR is possibly related to arterial stiffness in male subjects.


Symptomatic urinary tract infections following voiding cystourethrography.
The objective of this study was to assess the frequency of symptomatic urinary tract infections (UTIs) following voiding cystourethrography (VCUG) while using prophylactic antibiotics. Medical records of 421 patients who underwent a VCUG during a period of 4 years were reviewed. Three hundred forty-nine had a VCUG following a febrile UTI, and 72 had the test for evaluation of hydronephrosis. All received prophylactic antibiotics and were evaluated within 7-10 days following the VCUG. One hundred seventy-two children (41%) had an abnormal VCUG. Seven of 421 children (1.7%) had symptoms suggestive of UTI. Two had culture negative pyuria; one had Escherichia Coli UTI, and four had Pseudomonas aeruginosa UTI. On multivariate logistic regression analysis, the risk factors contributing to the development of UTI following VCUG were the presence of vesicoureteral reflux (VUR) and its severity (odds ratio [OR] 2.52; 95% confidence interval [CI] 2.24, 2.83, p =0.001; and OR 2.32; 95% CI 2.05,2.62, p =0.04, respectively). The incidence of VCUG-induced UTI in children receiving prophylactic antibiotic therapy is low. There is a relatively high rate of Pseudomonas UTI, especially in children with moderate to severe reflux. We recommend that children with symptoms suggesting a UTI following a VCUG should be treated for Pseudomonas aeruginosa pending culture results.


Missense variants in the X-linked gene PRPS1 cause retinal degeneration in females.
Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next-generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation.


Paraplegia after ductus ligation accompanied by injury to intercostal artery.
Paraplegia is a hitherto unreported complication of the surgical treatment of patent ductus arteriosus. This communication presents the case history of a 5-year-old girl in whom this serious complications developed after ductus ligation accompanied by injury to an intercostal artery.


Neuromuscular fatigability amplitude and aetiology are interrelated across muscles.
What is the central question of this study? Is neuromuscular fatigability interrelated between different muscle groups from the same individual during isometric all-out exercise? What is the main finding and its importance? Although the average decrease can vary between muscles, an individual demonstrates interrelated fatigability aetiology regardless of the muscle group tested. The inter-individual variability provides evidence of different profiles common between muscles, which can be regarded as an individual characteristic. Neuromuscular fatigability is commonly attributed to central and peripheral origins. However, there is strong evidence of interactions between these two mechanisms. According to the idea that peripheral fatigability might be centrally regulated, one can hypothesize that neuromuscular fatigability would be correlated between different muscle groups at the individual level. Thirty-two healthy participants (16 women and 16 men) completed two 5 min fatiguing exercises [60 isometric maximal voluntary contractions (MVCs)] with finger flexors (FFs) and ankle plantar flexors (PFs) in two randomized sessions. Neuromuscular testing was conducted before, during (every six MVCs) and directly after the fatigue procedure. The force asymptote (FA ) was calculated as the asymptote of the force-time relationship. Changes (post- vs. pre-fatigue) in the exercise-evoked force (ΔDb100 ), voluntary activation (ΔVA) and central activation ratio (∆CAR) were also investigated. Significant correlations were found between FFs and PFs for FA , ΔDb100 and ΔVA (r = 0.65, r = 0.63 and r = 0.50, respectively). A significant negative correlation between ∆CAR and ∆Db100 was evidenced for both PFs (r = -0.82) and FFs (r = -0.57). Neuromuscular fatigability is correlated between different muscle groups at the individual level. The results support the idea that a restrained motor drive prevents large peripheral perturbations and that individuals exhibit correlated fatigability aetiology regardless of the muscle group tested. Widely different central/peripheral profiles can be found amongst individuals, and a part of the fatigability aetiology can be regarded as an individual characteristic.


Two-step retrograde closed stenting: a novel method for treating canalicular lacerations in Chinese patients.
To evaluate the efficacy of two-step retrograde closed stenting for treating canalicular laceration. methods: Forty-eight consecutive canalicular laceration cases (48 eyes) were randomised and divided into two groups: a one-step group and a two-step group. In the two-step group (23 cases), the first step was performed in the outpatient department and included identifying the medial cut end of the canaliculus and probing under a slit-lamp microscope, followed by a retrograde canalicular stenting assisted by a memory titanium stylet. The second step was canalicular anastomosis, which was performed in the operating room. In the one-step group (25 cases), all of the surgical procedures were performed when preoperative preparations were simultaneously available. The time elapsed from the doctor visit to the treatment was 4.3 ± 2.4 h in the two-step group and 18.8 ± 6.3 h in the one-step group (P<0.01). The canalicular medial cut ends were found in all cases, but 8.6 ± 3.5 min was needed in the two-step group, and 51.4 ± 24.2 min was needed in the one-step group (P<0.01). The numerical rating scale for pain during surgery was 1.8 ± 1.2 in the two-step group and 5.4 ± 2.2 in the one-step group (P<0.01). One case (2.63%) in the two-step group and nine cases (36%) in the one-step group required other assisted methods to locate the medial cut end (P=0.007). Twenty-one cases (91.3%) in the two-step group and 20 cases (80%) in the one-step group achieved patent lacrimal drainage systems during a 12-month follow-up (P=0.528). The two-step canalicular anastomosis method allows an early search for the medial cut end of the canaliculus and improves the chances of finding it; it is also a quicker, less invasive method for treating canalicular lacerations.


Water vapor thermal therapy of lower urinary tract symptoms due to benign prostatic obstruction: efficacy and safety analysis of a real-world cohort of 211 patients.
This study assessed the efficacy, safety and durability outcomes of water vapor thermal therapy with Rezum in a real-world cohort of patients with lower urinary tract symptoms due to benign prostate obstruction. Consecutive, unselected patients undergoing Rezum treatment between January 2014 and August 2022 were candidates for this pragmatic, observational, longitudinal, single-center cohort study. Pre- and perioperative data were descriptively summarized. The primary outcome was surgical efficacy, determined by International Prostate Symptom Score (IPSS), Quality of Life (QoL) Score, maximum urinary flow rate (Qmax), post-void residual (PVR) volume and prostate volume (PV) at baseline, 2 months, 6 months, 1 year, 2 years, and > 2 years. A total of 211 patients were enrolled for analysis. Overall, catheter removal was successful in 92.4% of patients after a median of 5 days. A preoperative catheter and the presence of a median lobe increased the risk of unsuccessful catheter removal. In total, 5.7% of patients were reoperated after a median of 407 days. Comparing baseline to the longest median follow-up, the postoperative IPSS decreased significantly by 65.7%, the QoL Score declined by 66.7% (both until a maximum median of 4.5 years) and Qmax improved by 66.7% (until 3.9 years). Post-void residual volume and PV were reduced by 85.7% (3.7 years) and 47% (4.0 years), respectively. Clavien-Dindo complication ≤ II occurred in 11.8%. Rezum is a safe minimally invasive treatment option in a real-world patient cohort with a beneficial improvement of micturition symptoms and voiding function during follow-up.


Extracellular adenosine levels and cellular energy metabolism in ischemically preconditioned rat heart.
Microdialysis and 31P-NMR spectroscopy were used to test opposing hypotheses that ischemic preconditioning inhibits adenine nucleotide degradation and purine efflux, or that preconditioning activates cardiovascular adenosine formation to provide enhanced cardioprotection. 31P-NMR spectra and matching interstitial fluid (ISF) or venous effluent samples were obtained from Langendorff perfused rat hearts. Control hearts (n = 9) underwent 30 min of global normothermic ischemia and 30 min reperfusion. Preconditioned hearts (n = 6) were subjected to a 5 min ischemic episode and 10 min reflow prior to 30 min ischemia and 30 min reperfusion. Effects of repetitive ischemia-reperfusion (3 x 5 min ischemic episodes) on adenosine levels and energy metabolism were also assessed (n = 8). Preconditioning improved post-ischemic recovery of heart rate x left ventricular developed pressure (71 +/- 5 vs 43 +/- 8%, P < 0.05) and end-diastolic pressure (14 +/- 3 vs 29 +/- 4 mmHg, P < 0.05) compared with control hearts, respectively. Preconditioning did not alter intracellular ATP, phosphocreatine (PCr), inorganic phosphate (Pi), H+ or free Mg2+ during global ischemia, but improved recoveries of PCr, Pi, and delta GATP on reperfusion. ISF adenosine increased more than 20-fold during 30 min ischemia. The 5 min preconditioning episode increased ISF adenosine 3-fold, and reduced ISF adenosine and inosine during subsequent prolonged ischemia by up to 75%. Venous purine levels during reperfusion were also reduced by preconditioning. Accumulation of adenosine in ISF and venous effluent during repetitive ischemia was progressively reduced despite comparable changes in substrate for adenosine formation via 5'-nucleotidase, (5'-AMP), and in allosteric modulators of this enzyme (Mg2+, H+, Pi, ADP, ATP). (i) Ischemic preconditioning reduces interstitial and vascular adenosine levels during ischemia-reperfusion, (ii) reduced ISF adenosine during ischemia is not due to reduced ischemic depletion of adenine nucleotides in preconditioned rat hearts, (iii) preconditioning may inhibit adenosine formation via 5'-nucleotidase in ischemic rat hearts, and (iv) improved functional recovery with preconditioning is unrelated to metabolic/bioenergetic changes during the ischemic insult, but may be related to improved post-ischemic recovery of [Pi] and delta GATP in this model.


Chemical Effects on Breast Development, Function, and Cancer Risk: Existing Knowledge and New Opportunities.
Population studies show worrisome trends towards earlier breast development, difficulty in breastfeeding, and increasing rates of breast cancer in young women. Multiple epidemiological studies have linked these outcomes with chemical exposures, and experimental studies have shown that many of these chemicals generate similar effects in rodents, often by disrupting hormonal regulation. These endocrine-disrupting chemicals (EDCs) can alter the progression of mammary gland (MG) development, impair the ability to nourish offspring via lactation, increase mammary tissue density, and increase the propensity to develop cancer. However, current toxicological approaches to measuring the effects of chemical exposures on the MG are often inadequate to detect these effects, impairing our ability to identify exposures harmful to the breast and limiting opportunities for prevention. This paper describes key adverse outcomes for the MG, including impaired lactation, altered pubertal development, altered morphology (such as increased mammographic density), and cancer. It also summarizes evidence from humans and rodent models for exposures associated with these effects. We also review current toxicological practices for evaluating MG effects, highlight limitations of current methods, summarize debates related to how effects are interpreted in risk assessment, and make recommendations to strengthen assessment approaches. Increasing the rigor of MG assessment would improve our ability to identify chemicals of concern, regulate those chemicals based on their effects, and prevent exposures and associated adverse health effects.


Prostate cancer in 2011: Hitting old targets better and identifying new targets.
Options to treat late-stage castration-resistant prostate cancer continued to increase in 2011, as three agents with different mechanisms of action prolonged life and a fourth reduced the morbidity of skeletal metastases. These outcomes contrasted with the heightened controversy generated by the recommendation against PSA screening and other early detection strategies.


Complex network growth model: Possible isomorphism between nonextensive statistical mechanics and random geometry.
In the realm of Boltzmann-Gibbs statistical mechanics, there are three well known isomorphic connections with random geometry, namely, (i) the Kasteleyn-Fortuin theorem, which connects the λ → 1 limit of the λ-state Potts ferromagnet with bond percolation, (ii) the isomorphism, which connects the λ → 0 limit of the λ-state Potts ferromagnet with random resistor networks, and (iii) the de Gennes isomorphism, which connects the n → 0 limit of the n-vector ferromagnet with self-avoiding random walk in linear polymers. We provide here strong numerical evidence that a similar isomorphism appears to emerge connecting the energy q-exponential distribution ∝ e (with q = 4 / 3 and β ω = 10 / 3) optimizing, under simple constraints, the nonadditive entropy S with a specific geographic growth random model based on preferential attachment through exponentially distributed weighted links, ω being the characteristic weight.


Increased expression of ATP-binding cassette transporter A1 (ABCA1) as a possible mechanism for the protective effect of cilostazol against hepatic steatosis.
Cilostazol, a phosphodiesterase 3, has been widely used in patients with arterial disease and is known to have additional beneficial effects on dyslipidemia. However, the effect of cilostazol on hepatic steatosis has not been fully elucidated. We investigated the effect of cilostazol on hepatic ABCA1 expression and hepatic steatosis in diet-induced obesity mice model. Hepatic ABCA1 expression and lipid accumulation were analyzed in HepG2 cell lines treated with cilostazol. Male C57BL/6 mice were randomly divided into three groups: (1) fed normal chow diet with vehicle; (2) fed high-fat diet (HFD) with vehicle; (3) fed HFD with cilostazol. Cilostazol (30 mg/kg) was orally administered once daily for 9 weeks. Cilostazol significantly enhanced ABCA1 expression and restored ABCA1 expression reduced by palmitate in HepG2 cells. Cilostazol treatment ameliorated lipid accumulation induced by palmitate, and this effect was diminished when ABCA1 or LRP1 was silenced by small interference RNA. After silencing of LRP1, ABCA1 expression was decreased in HepG2 cells. Cilostazol significantly enhanced hepatic ABCA1 expression and decreased hepatic fat in HFD-fed mice. Hepatic expression of cleaved caspase-3 and PARP1 was also decreased in HFD-fed mice treated with cilostazol. Cilostazol ameliorated hepatic steatosis and increased ABCA1 expression in the hepatocytes. Enhancing ABCA1 expression with cilostazol represents a potential therapeutic avenue for treatment of hepatic steatosis.


Molecular mechanism of endocrine system impairment by 17α-methyltestosterone in gynogenic Pengze crucian carp offspring.
The effects of synthetic androgen 17α-methyltestosterone (MT) on endocrine impairment were examined in crucian carp. Immature 7-month old mono-female Pengze crucian carp (Pcc) F2 offspring were exposed to 50 and 100 μg/L of MT (week 2, 4, and 8). Gonadosomatic index, hepatosomatic index and intestine weight altered considerably and oocyte development was repressed. In the treatment groups, ovarian 11-ketotestosterone decreased, whereas 17β-estradiol and testosterone increased, and ovarian aromatase activities increased at week 4. However, in the brain tissue, those values significantly decreased. Quantitative RT-PCR analysis demonstrated changes in steroid receptor genes and upregulation of steroidogenic genes (Pcc-3bhsd, Pcc-11bhsd2 Pcc-cyp11a1), while the other three steroidogenic genes (Pcc-cyp17a1, Pcc-cyp19a1a and Pcc-star) decreased from week 4 to week 8. Ovarian, hepatic Pcc-vtg B and vitellogenin concentration increased in both 50 and 100 μg/L of MT exposure groups. This study adds further information regarding the effects of androgens on the development of previtellogenic oocytes, which suggests that MT could directly target estrogen signaling pathway, or indirectly affect steroidogenesis and vitellogenesis.


Transient depletion of dividing T lymphocytes in mice induces the emergence of regulatory T cells and dominant tolerance to islet allografts.
We previously showed that transient depletion of dividing T cells at the time of an allogeneic transplantation induces long-term tolerance to the allograft. Here we investigated the role of homeostatic perturbation and regulatory T cells (Treg) in such tolerance. Transient depletion of dividing T cells was induced at the time of an allogeneic pancreatic islets graft, by administration of ganciclovir for 14 days, into diabetic transgenic mice expressing a thymidine kinase (TK) conditional suicide gene in T cells. Allograft tolerance was obtained in 63% of treated mice. It was not due to global immunosuppression, permanent deletion or anergy of donor-alloantigens specific T cells but to a dominant tolerance process since lymphocytes from tolerant mice could transfer tolerance to naïve allografted recipients. The transient depletion of dividing T cells induces a 2- to 3-fold increase in the proportion of CD4(+)CD25(+)Foxp3(+) Treg, within 3 weeks that persisted only in allograft-bearing mice but not in nongrafted mice. Tolerance with similar increased proportion of Treg cells was also obtained after a cytostatic hydroxyurea treatment in normal mice. Thus, the transient depletion of dividing T cells represents a novel means of immuno-intervention based on disturbance of T-cell homeostasis and subsequent increase in Treg proportion.


Amoxicillin-degradation products formed under controlled environmental conditions: identification and determination in the aquatic environment.
Amoxicillin (AMX) is a widely used penicillin-type antibiotic whose presence in the environment has been widely investigated, despite its rapid hydrolysis to various degradation products (DPs). In this work, the formation of AMX DPs was studied in various aqueous solutions containing 100μgmL(-1) AMX. Three phosphate buffer solutions, at pH 5, pH 7 and pH 8, and a fourth buffer solution at pH 7 with the addition of the bivalent ions Mg(2+)and Ca(2) as chelating agents, were examined under controlled environmental conditions. In addition, two solutions from natural sources were examined secondary effluents and tap water. The obtained DPs were identified by their MS/MS, UV and NMR spectra (obtained from pure compounds isolated by preparative HPLC) as: AMX penicilloic acid (ADP1/2), AMX penilloic acid (ADP4/5) and phenol hydroxypyrazine (ADP6). Two additional detected DPs AMX 2',5'-diketopiperazine (ADP8/9), and AMX-S-oxide (ADP3) were reported and discussed in our previous publications. These DPs were then detected in secondary effluent and groundwater from a well located beneath agricultural fields continuously irrigated with secondary effluent. Concentrations in the secondary effluent were: ADP1/2, several micrograms per liter; ADP4/5, 0.15μgL(-1), and ADP8/9, 0.5μgL(-1). ADP6 were detected but not quantified. In the groundwater, only ADP8/9 was detected, at a concentration of 0.03μgL(-1). The detection and quantification of DPs of other investigated drugs is recommended as an integral part of any study, method or technique dealing with pharmaceutical residues in aquatic environments.


Value of multiparametric magnetic resonance imaging for evaluating chronic kidney disease and renal fibrosis.
To identify optimized MRI markers for evaluating chronic kidney disease (CKD) and renal interstitial fibrosis (IF). This prospective study included 43 patients with CKD and 20 controls. The CKD group was divided into mild and moderate-to-severe subgroups based on pathological results. Scanned sequences included T1 mapping, R2* mapping, intravoxel incoherent motion imaging, and diffusion-weighted imaging. One-way analyses of variance were used to compare MRI parameters among groups. Correlations of MRI parameters with estimated glomerular filtration rate (eGFR) and renal IF were analyzed using age as covariates. The support vector machine (SVM) model was used to evaluate the diagnostic efficacy of multiparametric MRI. Compared to control values, renal cortical apparent diffusion coefficient (cADC), medullary ADC (mADC), cortical pure diffusion coefficient (cDt), medullary Dt (mDt), cortical shifted apparent diffusion coefficient (csADC), and medullary sADC (msADC) values gradually decreased in the mild and moderate-to-severe groups, while cortical T1 (cT1) and medullary T1 (mT1) values gradually increased. Values of cADC, mADC, cDt, mDt, cT1, mT1, csADC, and msADC were significantly associated with eGFR and IF (p < 0.001). The SVM model indicated that multiparametric MRI combining cT1 and csADC can distinguish patients with CKD from controls with high accuracy (0.84), sensitivity (0.70), and specificity (0.92) (AUC: 0.96). Multiparametric MRI combining cT1 and cADC exhibited high accuracy (0.91), sensitivity (0.95), and specificity (0.81) for evaluating IF severity (AUC: 0.96). Multiparametric MRI combining T1 mapping and diffusion imaging may be of clinical utility in non-invasive assessment of CKD and IF. This study shows that multiparametric MRI combining T1 mapping and diffusion imaging may be clinically useful in the non-invasive assessment of chronic kidney disease (CKD) and interstitial fibrosis; this could provide information for risk stratification, diagnosis, treatment, and prognosis. • Optimized MRI markers for evaluating chronic kidney disease and renal interstitial fibrosis were investigated. • Renal cortex/medullary T1 values increased as interstitial fibrosis increased; cortical shifted apparent diffusion coefficient (csADC) correlated significantly with eGFR and interstitial fibrosis. • Support vector machine (SVM) combining cortical T1 (cT1) and csADC/cADC effectively identifies chronic kidney disease and accurately predicts renal interstitial fibrosis.


Evidence for cardiac sodium-calcium exchanger association with caveolin-3.
The interaction of cardiac Na+-Ca2+ exchange (NCX1) with caveolin proteins was investigated in sarcolemmal vesicles. Western blots of sarcolemmal vesicles revealed the presence of caveolin-1, -2, and -3. NCX1 co-fractionated more closely with caveolin-3 than caveolin-1 on sucrose density gradients. NCX1 has five possible caveolin-binding motifs and NCX1 co-precipitated specifically with caveolin-3. Molecular sieve column chromatography indicated that this co-precipitation was not due to incomplete solubilization of lipid raft microdomains. Cholesterol chelation in vesicles decreased NCX1 transport activity and caveolin-3 co-precipitation. NCX1 may play a role in caveolar transmembrane signaling in addition to its role in excitation-contraction coupling.


Special compression sutures: a new surgical technique to achieve a quick decrease in shunt volume caused by diffuse hemangiomatosis of the liver.
A new surgical technique for the management of shunting liver hemangiomas that otherwise would rapidly lead to intractable cardiac failure is presented. Rapid, significant reduction of shunt volume was achieved surgically by transhepatic compression sutures using PTFE pledgets and selective ligation of a large feeding vessel from the right hepatic artery.


Transcranial magnetic-stimulation mapping of the cortical topography of the human masseter muscle.
The cortical topography of several limb and trunk muscles has been disclosed using transcranial magnetic stimulation, but the corticomotor representation of the human jaw muscles has not yet been described. An experimental paradigm incorporating transcranial magnetic stimulation of verified sites on the scalp was used (a) to determine the cortical topography of the human masseter muscle and (b) to assess the reproducibility of the motor map, in seven healthy individuals. The results showed that the masseter was discretely represently on the motor and premotor cortex with interindividual variation in map area, volume and height (p < 0.05). Coefficients of variation and reliability were low (15-18%) and high (89-96%), respectively, for motor maps obtained at experimental sessions 2 weeks apart, indicating high reproducibility. The findings have clinical relevance in the management of patients with cerebral injury involving corticobulbar projections to the masseter.


Intrinsic hematopoietic stem cell/progenitor plasticity: Inversions.
Traditional concepts indicate that stem cells give rise to progenitor cells in a hierarchical system. We studied murine engraftable stem cells (ESCs) and progenitors in in vitro and found that ESC and progenitors exist in a reversible continuum, rather then a hierarchy. B6.SJL and BALB/c marrow cells were serially cultured with thrombopoietin (TPO), FLT-3 ligand (FLT-3L), and steel factor through cell cycle. Progenitors (high-proliferative potential colony-forming cells (HPP-CFC) and colony-forming unit culture (CFU-c)) and ESC capacity was determined. The cell cycle status of purified lineage(negative)rhodamine(low)Hoechst(low) stem cells was determined under the same conditions using tritiated thymidine incorporation and cell counts. We found an inverse relationship between progenitors and ESC, which occurred during the first cell cycle transit and was reversible. We have termed these progenitor/stem cell inversions and found that these inversions were consistently seen at 28-32 h of culture, representing early S-phase. We observed 13 major reversible increases in progenitor numbers from one time-point to another during the first cell cycle transit; this was coupled with 11 major ESC decreases and in 2 instances ESC were at baseline. These studies indicate that primitive marrow cells reversibly shift from ESC to progenitors without differentiation occurring. They exist as a fluctuating continuum.


Emergence of Lyme disease as a social problem: analysis of discourse using the media content.
Chronic Lyme disease (LD) is a matter of debate worldwide and has emerged as a social problem. We aim to analyze the media content and describe the transformation process of a collective pain into a social problem in France. Using social science methodology, a corpus of articles from 20 newspapers and videos from seven major TV stations from 1987 to 2017 were analyzed for discourse content. The speaking times and the frequency of interventions between doctors supporting the official guidelines and those against them were compared using the Mann-Whitney test and the Chi-square test, respectively. In France, the media discourse is carried through testimonials from patient organizations and a professor of infectiology who acted as a whistleblower (WB). We showed that the emergence of the LD alert in the media corresponds to the process described by social sciences as 'naming, blaming, claiming'. Since his first article in 2014, the WB has featured in 24% (22/89) of newspaper articles compared with 20% (18/89) for doctors defending the official guidelines (P = 0.52). Since his first appearance on a TV newscast in 2014, the WB has appeared in 45% (22/49) of news reports on LD with 24% of the speaking time compared with 22% (11/49) for doctors defending the official guidelines (P = 0.018). Media coverage of LD has been unbalanced since 2014 and promotes associations as well as the WB, who seems to be better identified than any of the different doctors defending the official guidelines.


Resident Physician Experiences With and Responses to Biased Patients.
Biased patient behavior negatively impacts resident well-being. Data on the prevalence and frequency of these encounters are lacking and are needed to guide the creation of institutional trainings and policies to support trainees. To evaluate the frequency of resident experiences with and responses to a range of biased patient behaviors. A retrospective survey was sent via email to 331 second- and third-year internal medicine residents from 3 academic medical centers in California and North Carolina. First-year residents were excluded owing to their limited interactions with patients at the time of participant recruitment. Data were collected from August 21 to November 25, 2019. Descriptive statistics were used to report the frequency of experience of various types of biased patient behavior, residents' responses, the factors impeding residents' responses, and residents' experiences and beliefs regarding training and policies. Overall, 232 of 331 residents (70%) participated; 116 (50%) were women; 116 of 247 (47%) were White (participants had the option of selecting >1 race/ethnicity); and 23 (10%) identified as lesbian, gay, bisexual, transgender, or queer. The frequency of resident-reported experience of types of biased patient behaviors varied. The most common behaviors-belittling comments and assumption of nonphysician status-were reported to be experienced 1 or more times per week by 14% of residents (32 of 231) and 17% of residents (38 of 230), respectively. Women, Black or Latinx, and Asian residents reported experiencing biased behavior more frequently. Forty-five percent of Black or Latinx residents (17 of 38) encountered instances of explicit epithets or rejection of care. All 70 Asian residents reported experiencing inquiries into their ethnic origins. Most women residents (110 of 115 [96%]) experienced role questioning behaviors, and 87% (100 of 115) experienced sexual harassment. The need to prioritize clinical care and a sense of futility in responding were the most common factors (cited by 34% of residents [76 of 227] and 25% of residents [56 of 227], respectively) significantly impeding responses to biased behaviors. Eighty-five percent of residents (191 of 226) never reported incidents to their institution. Eighty-nine percent of residents (206 of 232) identified training and policies as necessary or very necessary. This survey study suggests that biased patient behavior is experienced frequently by internal medicine residents. Non-White and women residents reported experiencing a disproportionate burden of these incidents. Residents' responses rarely included institutional involvement. Residency programs and health care systems should prioritize training and policies to address biased patient behavior and support affected residents.


Evaluation of enterotoxigenic Bacteroides fragilis correlation with the expression of cellular signaling pathway genes in Iranian patients with colorectal cancer.
Colorectal cancer (CRC) is one of the most common cancers all over the world, and dysbiosis in the gut microbiota may play a role in colorectal carcinogenesis. Bacteroides fragilis can lead to tumorigenesis by changing signaling pathways, including the WNT/β-catenin pathway. Therefore, in the present study, we investigated the correlation between the enterotoxigenic B. fragilis amount and the expression of signaling pathway genes involved in CRC. B. fragilis was determined in 30 tumors and adjacent healthy tissues by the qPCR method. Next, the relationship between enterotoxigenic B. fragilis and the expression of signaling pathway genes, including CCND1, TP53, BCL2, BAX, WNT, TCF, AXIN, APC, and CTNNB1 was investigated. Additionally, possible correlations between clinicopathological features of the tumor samples and the abundance of B. fragilis were analyzed. The results showed that B. fragilis was detected in 100% of tumor samples and 86% of healthy tissues. Additionally, enterotoxigenic B. fragilis colonized 47% of all samples, and bft-1 toxin was the most frequently found isotype among the samples. The analysis showed that the high level of B. fragilis has a significant relationship with the high expression of AXIN, CTNNB1, and BCL2 genes. On the other hand, our results did not show any possible correlation between this bacterium and the clinicopathological features of the tumor sample. B. fragilis had a higher abundance in the tumor samples than in healthy tissues, and this bacterium may lead to CRC by making changes in cellular signaling pathways and genes. Therefore, to better understand the physiological effects of B. fragilis on the inflammatory response and CRC, future research should focus on dissecting the molecular mechanisms by which this bacterium regulates cellular signaling pathways.


Tumor growth of suspected meningiomas in clinically healthy 80-year-olds: a follow up five years later.
The incidence of clinically silent meningiomas in 75-year-old individuals was determined five years ago in the Vienna Transdanube Ageing Study (VITA). At the time a watch-and-wait approach was recommended in cases of incidentally discovered meningiomas. 420 out of the initial cohort of 532 test persons underwent control investigations after 2.5 and 5 years. Six of the nine known tumors were measured again and the patients underwent clinical, neurological and psychological tests. Changes in tumor size were determined and all new tumors seen on MRI investigation were carefully reviewed. Tumor growth was minimal in all six cases that were followed over the entire period. Two of the original meningioma patients had died and one patient had undergone tumor resection. The watch-and-wait approach recommended after the VITA study was confirmed by the present investigation. Tumor growth was slow in all cases; no clinical symptoms have been registered thus far. The intervals between control investigations may even be prolonged depending on the location of the tumor. In this age group the operation appears to pose a greater risk than the presence of an asymptomatic tumor.


Prematurity and neonatal noxious events exert lasting effects on infant pain behaviour.
There is concern that exposure of preterm infants to noxious insults over a prolonged period may have long term effects on their developing nervous system. To investigate medium and long term effects of heel pricks in infants over the first year of life. Study 1-a longitudinal study, 2 days and 4 weeks after heel prick. Study 2-a cross sectional study over the first year of life. Study 1-13 healthy preterm (PT) infants. Study 2-63 full term (FT) and 62 PT infants, divided into 3 timed groups (0-20, 21-37 and 38-52 weeks postterm and corrected for prematurity). Threshold responses (flexion withdrawal (FWR) , gross body movements (GBM) and grimace (G)) to increasing mechanical force applied with Von Frey filaments. Study 1-Thresholds were all significantly lower (more sensitive) from the pricked heel compared to the contralateral side at 2 days and 4 weeks. Study 2-There were significant differences in threshold between PT and FT infants at all time points for both FWR (P=0.001, <0.001, <0.001) and GBM (P=<0.001, <0.001, 0.009 respectively), the preterm infants always being lower. The threshold for the FWR in FT infants steadily increased, but the threshold for the PT infants remained the same. GBM thresholds increased during the year in both FT and PT infants, but were always significantly lower in the ex-preterm group (P<0.012). Either PT birth or repetitive procedures associated with such birth alters the sensitivity threshold of PT infants compared with FT infants for at least the first year of life.


Granulocyte colony-stimulating factor plasma levels during clozapine- and olanzapine-induced granulocytopenia.
Recent case studies suggest that impaired granulopoiesis, well-known to occur during clozapine treatment, may also be observed when olanzapine is administered. The underlying mechanisms are unknown, but haematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF) are likely to be involved. We measured the plasma levels of G-CSF and of other cytokines longitudinally in a female patient who developed granulocytopenia twice, first during clozapine treatment and again when olanzapine was administered. G-CSF levels, but not those of other cytokines, closely paralleled granulocyte counts, yielding a significant positive correlation. G-CSF was not detectable in plasma when granulocytopenia occurred. Granulocytopenia resolved spontaneously despite continuing treatment with olanzapine. The present case suggests that clozapine and olanzapine both are able to induce transient granulocytopenia through a similar or common mechanism that does not involve a compensatory increase in G-CSF levels.


Isolation and culture of cells derived from human cerebral microvessels.
Microvessels were isolated from non-neoplastic human cerebral cortical fragments resected for treatment of intractable seizure disorder. The microvessels were incubated in modified Lewis medium with 20 or 30% fetal bovine serum. Within 1-2 weeks, two cell populations emerged from the isolates. One type of cells had polygonal morphology, showed density-dependent contact inhibition at confluence in vitro, showed lectin-binding characteristics of endothelium (but only moderate positivity for factor VIII antigen), demonstrated induction of gamma-glutamyl transpeptidase when exposed to astrocyte-conditioned media, and responded to insulin by a pronounced increase in DNA synthesis. The other variety of cells grew in vitro more slowly in irregular strands separated by clear zones, showed ultrastructural features of smooth muscle, and isoelectric focusing of cell proteins revealed the presence of smooth-muscle-specific alpha-isoactin. Both types of cells could be serially subcultured. The ability to isolate and grow the two cell types, tentatively identified as human cerebral microvascular endothelium and smooth muscle, may facilitate studies of human blood-brain barrier function as well as the pathogenesis of cerebral microangiopathies unique to the human brain.


What's new in pulmonary artery hypertension.
Pulmonary hypertension is a debilitating disease and has a poor prognosis. This article provides an overview of new treatments for this disease.


Pharmacological characterization of the effects of taurine on calcium uptake in the rat retina.
Taurine is known to increase ATP-dependent calcium ion (Ca2+) uptake in retinal membrane preparations and in isolated rod outer segments (ROS) under low calcium conditions (10 microM) (Pasantes-Morales and Ordóñez, 1982; Lombardini, 1991). In this report, ATP-dependent Ca2+ uptake in retinal membrane preparations was found to be inhibited by 5 microM cadmium (Cd2+), suggesting the involvement of cation channel activation. The activation of cGMP-gated cation channels, which are found in the ROS, is a crucial step in the phototransduction process. An inhibitor of cGMP-gated channels, LY83583, was found to inhibit taurine-stimulated ATP-dependent Ca2+ uptake but had no effect on ATP-dependent Ca2+ uptake in the absence of taurine, indicating that taurine may be increasing ATP-dependent Ca2+ uptake through a mechanism of action involving the opening of cGMP-gated channels. The activation of cGMP-gated channels with dibutyryl-cGMP and with phosphodiesterase inhibition using zaprinast caused an increase in ATP-dependent Ca2+ uptake in isolated ROS, but not in taurine-stimulated ATP-dependent Ca2+ uptake. LY83583 had the same effects in isolated ROS as in retinal membrane preparations. Another inhibitor of cGMP-gated channels, Rp-8-Br-PET-cGMPS, produced the same pattern of inhibition in isolated ROS as LY83583. Thus, there appears to be a causal link between taurine and the activation of the cGMP-gated channels in the ROS under conditions of low calcium concentration, a connection that suggests an important role for taurine in the visual signalling function of the retina.


How does Go/No-Go training lead to food devaluation? Separating the effects of motor inhibition and response valence.
Palatable, unhealthy food stimuli can be devalued via Go/No-Go (GNG) training that consistently pairs such stimuli with motor inhibition. However, it remains unclear whether this devaluation is caused via learned associations with motor inhibition or via inferential learning based on the valence of emitted motor responses. The present research disentangles the effects of motor assignment and response valence in GNG training through task instructions. In two studies, chocolate stimuli were consistently paired with motor inhibition ("no-go") or with motor excitation ("go"). Task instructions indicated that no-go responses were negatively valenced ("do not take") and that go responses were positively valenced ("take"), or identified no-go responses as positively valenced ("keep") and go as negatively valenced ("throw away"). The results show an effect of response valence on chocolate evaluations, but no effect of motor assignment: Chocolate stimuli were consistently devalued following pairings with a negatively valenced response, regardless of whether this response entailed motor inhibition or excitation. These findings align best with an inferential account of GNG training, suggesting that devaluation effects critically depend on inferential processes regarding motor response valence. GNG training procedures may, therefore, be optimised by disambiguating the valence of go and no-go motor responses prior to training.