Sex differences in subcortical auditory processing only partially explain higher prevalence of language disorders in males.
Males and females differ in their subcortical evoked responses to sound. For many evoked response measures, the sex difference is driven by a faster developmental decline of auditory processing in males. Using the frequency-following response (FFR), an evoked potential that reflects predominately midbrain processing of stimulus features, sex differences were identified in the response to the temporal envelope of speech. The pattern of later and smaller responses in males versus females is consistent with two of the three response features that track with language development and reading abilities. Therefore, here we analyzed subcortical response consistency, the third distinguishing feature of language ability. Furthermore, though the envelope is primarily a low-frequency response, the greatest sex differences were observed in harmonics encoding. To better understand these sex differences, we extended these findings to the temporal fine structure response, which is biased to high-frequency information. Using the same 516 participants as previously reported (Krizman et al., 2019), we analyzed the effect of sex across development on response consistency and the encoding of temporal fine structure, as indexed by the subtracted frequency-following response. We found that while males and females did not differ on response consistency, there was an effect of age on this measure. Moreover, while males still showed a faster decline in harmonic encoding, the magnitude and breadth of the sex differences were smaller (accounting for 2% variance) in the temporal fine structure response compared to the envelope response. These results suggest that sex differences are distinct, at least in part, from the differences that underlie language abilities and that developmental sex differences reflect subcortical auditory processing differences of both the temporal envelope and fine structure of sounds.


Genomic and Clinical Correlates of Adrenocortical Carcinoma in an Adult Patient with Li-Fraumeni Syndrome: A Case Report.
Li-Fraumeni Syndrome (LFS) is defined by germline mutations of the p53 tumour suppressor gene. Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that is commonly associated with LFS. Most LFS-linked ACC cases occur in children, and limited research has been dedicated to the clinical outcomes and genomics of adult cases with LFS-linked ACC. We report on a 34-year-old female who was diagnosed with three separate malignancies: stage III invasive ductal carcinoma of the right breast, metastatic ACC from the right adrenal gland, and grade 2 pleomorphic sarcoma of the left hand. Her invasive breast ductal carcinoma was treated with neoadjuvant chemotherapy, and she received a bilateral mastectomy after her LFS was confirmed with genetic blood testing. Adrenal ACC was initially treated with a right nephrectomy and adrenalectomy, followed by adjuvant mitotane and two lines of chemotherapy after disease recurrence. Her hand sarcoma was treated by second ray amputation. Further, we conducted deep next-generation sequencing of each of her unique tumour tissue samples using FoundationONE CDx. A whole-genome shot capture followed by in vitro sequencing performed by the Illumina® HiSeq platform revealed a germline P191fs*18 TP53 mutation across all three tissue samples. This case provides insight into the genomics and clinical characteristics of LFS-linked adult-onset ACC and demonstrated that p53 mutations were preserved throughout each malignancy, without apparent treatment pressures on genomic profiling. This case reinforces the critical importance of adopting best practices for LFS, which include the implementation of highly vigilant screening and management of care in a multidisciplinary setting.


Effect of maintenance azithromycin on established bronchiolitis obliterans syndrome in lung transplant patients.
Bronchiolitis obliterans syndrome (BOS), the main cause of late mortality following lung transplantation, is defined as an irreversible decline in forced expiratory volume in 1 s (FEV1). Previous studies using azithromycin for BOS in lung transplant patients have demonstrated a potential reversibility of the decline in FEV1. To examine whether initiating azithromycin reverses decline in FEV1 in lung transplant recipients with established BOS of at least three months. Pulmonary function tests were performed every three months in seven lung transplant recipients with established BOS of at least three months. FEV1 was recorded at six and three months before initiation, at time of initiation, and three, six, nine and 12 months postazithromycin initiation. The primary end point was change in FEV1. During the study, no immunosuppressive medication changes or acute rejection episodes occurred. Mean time from transplant to azithromycin initiation was 64 months (range 17 to 117 months). Mean time from BOS diagnosis to azithromycin initiation was 22 months (range three to 67 months). Rate of FEV1 decline from six months before azithromycin initiation, and rates of FEV1 increase from initiation to three and 12 months post-treatment initiation, were not statistically significant (P=0.32, P=0.16 and P=0.18, respectively). Following a trend toward improvement in the first three months after treatment initiation, FEV1 tended to stabilize. Although several studies address the possible benefit of maintenance azithromycin in lung transplant patients with BOS, the role of the drug remains unproven in these patients, and would best be addressed by a large randomized controlled trial.


Oxygen consumption and noise-induced TTS in humans.
Young adult men (N:16) were used to examine the effects of increased oxygen availability upon noise-induced TTS. In 2 sessions a day apart, Ss inhaled either medical grade air or 100% oxygen during monaural exposure in their better ear to 10 min of narrow-band noise centered a 3 kc/s at 100 db SPL. Oxygen consumption was recorded with a respirometer during oxygen breathing. Conditions were counterbalanced among Ss. TTS2 min at 4 kc/s was significantly less with oxygen inhalation, confirming a previous study; however, no relationship was found between amount of oxygen consumed and the amount of TTS during pure oxygen inhalation.


Compensating for instantaneous signal mixing in transfer entropy analysis of neurobiological time series.
The transfer entropy (TE) has recently emerged as a nonlinear model-free tool, framed in information theory, to detect directed interactions in coupled processes. Unfortunately, when applied to neurobiological time series TE is biased by signal cross-talk due to volume conduction. To compensate for this bias, in this study we introduce a modified TE measure which accounts for possible instantaneous effects between the analyzed time series. The new measure, denoted as compensated TE (cTE), is tested on simulated time series reproducing conditions typical of neuroscience applications, and on real magnetoencephalographic (MEG) multi-trial data measured during a visuo-tactile cognitive experiment. Simulations show that cTE performs similarly to TE in the absence of signal cross-talk, and prevents false positive detection of information transfer in the case of instantaneous mixing of uncoupled signals. When applied to MEG data, cTE detects significant information flow from the visual cortex to the somatosensory area during task execution, suggesting the activation of mechanisms of multisensory integration.


DNA capture-probe based separation of double-stranded polymerase chain reaction amplification products in poly(dimethylsiloxane) microfluidic channels.
Herein, we describe the development of a novel primer system that allows for the capture of double-stranded polymerase chain reaction (PCR) amplification products onto a microfluidic channel without any preliminary purification stages. We show that specially designed PCR primers consisting of the main primer sequence and an additional "tag sequence" linked through a poly(ethylene glycol) molecule can be used to generate ds-PCR amplification products tailed with ss-oligonucleotides of two forensically relevant genes (amelogenin and human c-fms (macrophage colony-stimulating factor) proto-oncogene for the CSF-1 receptor (CSF1PO). Furthermore, with a view to enriching and eluting the ds-PCR products of amplification on a capillary electrophoretic-based microfluidic device we describe the capture of the target ds-PCR products onto poly(dimethylsiloxane) microchannels modified with ss-oligonucleotide capture probes.


Fold catastrophes and the dependence of free-energy barriers to conformational transitions on applied force.
Applied mechanical force (f) can activate conformational change in molecules by reducing the height of a free-energy barrier (DeltaG(b)). In this paper, molecular dynamics simulations are carried out with umbrella sampling and self-consistent histogram methods to determine free-energy profiles for a coarse-grained model of a protein under an applied force. Applied force is shown to cause fold catastrophes, where free-energy minima are destabilized until they disappear. It is well-known that a fold catastrophe at force f = B implies the scaling DeltaG(b) approximately |B - f|(3/2) in the limit of DeltaG(b) --> 0, but it is not clear whether this scaling is accurate for physically relevant barrier heights. The simulation results show that the fold catastrophe scaling is in fact accurate in the physically relevant regime and that the two-parameter function DeltaG(b) = A(B - f)(3/2) is superior to the two-parameter linear function for parametrizing changes in free-energy barriers with applied force.


Elimination of transmissible spongiform encephalopathy infectivity and decontamination of surgical instruments by using radio-frequency gas-plasma treatment.
It has now been established that transmissible spongiform encephalopathy (TSE) infectivity, which is highly resistant to conventional methods of deactivation, can be transmitted iatrogenically by contaminated stainless steel. It is important that new methods are evaluated for effective removal of protein residues from surgical instruments. Here, radio-frequency (RF) gas-plasma treatment was investigated as a method of removing both the protein debris and TSE infectivity. Stainless-steel spheres contaminated with the 263K strain of scrapie and a variety of used surgical instruments, which had been cleaned by a hospital sterile-services department, were examined both before and after treatment by RF gas plasma, using scanning electron microscopy and energy-dispersive X-ray spectroscopic analysis. Transmission of scrapie from the contaminated spheres was examined in hamsters by the peripheral route of infection. RF gas-plasma treatment effectively removed residual organic residues on reprocessed surgical instruments and gross contamination both from orthopaedic blades and from the experimentally contaminated spheres. In vivo testing showed that RF gas-plasma treatment of scrapie-infected spheres eliminated transmission of infectivity. The infectivity of the TSE agent adsorbed on metal spheres could be removed effectively by gas-plasma cleaning with argon/oxygen mixtures. This treatment can effectively remove 'stubborn' residual contamination on surgical instruments.


A defect in the TUSC3 gene is associated with autosomal recessive mental retardation.
Recent studies have shown that autosomal recessive mental retardation (ARMR) is extremely heterogeneous, and there is reason to believe that the number of underlying gene defects goes into the thousands. To date, however, only four genes have been implicated in nonsyndromic ARMR (NS-ARMR): PRSS12 (neurotrypsin), CRBN (cereblon), CC2D1A, and GRIK2. As part of an ongoing systematic study aiming to identify ARMR genes, we investigated a large consanguineous family comprising seven patients with nonsyndromic ARMR in four sibships. Genome-wide SNP typing enabled us to map the relevant genetic defect to a 4.6 Mbp interval on chromosome 8. Haplotype analyses and copy-number studies led to the identification of a homozygous deletion partly removing TUSC3 (N33) in all patients. All obligate carriers of this family were heterozygous, but none of 192 unrelated healthy individuals from the same population carried this deletion. We excluded other disease-causing mutations in the coding regions of all genes within the linkage interval by sequencing; moreover, we verified the complete absence of a functional TUSC3 transcript in all patients through RT-PCR. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltransferase complex that catalyzes a pivotal step in the protein N-glycosylation process. Our data suggest that in contrast to other genetic defects of glycosylation, inactivation of TUSC3 causes nonsyndromic MR, a conclusion that is supported by a separate report in this issue of AJHG. TUSC3 is only the fifth gene implicated in NS-ARMR and the first for which mutations have been reported in more than one family.


Survival after Anticancer Treatment of Terminally Ill Patients with Ovarian Carcinoma.
Background: It remains unclear whether the end-of-life (EOL) treatment/environment impacts on survival after anticancer treatment in terminally ill women with ovarian carcinoma (OC). Objective: The aim of this investigation was to clarify how long those women actually survived after their last anticancer treatments and their hallmarks. Setting, Design, and Measurements: Between 2003 and 2011, 79 terminally ill women with OC were retrospectively analyzed as a single institutional study. Postcancer treatment survival (PCS), defined as the duration between the last date of the abovementioned "cancer treatment" and that of death from any cause, was analyzed on stratification by type of supportive care or where patients spend their EOL. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier and Cox regression analyses were employed to compare PCS between the two groups. Results: The median PCS of patients was 10.8 weeks. In the multivariable analysis, the performance status and EOL place retained their significance as independent prognostic factors of poorer PCS (performance status [2-3/0-1]: hazard ratio [HR] = 3.279 [95% confidence interval; CI 1.967-5.586; p < 0.0001], EOL place [hospital/home hospice]: HR = 0.574 [95% CI 0.355-0.913; p = 0.0188]). In the IPTW-adjusted cohort, the median PCS rates were 15.0 and 9.7 weeks in patients of home/hospice and hospital groups, respectively (p = 0.04). Also in the IPTW cohort, the EOL place retained its significance (IPTW-adjusted: HR [95% CI]: 1.548 [1.009-2.374], p = 0.045, multivariable adjusted with IPTW: HR [95% CI]: 1.670 [1.077-2.588], p = 0.022). Conclusion: Our current data may be hypothesis generating; it is possible that the EOL environment is a crucial prognostic factor for survival after anticancer treatment.


Angiogenesis in endometrial carcinoma.
Tumor angiogenesis is essential for tumor growth and metastases. Recently, microvessel density (MVD), a measure of tumor angiogenesis, has been found to have prognostic significance for predicting metastasis and survival in many tumor types. This study was conducted to determine how MVD was related to several clinicopathologic parameters and correlated with metastasis and survival in patients with endometrial carcinoma. From 1979 through 1989, 85 cases of clinical Stage I and II endometrial carcinomas treated initially by hysterectomy with pelvic lymph node dissection were reviewed histologically. All hysterectomy specimens were stained immunohistologically for factor VIII-related antigen. MVD was counted in a x200 field (x20 objective lens and x10 ocular lens, 0.785 mm2 per field) in the most active area of neovascularization. Results were expressed as the highest number of microvessels identified within any single x200 field. Statistical analysis included the Mann-Whitney U test, Kruskal-Wallis test of variance, and the Spearman rank correlation test. Survival was calculated using the Kaplan-Meier method and differences in survival were analyzed using the log rank test. MVD and several other prognostic parameters were examined for their correlation with progression free survival (PFS) and overall survival (OS) by a multivariate analysis according to the Cox proportional hazards model. MVD was significantly correlated with tumor grade (P = 0.0281), myometrial invasion (P = 0.0282), and lymph-vascular space invasion (P = 0.0073). There was no correlation between microvessel count and lymph node status and stage. Patients with a high MVD (> or =60) had significantly worse PFS and OS than those with a low MVD (<60) (log rank test, P = 0.0116 and P = 0.0096, respectively). Multivariate analysis showed that MVD correlated significantly and independently with PFS and OS. In this study, MVD was found to be an independent prognostic factor for PFS and OS in patients with endometrial carcinoma.


Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia.
Serotonin 5-HT1A receptors are promising targets in the management of schizophrenia but little information exists about affinity and efficacy of novel antipsychotics at these sites. We addressed this issue by comparing binding affinity at 5-HT1A receptors with dopamine rD2 receptors, which are important targets for antipsychotic drug action. Agonist efficacy at 5-HT1A receptors was determined for G-protein activation and adenylyl cyclase activity. Whereas haloperidol, thioridazine, risperidone and olanzapine did not interact with 5-HT1A receptors, other antipsychotic agents exhibited agonist properties at these sites. E(max) values (% effect induced by 10 microM of 5-HT) for G-protein activation at rat brain 5-HT1A receptors: sarizotan (66.5), bifeprunox (35.9), SSR181507 (25.8), nemonapride (25.7), ziprasidone (20.6), SLV313 (19), aripiprazole (15), tiospirone (8.9). These data were highly correlated with results obtained at recombinant human 5-HT1A receptors in determinations of G-protein activation and inhibition of forskolin-stimulated adenylyl cyclase. In binding-affinity determinations, the antipsychotics exhibited diverse properties at r5-HT1A receptors: sarizotan (pK(i)=8.65), SLV313 (8.64), SSR181507 (8.53), nemonapride (8.35), ziprasidone (8.30), tiospirone (8.22), aripiprazole (7.42), bifeprunox (7.19) and clozapine (6.31). The affinity ratios of the ligands at 5-HT1A vs. D2 receptors also varied widely: ziprasidone, SSR181507 and SLV313 had similar affinities whereas aripiprazole, nemonapride and bifeprunox were more potent at D2 than 5-HT1A receptors. Taken together, these data indicate that aripiprazole has low efficacy and modest affinity at 5-HT1A receptors, whereas bifeprunox has low affinity but high efficacy. In contrast, SSR181507 has intermediate efficacy but high affinity, and is likely to have more prominent 5-HT1A receptor agonist properties. Thus, the contribution of 5-HT1A receptor activation to the pharmacological profile of action of the antipsychotics will depend on the relative 5-HT1A/D2 affinities and on 5-HT1A agonist efficacy of the drugs.


Development of a multilocus sequence typing scheme for the opportunistic pathogen Pseudomonas aeruginosa.
A multilocus sequence typing (MLST) scheme has been developed for Pseudomonas aeruginosa which provides molecular typing data that are highly discriminatory and electronically portable between laboratories. MLST data confirm the data from previous studies that suggest that P. aeruginosa is best described as nonclonal but as having an epidemic population. The index of association was 0.17, indicating a freely recombining population; however, there was evidence of clusters of closely related strains or clonal complexes among the members of this population. It is apparent that the sequence types (STs) from single isolates, representing each of the present epidemic clones in the United Kingdom from Liverpool, Manchester, and the West Midlands, are not closely related to each other. This suggests distinct evolutionary origins for each of these epidemic clones in the United Kingdom. Furthermore, these clones are distinct from European clone C. Comparison of the results of MLST with those of toxA typing and serotyping revealed that strains with identical STs may possess different toxA types and diverse serotypes. Given that recombination is important in the population of P. aeruginosa, the lack of a linkage between toxA type and serotype is not surprising and reveals the strength of the MLST approach for obtaining a better understanding of the epidemiology of P. aeruginosa.


The induction of labour with prostaglandin F2alpha by intravenous infusion. I. Uterine activity, fetal heart rate and clinical condition of the newborns.
Attempt to induce labour with PGF2alpha was made for various indications in 22 primiparous and 27 multiparous patients being between the 35th and 44th weeks of pregnancy. Intravenous infusion of PGF2alpha was started with 3 mug/min. and increased in steps of 3 mug/min. at intervals of about one hour until labour-like contractions were recorded. This dose level was then maintained until delivery. Uterine activity and fetal heart rate was monitored prior to and throughout the infusion. The clinical condition of the newborns was also assessed by Apgar score and by physical examination one and four days after delivery. Labour was successfully induced with total doses ranging between 0.4 and 8.4 mg. In 88 per cent of the cases this resulted in vaginal deliveries within 2 to 12 hours. The latter part of the first stage as well as the second stage were remarkably short. Uterine hypertonus was observed in five cases (10%). Other types of abnormal uterine contractility patterns were fairly common. These were, however, not associated with pathological FHR changes except in one case where severe late decelerations were observed following marked uterine hyperactivity. The condition of the newborns was generally good and maternal side effects were very rare. PGF2alpha seems particularly valuable in cases of pre-term inductions where low Bishop scores are present but the risk of overstimulation demands careful supervision, if possible with cardiotochographic monitoring.


Differentiation of Acanthamoeba strains from infected corneas and the environment by using restriction endonuclease digestion of whole-cell DNA.
Restriction endonuclease digestion of Acanthamoeba whole-cell DNA was used to study the relationship between 33 morphologically identical strains from keratitis cases (30 strains), contact lens storage containers (2 strains), and soil (1 strain). Samples digested with BglII, EcoRI, or HindIII and separated by agarose gel electrophoresis contained detectable mitochondrial DNA restriction fragment length polymorphisms (RFLPs). By comparing RFLPs, the strains could be assigned to seven multiple-strain and three single-strain groups. The largest of these contained nine strains, eight of which were isolated in keratitis cases in various locations worldwide and may indicate a group particularly associated with keratitis. Restriction endonuclease analysis of whole-cell DNA is proposed as a valuable technique for detecting mitochondrial DNA RFLPs in the differentiation of morphologically identical Acanthamoeba strains and may therefore be useful in resolving the complex taxonomy of the genus, which has hitherto been founded on subjective morphological criteria.


Depressive symptoms and cigarette smoking among Native Hawaiians.
The present study estimated the prevalence of depressive symptoms and cigarette smoking and examined the relationship between depressive symptoms and cigarette smoking among native Hawaiians. Cross-sectional data from 524 rural, native Hawaiian from the Native Hawaiian Health Research Project are presented. Depressive symptoms were measured using the self-report Centre for Epidemiological Studies--Depression Scale. Information on smoking behavior and sociodemographic variables was collected. The prevalence of depressive symptoms was 15%, and significantly higher among participants with lower educational attainment. The prevalence of current smokers was 32%, and significantly higher among younger adults and participants with lower educational attainment. Regression analyses reported a significant relationship between CES-D scores and smoking status as well as between CES-D scores and number of cigarettes smoked daily. However, when education and age were included in the regression models, the relationships were attenuated. The findings and implications of this study are discussed.


HvALMT1 from barley is involved in the transport of organic anions.
Members of the ALMT gene family contribute to the Al(3+) resistance of several plant species by facilitating malate efflux from root cells. The first member of this family to be cloned and characterized, TaALMT1, is responsible for most of the natural variation of Al(3+) resistance in wheat. The current study describes the isolation and characterization of HvALMT1, the barley gene with the greatest sequence similarity to TaALMT1. HvALMT1 is located on chromosome 2H which has not been associated with Al(3+) resistance in barley. The relatively low levels of HvALMT1 expression detected in root and shoot tissues were independent of external aluminium or phosphorus supply. Transgenic barley plants transformed with the HvALMT1 promoter fused to the green fluorescent protein (GFP) indicated that expression of HvALMT1 was relatively high in stomatal guard cells and in root tissues containing expanding cells. GFP fused to the C-terminus of the full HvALMT1 protein localized to the plasma membrane and motile vesicles within the cytoplasm. HvALMT1 conferred both inward and outward currents when expressed in Xenopus laevis oocytes that were bathed in a range of anions including malate. Both malate uptake and efflux were confirmed in oocyte assays using [(14)C]malate as a radiotracer. It is suggested that HvALMT1 functions as an anion channel to facilitate organic anion transport in stomatal function and expanding cells.


Spreading and staining of human metaphase chromosomes on aminoalkylsilane-treated glass slides.
The properties of aminoalkylsilane-treated glass slides for the preparation of metaphase spreads and their staining quality have been studied and compared with those of slides which had only been cleaned in ethanol/ether. The parameters investigated were: (1) the average area of metaphases from cultures of blood from both healthy donors and haematology patients; (2) the influence of the positively charged 'coating' on the quality of quinacrine- and Giemsa-banding patterns; (3) non-specific background staining for these banding methods; (4) the number of metaphases as compared to the number of interphase cell nuclei per area of preparation; and (5) the Feulgen-staining intensities of chromosomes and chicken erythrocyte nuclei. The quality of metaphase preparations and the differential staining of chromosomes is better on aminoalkysilane-treated glass slides than that of preparations on routinely cleaned normal microscope slides. In the preparations on aminoalkylsilane-treated slides, the distribution of the cells over the glass surface is more homogeneous; and no influence could be detected on the relative frequency of metaphases as compared to the number of non-divided cell nuclei; the average area per metaphase is increased by about 10% and consequently the number of overlapping chromosomes is decreased. Preparations on aminoalkylsilane-treated glass, after Q-, G- and DAPI-banding procedures, always showed less binding of the staining compounds to the glass slide (a cleaner background) than those on routinely cleaned microscope glass slides. The Feulgen-pararosaniline staining intensities of human metaphase chromosomes and chicken erythrocyte nuclei are the same on aminoalkylsilane-treated slides and on routinely cleaned glass slides. Furthermore, the reproducibility and constancy of quinacrine banding was improved by development of an equilibrium staining method which does not require a washing procedure. The medium, containing 0.002% quinacrine, allows optimal staining results to be obtained for microphotography purposes within 30 min of staining (for visual inspection at least 90 min is required) and is used as the embedding medium. In combination with aminoalkylsilane-treated glass slides, this procedure leads to a clean background and reproducible banding patterns of excellent quality, the results being better and more constant than those of methods described before.


Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial.
Human-papillomavirus (HPV) testing is more sensitive, but less specific, than conventional cytology for detecting high-grade cervical intraepithelial neoplasia (CIN). We assessed whether HPV testing with triage by p16-INK4A overexpression can increase specificity while maintaining sensitivity. HPV-positive women were enrolled between June 10, 2003, and Dec 31, 2004 in a multicentre randomised controlled trial, which compared stand-alone HPV testing by Hybrid Capture 2 (experimental group) with conventional cytology, were referred for colposcopy. In seven of nine centres, cytospin preparations from these women were tested for p16-INK4A overexpression by immunostaining. The sensitivity and specificity for CIN grade 2 or more, determined at blind review of histology, were calculated for these women. We also estimated the relative sensitivity and relative referral to colposcopy that would have been obtained by HPV testing with p16-INK4A triage compared with conventional cytology. This trial is registered as a Standard Randomised Controlled Trial, number ISRCTN81678807. 24 661 women were randomly assigned to the experimental group. 1137 women (74% of those undergoing colposcopy in relevant centres), including 50 with CIN2 and 42 with CIN3 or cancer, had valid p16-INK4A immunostaining. For the endpoint of CIN2+, sensitivity and specificity of p16-INK4A (deemed positive with any number of stained cells-except endocervical, metaplastic, and atrophic cells if morphologically normal) in HPV-positive women of any age were 88% (81 of 92; 95% CI 80-94) and 61% (633 of 1045; 57-64), respectively. In the 35-60-year age group, the relative sensitivity of HPV testing and p16-INK4A triage versus conventional cytology for CIN2+ was 1.53 (95% CI 1.15-2.02) and relative referral was 1.08 (0.96-1.21). In the 25-34-year age group, relative sensitivity was 3.01 (1.82-5.17) and relative referral was 1.15 (0.96-1.37). In the latter age group, when 5% or more stained cells were deemed positive, the corresponding values were 2.06 (1.20-3.68) and 0.58 (0.46-0.73), respectively. HPV testing with p16-INK4A triage produces a significant increase in sensitivity compared with conventional cytology, with no substantial increase in referral to colposcopy.


[A case report of human lagochilascariasis coming from Pará State, Brazil].
A new case of lagochilascariasis is reported in a child from Xinguara, PA, Brazil. The patient had an abscess in the right cervical region, which was drained at the Clinical Hospital of UFG. Eggs and adult stages of Lagochilascaris minor were found in the secretion of the abscess. Treatment with albendazol, at a dosage of 400 mg/day for 30 days, associated with antibiotics promoted regression of the lesion.


Independent pathways leading to apoptotic cell death, oxidative burst and defense gene expression in response to elicitin in tobacco cell suspension culture.
We characterized pharmacologically the hypersensitive cell death of tobacco BY-2 cells that followed treatments with Escherichia coli preparations of INF1, the major secreted elicitin of the late blight pathogen Phytophthora infestans. INF1 elicitin treatments resulted in fragmentation and 180 bp laddering of tobacco DNA as early as 3 h post-treatment. INF1 elicitin also induced rapid accumulation of H2O2 typical of oxidative burst, and the expression of defense genes such as phenylalanine ammonia-lyase (PAL) gene at 1 h and 3 h after elicitin treatment, respectively. To investigate the involvement of the oxidative burst and/or the expression of defense genes in the signal transduction pathways leading to hypersensitive cell death, we analyzed the effect of several chemical inhibitors of signal transduction pathways on the various responses. The results indicated that (a) the cell death required serine proteases, Ca2+ and protein kinases, (b) the oxidative burst was involved in Ca2+ and protein kinase mediated pathways, but elicitin-induced AOS was neither necessary nor sufficient for cell death and PAL gene expression, and (c) the signaling pathway of PAL gene expression required protein kinases. These results suggest that the three signal transduction pathways leading to cell death, oxidative burst and expression of defense genes branch in the early stages that follow elicitin recognition by tobacco cells.


Reducing urinary tract infections in colon and rectal surgery.
Urinary tract infection is associated with increased morbidity, mortality, and healthcare costs. Colon and rectal surgery has been shown to be an independent risk factor for urinary tract infection. Decreased length of the indwelling urinary catheter may play a role in decreasing the rate of urinary tract infection. The aim of this study was to investigate the effect of standardized indwelling urinary catheter management on urinary tract infection. This was a prospective cohort study. This study was conducted in an urban academic tertiary care center. All of the patients were undergoing colon or rectal resection from 2010 to 2012 at a single National Surgical Quality Improvement Program participating institution. Intervention 1 (group 1) included implementation of a daily electronic order prompt requiring justification for an indwelling urinary catheter for >24 hours. Intervention 2 (group 2) included intervention 1 plus sterile intraoperative placement of a urinary catheter after the antiseptic preparation and draping of the patient. The primary outcome measured was urinary tract infection rate. A total of 811 patients were identified (control = 215; group 1 = 476; group 2 = 120). Patient demographics and comorbidities were similar among the groups. No differences existed in the proportion of proctectomy among the groups. Urinary tract infection rate decreased significantly with the implementation of each intervention (control, 6.9%; group 1, 2.7%; group 2, 0.8%; p = 0.004). The lone urinary tract infection in group 2 involved ureteral reconstruction and stent placement at the time of surgery. This study was limited by its small sample size and single institution design. The implementation of 2 low-cost practice interventions was associated with a statistically significant decrease in urinary tract infection in patients undergoing colorectal surgery at an academic tertiary care center.


Is severe visceral leishmaniasis a systemic inflammatory response syndrome? A case control study.
The objective of the study is to identify the main risk factors for death by New World visceral leishmaniasis and establish a coherent pathogenic substrate of severe disease based on clinical findings. Seventy-six deceased inpatients and 320 successfully treated inpatients with VL were studied in a case control study. Bacterial infection and bleeding were mutually exclusive events leading to death. Five risk factors were unique for death by bacterial infection (malnutrition, pulmonary rales, severe anemia, severe absolute neutropenia and higher neutrophil count), while another six were unique for death by bleeding (jaundice, severe relative neutropenia, severe thrombocytopenia, liver injury, kidney failure, higher bone marrow parasite load). Bacterial infection, bleeding, severe anemia, diarrhea, dyspnea, edema, jaundice and bone marrow parasite load were the main syndromes of visceral leishmaniasis among successfully treated patients. The data support the idea that bacterial infections are due to immune paralysis. Broad organ and system involvement is plausibly due to the high production of proinflammatory cytokines, whose actions fit well with visceral leishmaniasis. The syndromes and causative mediators are typical of a slowly developing systemic inflammatory response syndrome.


C-reactive protein, fibrinogen, lipoprotein (a), and lipid profile levels and platelet counts in ischemic stroke patients.
To ascertain the most prevalent risk factor for stroke. We performed a descriptive and analytical prospective study on patients with stroke admitted to the neurology wards of Imam Hospital, Tabriz, Iran during 2004 and 2005. The study comprised 100 ischemic stroke (IS) patients consisting of 46 men and 54 women with a mean age of 67 +/- 15, and 100 age and gender matched apparently healthy subjects. Plasma levels of C-Reactive protein (CRP), fibrinogen, platelet counts, lipoprotein (a) (LP (a)), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC), and triglycerides (TG) were measured in both patients and controls. Background disease was also investigated in the patients. Hemorrhagic and embolic stroke patients were excluded from the study. We found no significant difference in serum fibrinogen, HDL-c levels, and platelet counts between patients and control subjects, however, levels of LP (a), TG, LDH-c, and CRP were significantly higher in patients than controls. Among the predisposing background illnesses, the most common risk factors were hypertension and hyperlipidemia. The frequency of studied risk factors among patients was: no risk factors (20%), one risk factor (32%), 2 risk factors (36%), and 3 risk factors (12%). Hypertension was the most prevalent background disease in IS patients. We also found that although there is close relationship in the incidence of IS with levels of LP (a), TC, TG, LDL-c, and CRP, the cutoff point frequency of fibrinogen, CRP, LP (a), and platelet counts was variable from patient to patient.


Rhabdomyolysis Following Recovery from Severe COVID-19: A Case Report.
BACKGROUND Rhabdomyolysis occurs when muscle injury leads to the release of muscle cell constituents into circulation, often leading to significant systemic complications. There are many causes of rhabdomyolysis, and the etiology is often multifactorial or unclear. Current data suggest that acute COVID-19 may cause muscle injury that can lead to rhabdomyolysis, particularly in cases of severe illness requiring prolonged hospitalization; however, data on the long-term effects of COVID-19 on the musculoskeletal system are lacking. CASE REPORT We present a case of a woman with generalized weakness 1 week following discharge from the hospital after a prolonged admission for severe COVID-19. She was found to have acute kidney injury and elevated creatine kinase (CK) of 1775 U/L (normal 36-234 U/L). Her home medications, including her statin, were held, but her CK continued to rise, peaking at 15 085 U/L, and she developed renal failure necessitating renal replacement therapy. A thorough work-up for the underlying etiology of her rhabdomyolysis was pursued, including testing for autoimmune myositis, statin-associated necrotizing autoimmune myositis, and a muscle biopsy, which were all unrevealing. Ultimately, the patient's rhabdomyolysis was determined to likely be secondary to a post-viral myopathy from COVID-19. A toxic myopathy from medication use or a delayed critical illness myopathy from her recent prolonged hospitalization could have also contributed. CONCLUSIONS This case highlights the wide differential diagnosis of rhabdomyolysis in the setting of recent COVID-19 and prolonged hospitalization. It demonstrates the possibility that muscle injury and resultant rhabdomyolysis may be a late complication of COVID-19 that is not yet fully described in the literature.


A Portable Magnetic Particle Spectrometer for Future Rapid and Wash-Free Bioassays.
Nowadays, there is an increasing demand for more accessible routine diagnostics for patients with respect to high accuracy, ease of use, and low cost. However, the quantitative and high accuracy bioassays in large hospitals and laboratories usually require trained technicians and equipment that is both bulky and expensive. In addition, the multistep bioassays and long turnaround time could severely affect the disease surveillance and control especially in pandemics such as influenza and COVID-19. In view of this, a portable, quantitative bioassay device will be valuable in regions with scarce medical resources and help relieve burden on local healthcare systems. Herein, we introduce the MagiCoil diagnostic device, an inexpensive, portable, quantitative, and rapid bioassay platform based on the magnetic particle spectrometer (MPS) technique. MPS detects the dynamic magnetic responses of magnetic nanoparticles (MNPs) and uses the harmonics from oscillating MNPs as metrics for sensitive and quantitative bioassays. This device does not require trained technicians to operate and employs a fully automatic, one-step, and wash-free assay with a user friendly smartphone interface. Using a streptavidin-biotin binding system as a model, we show that the detection limit of the current portable device for streptavidin is 64 nM (equal to 5.12 pmole). In addition, this MPS technique is very versatile and allows for the detection of different diseases just by changing the surface modifications on MNPs. Although MPS-based bioassays show high sensitivities as reported in many literatures, at the current stage, this portable device faces insufficient sensitivity and needs further improvements. It is foreseen that this kind of portable device can transform the multistep, laboratory-based bioassays to one-step field testing in nonclinical settings such as schools, homes, offices, etc.


A murine recombinant retrovirus containing the src oncogene transforms erythroid precursor cells in vitro.
A murine retrovirus (MRSV) containing the src gene of Rous sarcoma virus has been shown to cause an erythroproliferative disease in mice (S. M. Anderson and E. M. Scolnick, J. Virol. 46:594-605, 1983). We now demonstrate that this same virus can transform erythroid progenitor cells in vitro. Infection of fetal liver cells or spleen and bone marrow cells from phenylhydrazine-treated adult mice gave rise to colonies of erythroid cells which grew in methylcellulose under conditions not favorable for the growth of normal erythroid cells. The presence of pp60src in the transformed erythroid cells was demonstrated by an immune complex protein kinase assay. The time course of appearance and subsequent differentiation of erythroid colonies indicated that the target cell for MRSV was a 6- to 8-day burst-forming unit. Differentiation of the erythroid progenitors was not blocked by the presence of pp60src, and the cells retained sensitivity to the hormone erythropoietin. In fact, the transformed cells exhibited increased hormone sensitivity since the number, the size, and the extent of hemoglobinization of the colonies were all increased by the addition of small amounts of erythropoietin. MRSV was not susceptible to restriction by the Fv-2 locus, as MRSV could transform hematopoietic cells from C57BL/6 mice. These results indicate that (i) the erythroid proliferation observed in vivo is caused by a direct effect of MRSV on erythroid progenitors and (ii) the transformed erythroid precursors acquire a growth advantage over uninfected cells without losing the ability to differentiate and respond to physiologic regulators.


The potential influence of diabetic history on peripheral blood flow in superficial skin.
Vascular complication occurrence increases with the duration of diabetes. The present study compared the peripheral blood flow in superficial skin among subjects with a short or long history of diabetes as compared to a healthy control group. Thirty-two subjects with type 2 diabetes were recruited and stratified into a group of those with a short history of diabetes (i.e., shorter than or equal to ten years) and a group of those with a long history of diabetes (i.e., over ten years). Thirty-eight healthy age-matched volunteers were recruited as the control. The blood flow velocity of the superficial small veins in the skin over the base of the 1st metatarsal bone was measured by ultrasound biomicroscopy. The blood flow (flux) of the cutaneous microcirculation over the base of the 1st metatarsal bone (Flux1) and over the distal 1st phalanges bone (Flux2) was measured by Laser Doppler Flowmetry. One-way analysis of variance was used to analyze the differences between the three groups. No significant between-group difference was found in any outcome (all P>0.05). However, the group with a long history of diabetes tended to have a more reduced blood flow than did the healthy control group. A difference was found between the diabetes group and the healthy control in any outcomes. A trend of hemodynamic changes in the three groups was observed, but the difference did not reach significance. Ten years seems to be the time when angiopathy becomes noticeable among people with diabetes.


ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay.
Both p150 and p110 isoforms of ADAR1 convert adenosine to inosine in double-stranded RNA (dsRNA). ADAR1p150 suppresses the dsRNA-sensing mechanism that activates MDA5-MAVS-IFN signaling in the cytoplasm. In contrast, the biological function of the ADAR1p110 isoform, which is usually located in the nucleus, is largely unknown. Here, we show that stress-activated phosphorylation of ADAR1p110 by MKK6-p38-MSK MAP kinases promotes its binding to Exportin-5 and its export from the nucleus. After translocating to the cytoplasm, ADAR1p110 suppresses apoptosis in stressed cells by protecting many antiapoptotic gene transcripts that contain 3'-untranslated-region dsRNA structures primarily comprising inverted Alu repeats. ADAR1p110 competitively inhibits binding of Staufen1 to the 3'-untranslated-region dsRNAs and antagonizes Staufen1-mediated mRNA decay. Our study reveals a new stress-response mechanism in which human ADAR1p110 and Staufen1 regulate surveillance of a set of mRNAs required for survival of stressed cells.


A Review of CYP3A Drug-Drug Interaction Studies: Practical Guidelines for Patients Using Targeted Oral Anticancer Drugs.
Many oral anticancer drugs are metabolized by CYP3A. Clinical drug-drug interaction (DDI) studies often only examine the effect of strong CYP3A inhibitors and inducers. The effect of moderate or weak inhibitors or inducers can be examined using physiologically based pharmacokinetic simulations, but data from these simulations are not always available early after approval of a drug. In this review we provide recommendations for clinical practice on how to deal with DDIs of oral anticancer drugs if only data from strong CYP3A inhibitors or inducers is available. These recommendations were based on reviewed data of oral anticancer drugs primarily metabolized by CYP3A and approved for the treatment of solid tumors from January 1st, 2013 to December 31st, 2015. In addition, three drugs that were registered before the new EMA guideline was issued (i.e., everolimus, imatinib, and sunitinib), were reviewed. DDIs are often complex, but if no data is available from moderate CYP3A inhibitors/inducers, a change in exposure of 50% compared with strong inhibitors/inducers can be assumed. No a priori dose adaptations are indicated for weak inhibitors/inducers, because their interacting effect is small. In case pharmacologically active metabolites are involved, the metabolic pathway, the ratio of the parent to the metabolites, and the potency of the metabolites should be taken into account.


Allelic variant in CTLA4 is associated with thyroid failure and faster β-cell exhaustion in latent autoimmune diabetes in adults.
The aim of the study was to investigate the role of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) G6230A variant on the susceptibility of latent autoimmune diabetes in adults (LADA) as a whole and in the subset of patients who share autoimmune thyroid disease (AITD). The study included 202 LADA, 1373 patients with early onset type 1 diabetes (T1D), 130 patients with late-onset T1D, 188 patients with non-autoimmune diabetes and 1904 healthy controls. Thyrotropin (thyrotropin-stimulating hormone; TSH) and antibodies against thyroid peroxidase were analyzed in all patients. The CTLA4 G6230A variant was assessed in LADA, early and late-onset T1D patients as well as in the controls. The frequency of CTLA4 G alleles and genotypes in LADA patients did not differ significantly from that in the other groups, regardless of its association with AITD. We found an increased frequency of G allele-containing genotypes within LADA patients who had higher TSH compared with those with normal TSH (P = 0.002). Moreover, LADA patients carrying G allele-containing genotypes were more likely to require insulin therapy within 4 years of diagnosis (P = 0.002). The G6230A CTLA4 variant does not confer susceptibility to LADA in Sardinian patients even when associated with AITD. However, it helps identify a particular subset of LADA patients with more clinically severe disease, both for thyroid dysfunction and diabetes.


Diagnosis of breast cancer using elastic-scattering spectroscopy: preliminary clinical results.
We report on the first stages of a clinical study designed to test elastic-scattering spectroscopy, mediated by fiberoptic probes, for three specific clinical applications in breast-tissue diagnosis: (1) a transdermal-needle (interstitial) measurement for instant diagnosis with minimal invasiveness similar to fine-needle aspiration but with sensitivity to a larger tissue volume, (2) a hand-held diagnostic probe for use in assessing tumor/resection margins during open surgery, and (3) use of the same probe for real-time assessment of the "sentinel" node during surgery to determine the presence or absence of tumor (metastatic). Preliminary results from in vivo measurements on 31 women are encouraging. Optical spectra were measured on 72 histology sites in breast tissue, and 54 histology sites in sentinel nodes. Two different artificial intelligence methods of spectral classification were studied. Artificial neural networks yielded sensitivities of 69% and 58%, and specificities of 85% and 93%, for breast tissue and sentinel nodes, respectively. Hierarchical cluster analysis yielded sensitivities of 67% and 91%, and specificities of 79% and 77%, for breast tissue and sentinel nodes, respectively. These values are expected to improve as the data sets continue to grow and more sophisticated data preprocessing is employed. The study will enroll up to 400 patients over the next two years.


Interleukin-1 Ligands and Receptors in Lumpfish (Cyclopterus lumpus L.): Molecular Characterization, Phylogeny, Gene Expression, and Transcriptome Analyses.
The interleukin (IL)-1 family play a fundamental role as immune system modulators. Our previous transcriptome-analyses of leukocytes from lumpfish (Cyclopterus lumpus L.) showed that IL-1β was among the most highly upregulated genes following bacterial exposure. In the present study, we characterized IL-1 signaling pathways, identified and characterized four ligands of the IL-1 family in lumpfish; IL-1β type I and type II, IL-18, and the novel IL-1 family members (nIL-1F), both at mRNA and gene levels. The two IL-1β in lumpfish is termed IL-1β1 (type II) and IL-1β2 (type I). Furthermore, a comprehensive phylogenetic analysis of 277 IL-1 ligands showed that nIL-1F, in common with IL-1β, likely represents an ancestral gene, as representatives for nIL-1F were found in cartilaginous and lobe-finned fish, in addition to teleosts. This shows that nIL-1F is not exclusively present in teleosts as previously suggested. Our analyses of exon-intron structures, intron phases, phylogeny and synteny clearly show the separation of IL-1β into groups; type I and type II, which likely is a result of the third whole genome duplication (3R WGD). The phylogenetic analysis shows that most teleosts have both type I and type II. Furthermore, we have determined transcription levels of the IL-1 ligands in leukocytes and 16 different tissues, and their responses upon in vitro stimulation with seven different ligands. In addition, we have identified the IL-1 receptors IL-1R1, IL-1R2, IL-1R4 (ST2/IL-33 receptor/IL-1RL), IL-1R5 (IL-18R1), and partial sequences of DIGIRR and IL-1R3 (IL-RAcP). Identification of immune molecules and description of innate responses in lumpfish is interesting for comparative and evolutionary studies and our study constitutes a solid basis for further functional analyses of IL-1 ligands and receptors in lumpfish. Furthermore, since lumpfish are now farmed in large numbers to be used as cleaner fish for removal of sea lice on farmed salmon, in-depth knowledge of key immune molecules, signaling pathways and innate immune responses is needed, as the basis for design of efficient immune prophylactic measures such as vaccination.


Mental patients' attitudes toward hospital staff. A review of quantitative research.
Relatively few social scientists have collected quantitative data on the attitudes of patients toward the staff of mental hospitals. The present report is a review of this body of research, with special consideration given to ascertaining the degree of patients' favorableness to staff. Results indicated that in 21 of the 27 different samples reviewed (78%), patients had favorable attitudes. Patients proved to be somewhat more favorable to staff at mental hospitals generally than staff at their own institution. Type of hospital and time of study had a negligible impact on patients' views. Staff in lower ranks in the hospital hierarchy or in nontherapeutic roles usually received lower evaluations. A content analysis of the attitude measures revealed that patients are quite positive about staff's accessibility, receptivity, support, and training, but somewhat negative toward staff's permissiveness and control. Few social or psychiatric variables were observed to affect patients' responses.


Examining the relationship between clinical monitoring and suicide risk among patients with depression: matched case-control study and instrumental variable approaches.
To assess the relationship between closer monitoring of depressed patients during high-risk treatment periods and death from suicide, using two analytic approaches. VA patients receiving depression treatment between 1999 and 2004. First, a case-control design was used, adjusting for age, gender, and high-risk days (1,032 cases and 2,058 controls). Second, an instrumental variable (IV) approach (N=714,106) was used, with IVs of (1) average monitoring rates in the VA facility of most use and (2) monitoring rates of VA facilities weighted inversely by distance from patients' residences. The case-control approach indicated a modest increase in suicide risk with each additional visit (odds ratio=1.02; 95 percent confidence interval=1.002, 1.04). The "facility used" IV estimate indicated near zero change in risk (0.0008 percent increase; p=.97) with each additional visit, while the distance-weighted IV estimate indicated a 0.032 percent decrease in risk (p=.29). An alternative analysis assuming a threshold effect of ≥4 visits during high-risk periods also showed a decrease (0.15 percent; p=.08) using the distance IV. The IV approach appeared to address the selection bias more appropriately than the case-control analysis. Neither analysis clearly indicated that closer monitoring during high-risk periods was significantly associated with reduced suicide risks, but the distance-weighted IV estimate suggested a potentially protective effect.


Gastric perforation after endoscopic treatment of a Dieulafoy's lesion.
Dieulafoy's vascular malformation is an underdiagnosed cause of massive, often recurrent upper gastrointestinal hemorrhage. Attempted endoscopic treatment of Dieulafoy's lesion has been recommended prior to surgery in many instances, but may occasionally be employed as primary therapy in patients that are not considered good "operative risks." Although generally considered safe and effective therapy for nonvariceal hemorrhage, combination therapy by injection and thermocoagulation techniques may result in perforation. We present a patient with a Dieulafoy's lesion of the stomach that illustrates both the efficacy and risks of combination endoscopic therapy for nonvariceal gastrointestinal hemorrhage.


Hospital-Based Back Surgery: Geospatial-Temporal, Explanatory, and Predictive Models.
Hospital-based back surgery in the United States increased by 60% from January 2012 to December 2017, yet the supply of neurosurgeons remained relatively constant. During this time, adult obesity grew by 5%. This study aimed to evaluate the demand and associated costs for hospital-based back surgery by geolocation over time to evaluate provider practice variation. The study then leveraged hierarchical time series to generate tight demand forecasts on an unobserved test set. Finally, explanatory financial, technical, workload, geographical, and temporal factors as well as state-level obesity rates were investigated as predictors for the demand for hospital-based back surgery. Hospital data from January 2012 to December 2017 were used to generate geospatial-temporal maps and a video of the Current Procedural Terminology codes beginning with the digit 63 claims. Hierarchical time series modeling provided forecasts for each state, the census regions, and the nation for an unobserved test set and then again for the out-years of 2018 and 2019. Stepwise regression, lasso regression, ridge regression, elastic net, and gradient-boosted random forests were built on a training set and evaluated on a test set to evaluate variables important to explaining the demand for hospital-based back surgery. Widespread, unexplained practice variation over time was seen using geographical information systems (GIS) multimedia mapping. Hierarchical time series provided accurate forecasts on a blind dataset and suggested a 6.52% (from 497,325 procedures in 2017 to 529,777 in 2018) growth of hospital-based back surgery in 2018 (529,777 and up to 13.00% by 2019 [from 497,325 procedures in 2017 to 563,023 procedures in 2019]). The increase in payments by 2019 are estimated to be US $323.9 million. Extreme gradient-boosted random forests beat constrained and unconstrained regression models on a 20% unobserved test set and suggested that obesity is one of the most important factors in explaining the increase in demand for hospital-based back surgery. Practice variation and obesity are factors to consider when estimating demand for hospital-based back surgery. Federal, state, and local planners should evaluate demand-side and supply-side interventions for this emerging problem.


Simultaneous analysis of irbesartan and hydrochlorothiazide: an improved HPLC method with the aid of a chemometric protocol.
Experimental design method was used for HPLC determination of irbesartan and hydrochlorothiazide in combined dosage forms. The traditional approach for optimization of experiments is time-consuming, involves a large number of runs and does not allow establishing the multiple interacting parameters. The main advantages of the experimental design method include the simultaneous screening of a larger number of factors affecting response and the estimation of possible interactions. On the basis of preliminary experiments, three factors-independent variables were selected as inputs (methanol content, pH of the mobile phase and temperature) and as dependent variables, five responses (resolution, symmetry of irbesartan peak, symmetry of hydrochlorothiazide peak, retention factor of irbesartan and retention factor of hydrochlorothiazide) were chosen. A full 23 factorial design, where factors were examined at two different levels ("low" and "high") was used to determine which factors had an effect on the studied response. Afterwards, experimental design was used to optimize these influent parameters in the previously selected experimental domain. The novelty of our method lies in the optimization step accomplished by Derringer's desirability function. After optimizing the experimental conditions a separation was conducted on a Supelcosil C(18) (150 mm × 4.6 mm, 5 mm particle size) column with a mobile phase consisting of methanol-tetrahydrofuran-acetate buffer 47:10:43 v/v/v, pH 6.5 and a column temperature of 25 °C. The developed method was successfully applied to the simultaneous separation of these drug-active compounds in their commercial pharmaceutical dosage forms.


Isolated foot metastasis of squamous cell carcinoma of the lung: a rare location.
Squamous cell carcinoma of the lung usually presents as a local rather than a metastatic disease. We present a 55-year-old male who was referred to the orthopedics and traumatology clinic for evaluation of pain and discomfort around the left ankle 2 months after diagnosis of locally advanced non-small cell (squamous cell) lung cancer. Physical examination revealed nonspecific pain and tenderness around the ankle. T2-weighted MR images showed lesions like a bone marrow edema around the talar head and neck. Whole body dynamic bone scan revealed a metastatic lesion only in the foot. The patient died 4 months after diagnosis of the metastasis. Early diagnosis of foot metastasis may be challenging and delays in diagnosis of up to 24 months have been reported. Foot metastases are usually associated with advanced metastatic disease and survival rates are poor. Although metastatic disease of the foot is rare, it should be considered in the diagnosis of a painful foot in the elderly lung cancer patients. Palliative treatments such as pain relief medications should be chosen for patients with an expectancy of short survival whereas aggressive approaches may be applied for those with longer survival expectations.


Transcriptional Repression of the APC/C Activator Genes CCS52A1/A2 by the Mediator Complex Subunit MED16 Controls Endoreduplication and Cell Growth in Arabidopsis.
Endoreduplication, the replication of the nuclear genome in the absence of mitosis, is often associated with cell growth and differentiation in plants and animals, but the molecular mechanisms underlying endoreduplication in plants have not been fully elucidated. Here, we show that the Mediator complex subunit MED16 acts as a negative regulator of endoreduplication to influence cell growth in Arabidopsis (Arabidopsis thaliana). The med16 mutant exhibits larger and more numerous cells than the wild type, resulting in enlarged organs. The large cells in med16 are associated with high DNA ploidy levels. MED16 associates with the promoters of the Anaphase Promoting Complex/Cyclosome activators CELL CYCLE SWITCH52 A1 (CCS52A1) and CCS52A2 (encoding important factors for endoreduplication and cell growth) and represses their expression. MED16 interacts physically with the transcriptional repressor DEL1 to repress the expression of CCS52A2 Genetic analysis suggested that MED16 is partially dependent on CCS52A1/A2 to control endoreduplication and cell growth. Our results indicate that the transcriptional repression of CCS52A1/A2 by MED16 regulates endoreduplication and cell growth in Arabidopsis.


Allogeneic hematopoietic stem cell transplantation recipients have defects of both switched and igm memory B cells.
Allogeneic hematopoietic stem cell transplant (HSCT) recipients were assessed to elucidate memory B cell defects underlying their increased susceptibility to infections, particularly by encapsulated bacteria. Circulating IgM memory B cells (CD19+, CD27+, IgM+) and switched memory B cells (CD19+, CD27+, IgM(-)) were enumerated in allogeneic HSCT recipients (n = 37) and healthy controls (n = 35). T lymphocyte subpopulations and serum levels of immunoglobulins, including IgG subclasses, and antibodies to pneumococcal polysaccharides were also assayed. Allogeneic HSCT recipients were deficient in both switched memory and IgM memory B cells compared to healthy controls (both P < .0001), irrespective of time post-HSCT. Switched memory B cell deficiency correlated with CD4+ T cell deficiency, and both correlated with serum levels of IgG1 (P < .0001), possibly reflecting impaired B cell isotype switching in germinal centres. "Steady-state" serum levels of antibodies to pneumococcal polysaccharides did not correlate with circulating memory B cells. Graft-versus-host disease (GVHD) was associated with lower IgM memory B cell counts and lower serum levels of IgG2, IgG4, IgA, and pneumococcal antibodies. The increased susceptibility of allogeneic HSCT patients to infection may reflect a combination of memory B cell defects, which are most common in patients with a history of GVHD.


Assessing regional variations in the effect of the removal of user fees on facility-based deliveries in rural Zambia.
Maternal health remains a concern in sub-Saharan Africa, where maternal mortality averages 680 per 100,000 live births and almost 50% of the approximately 350,000 annual maternal deaths occur. Improving access to skilled birth assistance is paramount to reducing this average, and user fee reductions could help. The aim of this research was to analyse the effect of user fee removal in rural areas of Zambia on the use of health facilities for childbirth. The analysis incorporates supply-side factors, including quantitative measures of service quality in the assessment. The analysis uses quarterly longitudinal data covering 2003 (q1)-2008 (q4) and controls for unobserved heterogeneity, spatial dependence and quantitative supply-side factors within an Interrupted Time Series design. User fee removal was found to initially increase aggregate facility-based deliveries. Drug availability, the presence of traditional birth attendants, social factors and cultural factors also influenced facility-based deliveries at the national level. Although user fees matter, to a degree, service quality is a relatively more important contributor to the promotion of facility-based deliveries. Thus, in the short-term, strengthening and improving community-based interventions could lead to further increases in facility-based deliveries.


Affordable dispersion mitigation method for the next generation RF-over-fiber optical channels.
Next-generation analog radio frequency over fiber (RFoF) links will require dispersion compensation. Most dispersion compensation methods are based on additional optical elements. Therefore, these solutions may be inadequate for low-cost channels. In this work, we suggest a novel low-cost dispersion compensation solution for RFoF links. The method is based on two properties, which are common in these links: the modulation depth in analog RFoF links is lower than in digital links (and to avoid nonlinearities, it may be deliberately set to a small value), and the data are carried by a high-frequency carrier. It is shown that with these properties, the optical channel behaves approximately as a linear system. The distortion occurs in the linear domain and in the third-harmonic regime. Since the third-harmonic distortions are usually smaller than the back-to-back distortions, they are linear in the power domain. We therefore suggest using a simple low-cost electronic filter to compensate the dispersion distortions. The performance of this technique is presented both analytically and with a numerical simulation. These preliminary results are very encouraging and point to an inexpensive solution for next-generation RFoF links to the home.


The hyperthermophilic origin of life revisited.
We revisit the case for the hyperthermophilic scenario for the origin of life and the last common ancestor. Evidence includes studies of phylogenetic trees, rRNA, G and C content, hyperthermophilic proteins, correlations between maximal temperature tolerances and genetic distances, saline stabilization of DNA/RNA, and the inferred climatic temperatures of the early Earth. Although some doubts remain, the case for hot biogenesis and the last common ancestor has gotten stronger.


[Frequency of chromosome aberrations induced by a single exposure to stress in rats selected for excitability of the nervous system].
The effect of short-term emotional and algesic stress on chromosomal aberration rate in bone marrow cells was studied in four lines of rats selected for excitability of the nervous system. The exposure induced an increase in chromosomal aberration rate only in highly excitable animals; the effect was classified as a low mutagenic. Possible mechanisms of the effect of stress factors on the chromosomal apparatus of cells are discussed.


Snake bite on scrotum--a case report.
A 22-year old man was bitten by a snake on his scrotum. This interesting and unusual case occurred in the rural area of District Aligarh, India. The uniqueness of the case lies in the fact that scrotum is an extremely rare and unusual site for snake bite. Further, with negligible local signs of envenoming the patient presented with classical signs of neurotoxicity. Due to numerous superstitions associated with snake bite, the patient was treated with traditional home made ointment before coming to hospital. The authors realized that the case may be brought to the notice of the readers because the scrotal bite by the snake with no local signs of envenomation is the first reported case.


A large Alu-mediated deletion, identified by PCR, as the molecular basis for glycogen storage disease type II (GSDII).
Glycogen storage disease type II (GSDII) is an autosomal recessive disorder resulting from inherited deficiency of the enzyme lysosomal acid alpha-glucosidase. Over 40 different mutations have been described but no large deletions have been previously identified. We now describe a homozygous large (9-kb) deletion extending from IVS 15 to 4 kb downstream of the terminal exon (exon 20), detected by polymerase chain reaction (PCR)-based methods. The deletion was initially suspected because of failure to amplify a contiguous group of exons by PCR. We hypothesized an Alu/Alu recombination, based on our prior demonstration by Southern blotting of Alu elements in the regions potentially flanking the deletion. Additional sequence analysis of genomic fragments confirmed the presence of Alu elements and allowed the design of flanking primers for PCR amplification. Amplification resulted in a smaller than normal fragment (0.7 vs. 10 kb) in homozygosity in the proband and in heterozygosity in her parents. Cloning and sequencing of the smaller than normal 0.7-kb deletion fragment revealed an Alu/Alu deletion junction. In heterozygosity this deletion would not be detected by currently standard PCR mutation detection methods. Based on other Alu-mediated deletions, this deletion is likely to be recurrent and should be screened for in all non-consanguineous GSDII patients, particularly when only one mutation has been identified and none of the 12 single-nucleotide polymorphisms in the deleted region are heterozygous. These observations also suggest that initial characterization of genes at disease-causing loci should include a search for Alu and other repetitive elements to facilitate subsequent PCR-based mutation analysis.


Adolescents, young adults, and cancer--the international challenge.
Cancer in adolescents and young adults is an important public health issue, because there are approximately 1 million new cases annually. The distribution of diseases in this age group varies geographically, contributing to differences in survival rates. Although an overall survival rate exceeding 80 % has been reported in optimal circumstances, emerging knowledge about distinctions in tumor biology and enhanced clinical accrual to clinical trials should lead to further gains. The challenges of cancer survivorship demand further attention with a particular focus on the quality of life of survivors and amelioration of the long-term complications of treatment. Programs in cancer screening and prevention provide potential for considerable benefits in this age group. A renewed perspective on the adolescent and young adult cohort is required; and, in all of these opportunities for change, there are important roles to be played by advocacy groups internationally.


Brain metabolites in chronic migraine patients with medication overuse headache.
Medication overuse headache may be associated with widespread alterations along the thalamocortical pathway, a pathway involved in pain perception and disease progression. This study addressed whether brain metabolites in key regions of the thalamocortical pathway differed between chronic migraine patients with medication overuse headache and without medication overuse headache. Magnetic resonance spectroscopic imaging was used to map metabolites in the bilateral anterior cingulate cortices, mid cingulate cortices, posterior cingulate cortices, and the thalami. Sixteen patients with medication overuse headache were compared with 16 matched patients without medication overuse headache and 16 matched healthy controls. Glutamate and glutamine in the right mid cingulate cortex and myo-inositol in the left anterior cingulate cortex were significantly higher in patients with medication overuse headache than patients without medication overuse headache, but similar to healthy controls. Both patient groups exhibited reduced N-acetyl-aspartate and creatine in the thalamus, reduced myo-inositol in the right anterior cingulate cortex, and elevated choline in the right mid cingulate cortex. Finally, a negative association between myo-inositol laterality index in the anterior cingulate cortices and number of days per month with acute medication use was found across all patients. Patients with medication overuse headache were characterized by a distinct concentration profile of myo-inositol, a glial marker, in the anterior cingulate cortices that may have arisen from medication overuse and could contribute to the development of medication overuse headache.


Toxicity of amorphous silica nanoparticles on eukaryotic cell model is determined by particle agglomeration and serum protein adsorption effects.
Cell cultures form the basis of most biological assays conducted to assess the cytotoxicity of nanomaterials. Since the molecular environment of nanoparticles exerts influence on their physicochemical properties, it can have an impact on nanotoxicity. Here, toxicity of silica nanoparticles upon delivery by fluid-phase uptake is studied in a 3T3 fibroblast cell line. Based on XTT viability assay, cytotoxicity is shown to be a function of (1) particle concentration and (2) of fetal calf serum (FCS) content in the cell culture medium. Application of dynamic light scattering shows that both parameters affect particle agglomeration. The DLS experiments verify the stability of the nanoparticles in culture medium without FCS over a wide range of particle concentrations. The related toxicity can be mainly accounted for by single silica nanoparticles and small agglomerates. In contrast, agglomeration of silica nanoparticles in all FCS-containing media is observed, resulting in a decrease of the associated toxicity. This result has implications for the evaluation of the cytotoxic potential of silica nanoparticles and possibly also other nanomaterials in standard cell culture.


High-level molecular diversity of copper-zinc superoxide dismutase genes among and within species of arbuscular Mycorrhizal fungi.
In the ecologically important arbuscular mycorrhizal fungi (AMF), Sod1 encodes a functional polypeptide that confers increased tolerance to oxidative stress and that is upregulated inside the roots during early steps of the symbiosis with host plants. It is still unclear whether its expression is directed at scavenging reactive oxygen species (ROS) produced by the host, if it plays a role in the fungus-host dialogue, or if it is a consequence of oxidative stress from the surrounding environment. All these possibilities are equally likely, and molecular variation at the Sod1 locus can possibly have adaptive implications for one or all of the three mentioned functions. In this paper, we analyzed the diversity of the Sod1 gene in six AMF species, as well as 14 Glomus intraradices isolates from a single natural population. By sequencing this locus, we identified a large amount of nucleotide and amino acid molecular diversity both among AMF species and individuals, suggesting a rapid divergence of its codons. The Sod1 gene was monomorphic within each isolate we analyzed, and quantitative PCR strongly suggest this locus is present as a single copy in G. intraradices. Maximum-likelihood analyses performed using a variety of models for codon evolution indicated that a number of amino acid sites most likely evolved under the regime of positive selection among AMF species. In addition, we found that some isolates of G. intraradices from a natural population harbor very divergent orthologous Sod1 sequences, and our analysis suggested that diversifying selection, rather than recombination, was responsible for the persistence of this molecular diversity within the AMF population.


Apical anatomy in mesial and mesiobuccal roots of permanent first molars.
The purpose of this in vitro study was to investigate the canal configuration types, and the prevalence and location of anatomical variations in the mesiobuccal (MB) and mesial roots of permanent maxillary and mandibular first molars after instrumentation. The number and the type of canals were determined before instrumentation using conventional methods. All root canals from the 47 MB roots and 42 mesial roots were then instrumented to size #30 with ProFile .04 taper rotary instruments in a crown-down method and then filled with a single gutta-percha cone and sealer. Transverse 1 mm-thick cross-sections at 2, 3, 4, and 5 mm from the apex were obtained, stained and examined using a stereomicroscope. The canal configuration types and the prevalence and location of isthmi and accessory canals in roots with two canals were evaluated. The prevalence of two canals was 80.8% in the maxillary MB roots and 95.2% in the mandibular mesial roots. There were six types of canal configurations in the instrumented root apices. The prevalence of anatomical variations was highest at the apical 4 mm level, and was more frequent in mandibular first molars, and in roots with Weine type III canal. chi test showed that the prevalence of the anatomical variations was statistically higher in the maxillary MB roots with Weine type III canals than in those with Weine type II canals (p < 0.05). Different canal configurations were often found at different levels in the same root. The results indicate that anatomical variations persist following instrumentation of roots with two canals in first molars. These anatomical variations should be considered during surgical or nonsurgical endodontic procedures of the permanent first molars.


Initial resistance to companion drugs should not be considered an exclusion criterion for the shorter multidrug-resistant tuberculosis treatment regimen.
We investigated whether companion drug resistance was associated with adverse outcomes of the shorter multidrug-resistant tuberculosis (MDR-TB) treatment regimen in Bangladesh after adjustment for fluoroquinolone resistance. MDR-TB/rifampicin-resistant tuberculosis patients registered for treatment with a standardized gatifloxacin-based shorter MDR-TB treatment regimen were selected for the study. Drug resistance was determined by the proportion method, gatifloxacin and isoniazid minimum inhibitory concentration testing for selected isolates, and whole-genome sequencing. Low-level fluoroquinolone resistance and high-level fluoroquinolone resistance were the most important predictors of adverse outcomes, with pyrazinamide resistance having a significant yet lower impact. In patients with fluoroquinolone-/second-line-injectable-susceptible tuberculosis, non-eligibility for the shorter MDR-TB treatment regimen (initial resistance to pyrazinamide, ethionamide, or ethambutol) was not associated with adverse outcome (adjusted odds ratio 1.01; 95% confidence interval 0.4-2.8). Kanamycin resistance was uncommon (1.3%). Increasing levels of resistance to isoniazid predicted treatment failure, also in a subgroup of patients with high-level fluoroquinolone-resistant tuberculosis. Our results suggest that resistance to companion drugs in the shorter MDR-TB treatment regimen, except kanamycin resistance, is of no clinical importance as long as fluoroquinolone susceptibility is preserved. Hence, contrary to current WHO guidelines, exclusions to the standard regimen are justified only in the case of fluoroquinolone resistance. and possibly kanamycin resistance.


Primate DRB6 pseudogenes: clue to the evolutionary origin of the HLA-DR2 haplotype.
The HLA-DR2 haplotype contains three beta-chain encoding DRB genes and one alpha-chain encoding DRA gene. Of the three DRB genes, two are presumably functional (HLA-DRB1 and HLA-DRB5), whereas the third (HLA-DRBVI) is a pseudogene. A pseudogene closely related to HLA-DRBVI is present in the chimpanzee (Patr-DRB6) and in the gorilla (Gogo-DRB6). We sequenced the HLA-DRBVI and Patr-DRB6 pseudogenes (all exons and most of the introns), and compared the sequence to that of the Gogo-DRB6 gene (of which only the exon sequence is available). All three pseudogenes seem to lack exon 1 and contain other deletions responsible for shifts in the translational reading frame. At least the HLA-DRBVI pseudogene, however, seems to be transcribed nevertheless. The chimpanzee pseudogene contains two inserts in intron 2, one of which is an Alu repeat belonging to the Sb subfamily, while the other remains unidentified. These inserts are lacking in the human gene. A comparison with sequences published by other investigators revealed the presence of the HLA-DRBVI pseudogene also in the DR1 and DRw10 haplotypes. Measurements of genetic distances indicate DRB6 to be closely related to the DRB2 pseudogene and to the HLA-DRB4 functional gene. In humans, gorillas, and chimpanzees, the DRB6 pseudogene is associated with the same functional gene (DRB5) indicating that this linkage disequilibrium is at least six million years old and that DR2 is one of the oldest DR haplotypes in higher primates.


Sexuality post gynaecological cancer treatment: a qualitative study with South African women.
This study investigated women's experiences of their sexuality post gynaecological cancer treatment. Using a holistic sexuality framework, the study explored how women felt their sexual functioning, sexual relationships and sexual identity had been affected by treatment. The study was qualitative in nature and made use of an interpretive descriptive design. Data were analysed using thematic analysis. Data collection took place at a follow-up clinic within the gynaeoncology unit at a public-sector tertiary hospital in Cape Town, South Africa. Purposive sampling was used to recruit participants, and the final sample consisted of 34 women aged 29-70 ([Formula: see text]=52). All women had received a gynaecological cancer diagnosis and had been treated with either surgery, chemotherapy, radiation or a combination of these. On average, the participants were between 12 and 30 months post treatment. Women expressed how their sexual functioning post treatment was both nuanced and complex, how heteronormative gender expectations influenced their intimate relationships, and how they experienced a re-embodiment of their sexual subjectivity post treatment. Participants felt that more sexual functioning information from healthcare providers, as well as peer support groups, would assist them in navigating the sexuality changes they experienced. The findings of this study broaden conceptualisations of sexuality post treatment by detailing the ways that it is complex, nuanced, relational and ever shifting. More research is needed about how to incorporate holistic psychosexual support post treatment into the public healthcare system in South Africa.


Investigating the effect of education on health-promoting lifestyle among the elderly of Ramsar in 2017.
Providing and enhancing the level of health are one of the essential needs of all people, and implementation of health promotion lifestyle is the most important and effective factor in maintaining and improving the health of the elderly. The present study aimed at defining the effect of aging on health-promoting lifestyle. This randomized clinical trial was conducted on 72 individuals from the retirees clubs of Education department, Social Security, and Health centers in Ramsar, in 2017. Sampling was done randomly with blocking and random allocation in two groups: Experimental and control. Data were collected in two steps by Demographic profile questionnaire, AMT, ADL, OHI and HPlP II which validity and reliability of them were confirmed. Participants attended eight training sessions (twice each week). Data analysis was performed with the use of SPSS 18 and descriptive (Frequency) and analytic tests (Chi-square, Fisher's exact test, Independent Sample t test and Paired Sample t test) with a significance level of 0.05. The results showed that the mean age of the elderly was 64.4 ± 4.1 years. The mean score of lifestyle enhancement was 148.59 and 173.25 before and after training in the experimental group, respectively. Based on the results of paired t-test (P < 0. 323), there was no significant difference between the mean life expectancy of elderly health promotion in control group before and after educational intervention; however, there was a significant difference between the two groups before and after training (P = 0.001). Educational programs play an important role in integrating health-promoting lifestyle to encourage the elderly to accept more accountability regarding health, sustained physical fitness, proper nutrition, healthy interpersonal relationships, expected spiritual growth, and the proper management of stress and anxiety in life.


Fixed-dose combination therapy for the prevention of cardiovascular disease.
This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of fixed-dose combination therapy on optimising CVD risk factors and reducing CVD fatal and non-fatal events for both primary and secondary prevention of CVD. Details of CVD events and risk factors included are listed in the methods. We will also determine any adverse events associated with taking fixed-dose combination therapy. This will include studies conducted in both developed and developing regions of the world.


Impaired left ventricular filling dynamics during percutaneous transluminal angioplasty for coronary artery disease.
The effects of brief periods of major coronary artery occlusion on global and regional peak left ventricular (LV) filling rates were studied during angioplasty in 10 patients. No patient had had a previous myocardial infarction. High-fidelity LV pressure and volume were determined by angiography before and 20 and 50 seconds after the onset of transluminal coronary occlusion and soon after the last balloon inflation. Segmental wall motion was analyzed frame by frame along 20 hemiaxes. Global peak filling rate decreased significantly both after 20 (29%, p less than 0.05) and 50 seconds (27%, p less than 0.05) from the onset of the occlusion. The term sigma delta t1 was defined as the sum of the absolute values of the time differences from the occurrence of global peak filling rate and the segmental peak filling rate in 20 segments. This variable increased significantly during both periods of transluminal occlusion (by 73% and by 72% [both p less than 0.005], respectively), indicating asynchrony in the occurrence of regional peak filling rate. Simultaneously, the sum of intervals between aortic valve closure (end systole) and occurrence of peak segmental shortening, sigma delta t2, measured in the 20 segments, increased by 63% after 20 seconds and by 87% after 50 seconds (both p less than 0.005), showing major asynchrony in segmental contraction. A significant negative correlation was found between global peak filling rate and both sigma delta t1 and sigma delta t2 (r = 0.64, p less than 0.001 and r = 0.70, p less than 0.0001, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Male Breast Huge Malignant Phyllodes.
Introduction: Phyllodes tumors are rare breast tumors. The best treatment is wide local excision with 1 cm safety margin unless metastatic. The three pathological types (benign, borderline and malignant were reported in men. Case presentation: A 73year-old male with huge left breast swelling extending from the clavicle to the left hypochondriac region. Core needle biopsy suggested malignant phyllodes tumor. Postcontrast CT revealed a huge mass seen at the left anterolateral chest wall measuring about (22 x 25 x 26 cm). Simple mastectomy was performed en bloc with the tumor. The microscopic examination led to the diagnosis of high grade malignant phyllodes. IHC showed diffuse positive vimentin, CD10 and negative CK in the neoplastic cells. The patient lost follow up for three months.Then he was presented with fungating local recurrence with bilateral metastatic pulmonary. The patient underwent palliative excision. After the second surgery, he was prepared for palliative chemoradiotherapy but the patient died one month later at home. Discussion and conclusions: Very few cases of phyllodes tumor were reported in men. Pathologically, phyllodes tumors are subdivided into three types: benign, borderline and malignant according to mitotic frequency, nature of margins, stromal growth, cellularity and atypia. Malignant phyllodes tumors tend to spread via hematological route mainly to the lung, then to the bone. Phyllodes tumors even benign type tend to recur even after complete excision with higher tendency for malignant cases. Wide local excision is the standard of care for phyllodes tumors with or without adjuvant radiotherapy in malignant lesions- with no proved value for chemotherapy or hormonal therapy.


Family environments, adrenarche, and sexual maturation: a longitudinal test of a life history model.
Life history theorists have proposed that humans have evolved to be sensitive to specific features of early childhood environments and that exposure to different environments biases children toward development of different reproductive strategies, including differential pubertal timing. The current research provides a longitudinal test of this theory. Assessments of family environments, based on interviews with mothers and fathers, were conducted in preschool, and children were then followed prospectively through middle childhood. Adrenal hormones were assayed in a selected subsample of 120 children (73 girls) at age 7, and parent and child reports of secondary sexual characteristics were collected in the full female sample of 180 girls at age 11. Higher quality parental investment (from both mothers and fathers) and less father-reported Marital Conflict/Depression forecast later adrenarche. Older age at menarche in mothers, higher socioeconomic status, greater mother-based Parental Supportiveness, and lower third-grade body mass index each uniquely and significantly predicted later sexual development in daughters. Consistent with a life history perspective, quality of parental investment emerged as a central feature of the proximal family environment in relation to pubertal timing.


The NZB X SWR model of lupus nephritis. I. Cross-reactive idiotypes of monoclonal anti-DNA antibodies in relation to antigenic specificity, charge, and allotype. Identification of interconnected idiotype families inherited from the normal SWR and the autoimmune NZB parents.
The incidence of lupus nephritis is low in autoimmune NZB mice, but when they are crossed with normal SWR mice, almost 100% of the female F1 hybrids (SNF1) develop lethal glomerulonephritis. In a previous study we showed that anti-DNA auto-antibodies produced by the SNF1 mice were qualitatively different from those made by the NZB parents with respect to their isotype, charge, and antigenic specificity patterns. Here we studied idiotypic cross-reactions among the 65 monoclonal anti-DNA antibodies that were derived from four NZB and seven SNF1 mice. A library of 15 anti-idiotypic antibodies were prepared by immunizing rabbits with 15 monoclonal anti-DNA antibodies selected from the panel of 65. We identified 10 cross-reactive idiotype (CRI) families among this large collection of autoantibodies. Five of these CRI families were restricted to cationic anti-DNA antibodies that were exclusively of SNF1 origin, and the strongly cross-reacting members were predominantly IgG2b auto-antibodies with the allotype of the normal SWR parent. The cationic anti-DNA CRI families could be grouped into an interrelated cluster called the Id564 cluster. The other five anti-DNA CRI families were not restricted to any particular parental allotype or charge, although two of these CRI were shared exclusively by SNF1-derived autoantibodies and four of these CRI families could also be grouped into an idiotypically interrelated cluster called the Id512 cluster. In the case of seven out of the 10 CRI families, the idiotypic determinants detected were close to the antigen-binding site of the anti-DNA antibodies. The results indicate that the idiotypic repertoire of anti-DNA autoantibodies produced by the SNF1 mice is different from the NZB parents, and potentially pathogenic (cationic) antibodies produced by the SNF1 mice that are encoded by genes from the normal SWR parent can be identified as distinct CRI families. In the accompanying paper we demonstrate the role of these anti-DNA CRI families in the development of lupus nephritis.


Synthesis of Adenine-based Fluorescent and Naked-eye Chemosensors: Specific DNA Probes for The Detection of Bacterial Pathogens.
A rapid and confident tool to identify and diagnose bacterial pathogens with more accuracy using DNA as fingerprints is necessary. Herein, we report a smart chemosensor having a terminal adenine sticking to the thymine of single-stranded DNA (ssDNA) through supramolecular interactions and, which leaves ssDNA when the same ssDNA matches with the targeting desired DNA. We have synthesized a naked-eye coloured chemosensor with carbazole. As a model genetic material, DNA of Clavibacter michiganensis subsp. michiganensis was hybridized to ssDNA and immobilized over nitrocellulose membrane. The prepared adenine-chemosensor, by passing through the nitrocellulose-ssDNA membrane caused the formation of ssDNA nitrocellulose-ssDNA-adenine-chemosensor. FTIR results of the immobilized ssDNAs showed that the matching of same ssDNA releases the adenine-chemosensor from the surface of nitrocellulose-ssDNA that results in formation of the double stranded DNA. The selectivity of chemosensor was also confirmed with different bacterial DNA (Bacillus subtilis) as control. These data highlights accurate and reliable results of a new diagnostic kit prototype promising for further studies, which is able to diagnose DNA quickly and precisely.


Neuroimmunology of dancing eye syndrome in children.
Clinical, histopathological, and laboratory evidence suggest that dancing eye syndrome/opsoclonus-mycoclonus syndrome is an immune-mediated and probably autoimmune disorder. There is a clear, but not invariable, association with neuroblastoma or ganglioneuroma in children, and with a miscellany of neoplasms in adults. Direct support, i.e. the identification of antibodies against cell-surface antigens in neurons, is lacking but the nature of other evidence is such that the case for use of immunomodulatory therapeutic strategies is compelling. Because at least 85% of children affected by the condition are left with permanent cognitive deficits, notwithstanding a favourable initial neurological response to, say, steroid or adrenocorticotrophic hormone, therapeutic stakes are high. There is an urgent need for controlled therapeutic trials which, because of the comparative rarity of the condition in children, will require international collaboration to expedite studies.


The Microstructure of Attentional Control in the Dorsal Attention Network.
The top-down control of attention involves command signals arising chiefly in the dorsal attention network (DAN) in frontal and parietal cortex and propagating to sensory cortex to enable the selective processing of incoming stimuli based on their behavioral relevance. Consistent with this view, the DAN is active during preparatory (anticipatory) attention for relevant events and objects, which, in vision, may be defined by different stimulus attributes including their spatial location, color, motion, or form. How this network is organized to support different forms of preparatory attention to different stimulus attributes remains unclear. We propose that, within the DAN, there exist functional microstructures (patterns of activity) specific for controlling attention based on the specific information to be attended. To test this, we contrasted preparatory attention to stimulus location (spatial attention) and to stimulus color (feature attention), and used multivoxel pattern analysis to characterize the corresponding patterns of activity within the DAN. We observed different multivoxel patterns of BOLD activation within the DAN for the control of spatial attention (attending left vs. right) and feature attention (attending red vs. green). These patterns of activity for spatial and feature attentional control showed limited overlap with each other within the DAN. Our findings thus support a model in which the DAN has different functional microstructures for distinctive forms of top-down control of visual attention.


Production of epidermal growth factor in Escherichia coli from a synthetic gene.
Mouse epidermal growth factor (EGF) is under investigation as a deflecting agent for sheep. Substantial quantities of the pure protein are required for these studies and to supply this need a gene for the protein was synthesized and inserted into plasmid vectors to direct the expression of EGF polypeptide, or fusion proteins containing the EGF peptide sequence, in transformed Escherichia coli. Mature EGF was released by lysine specific proteolysis of a fusion protein consisting of part of the E. coli TrpE protein, a lysine linker and EGF polypeptide. The EGF was purified and characterized and was found to be biologically active.