The V-Y latissimus dorsi musculocutaneous flap in the reconstruction of large posterior chest wall defects.
Posterior chest wall defects are frequently encountered after excision of tumors as a result of trauma or in the setting of wound dehiscence after spine surgery. Various pedicled fasciocutaneous and musculocutaneous flaps have been described for the coverage of these wounds. The advent of perforator flaps has allowed the preservation of muscle function but their bulk is limited. Musculocutaneous flaps remain widely employed. The trapezius and the latissimus dorsi (LD) flaps have been used extensively for upper and middle posterior chest wounds, respectively. Their bulk allows for obliteration of the dead space in deep wounds. The average width of the LD skin paddle is limited to 10-12 cm if closure of the donor site is expected without skin grafting. In 2001 a modification of the skin paddle design was introduced in order to allow large flaps to be raised without requiring grafts or flaps for donor site closure. This V-Y pattern allows coverage of large anterior chest defects after mastectomy. We have modified this flap to allow its use for posterior chest wall defects. We describe the flap design, its indications, and its limitations with three clinical cases. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.


Structural basis underlying complex assembly and conformational transition of the type I R-M system.
Type I restriction-modification (R-M) systems are multisubunit enzymes with separate DNA-recognition (S), methylation (M), and restriction (R) subunits. Despite extensive studies spanning five decades, the detailed molecular mechanisms underlying subunit assembly and conformational transition are still unclear due to the lack of high-resolution structural information. Here, we report the atomic structure of a type I MTase complex (2M+1S) bound to DNA and cofactor S-adenosyl methionine in the "open" form. The intermolecular interactions between M and S subunits are mediated by a four-helix bundle motif, which also determines the specificity of the interaction. Structural comparison between open and previously reported low-resolution "closed" structures identifies the huge conformational changes within the MTase complex. Furthermore, biochemical results show that R subunits prefer to load onto the closed form MTase. Based on our results, we proposed an updated model for the complex assembly. The work reported here provides guidelines for future applications in molecular biology.


Intrinsic strong light-matter coupling with self-hybridized bound states in the continuum in van der Waals metasurfaces.
Photonic bound states in the continuum (BICs) provide a standout platform for strong light-matter coupling with transition metal dichalcogenides (TMDCs) but have so far mostly been implemented as traditional all-dielectric metasurfaces with adjacent TMDC layers, incurring limitations related to strain, mode overlap and material integration. Here, we demonstrate intrinsic strong coupling in BIC-driven metasurfaces composed of nanostructured bulk tungsten disulfide (WS2) and exhibiting resonances with sharp, tailored linewidths and selective enhancement of light-matter interactions. Tuning of the BIC resonances across the exciton resonance in bulk WS2 is achieved by varying the metasurface unit cells, enabling strong coupling with an anticrossing pattern and a Rabi splitting of 116 meV. Crucially, the coupling strength itself can be controlled and is shown to be independent of material-intrinsic losses. Our self-hybridized metasurface platform can readily incorporate other TMDCs or excitonic materials to deliver fundamental insights and practical device concepts for polaritonic applications.


Large volume injection in gas chromatography using the through oven transfer adsorption desorption interface operating under vacuum.
The present work describes a modification of the Through Oven Transfer Adsorption Desorption (TOTAD) interface, consisting of coupling a vacuum system to reduce the consumption of the helium needed to totally remove the eluent for large volume injection (LVI) in gas chromatography (GC). Two different retention materials in the liner of the TOTAD interface were evaluated: Tenax TA, which was seen to be unsuitable for working under vacuum conditions, and polydimethylsiloxane (PDMS), which provided satisfactory repeatability as well as a good sensitivity. No variability was observed in the retention times in either case. Solutions containing organophosphorous pesticides in two different solvents, a polar (methanol/water) and a non-polar (hexane) solvent, were used to evaluate the modification. The vacuum system coupled to the TOTAD interface allowed up to 90% helium to be saved without affecting the performance.


Risk of subsequent cytological abnormality and cancer among women with a history of cervical intraepithelial neoplasia: a comparative study.
A longitudinal study of 1,281 women with a histological diagnosis of cervical intraepithelial neoplasia (CIN) during 1974-76 is presented. After 12 years of follow-up, 30 percent of the women had further cytological abnormalities reported. The rate of subsequent abnormality was highest during the first 12 months of follow-up; thereafter, there was no evidence of any decline in the rate of subsequent abnormality with increasing duration of follow-up. Women from the CIN cohort had twice as many later cytological abnormalities as an age-matched cohort of women who were negatively screened during 1974-76 (excluding abnormalities within 12 months of entry to the study and after adjustment for smear frequency). The CIN cohort remained at substantially greater risk for a subsequent diagnosis of squamous cell carcinoma of the cervix compared with the control group of negatively-screened women (rate ratio 19.8, 95 percent confidence interval 2.4-163.6, P less than 0.01). These results indicate that women who have received surgical intervention for CIN continue to have substantial morbidity from cervical abnormalities during medium-term follow-up.


Circular dichroism studies on cytochrome c peroxidase from baker's yeast (Saccharomyces cerevisiae).
Circular dichroism spectra of cytochrome c peroxidase from baker's yeast, those of the reduced enzyme, the carbonyl, cyanide and fluoride derivatives and the hydrogen peroxide compound, Compound I, have been recorded in the wavelength range 200 to 660 nm. All derivatives show negative Soret Cotton effects. The results suggest that the heme group is surrounded by tightly packed amino acid sidechains and that there is a histidine residue bound to the fifth coordination site of the heme iron. The native ferric enzyme is probably pentacoordinated. The circular dichroism spectra of the ligand compounds indicate that the ligands form a nonlinear bond to the heme iron as a result of steric hindrance in the vicinity of the heme. The spectrum of Compound I shows no perturbation of the porphyrin symmetry. The dichroic spectrum of the native enzyme in the far-ultraviolet wave-length region suggests that the secondary structure consists of roughly equal amounts of alpha-helical, beta-structure and unordered structure. After the removal of the heme group no great changes in the secondary structure can be observed.


Transient activation of oocyte 5S RNA genes in Xenopus embryos by raising the level of the trans-acting factor TFIIIA.
The concentration of the trans-acting factor, TFIIIA, required for the activation of 5S RNA genes in Xenopus can be elevated in developing embryos by injecting a synthetic full-length mRNA into fertilized eggs. 5S RNA genes are activated by the increased factor concentration at the mid-blastula transition through mid-gastrulation. The activated oocyte 5S RNA genes are then inactivated, leaving the TFIIIA-enhanced embryos with the same profile of differential 5S RNA gene activity as control embryos, i.e., synthesizing mainly somatic 5S RNA. Inactivation of the oocyte 5S RNA genes is complete by neurulation and can occur in the absence of DNA replication. We propose that this loss of gene activity is due at least in part to destabilization of transcription complexes that are associated with oocyte 5S RNA genes.


Low BMI-1 expression is associated with an activated BMI-1-driven signature, vascular invasion, and hormone receptor loss in endometrial carcinoma.
We studied the expression of polycomb group (PcG) protein BMI-1 in a large population-based patient series of endometrial carcinomas in relation to clinical and molecular phenotype. Also, 57 fresh frozen endometrial carcinomas were studied for the relationship between BMI-1 protein expression, BMI-1 mRNA level, and activation of an 11-gene signature reported to represent a BMI-1-driven pathway. BMI-1 protein expression was significantly weaker in tumours with vascular invasion (P<0.0001), deep myometrial infiltration (P=0.004), and loss of oestrogen receptor (ER) (P<0.0001) and progesterone receptors (PR) (P=0.03). Low BMI-1 protein expression was highly associated with low BMI-1 mRNA expression (P=0.002), and similarly low BMI-1 mRNA expression correlated significantly with vascular invasion, ER and PR loss, and histologic grade 3. In contrast, activation of the reported 11-gene signature, supposed to represent a BMI-1-driven pathway, correlated with low mRNA expression of BMI-1 (P<0.001), hormone receptor loss, presence of vascular invasion, and poor prognosis. We conclude that BMI-1 protein and mRNA expression are significantly correlated and that BMI-1 expression is inversely associated with activation of the 11-gene signature. Loss of BMI-1 seems to be associated with an aggressive phenotype in endometrial carcinomas.


The biology, pathogenesis and clinical aspects of acute lymphoblastic leukemia in children with Down syndrome.
Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (DS-ALL). Although the etiology of this higher risk of developing leukemia remains largely unclear, the recent identification of CRLF2 (cytokine receptor like factor 2) and JAK2 mutations and study of the effect of trisomy of Hmgn1 and Dyrk1a (dual-specificity tyrosine phosphorylation-regulated kinase 1A) on B-cell development have shed significant new light on the disease process. Here we focus on the clinical features, biology and genetics of ALL in children with DS. We review the unique characteristics of DS-ALL on both the clinical and molecular levels and discuss the differences in treatments and outcomes in ALL in children with DS compared with those without DS. The identification of new biological insights is expected to pave the way for novel targeted therapies.


Randomized Incremental Construction of Delaunay Triangulations of Nice Point Sets.
Randomized incremental construction (RIC) is one of the most important paradigms for building geometric data structures. Clarkson and Shor developed a general theory that led to numerous algorithms which are both simple and efficient in theory and in practice. Randomized incremental constructions are usually space-optimal and time-optimal in the worst case, as exemplified by the construction of convex hulls, Delaunay triangulations, and arrangements of line segments. However, the worst-case scenario occurs rarely in practice and we would like to understand how RIC behaves when the input is nice in the sense that the associated output is significantly smaller than in the worst case. For example, it is known that the Delaunay triangulation of nicely distributed points in E d or on polyhedral surfaces in E 3 has linear complexity, as opposed to a worst-case complexity of Θ ( n ⌊ d / 2 ⌋ ) in the first case and quadratic in the second. The standard analysis does not provide accurate bounds on the complexity of such cases and we aim at establishing such bounds in this paper. More precisely, we will show that, in the two cases above and variants of them, the complexity of the usual RIC is O ( n log n ) , which is optimal. In other words, without any modification, RIC nicely adapts to good cases of practical value. At the heart of our proof is a bound on the complexity of the Delaunay triangulation of random subsets of ε -nets. Along the way, we prove a probabilistic lemma for sampling without replacement, which may be of independent interest.


Effects of nitric oxide inhibition by methylene blue in cirrhotic patients with ascites.
Increased endogenous nitric oxide production has been proposed as an important mediator of the peripheral arterial vasodilation and the hyperdynamic circulation in cirrhosis, whereas a decreased intrahepatic production of nitric oxide has been implicated in the pathogenesis of portal hypertension. The present study investigated the possible beneficial effects of methylene blue, which is a potent inhibitor of guanylate cyclase and nitric oxide synthase, on hyperdynamic circulation and renal function in cirrhotic patients with ascites together with the effects on portal hemodynamics. Twenty patients were evaluated at baseline and during 2 consecutive 4-hr periods after the administration of methylene blue at a dose of 3 mg/kg (10 patients) or placebo (10 patients). Mean arterial pressure, heart rate, cardiac output, systemic vascular resistance, plasma active renin, plasma aldosterone, plasma antidiuretic hormone, serum urea, serum creatinine, serum sodium, urinary flow rate, glomerular filtration rate, effective renal plasma flow, portal flow volume, and portal vein velocity were not modified by methylene blue or placebo. Urinary sodium excretion, fractional sodium excretion and serum nitric oxide levels were significantly decreased 4 hr after methylene blue administration (P < 0.05), to return toward basal levels over a further 4-hr period. It is concluded that methylene blue, at the dose used in the present study, has no effect on systemic and portal hemodynamics in cirrhotic patients with ascites. The reduction in renal sodium excretion, in the absence of changes in renal function and hemodynamics, suggests, at least partly, a direct antinatriuretic effect of methylene blue.


Small Vessel Disease and Associations with Cerebrospinal Fluid Amyloid, Tau, and Neurodegeneration (ATN) Biomarkers and Cognition in Young Onset Dementia.
Small vessel disease (SVD) and Alzheimer's disease (AD) frequently coexist; however, it remains unclear how they collectively affect cognition. We investigated associations between SVD and AD biomarkers, namely amyloid, tau, and neurodegeneration (ATN) in young onset dementia (YOD) and explored how SVD and ATN interact to affect cognition. 80 YOD individuals were recruited from a memory clinic. SVD burden (SVD+) was operationalized as a score >1 on the Staals scale and ATN was measured using cerebrospinal fluid (CSF). SVD+ was associated with lower CSF Aβ1-42 (B = -0.20, 95% CI: -0.32 to -0.08) and greater neurodegeneration, indexed as hippocampal atrophy (B = -0.24, 95% CI: -0.40 to -0.04). SVD+ was not associated with tau. Cognitive impairment was associated with CSF Aβ1-42 (B = -0.35, 95% CI: -0.55 to -0.18) but not SVD. Rather, SVD was indirectly associated with cognition via reduced CSF Aβ1-42, specifically with global cognition (B = -0.03, 95% CI: -0.09 to -0.01) and memory (B = 0.08, 95% CI: -.01 to .21). SVD was indirectly associated with cognition via increased neurodegeneration in grey matter (Global cognition: B = -0.06, 95% CI: -0.17 to -0.03; Memory: B = 0.05, 95% CI: 0.01 to 0.18) and the hippocampus (Global cognition: B = -0.05, 95% CI: -0.11 to -0.01; Memory: B = 0.06, 95% CI: 0.01 to 0.17). In YOD, SVD burden was associated with AD pathology, namely CSF Aβ1-42. SVD indirectly contributed to cognitive impairment via reducing CSF Aβ1-42 and increasing neurodegeneration.


Homeostasis of serine enantiomers is disrupted in the post-mortem caudate putamen and cerebrospinal fluid of living Parkinson's disease patients.
L-serine generated in astrocytes plays a pivotal role in modulating essential neurometabolic processes, while its enantiomer, D-serine, specifically regulates NMDA receptor (NMDAR) signalling. Despite their physiological relevance in modulating cerebral activity, serine enantiomers metabolism in Parkinson's disease (PD) remains elusive. Using High-Performance Liquid Chromatography (HPLC), we measured D- and L-serine levels along with other amino acids known to modulate NMDAR function, such as L-glutamate, L-aspartate, D-aspartate, and glycine, in the post-mortem caudate putamen (CPu) and superior frontal gyrus (SFG) of PD patients. Moreover, we examined these amino acids in the cerebrospinal fluid (CSF) of de novo living PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients versus subjects with other neurological disorders (OND), used as control. We found higher D-serine and L-serine levels in the CPu of PD patients but not in the SFG, a cerebral region that, in contrast to the CPu, is not innervated by nigral dopaminergic terminals. We also highlighted a significant elevation of both serine enantiomers in the CSF samples from PD but not in those of AD and ALS patients, compared with control subjects. By contrast, none or only minor changes were found in the amount of other NMDAR modulating amino acids. Our findings identify D-serine and L-serine level upregulation as a biochemical signature associated with nigrostriatal dopaminergic degeneration in PD.


[Action of adenosine 5'-triphosphate and effects of various purinergic receptor blocking agents on the movements of an isolated guinea pig gallbladder].
Exogenously applied adenosine 5'-triphosphate (ATP) caused a biphasic response; a quick relaxation followed by a slow contraction. This response was not affected by atropine, phentolamine, propranolol and tetrodotoxin. Theophylline, quinidine and IBMX reduced ATP-induced contraction and had no effect on ATP-induced relaxation. On the other hand, apamin reduced ATP-induced relaxation and had no effect on ATP-induced contraction. Indomethacin remarkedly reduced ATP-induced contraction without affecting the relaxation. It was suggested that there were two types of receptors (apamin sensitive and apamin resistant) in the guinea-pig gallbladder.


Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study.
A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma. Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%. Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.


Berberine inhibits proliferation and induces G0/G1 phase arrest in colorectal cancer cells by downregulating IGF2BP3.
Berberine (BBR) is one of isoquinoline alkaloids from Coptidis Rhizoma and possesses extensive pharmacological activities, including anti-colorectal cancer (CRC) activity. However, the detailed mechanisms remain to be determined. The current study aims to investigate the ability and the potential mechanism of BBR against CRC. By mining recognized CRC datasets and RNA-seq results of cells and tumors treated with BBR for perform bioinformatics analysis to find key targets IGF2BP3. Overexpression and knockdown of IGF2BP3 assays were used to explore the biological role of IGF2BP3 in the process of BBR against CRC. Our results showed that BBR inhibits proliferation and induces G0/G1 phase arrest in CRC cells by downregulating IGF2BP3. Specifically, Knockdown of IGF2BP3 could suppress the PI3K/AKT pathway to inhibit cell proliferation and cycle transition. The negative effects of BBR in CRC cells could be rescued by overexpressing IGF2BP3. Our data might provide a theoretical basis for the future use of BBR in colorectal cancer prevention.


Testosterone-down-regulated Akt pathway during cardiac ischemia/reperfusion: a mechanism involving BAD, Bcl-2 and FOXO3a.
Lower levels of myocardial Akt activity in males are associated with a higher incidence of heart failure and worsened cardiac function after ischemia/reperfusion (I/R). While Akt activation by estrogen provides cardioprotection in females, no information exists regarding the effect of testosterone on the myocardial Akt pathway following I/R. We hypothesized that following I/R: (1) endogenous testosterone will decrease myocardial Akt activation in male hearts; (2) endogenous testosterone will mediate downstream signals of Akt, including Bad, Bcl-2, and FOXO3a; (3) administration of exogenous testosterone will recapitulate negative effects on the Akt pathway in castrated male hearts. Rat hearts from age-matched adult males, females, castrated males, males with androgen receptor blocker-flutamide, castrated males with chronic 5α-dihydrotestosterone (DHT) implantation, or acute testosterone infusion (ATI) (n = 9/group) were subjected to I/R (Langendorff). Castration or flutamide treatment significantly up-regulated myocardial Akt activation, increased downstream apoptosis-regulatory molecules p-Bad, Bcl-2, p-FOXO3a, but reduced Fas-L, consistent with decreased myocardial injury in male hearts following I/R. ATI administration, but not chronic DHT, reversed these effects on Akt signaling associated with further exacerbated cardiac dysfunction in castrated males. Notably, lower levels of MnSOD were observed in male hearts, and castration or flutamide treatment restored myocardial MnSOD expression to the levels of females in male hearts after I/R. Our study represents the initial evidence of testosterone-induced down-regulation of the Akt pathway in male hearts following I/R, thereby mediating cardiac injury through decreased p-Bad, reduced ratio of Bcl-2/Bax in the cytoplasm, and increased FOXO3a in the nucleus.


A Comparative Study Utilizing the Voice Handicap Index-10 (VHI-10) in Teachers and the General Population of Kuwait.
The objective of this study was to determine the prevalence of voice handicap perception of teachers in Kuwait and compare them within the general population by using the validated Arabic version of the voice handicap index-10 (VHI-10). Moreover, we explored variations within the teaching profession itself with regards to specific characteristics. The study was a cross-sectional survey design, in which participants from all governates of Kuwait (1820 teachers and 755 controls) completed the validated Arabic VHI-10, health-related, and demographic questions. The questionnaires were distributed among a random sample of elementary, middle, and high school teachers of both genders, and a random sample of the control population. The mean VHI-10 of teachers was significantly higher than nonteachers (mean VHI-10 of teachers = 5.7, mean VHI-10 of nonteachers = 3.7, P < 0.001). Furthermore, there was a significant difference between teachers and controls in those who scored >11 in the VHI-10 (>11 = 17.6%, 10.2% respectively, P = <0.001). Female teachers scored a higher mean VHI-10 than male teachers (B = 0.66, P < 0.001). There was no difference in the mean VHI-10 among the different teaching class levels. However, elementary school teachers were the most group to exceed the cut-off point (VHI-10 >11) (Odds Ratio = 1.38, P = 0.04). With regards to smoking, we found no difference in the mean VHI-10 and scoring >11 in the questionnaire. Art and science teachers had the highest mean VHI-10 (P = 0.005 and 0.03, respectively). The results of the study revealed a higher perception of voice handicap in teachers than nonteachers. Therefore, emphasis should be on teachers in order to prevent voice damage.


The effect of renewable energy development, market regulation, and environmental innovation on CO2 emissions in BRICS countries.
The relationship between energy, environment, and economic growth has been received a lot of attention recently among scientific studies, but environmental sustainability remains a global issue. Renewable energy development, green technological innovations, and regulatory policy mechanisms can all help to reduce greenhouse gas emissions and support environmental sustainability. The purpose of this study was to look at the influence of renewable energy development, market regulation, and environment-related innovation on CO2 emissions in the BRICS countries from 1990 to 2020. For empirical analysis, it uses second-generation panel unit root test and updated linear and nonlinear cointegration techniques. To this end, this study employs symmetric and asymmetric approach to linear and nonlinear relationship among study variables. The findings indicate that there is long-run symmetric and asymmetric relationship between renewable energy development, market regulation, environment-related innovation, and CO2 emissions. The market regulation plays significant mediating role in relation between renewable energy development, environment-related innovation, and CO2 emissions. Our findings suggest that BRICS countries need to more focus on the environment-related innovation and renewable energy development. They should design market-based environmental regulation policies, emphasize on environmental taxes, expand renewable energy development, and environment-related innovations. Such strategies are key to limiting CO2 emissions and gain environmental sustainable.


Ultrasound or MR elastography of liver: which one shall I use?
Liver stiffness is now a well-established noninvasive biomarker for assessing fibrosis in chronic liver disease. MRI-based and ultrasound-based dynamic elastography techniques have been introduced for assessment of liver stiffness and useful in clinical staging of hepatic fibrosis. Several different elastography techniques are now available with each method having inherent strengths and limitations. The published literature generally indicates that MR elastography has a higher diagnostic performance and fewer technical failures than ultrasound-based elastography techniques in assessing hepatic fibrosis. There is also significant potential to further develop elastography techniques to implement multiparametric methods that have promise for distinguishing between processes such as inflammation, fibrosis, venous congestion, and portal hypertension that can result in increased liver stiffness. In this commentary, we compare MR and ultrasound elastography methods and their utility in clinical practice.


Bacteriocin (klebocin) typing of clinical isolates of Klebsiella pneumoniae.
Three-hundred-forty-two clinical isolates of Klebsiella pneumoniae were subjected to bacteriocin (klebocin) typing using six standard klebocin-producer strains (153-158). The overall typability was 72.8 per cent. The predominant klebocin types found were 244 (14.3 per cent), 313 (13.7 per cent) and 113 (7.6 per cent). Klebocin types 314 and 111 each contributed 5.2 per cent to the total number of isolates. No significant correlation was observed between the source of isolation and the klebocin type.


Comparative micelle structure. IV. The similarity between caprine alphas-casein and bovine alphas-3- casein.
The major component of caprine (goat) alphas-casein has been isolated by DEAE-and CM-cellulose chromatography in buffers containing urea and 2-mercaptoethanol. The protein has a molecular weight of 25700 as determined by gel filtration on Sepharose 6B in guanidine hydrochloride. Its composition, Asp17, Thr14, Ser14, Glu45, Pro18, Gly4, Ala10, Cys2, Val12, Met4, Ile12, Leu12, Tyr11, Phe8, His5, Lys22, Arg6, Trp2 and 7 phosphate residues, is much closer to that of bovine alphas3-casein than to bovine alphas1-casein. The caprin alphas-casein is more easily precipitated with Ca2+ than bovine alphas3-casein at 37 degrees C, pH 6.8, which in turn is more easily precipitated than bovine alphas1-casein.


Global brain volume and N-acetyl-aspartate decline over seven decades of normal aging.
We characterize the whole-brain N-acetyl-aspartate (WBNAA) and brain tissue fractions across the adult lifespan and test the hypothesis that, despite age-related atrophy, neuronal integrity (reflected by WBNAA) is preserved in normal aging. Two-hundred-and-seven participants: 133 cognitively intact older adults (73.6 ± 7.4 mean ± standard deviation, range: 60-90 year old) and 84 young (37.9 ± 11, range: 21-59 year old) were scanned with proton magnetic resonance spectroscopy and T1-weighted MRI. Their WBNAA, fractional brain parenchyma, and gray and white matter volumes (fBPV, fGM, and fWM) were compared and modeled as functions of age and sex. Compared with young, older-adults' WBNAA was lower by ~35%, and fBPV, fGM and fWM were lower by ~10%. Linear regressions found 0.5%/year WBNAA and 0.2%/year fBPV and fGM declines, whereas fWM rose to age ~40 years, and declined thereafter. fBPV and fGM were 1.8% and 4% higher in women, with no sex decline rates difference. We conclude that contrary to our hypothesis, atrophy was accompanied by WBNAA decline. Across the entire age range, women's brains showed less atrophy than men's. Formulas to estimate WBNAA and brain tissue fractions in healthy adults are provided to help differentiate normal from abnormal aging.


Patient characteristics of Medicare beneficiaries who report not getting influenza and pneumococcal vaccinations, 2001-2013.
Background: Despite long standing recommendations of pneumococcal and influenza vaccination for adults age 65 years and older and wide-spread availability to vaccination services, vaccination coverage in the United states is low. We sought to explore reasons patients reportedly did not receive these vaccines.Methods: We used publicly available data from the Medicare Current Beneficiary Survey, a continuous panel survey of a representative sample of the Medicare population, as well as Medicare enrollment data. We explored questions pertaining to influenza and pneumococcal vaccination status, self-reported reasons for being unvaccinated and patient perspectives toward health care utilization.Results: The majority of the respondents who did not receive vaccines for influenza or pneumococcal disease reported that they did not know it was needed or that their doctor did not recommend it. Respondents who were not vaccinated against influenza reported concerns about side effects. Coverage for both vaccines was lower among respondents in the Southeast region and among those who are dual-eligible or less engaged in healthcare utilization. Little difference was observed by gender, urban status, or Part C enrollment for influenza respondents. Higher pneumococcal vaccine coverage was found among females as well as those living in urban settings or enrolled in Medicare Part C.Conclusions: Implementation of the national guidelines calling for all health care professions - whether they provide vaccinations or not - to take steps to help ensure adults are fully immunized is critical. Tailored communication to beneficiaries that addresses the importance of both vaccines as well as key barriers, like side effects, is also needed.


Photoreceptor cell differentiation in retinoblastoma demonstrated by a new immunohistochemical marker mucin-like glycoprotein associated with photoreceptor cells (MLGAPC).
For further understanding of specific differentiation in retinoblastoma, we studied the expression of newly detected mucin-like glycoprotein associated with photoreceptor cells (MLGAPC), which is specific for photoreceptor cells of retina and analogous to interphotoreceptor matrix proteoglycan-1 (IMPG1). Surgically enucleated retinoblastomas (n=21; undifferentiated type, n=15, differentiated type, n=6) were immunohistochemically studied with a polyclonal antibody against MLGAPC, and 17/21 cases (81%) showed positive staining of tumour cells. We classified various staining patterns and structures into four groups: type 1 showing a granular intracellular scattered staining pattern with round small cells; type 2 showing a reticular staining pattern between spindle-shaped tumour cells; type 3 showing radiating staining from the centre of Homer-Wright rosettes; type 4 showing ring-shaped, radiating and granular staining associated with Flexner-Wintersteiner rosettes. Eleven of 15 undifferentiated retinoblastomas (73%) showed type 1 or 2, and all the six differentiated cases showed type 3 or 4. Image analysis of immunostaining revealed an increase in MLGAPC-positive area from 0.48% in undifferentiated cases to 1.60% in differentiated cases, and a negative correlation was shown between mitotic frequency and MLGAPC-positive area. This study proved MLGAPC as a valuable marker of retinoblastoma, and that photoreceptor differentiation takes place even in 'undifferentiated' retinoblastoma.


Cessation of reproduction-related spine elongation after multiple breeding cycles in female naked mole-rats.
The breeding female or "queen" naked mole-rat has a uniquely elongated body morphology attributed to the lengthening of the lumbar vertebral column that occurs during pregnancy. It is unknown whether this vertebral growth is a continuous process, or associated only with early reproductive experience. We compared pregnancy-related bone elongation in nascent primiparous queens and established queens to determine if this vertebral expansion was a lifelong process in these females. We also investigated the impact of lactation on vertebral elongation in these mole-rats because it is known to be a time of significant bone loss in other mammals. Our data show that after eight or more pregnancies, established queens no longer experienced a net gain in lumbar spine length over the reproductive cycle, whereas the nascent breeders demonstrated significant spine lengthening over this time. Despite the lack of net spine lengthening in established breeders, our results indicated that these queens still experienced some pregnancy-specific vertebral elongation. In naked mole-rats, pregnancy-induced bone elongation may serve the dual purposes of first lengthening the spine, and then once optimal spine size is achieved, serving as a homeostatic mechanism that prepares the spine for the mineral demands of lactation. Anat Rec, 2009. (c) 2008 Wiley-Liss, Inc.


e-Learning system ERM for medical radiation physics education.
The objective of this paper is to present the Education for Radiation in Medicine (ERM) e-Learning System. The system was developed, tested and piloted in the Inter-University Medical Physics Centre, Plovdiv, Bulgaria. It was based on the results of EU Project TEMPUS S-JEP 09826. The ERM e-Learning System is an integrated on-line system for remote education covering aspects of Medical Radiation Physics education (M.Sc. level). It provides user-friendly interface and optimised functionality with three different access levels: trainee, professor and administrator. The minimum server requirements and the standard client side working environment turn the system into a good, cost effective and easy to support solution for remote education.


Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials of Orthopaedic Surgical Interventions.
The selective reporting of a subset of the outcomes that had been originally reported to a registry is a potential threat to the validity of evidence-based medicine. The extent of selective reporting has not been described for randomized controlled trials (RCTs) assessing the effectiveness of orthopaedic surgical interventions. The objective of this study was (1) to determine the percentage of orthopaedic surgical RCTs published in high-impact orthopaedic journals that were reported to have been registered, (2) to evaluate the consistency between the primary outcome measures recorded in the registry and those reported in the article, and (3) to evaluate whether selective reporting favored statistically significant outcomes. We searched PubMed for articles on RCTs assessing orthopaedic surgical interventions indexed from January 2010 through December 2014 and published in the ten orthopaedic journals with the highest impact factors. For every article in which the authors reported registration of the RCT, we extracted the number and nature of the outcome measures from the article and the corresponding information from the registry. We then evaluated the consistency between the primary outcome measures reported in the registry and those reported in the published article. Moreover, we evaluated whether selective reporting favored statistically significant outcomes. Of the 362 articles on orthopaedic surgical RCTs, ninety (24.9%) reported that the RCT had been registered and thirty-four (37.8%) of the ninety had been registered adequately (registered before the study end with a clear description of the primary outcome measure and its time frame, with no substantial change after the study end). Twenty-six reports were eligible for our evaluation of the consistency between the registered primary outcome measures and those reported in the published article. This analysis identified one or multiple major discrepancies for fourteen articles, eight of which favored statistically significant results. Few articles on orthopaedic surgical RCTs reported registration of the trial, and even fewer of these trials were registered adequately. Inconsistencies between registered primary outcome measures and those reported in the published articles, as well as selective outcome reporting favoring statistically significant outcomes, were prevalent. Although trial registration is now the rule, it is currently far from optimal for orthopaedic surgical RCTs, and selective outcome reporting is prevalent. Full involvement of authors, editors, and reviewers is necessary to ensure publication of quality, unbiased results.


Multi-site phosphorylation in ox-kidney branched-chain 2-oxoacid dehydrogenase complex.
Tryptic [32P]phosphopeptides were prepared from [32P]phosphorylated ox-kidney branched-chain complex and analysed by high-voltage paper electrophoresis at pH 1.9. In the maximally phosphorylated complex 3 tryptic [32P]phosphopeptides were identified (TA, TB, TC). RF-values relative to N6-dinitrophenyllysine were (mean +/- SEM for 25 obs.): TA, 1.53 +/- 0.03; TB, 1.07 +/- 0.02; TC, 0.65 +/- 0.01. Relative rates of phosphorylation were TA greater than TB greater than TC. Phosphorylation of TA reached a maximum when about 66% of the complex was inactivated. Phosphorylation of TB and TC was associated mainly with 66-95% inactivation of the complex.


ICD Knowledge and Attitudes at End of Life in a Diverse and Vulnerable Patient Population.
Studies thus far lacking diversity show many patients with implantable cardioverter defibrillators (ICDs) have poor understanding of ICD functioning, preventing informed decision-making near end of life (EOL). To describe knowledge, perceptions, and preferences regarding ICDs among patients nearing EOL in a diverse, safety-net hospital population. A cross sectional phone survey of patients with ICDs nearing EOL from a safety-net hospital was performed. The survey assessed knowledge, perceptions, and preferences regarding their ICD. Nearly half (46%) of patients falsely believed turning off shocking function would stop the heart, 69% were unaware that disabling ICDs does not require surgery, and 88% said no doctor had ever discussed the option of deactivation of shocking therapy with them. Challenges in health care delivery in a safety-net hospital patient population may result in patients being poorly equipped to align ICD settings with goals of care when nearing EOL.


Applications of atomic force microscopy in immunology.
Cellular mechanics, a major regulating factor of cellular architecture and biological functions, responds to intrinsic stresses and extrinsic forces exerted by other cells and the extracellular matrix in the microenvironment. Cellular mechanics also acts as a fundamental mediator in complicated immune responses, such as cell migration, immune cell activation, and pathogen clearance. The principle of atomic force microscopy (AFM) and its three running modes are introduced for the mechanical characterization of living cells. The peak force tapping mode provides the most delicate and desirable virtues to collect high-resolution images of morphology and force curves. For a concrete description of AFM capabilities, three AFM applications are discussed. These applications include the dynamic progress of a neutrophil-extracellular-trap release by neutrophils, the immunological functions of macrophages, and the membrane pore formation mediated by perforin, streptolysin O, gasdermin D, or membrane attack complex.


Anterior cricoid split for subglottic stenosis.
Subglottic stenosis is a common problem that often results from ventilatory support necessary in the premature infant. Previous methods of treatment include tracheostomy with dilatation of the stenosis, steroid injections, and procedures to stent the trachea. Results of these methods have been unsatisfactory because of the multiple procedures needed to obtain an adequate airway as well as the high mortality from long-term tracheostomy in infants. In the past 2 years, seven infants have undergone an anterior cricoid split for tight subglottic stenosis and airway obstruction. Of the seven patients, six were premature, five of whom required ventilatory support ranging from 4 to 30+ days. Each child presented in respiratory distress with symptoms present in five children from 1 to 11 months (mean 3.8) after birth. Bronchoscopy identified the site of obstruction in each case as subglottic, with a narrow lumen, usually less than 2.5 mm in diameter. Anterior cricoid split was performed at ages ranging from 2 to 11 months (mean 5.0). All children were extubated at 10 to 14 days and subsequently discharged home asymptomatic; none required postoperative tracheostomy. Complications developed in five children, including atelectasis, otitis media, phlebitis, and tracheocutaneous fistula in two, one of whom required operative closure. One child was rebronchoscoped at 3 weeks postoperatively for bronchospasm, which resolved on aminophylline. The subglottic trachea was normal. At follow-up ranging from 2 to 21 months (mean 8.3), no child has symptoms referrable to the subglottic region. In one patient, a brief period of respiratory distress recurred 3 months postoperatively due to tracheomalacia.(ABSTRACT TRUNCATED AT 250 WORDS)


Hepatocyte growth factor induces collagenase (matrix metalloproteinase-1) via the transcription factor Ets-1 in human hepatic stellate cell line.
Although hepatocyte growth factor recently has been shown to decrease hepatic fibrosis in animal models, the molecular mechanisms of this effects remain to be elucidated. We investigated regulation of collagenase expression by hepatocyte growth factor in hepatic stellate cells. A human hepatic stellate cell line, LI90, was treated with hepatocyte growth factor. Expression of collagenase, 72 kDa gelatinase, procollagen alpha 1(I), tissue inhibitor of matrix metalloproteinase-1, transforming growth factor-beta 1, or Ets-1, and carboxyterminal telopeptide of type I collagen was examined. Ets-1 binding activity was determined by gel mobility shift assay, collagenase promoter activity was evaluated by reporter gene assay. LI90 cells were also transfected with Ets-1 antisense oligonucleotides with or without hepatocyte growth factor. Hepatocyte growth factor increased expression of collagenase mRNA and protein, and an increase in Ets-1 mRNA preceded the increase in collagenase mRNA. Collagenase activity and protein, and a degradation product of type I collagen were increased in the medium. Nuclear extracts from treated LI90 cells also showed increased Ets-1 binding activity. Hepatocyte growth factor and cotransfection of Ets-1 enhanced promoter activity of collagenase gene. Furthermore, treatment of LI90 cells with Ets-1 antisense oligonucleotides downregulated basal and hepatocyte growth factor-induced Ets-1 and collagenase mRNA expression. Collectively, the results suggest that hepatocyte growth factor increases collagenase expression in hepatic stellate cells via the Ets-1 transcription factor-dependent manner.


Cardiometabolic and Mental Health in Women With Early Gestational Diabetes Mellitus: A Prospective Cohort Study.
Early diagnosis and treatment of gestational diabetes (GDM) may reduce adverse obstetric and neonatal outcomes, especially in high-risk women. However, there is a lack of data for other outcomes. We compared cardiometabolic and mental health outcomes in women with early (eGDM) and classical (cGDM) GDM. This prospective cohort included 1185 All women with cGDM and 76 women with eGDM. The eGDM group had GDM risk factors (BMI >30 kg/m2, family history of diabetes, history of GDM, ethnicity), were tested at <20 weeks gestational age, and diagnosed using American Diabetes Association prediabetes criteria. All women underwent lifestyle adaptations. Obstetric, neonatal, mental, and cardiometabolic outcomes were assessed during pregnancy and postpartum. The eGDM group had lower gestational weight gain than cGDM (10.7 ± 6.2 vs 12.6 ± 6.4; P = 0.03) but needed more medical treatment (66% vs 42%; P < 0.001). They had similar rates of adverse maternal and neonatal outcomes, except for increased large-for-gestational-age infants (25% vs 15%; P = 0.02). Mental health during pregnancy and postpartum did not differ between groups. eGDM had more atherogenic postpartum lipid profile than cGDM (P ≤ 0.001). In eGDM, the postpartum prevalence of the metabolic syndrome (MetS) was 1.8-fold, prediabetes was 3.1-fold, and diabetes was 7.4-fold higher than cGDM (waist circumference-based MetS: 62% vs 34%/BMI-based MetS: 46% vs 24%; prediabetes: 47.5% vs 15.3%; diabetes: 11.9% vs 1.6%, all P < 0.001). These differences remained unchanged after adjusting for GDM risk factors. Compared with cGDM, eGDM was not associated with differences in mental health, but with increased adverse cardiometabolic outcomes, independent of GDM risk factors and gestational weight gain. This hints to a preexisting risk profile in eGDM.


The combinational therapy of trastuzumab and cetuximab inhibits tumor growth in a patient-derived tumor xenograft model of gastric cancer.
Gastric cancer (GC) is one of the leading causes of cancer mortality worldwide. Although therapeutic strategies for GC have improved, the prognosis for advanced GC remains poor. Herein, the present study sought to design a personalized cancer therapy specific to a stage III GC patient. The tumor was surgically removed and was used to establish a patient-derived tumor xenograft (PDTX) model utilizing nude mice. Various molecular-targeted anticancer treatments were tested in the study, including control (no treatment), bevacizumab, cetuximab, bevacizumab + cetuximab, trastuzumab, and trastuzumab + cetuximab. Trastuzumab + cetuximab treatment exhibited the best antitumor growth effect, followed by trastuzumab, bevacizumab + cetuximab, cetuximab, and bevacizumab. Similarly, trastuzumab + cetuximab was also the most effective treatment at inducing apoptosis and cell cycle arrest in primary cultures of the patient's gastric cancer cells. Among all treatments tested in the study, trastuzumab + cetuximab showed the most profound effect in reducing the protein expression of proliferation and metastatic markers (VEGF, MMP-7, EGFT, Ki-67 and, PCNA) in tumors obtained from PDTX models, which may be the mechanism underlying the profound antitumor growth effect exerted by trastuzumab + cetuximab. The data indicate that trastuzumab + cetuximab combinational therapy should be the most effective antitumor growth therapy for the GC patient whom we took the cancer cells from.


Nitrite reductase of Nitrosomonas europaea is not essential for production of gaseous nitrogen oxides and confers tolerance to nitrite.
A gene that encodes a periplasmic copper-type nitrite reductase (NirK) was identified in Nitrosomonas europaea. Disruption of this gene resulted in the disappearance of Nir activity in cell extracts. The nitrite tolerance of NirK-deficient cells was lower than that of wild-type cells. Unexpectedly, NirK-deficient cells still produced nitric oxide (NO) and nitrous oxide (N(2)O), the latter in greater amounts than that of wild-type cells. This demonstrates that NirK is not essential for the production of NO and N(2)O by N. europaea. Inactivation of the putative fnr gene showed that Fnr is not essential for the expression of nirK.


Effect of smoking and soft tissue release on risk of revision after total knee arthroplasty: a case- control study.
Increasing utilization of primary total knee arthroplasty (TKA) is projected to expand demand for revision TKA. Revision TKAs are procedurally complex and incur high costs on our financially constrained healthcare system. The purpose of this study was to use a case-control design to identify factors predisposing to revision TKA, particularly demographic, clinical and perioperative technical factors. We conducted a case control study to investigate patient, surgical and perioperative factors associated with greater risk of revision TKA. We included patients who received TKA at a tertiary center between 1996 and 2009. Cases (patients that had primary and revision TKA) were matched to controls (patients with primary TKA that was not revised) in a 1:2 ratio and risk of revision examined using conditional logistic regression. We identified 146 cases and 290 controls. Patient factors independently associated with revision included male sex (OR 1.73; 95% CI 1.06-2.81) and smoking (OR 2.87; 1.33-6.19). Older age was associated with decreased risk (OR 0.83 per 5-year increment; 95% CI 0.75-0.92). Lateral release was the only technical factor associated with revision (OR 1.92; 1.07-3.43). In this case control study younger patient age, male gender, soft tissue release and active smoking status were associated with increased revision risk. Although we do not know whether the risk of smoking arises from short- or long-term exposure, smoking cessation prior to TKA should be considered as an intervention for decreasing revision risk.


Understanding the reliability of trial outcome measures: The example of angiographic results of surgical or endovascular treatments of aneurysms.
The reliability of outcome measures is of central importance in clinical research. Studies of reliability remain rare in the neurovascular field. A narrative review of the history (1997-2021) of reporting angiographic results of the surgical or endovascular treatments of aneurysms serves to illustrate the importance of precisely defining outcome measures. We also review how the reliability of an angiographic classification system was studied. Outcome measures are commonly used without precise definitions. When definitions or classification systems exist, they are rarely verified for their reliability. Twenty-five years following its introduction, a classification of angiographic results of aneurysm treatments is still being studied and modified. The reliability of outcome measures should be made a research priority if we are to practice outcome-based medical or surgical care.


Glycoproteomic characterization of recombinant mouse α-dystroglycan.
α-Dystroglycan (DG) is a key component of the dystrophin-glycoprotein complex. Aberrant glycosylation of the protein has been linked to various forms of congenital muscular dystrophy. Unusually α-DG has previously been demonstrated to be modified with both O-N-acetylgalactosamine and O-mannose initiated glycans. In the present study, Fc-tagged recombinant mouse α-DG was expressed and purified from human embryonic kidney 293T cells. α-DG glycopeptides were characterized by glycoproteomic strategies using both nano-liquid chromatography matrix-assisted laser desorption ionization and electrospray tandem mass spectrometry. A total of 14 different peptide sequences and 38 glycopeptides were identified which displayed heterogeneous O-glycosylation. These data provide new insights into the complex domain-specific O-glycosylation of α-DG.


Effect of exogenous L-dopa on behavior in the rat: an in vivo voltammetric study.
L-DOPA was administered intraperitoneally (i.p.) or intraventricularly (i.v.t.) to freely moving rats to investigate the effects of exogenous L-DOPA itself on behavior. Striatal dopamine (DA) in the extracellular fluid was examined with microcomputer-controlled in vivo voltammetry, and behavioral change was observed. When L-DOPA was administered (i.p.) after pretreatment with benserazide, a peripheral DOPA decarboxylase inhibitor, behavioral change was elicited before the elevation in DA and suppressed before its reduction. After pretreatment with NSD-1015, a central DOPA decarboxylase inhibitor, behavioral change was also elicited, although DA was still not increased. When L-DOPA was injected (i.v.t.), the behavioral effect was manifested at once; DA was still unchanged at this time, but it increased after behavioral activity reached the maximum level. L-DOPA was also injected (i.v.t.) into rats with striatal lesions induced by 6-hydroxydopamine (i.v.t.). Behavioral change was manifested promptly after the injection. When the dose-response curves to different dosages of L-DOPA were examined in normal rats without striatal lesions, it was found to exhibit a steeper rise than that of DA. Finally, when rats were injected (i.p. or i.v.t.) with 3-O-methyl-DOPA (3-methoxytyrosine), a major metabolite of L-DOPA, no behavioral change was elicited, and no increase in DA was recognized. These experimental results indicated that L-DOPA is related directly to the manifestation of behavioral change.


Human placental glutamate dehydrogenase. Purification--kinetic and regulatory properties--physicochemical studies.
Glutamate dehydrogenase (EC. 22.214.171.124) has been purified more than 9,000 times from human placental alcoholic subfractions as a homogenous protein of 55,155 daltons (subunit molecular weight). Kinetic constants for the reverse reaction (reductive amination of alpha-ketoglutarate) have been shown to be similar to those of the bovine liver enzyme, while the kinetic constants for the forward reaction were markedly different as well as some regulatory properties (lack of activation by ADP in the reverse reaction). The amino acid composition differs from the bovine liver enzyme composition. Furthermore, the tryptic peptide patterns of the placental enzyme and the human liver enzyme have been compared. Besides the low specific activity of this enzyme, the results indicate that human placental glutamate dehydrogenase is closely related to other mammalian glutamate dehydrogenases.


Bleomycin-metal interaction: ferrous iron-initiated chemiluminescence.
Chemiluminescence often accompanies the spontaneous degradation of intermediates in an electronically excited state. The interaction of iron with bleomycin results in the activation of bleomycin to a reactive intermediate which can alter DNA or undergo self-inactivation. This report demonstrates that the interaction of ferrous iron with bleomycin results in chemiluminescence, that this response is iron-specific and that the presence of DNA prevents the generation of chemiluminescence. These observations suggest that the activated bleomycin intermediate may be in an electronically excited state.


Inhibition of central nervous system aromatase activity: a mechanism for fenarimol-induced infertility in the male rat.
Fenarimol (alpha-(2-chlorophenyl)-alpha(4-chlorophenyl)-5-pyrimidine-methanol), a pyrimidine carbinol agricultural fungicide, was previously reported to cause a dose-related decrease in fertility in rats (K. S. Hirsch, E. R. Adams, D. G. Hoffman, J. K. Markham, and N. V. Owen (1986), Toxicol. Appl. Pharmacol. 86, 391-399). Based on the results of a number of reproduction studies (K. S. Hirsch, E. R. Adams, D. G. Hoffman, J. K. Markham, and N. V. Owen (1986), Toxicol. Appl. Pharmacol. 86, 391-399), the infertility appeared to be associated with an impairment of male sexual behavior. When [14C]fenarimol was administered to the dam, high concentrations of radioactivity were observed in the neonatal hypothalamus, which functions in the development and subsequent expression of male sexual behavior. In the present studies fenarimol exhibited neither antiandrogenic nor antiestrogenic activities. The compound did, however, prevent the increase in nuclear estrogen receptors in the brain which normally occurs in the male during the early postnatal period. These results suggested that fenarimol might be acting to inhibit estrogen biosynthesis (via the aromatase enzyme complex) within the central nervous system. [3H]Testosterone was administered to neonatal rats, and the tritiated metabolites were isolated. Testosterone and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) concentrations were similar in all treatment groups. Tritiated estrogens were detected in the brain cell nuclei from control neonates but not in neonates exposed to fenarimol. Fenarimol was also observed to inhibit rat ovarian aromatase activity in vitro. These data indicate that the decrease in male sexual behavior and the infertility associated with exposure to fenarimol were, most likely, due to inhibition of aromatase activity within the central nervous system.


Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression.
Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on expression changes along the sequence "gallstones → dysplasia → GBC". In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncRNAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r2 = 0.26) and three cis-C22orf34-eQTLs (r2 = 0.24). Only LINC00662 showed a genotyped-based serum expression associated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04-1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk.


High expression of a plectasin-derived peptide NZ2114 in Pichia pastoris and its pharmacodynamics, postantibiotic and synergy against Staphylococcus aureus.
NZ2114, a new variant of plectasin, was overexpressed in Pichia pastoris X-33 via pPICZαA for the first time. The total secreted protein of fermentation supernatant reached 2,390 mg/l (29 °C) and 2,310 mg/l (25 °C), and the recombinant NZ2114 (rNZ2114) reached 860 mg/l (29 °C) and 1,309 mg/l (25 °C) at 96 h induction in a 5-l fermentor, respectively.The rNZ2114 was purified by cation exchange chromatography, and its yield was 583 mg/l with 94.8 % purity. The minimal inhibitory concentration (MIC) of rNZ2114 to four ATCC strains of Staphyloccocus aureus was evaluated from 0.028 to 0.90 μM. Meanwhile, it showed potent activity (0.11-0.90 μM) to 20 clinical isolates of MRSA. The rNZ2114 killed over 99.9 % of tested S. aureus (ATCC 25923 and ATCC 43300) in Mueller-Hinton medium within 6 h when treated with 4 × MIC. The postantibiotic effect of rNZ2114 to S. aureus ATCC 25923 and ATCC 43300 was 18.6-45.6 and 1.7-3.5 h under 1×, 2×, and 4× MIC, respectively. The fractional inhibitory concentration index (FICI) indicated a synergistic effect between rNZ2114 and kanamycin, streptomycin, and vancomycin against S. aureus ATCC 25923 (FICI = 0.125), and additivity between rNZ2114 and ampicillin, spectinomycin (FICI = 0.625), respectively. To S. aureus ATCC 43300 [methicillin-resistant S. aureus (MRSA)], rNZ2114 showed a synergistic effect (FICI = 0.125-0.3125) with kanamycin, ampicillin, streptomycin, and vancomycin, and antagonism with spectinomycin (FICI = 8.0625). The rNZ2114 caused only less than 0.1 % hemolytic activity in the concentration of 128 μg/ml, and showed a good thermostability from 20 to 80 °C. In addition, it exhibited the highest activity at pH 8.0. These results suggested that large-scale production of NZ2114 is feasible using the P. pastoris expression system, and it could be a new potential antimicrobial agent for the prevention and treatment of S. aureus especially for MRSA infections.


The contribution of four immunogenetic markers for predicting persistent activity in patients with recent-onset rheumatoid arthritis or undifferentiated arthritis.
We assessed the contribution of four baseline markers-HLA-DRB1 shared epitope (SE), -308 tumor necrosis factor α gene promoter polymorphism, rheumatoid factor, and anticitrullinated peptide antibodies-for predicting persistent activity (DAS28 score ≥2.6) after one year of followup in a cohort of 201 patients with recent-onset rheumatoid arthritis (RA) or undifferentiated arthritis (UA) aged 16 years or older who had a 4-week to 12-month history of swelling of at least two joints. Patients had not been previously treated with corticosteroids or disease-modifying antirheumatic drugs (DMARD). In the best logistic regression model, only two variables were retained: SE positivity and number of DMARD administered (area under the curve = 76.4%; 95% CI: 69.2%, 84.4%; P < 0.001). The best linear regression model also included these two variables, explaining only 22.5% of the variability of DAS28 score. In this study, given an equal number of DMARD administered, the probability of persistent activity in patients with recent-onset RA or UA was significantly influenced by SE presence.


Open-labeled randomized controlled trial to compare diuretic therapy with recombinant human serum albumin and diuretic therapy for therapeutic treatment of ascites in patients with advanced liver cirrhosis: An exploratory trial.
There have been only a few trials demonstrating additional effects of human serum albumin (HSA) on diuretic therapy in patients with cirrhotic ascites. We aimed to evaluate the safety and efficacy of recombinant HSA, KD-294, treatment in patients with cirrhotic ascites. The inclusion criteria were patients 20-75 years of age, with cirrhotic ascites and a serum albumin concentration of less than 3.0 g/dL. Eighty-five patients were registered and 71 patients underwent randomization. Enrolled patients received oral spironolactone at 50 mg/day and i.v. furosemide at 20 mg/day in addition to low-sodium diet. They were divided randomly into a KD-294 treatment group (n = 35) or non-treatment control group (n = 36). Patients in the KD-294 group received KD-294 at 25 g/day for up to 5 days and those in the control group continued the diuretic therapy. They were followed up for 5 weeks. KD-294 was well tolerated. A correlation between the increases in serum albumin and decreases in bodyweight was not shown. However, changes of plasma renin concentration (PRC) showed a significant decrease in the KD-294 group compared with the control group. As a result of this exploratory analysis, patients with high PRC showed a significant correlation between increases in serum albumin and decreases in bodyweight. The present data do not show efficacy in all patients with cirrhotic ascites, however, they suggest that additional effects of HSA on diuretic therapy are expected in high PRC patients.


Clinical comparison of the autologous quadriceps tendon (BQT) and the autologous patella tendon (BPTB) for the reconstruction of the anterior cruciate ligament.
The use of the BPTB-autograft is a very common method for ACL reconstruction. Nevertheless, the problem of the typical donor-site-morbidity is unresolved. Recently, a transplant of quadriceps tendon, with an attached bone block (BQT) has been increasingly relied upon. The purpose of this study was to examine the clinical results of a group of patients after arthroscopic ACL reconstruction using either BPTB or quadriceps tendon autograft after a minimum follow-up of 2 years in terms of knee joint stability and function using both subjective and objective criteria. Retrospective study. A total of 260 patients with ACL ruptures were operated between 1995 and 2000; 124 received a BQT-autograft, including 8 revisions; 136 patients received a BPTB-autograft, exclusively primary interventions. The results were evaluated using the IKDC-, Noyes- and Lysholm-Scores. It was possible to re-evaluate 194 patients after a minimum follow-up period of 2 years, 64 of 260 patients (25%) were lost to follow-up. Ninety-seven percent of the operated knee joints in the BPTB-group were judged as normal or almost normal with the IKDC evaluation, as were 83% in the BQT-group (P < or = 0.001). The BQT-group showed a significantly better result in the evaluation of the donor-site-morbidity. We found no significant differences in the functional outcome according to the Lysholm- and Noyes-Score. In comparison to the results after using a BQT-transplant for reconstruction of a ruptured ACL the use of the BPTB-transplant is in favour concerning patient satisfaction and IKDC evaluation. For patients with activities involving kneeling or prolonged flexion of the knee joint BQT-transplants can be a good alternative, however.


Child control of food choices in Head Start families.
To describe parents' perceived feeding practices of their Head Start children as related to 6 feeding constructs based on the literature about the division of mealtime responsibilities. A qualitative study involving 45-minute audiotaped and transcribed discussion groups with items that probed constructs of interest. Five discussion groups were conducted in local, urban Head Start sites in a north central state. Head Start staff recruited 29 limited-income parents. Parental comments were coded into categories related to the 6 feeding constructs and perceived barriers to their implementation. Researchers independently coded the discussion group transcripts based on common themes and feeding constructs. Codes were discussed until consensus was reached and data analyzed using Ethnograph 5.0. Parents frequently reported that their children decided which foods were offered for meals and snacks. Most parents reported such child control of foods to be a barrier to pleasant meal times. Nutrition educators can suggest solutions to improve parental self-efficacy for practicing mealtime responsibilities, such as offering a choice of several healthy foods from which a child might choose. The importance of planned meal and snack times might be promoted based on aiding children's appetites at meals and reducing mealtime conflicts.


Problems of interpretation of serum concentrations of alpha-foetoprotein (AFP) in patients receiving cytotoxic chemotherapy for malignant germ cell tumours.
Serial determinations of serum alpha-foetoprotein (AFP) concentrations are well established in monitoring the response to therapy of malignant germ cell tumours. Using a radioimmunoassay (RIA) with a sensitivity down to 2kul-1 the majority (57%) of 28 patients with non-AFP producing germ cell tumours had measurable immunologically-reactive AFP in their serum while on treatment. Follow-up for 11-43 months (mean 27) without evidence of tumour activity indicated that this immunologically-reactive AFP was unlikely to be produced by tumour. In patients where the initial serum AFP was raised prior to chemotherapy the AFP concentration did not fall to the normal range at the end of the treatment in 16 (32%) of 41 patients. Follow-up of these patients for 9-48 months (mean 27) has resulted in 5 (12%) relapses in this group. Serum AFP greater than 20kul-1 three months after stopping chemotherapy was a good indicator of residual active tumour and 4 (57%) of 7 patients in this group relapsed. The production of detectable serum AFP is probably related to the type of chemotherapy used and only 7 (14%) of 51 patients treated for gestational choriocarcinoma had detectable AFP concentrations while on cytotoxic chemotherapy. The problem of interpretation of serum AFP concentration in patients with malignant germ cell tumour stresses the need to determine whether there are differences between AFP produced by germ cell tumours and that produced at other sites as a basis for a sensitive assay system able to discriminate between them.


Efficacy of anakinra for various types of crystal-induced arthritis in complex hospitalized patients: a case series and review of the literature.
There are few data on anakinra use after failure of conventional medications for crystal-induced peripheral arthritis and/or crowned dens syndrome among complex hospitalized patients. We retrospectively analyzed the outcome of six patients affected with subacute crystal-induced arthritis who had received anakinra in second or third line therapy, including three patients with crowned dens syndrome and three others with gouty arthritis. Patients' comorbidities, reasons for anakinra use and associated drugs, and outcomes were recorded. All patients presented with elevated inflammatory syndrome, systemic symptoms with poly/oligoarthritis. Except for absolute contraindications, all patients were previously treated with full or decreased dose of NSAID, colchicine, and/or glucocorticoids, with unsatisfactory response. All three gouty patients exhibited complete responses in all acute involvements under anakinra within 3 to 5 days, including one of them who needed the reintroduction of colchicine treatment that was previously unsuccessful. Crowned dens syndrome patients, including two with pseudogout and one with subacute hydroxyapatite deposition disease, needed 9 to 11 days to achieve complete response. Tolerance to anakinra was good. In case series of complex hospitalized patients, anakinra showed good activity in crowned dens syndrome and associated crystal-induced peripheral arthritis, with longer treatment duration than in gouty arthritis.


Is digital arteries recanalization useful to preserve the foot functionality and avoid toes amputation, after pedal recanalization? Clinical results.
The authors aimed to assess clinical results following percutaneous transluminal angioplasty (PTA) of pedal arteries and digital branches in order to avoid minor amputations or support surgical skin incisions, in patients with CLI and distal wounds on the toes. Baseline, procedural and mid-term outcome data of all consecutive patients with CLI and ulcerative lesion on the toes, in which endovascular treatment of the foot arteries and digital branches was attempted, were prospectively collected between January 2010 and January 2011. The primary end-point was acute success (i.e. technical, angiographic and procedural success). Secondary end-points included limb, foot and toes salvage rates, minor amputations, reocclusion/restenosis and repeat treatment. 1057 consecutive patients with CLI were treated and in 24 cases (2.3%), after tibial and foot arteries PTA, related to the presence of arterial lesion (stenosis/occlusion) in the digital branches, the recanalization of the target vessel was performed. Acute technical success was achieved in 100% of cases, with adequate angiographic results without peri-procedural complications. Clinical improvement was obtained and maintained after an average of 9 months. Amputation was avoided in 9 patients (37.5%), in 8 patients (29.6%) amputation involved only a distal phalange, in 5 patients (20.8%) toe amputations was necessary, in 2 patients (8.4%) trans-metatarsal amputation was performed. No below the ankle (BTA) or major amputations were performed. Endovascular recanalization of digital branches in patients with CLI and distal wounds on the toes is feasible and safe; represent a support to avoid minor amputations or surgical skin lesion healing.


High-resolution copy number analysis of clear cell endometrial carcinoma.
Uterine cancer is the 6th leading cause of cancer death amongst American women. Most uterine cancers are endometrial carcinomas (ECs), which are classified into histological subtypes including endometrioid, serous, and clear cell ECs. Somatic copy number alterations (SCNAs) are frequent in serous EC, infrequent in endometrioid ECs, and poorly defined in clear cell ECs. The purpose of this study was to evaluate the occurrence of SCNAs in clinically diagnosed clear cell ECs. Paired tumor-normal DNAs for 51 ECs were hybridized to Illumina Infinium HumanHap650Y or Human660W-Quad Beadchips. Copy number calls were made using the Hidden Markov Model based SNP-FASST2 segmentation algorithm within Nexus Copy Number software (v.6.1). High-level SCNAs were defined as gain of ≥5 copies or homozygous deletion, both <10Mb. GISTIC 1.0, in Nexus, was used to identify statistically significant SCNAs, corrected for multiple testing. One or more high-level SCNAs were detected in 50% of 6 clear cell ECs, 78.6% of 28 serous ECs, and 17.6% of 17 endometrioid ECs. A positive association was found between high-level SCNAs and TP53 mutation across ECs (two-tailed p value<0.0001). Classifying tumors according to POLE, MSI, and TP53 status yielded four molecular subgroups; copy number altered tumors were more frequent in the TP53-mutated subgroup (95.8%) than in the unspecified subgroup (22.2%), and absent from the POLE and MSI subgroups. In conclusion, our study provides evidence of inter-tumor heterogeneity in the extent to which SCNAs occur in clinically diagnosed clear cell EC, and across molecular subgroups of EC. The co-occurrence of high-level SCNAs and TP53 mutations in some clear cell ECs is consistent with the view that a subset of clinically diagnosed clear cell ECs have molecular similarities to serous ECs.


Optimization of bioleaching conditions for metal removal from CCA-treated wood by using an unknown Polyporales sp. KUC8959.
The purpose of this study was to investigate the effect of extraction conditions (i.e., culture filtrate concentration, extraction temperature, and extraction time) on the removal of metals from chromated copper arsenate (CCA)-treated wood particles by using an unknown Polyporales sp. KUC8959. As the first research, a 20-run central composite design using response surface methodology was applied to optimize the system and construct the models, which predicted metal removal by bioleaching. The coefficients of determination of fitted models were 0.874-0.989, which indicated that the models can predict the metal removal yield accurately under various conditions. The Cu removal model suggested that the following conditions, culture filtrate concentration of 45.8%, extraction temperature of 34.2 °C, and extraction time of 20.6 h, were required for maximal removal of Cu (82.1%). The model predicted that extraction conditions of increased severity would result in complete removal of Cr and As from CCA-treated wood particles. In order to confirm actual metals removal efficiency, metals extraction was subsequently conducted under optimal bioleaching condition evaluated in this study. By applying the model, we demonstrated 83.9% Cu, 96.0% Cr, and 99.3% As removal from treated wood particles.


Prospective Cohort Real-World Study on Neuroendocrine Tumor Patient's Quality of Life During Peptide Receptor Radionuclide Therapy With 177Lu-DOTATATE.
The aim of this study was to report lutetium-177 (177Lu)-DOTATATE radionuclide therapy from a patient perspective and their health-related quality of life. This prospective cohort study, including adult patients treated with 177Lu-DOTATATE. At the beginning of the follow-up (T1), socioeconomic and clinical information was collected, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30-v3 and GI.NET21 were applied. Follow-up was performed at the third cycle (T2) and 3 months after the end of treatment (T3). Student t test for paired samples was used to compare quality of life at T1, T2, and T3. Thirty-eight patients with stage IV disease and mean age of 52.54 (standard deviation, 12.49) years were included. The most prevalent site was the gastrointestinal tract (39.7%). Global health improved between T2 and T3 (P = 0.022) and T1 and T3 (P = 0.038). Functional scales did not indicate significant changes between the periods. Regarding symptoms, significant improvements in nausea and vomiting and gastrointestinal symptoms were observed between T2 and T3 (P = 0.012 and 0.029) and T1 and T3 (P = 0.012 and 0.011), respectively. 177Lu-DOTATATE therapy improved global health and reduced disease-related symptoms in NET patients, positively impacting health-related quality of life.


Adrenocortical pregnenolone-binding protein: identification and antibody development.
Pregnenolone-binding activity isolated from the cytosol of the guinea pig adrenal cortex appears to correspond to a Mr 34,000 protein when examined by SDS-polyacrylamide gel electrophoresis during different stages of purification. To verify this finding the Mr 34,000 protein band was eluted from the SDS gel and used to generate a polyclonal antibody. Immobilized anti 34,000 IgG on protein A-Sepharose was found to extract pregnenolone-binding activity from solution in contrast to pre-immune IgG and an antibody raised against a Mr 30,000 protein isolated simultaneously. In addition, protein eluted from the protein A-anti 34,000 IgG complex exhibited the expected molecular weight of 34,000 when examined on an SDS gel. These results, thus, confirm that the pregnenolone-binding protein is indeed a protein of Mr 34,000.


A marine microbiome antifungal targets urgent-threat drug-resistant fungi.
New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Candida auris. Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug-resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as C. auris.


Action and reaction: the biological response to siRNA and its delivery vehicles.
RNA interference (RNAi)-based therapeutics have significant potential for the treatment of human disease. Safe and effective delivery of RNA to target tissues remains a major barrier to realizing its clinical potential. Several factors can affect the in vivo performance of short interfering RNA (siRNA) delivery formulations, including siRNA sequence, structure, chemical modification, and delivery formulation. This review provides an introduction to the principles underlying the pharmacokinetics and pharmacodynamics of systemically administered siRNA and its delivery formulations, including the factors that lead to its degradation, clearance, and tissue uptake, as well as its potential for immunogenicity, toxicity, and off-target effects within the body.


Sporotrichosis in an unusual location--dermatologically and geographically.
We report the unusual fixed cutaneous variety of sporotrichosis in a patient hailing from Uttarkashi (Uttar Pradesh) in the north-western part of India.


Reciprocal homologous recombination in or near antibody VDJ genes.
To determine if rearranged heavy chain variable (VDJ) genes can recombine with each other by crossing over of DNA strands, we constructed a transgene that contained a promoter, VDJ gene, reporter gene to detect crossover events, intron enhancer, matrix attachment region, and constant gene for IgM (C mu). Following immunization of transgenic mice, hybrid molecules were isolated from B cell DNA which contained the transgene recombined with the endogenous IgH locus. Reciprocal products of crossovers were detected by plasmid rescue and PCR amplification, and they were sequenced. Recombination occurred somewhere within 147 bp of homology that contained the JH4 gene segment and 3' flanking DNA. The recombined transgenes had a 20-fold increase in mutation in the VDJ region compared to nonrecombined transgenes, which indicates that DNA sequences 3' of the C mu gene in the endogenous IgH locus are necessary for full activity of the mutator mechanism. The recovery of recombinants between VDJ transgenes and endogenous VDJ genes raises the possibility that reciprocal recombination may somatically diversify rearranged genes between maternal and paternal alleles.


Interaction of lipids with the plasma membrane of sperm cells. III. Antifusigenic effect by phosphatidylserine.
Addition of 10% phosphatidylserine to dipalmitoyl-phosphatidylcholine liposomes, containing 3H-cholesterol or 14C-phosphatidylcholine, inhibited interactions between liposomes and rabbit spermatozoa. Phosphatidylserine also caused an apparent decrease in the inhibitory effect of cholesterol-bearing liposomes on sperm fertilizing ability.


A diachronic examination of biomechanical changes in skeletal remains from Tombos in ancient Nubia.
Using morphometric assessment, we diachronically analyse mechanical stress and limb function at the Tombos (modern Sudan) archaeological site through time and changing socioeconomic circumstances. Based on previous research, we expect that during the Third Intermediate/Napatan (c. 1070-656 BCE) people were larger and more physically active than in the New Kingdom (∼1400-1070 BCE). On the appendicular skeleton of adults 57 measurements were obtained on individuals from 67 discrete burials and 370 commingled skeletal elements. These raw measurements were analysed statistically. Individuals from the discrete burials were used to calculate body mass and estimate mechanical behaviour (torsional and bending rigidity of long bones) modeled using beam theory across several bones of the upper and lower limbs. Body mass estimates for both sexes show people during the Third Intermediate/Napatan period were statistically significantly larger. On the upper limb for both sexes, variation reflects joint stabilisation and actions of flexion and extension at the elbow and/or supination/pronation of the forearm. On the lower limb, females show variation related to weight bearing activities and foot flexion; male variation is related to weight bearing activities, joint movement and stabilisation. These data point to altered habitual behaviour and physical activity for both sexes at Tombos through time. Suggested causes for both sexes include increased agricultural activities, and for males increased granite quarrying and equestrian activities. Using analyses of multiple bones of the upper and lower limbs in conjunction with biomechanical analyses, this study demonstrates the importance of the examination of physical activities in past populations, highlighting changes that can occur with sociopolitical transitions.


Increased subcortical neural responses to repeating auditory stimulation in children with autism spectrum disorder.
Recent research has highlighted atypical reactivity to sensory stimulation as a core symptom in children with autism spectrum disorder (ASD). However, little is known about the dysfunctional neurological mechanisms underlying these aberrant sensitivities. Here we tested the hypothesis that the ability to filter out auditory repeated information is deficient in children with ASD already from subcortical levels, yielding to auditory sensitivities. We recorded the frequency-following response (FFR), a non-invasive measure of the neural tracking of the periodic characteristics of a sound in the subcortical auditory system, to compare repetition-related effects in children with ASD and typically developing children. Results revealed an increase of the FFR with stimulus repetition in children with ASD compared to their peers. Moreover, such defective early sensory encoding of stimulus redundancy was associated with sensory overload. These results highlight that auditory sensitivities in ASD emerge already at the level of the subcortical auditory system.


[Does the ingestion of caustics produce irreversible motor changes in the esophagus? Manometric study of 17 cases].
During the acute period of caustic esophagitis, important alterations in esophageal motor function appear. However, it is not known if these alterations persist later. To determine whether motor disorders persist (after the aggression) in the esophagus that has suffered caustic aggression, a manometric study was made in two groups of patients classified as mild (9 cases) or severe esophagitis (8 cases), and results were compared with those of a control group. Patients who had developed stenosis or suffered the caustic aggression less than a year earlier were excluded. The probable existence of motor anomalies could determine the appearance of dysphagia or reduce the effectiveness of motor clearance of the esophageal body, thus conditioning a situation of esophageal defenselessness against physiological or eventual abnormal episodes of gastroesophageal reflux (RGE). Our results indicate that in a variable percentage of cases some peristaltic dysfunctions can persist in the esophageal body in relation to the severity of the initial lesion.


The prevalence and risk factors of stroke in patients with chronic schizophrenia.
To investigate the stroke risk and risk factors in patients with chronic schizophrenia. This study was a large-sample, cross-sectional survey. A total of 363 patients with chronic schizophrenia were selected from the Changping Traditional Chinese Medicine Hospital, Beijing, in August 2014. The patients were divided into either stroke group or control group based on the presence of stroke. Clinical evaluation included positive and negative syndrome scale assessment and a detailed questionnaire to collect the general information and disease-related conditions. The prevalence of stroke was 16.5% (60 cases). Stroke and control groups showed a significant difference in age, sex, smoking, combined medication, doses, negative factor score in positive and negative syndrome scale, body mass index, waist circumference, and systolic blood pressure. Multivariate analysis showed that a number of factors are significantly related to stroke, including age, sex, smoking, combined medication, doses, body mass index, and systolic blood pressure. The prevalence of stroke is relatively higher in Chinese patients with chronic schizophrenia. Chronic schizophrenia patients are more likely to suffer from stroke; meanwhile, a number of risk factors were identified, including old age, female sex, smoking history, combined medication with a variety of drugs, high doses, obesity, and high blood pressure.


Mental retardation, craniofacial dysmorphism, hypogonadism, diabetes mellitus and epilepsy in four siblings. A "new" mental retardation syndrome.
In this report we describe a distinct and apparently new mental retardation syndrome in four siblings: three brothers and one sister. They present slight to moderate mental retardation associated with a peculiar craniofacial dysmorphism (4/4), hypergonadotrophic hypogonadism (4/4), eunuchoid habitus (4/4), diabetes mellitus (4/4) and epilepsy (3/4).


Synergistic effect of long-term feed deprivation and temperature on the cellular physiology of meagre (Argyrosomus regius).
The present study investigates the effects of water temperature under prolonged feed deprivation on meagre's (Argyrosomus regius) antioxidant defense system and apoptotic pathway. Therefore, triplicate groups of fish were subjected to 4 water temperatures (17, 20, 23, 26 °C) and deprived of feed for 60 days. Heat shock response (HSR) indicators (Hsp70 and Hsp90), activation of MAPK family members, uniquitination, antioxidant enzymatic activities of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR), and apoptotic indicators such as caspases levels and the ratio of Bax/Bcl-2 were determined in liver and muscle samples that were collected on days 0, 14, 41 and 60. Long term feed deprivation and temperature variations resulted in granulomatosis, HSR induction, MAPK activation, ubiquitination, and triggering of the antioxidant defense and apoptotic machinery of the meagre. Although these responses were differentially expressed at each different imposed temperatures, the most significant variations were mainly observed below 20 °C and above 23 °C. Correlation analysis showed a significant relation between the examined indicators. Thus, the obtained data herein indicated that long term food deprivation induces oxidative stress in fish.


Smoking and mortality in 81,344 drivers in Guangzhou, China.
Previous studies on drivers focused on the effect of their exposure to vehicle exhaust and there is little evidence of the effect of smoking. This cohort analytical study aimed to examine the mortality of drivers relative to smoking and professional driving in Guangzhou, China. Information on demographic characteristics, type of driver (professional and non-professional), smoking, and drinking were retrieved from medical records of drivers who applied for driving licences from March to December 1992. Vital status and causes of death of 81,344 men aged 30 or above were ascertained to the end of September 1999 (follow up, mean=7.14 years, median=7.17 years). At baseline, the mean (SD) age was 40.8 (5.6) years. One third were professional drivers; 49.0% were daily smokers. 858 Deaths were identified. The relative risk of overall mortality for ever smoking was 1.24 (95% confidence interval (95% CI) 1.07 to 1.44) after adjusting for age, alcohol drinking, education, and type of drivers. Compared with non-professional drivers, professional drivers had similar risks of death, and their relative risk of overall mortality for ever smoking was 1.35 (1.06 to 1.71). Smoking is a more important cause of death than professional driving itself. The results show serious public health problems in the early stage of the tobacco epidemic and support urgent measures to help drivers stop smoking.


The problem of human leptospirosis in Barbados.
The results of a retrospective study of human leptospirosis cases occurring in Barbados during the period 19-68-74, and of serological findings among high risk occupational groups, fever cases and health centre patients monitored for the disease during 1975-77, indicate that infection by serotype fort-bragg of the Autumnalis group is widespread in this Caribbean island. The occupational groups most affected are sanitation workers and sugar-cane workers. Results of serological tests conducted at the principle hospital are comparable with the results obtained by the microscopic agglutination reference test procedure conducted at the Pan American Zoonosis Centre (CEPANZO).


Histomorphometric diagnostics of renal osteopathy in chronic dialysis patients at high risk of cardiovascular disease.
Chronic kidney disease-mineral and bone disorder (CKD-MBD) ranks among clinically and pathogenetically significant complications in patients with CKD. Numerous factors are involved in its development, and histomorphometric analysis of the bone tissue is still necessary for accurate diagnosis. The open, pilot, prospective study aimed at performing a comprehensive histomorphometric bone analysis in 26 dialysis patients and assessing the relationships of different types of CKD-MBD to selected parameters of calcium and phosphate metabolism, densitometry, activity of parathyroid glands, presence of diabetes mellitus, and duration of dialysis treatment. Comparison of the histomorphometric characteristics demonstrated statistically significant correlations between the volume of bone trabeculae and s-procollagen 1 (.754) as well as s-calcitonin (.856). Similarly, there was a positive correlation between the size of tetracycline lines and volume of bone trabeculae (.705) and a strong negative correlation with the thickness of trabeculae (-.442). When assessing the serum levels of s-osteoprotegerin and serum RANKL, there was a correlation with osteoid thickness and bone trabeculae thickness. In case of s-osteoprotegerin, a statistical power was demonstrated in relation to osteoid thickness (.880); in case of s-RANKL, a statistical power was demonstrated in relation to the thickness of trabeculae (.830). When assessing the influence of dialysis duration, relationships to the volume of trabecular bone (.665) and volume of bone trabeculae (.949) were demonstrated. Finally, a relationship between s-1,25-hydroxyvitamin D and s-osteoprotegerin was observed (.739); also the relationships demonstrated were significantly lower volume of bone trabeculae in men (p = 0.067) and lower values of s-osteocalcin and s-procollagen 1 in diabetic patients (p = 0.014). The results provide new noninvasive possibilities of CKD-MBD detection that are based on selected serum parameters of bone metabolism. Presented are possibilities of noninvasive assessment of different types of CKD-MBD using serum osteomarkers in relation to comprehensive CKD-MBD histomorphometry.


Thiaisoleucine and protein synthesis.
Thiaisoleucine is an isoleucine analogue having the gamma-methylene group of the valerianic carbon chain substituted by a sulphur atom. It has been demonstrated that thiaisoleucine is activated and transferred to tRNAIle by rat liver aminoacyl-tRNA synthetase and inhibits isoleucine incorporation into polypeptides in protein synthesizing systems from rat liver or rabbit reticulocytes, whereas it does not affect either leucine incorporation or ribosome run-off or polypeptide chain elongation rate. All tests were performed in comparison with O-methyl-threonine, an isoleucine analogue with the gamma-methylene group substituted by an oxygen atom. In all the reactions studied, both thiaisoleucine and O-methyl-threonine act as competitive inhibitors of isoleucine. With respect to O-methyl-threonine, thiaisoleucine shows higher activity as an isoleucine inhibitor.


[NO-dependent mechanisms of ecdysterone protective action on the heart and vessels in streptozotocin-induced diabetes mellitus in rats].
Ecdysterone (100 ng/100 g) chronic oral administration (2 months after STZ (5 mg/100 g) administration) normalized plasma glucose levels in rats. This potent hypoglycemic effect of ecdysterone depend on inhibition of non-constitutive NO synthesis by Ca(2+)-independent iNOS and NADP-dependent nitrate reductase as well as inhibition of L-arginine degradation by arginase result in up-regulation of Ca(2+)-dependent constitutive NO synthesis by eNOS or mithochondrial nNOS in heart and aorta of rats.


[Evaluation of renal cyclic adenosine monophosphate, serum parathyroid hormone and phosphate reabsorption in recurrent calcium urolithiasis, healthy controls and hyperparathyroidism (author's transl)].
In three groups (n = 12 each) of male controls (22--43 years), patients with recurring calcium urolithiasis (21--36 years) and hyperparathyroidism (HPT; 17--71 years) proven by surgery renal cyclic adenosine monophosphate (RcAMP), fractional tubular phosphate reabsorption and serum parathyroid hormone (PTH) were measured during endogenous creatinine clearance. RcAMP (muMol/g creatinine) was: controls 1.48 +/- SEM 0.27; stone formers 2.037 +/- 0.343 (not significantly different); HPT 6.234 +/- 0.454 (p less than 0.001). There is no overlap between HPT and controls. Phosphate reabsorption is least in HPT (0.84 +/- 0.015), higher in controls (0.924 +/- 0.004) and stone formers (0.941 +/- 0.007). All differences are statistically significant. Under the conditions selected (moderate hydration of individuals) Serum PHT (pg-equiv/ml) is lowest in stome formers (less than 100--339), higher in controls (less than 100--933) and HPT (400--1150). there is no overlap in PHT between the former and the latter group but a marked one between controls and HPT. For clinical purposes the resulting diagnostic uncertainty in a given patient can be overcome by additional determinations of RcAMP and ionised serum calcium: when referring to serum PTH HPT patients fall outside, RCU patients within 2 standard deviations of either parameter in control subjects. This procedure presently appears superior to those proposed in the past (urinary cAMP etc.) but requires confirmation in larger patient populations. Moreover, since HPT prevails in middle and upper age decades, their RcAMP values and those of RCU patients should be related to a range seen in closely age- and sex-matched controls.