Risk assessment, remedial decisions and the challenge to protect public health: the perchlorate case study.
While scientists have a responsibility to defer judgment in the absence of conclusive data, public health and ecological protection require that government regulators make decisions based on available information. The risk assessment paradigm has evolved to help risk managers balance risks to public health with the cost of pollution control and remediation. Risk assessments are designed to be reasonably protective of public health, however the time and money required to develop and evaluate a robust scientific database can significantly delay regulatory action while exposures continue. The federal assessment of perchlorate, a component of rocket fuel and a thyroid toxicant, is presented here as a case study that demonstrates some of the limitations of risk assessment in protecting public health. Perchlorate was detected in a city well field that lies beneath a military training range at Aberdeen Proving Ground, a U.S. Army garrison in Maryland. Cleanup was put on hold, pending promulgation of a national drinking water standard for perchlorate. This case study (1) illustrates the challenge of preventing chemical exposures in the absence of promulgated standards, and (2) makes recommendations for approaches to preventing exposures to chemicals of unknown, or uncertain toxicity before they occur.


Pro-MMP-9 activation by the MT1-MMP/MMP-2 axis and MMP-3: role of TIMP-2 and plasma membranes.
MMP-9 (gelatinase B) is produced in a latent form (pro-MMP-9) that requires activation to achieve catalytic activity. Previously, we showed that MMP-2 (gelatinase A) is an activator of pro-MMP-9 in solution. However, in cultured cells pro-MMP-9 remains in a latent form even in the presence of MMP-2. Since pro-MMP-2 is activated on the cell surface by MT1-MMP in a process that requires TIMP-2, we investigated the role of the MT1-MMP/MMP-2 axis and TIMPs in mediating pro-MMP-9 activation. Full pro-MMP-9 activation was accomplished via a cascade of zymogen activation initiated by MT1-MMP and mediated by MMP-2 in a process that is tightly regulated by TIMPs. We show that TIMP-2 by regulating pro-MMP-2 activation can also act as a positive regulator of pro-MMP-9 activation. Also, activation of pro-MMP-9 by MMP-2 or MMP-3 was more efficient in the presence of purified plasma membrane fractions than activation in a soluble phase or in live cells, suggesting that concentration of pro-MMP-9 in the pericellular space may favor activation and catalytic competence.


Plasmid DNA adsorbed to pH-sensitive liposomes efficiently transforms the target cells.
We have previously reported that plasmid DNA entrapped in the pH-sensitive immunoliposomes effectively transforms the target cells (Proc. Natl. Acad. Sci. USA, in press). In the present study, we demonstrate that DNA adsorbed on the same liposome also transforms the target cells. The transformation activity is antibody dependent, as liposomes containing no targeting antibody had reduced activity. The activity could be significantly inhibited by excess non-specific DNA (salmon sperm). Since some DNA are likely adsorbed to the liposomes during the entrapment process, the activity of the entrapped DNA is partially accounted for by the adsorbed DNA. The possibility of developing a simple DNA-mediated transfection protocol using liposome adsorbed DNA is discussed.


Selective role of the catalytic PI3K subunit p110β in impaired higher order cognition in fragile X syndrome.
Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110β plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110β, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110β in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110β knockdown. Our results suggest that FMRP-mediated control of p110β is crucial for neuronal protein synthesis and cognition.


Customized vs population-based growth charts to identify neonates at risk of adverse outcome: systematic review and Bayesian meta-analysis of observational studies.
To compare the effectiveness of customized vs population-based growth charts for the prediction of adverse pregnancy outcomes. MEDLINE, ClinicalTrials.gov and The Cochrane Library were searched up to 31 May 2016 to identify interventional and observational studies comparing adverse outcomes among large- (LGA) and small- (SGA) for-gestational-age neonates, when classified according to customized vs population-based growth charts. Perinatal mortality and admission to the neonatal intensive care unit (NICU) of both SGA and LGA neonates, intrauterine fetal demise (IUFD) and neonatal mortality of SGA neonates, and neonatal shoulder dystocia and hypoglycemia as well as maternal third- and fourth-degree perineal lacerations in LGA pregnancies were evaluated. The electronic search identified 237 records that were examined based on title and abstract, of which 27 full-text articles were examined for eligibility. After excluding seven articles, 20 observational studies were included in a Bayesian meta-analysis. Neonates classified as SGA according to customized growth charts had higher risks of IUFD (odds ratio (OR), 7.8 (95% CI, 4.2-12.3)), neonatal death (OR, 3.5 (95% CI, 1.1-8.0)), perinatal death (OR, 5.8 (95% CI, 3.8-7.8)) and NICU admission (OR, 3.6 (95% CI, 2.0-5.5)) than did non-SGA cases. Neonates classified as SGA according to population-based growth charts also had increased risk for adverse outcomes, albeit the point estimates of the pooled ORs were smaller: IUFD (OR, 3.3 (95% CI, 1.9-5.0)), neonatal death (OR, 2.9 (95% CI, 1.2-4.5)), perinatal death (OR, 4.0 (95% CI, 2.8-5.1)) and NICU admission (OR, 2.4 (95% CI, 1.7-3.2)). For LGA vs non-LGA, there were no differences in pooled ORs for perinatal death, NICU admission, hypoglycemia and maternal third- and fourth-degree perineal lacerations when classified according to either the customized or the population-based approach. In contrast, both approaches indicated that LGA neonates are at increased risk for shoulder dystocia than are non-LGA ones (OR, 7.4 (95% CI, 4.9-9.8) using customized charts; OR, 8.0 (95% CI, 5.3-10.1) using population-based charts). Both customized and population-based growth charts can identify SGA neonates at risk for adverse outcomes. Although the point estimates of the pooled ORs may differ for some outcomes, the overlapping CIs and lack of direct comparisons prevent conclusions from being drawn on the superiority of one method. Future clinical trials should compare directly the two approaches in the management of fetuses of abnormal size. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.


Multidisciplinary aerodigestive program at a children's hospital: A protocol for a prospective observational study.
Children with complex chronic multisystemic diseases frequently require care from multiple pediatric subspecialists. The aerodigestive program is a multidisciplinary program that diagnoses and treats pediatric patients with complex multi-systematic problems affecting airway, breathing, feeding, swallowing, or growth. The aim of this study is to present the protocol of the aerodigestive program of a children's hospital. This study is a prospective study to evaluate and compare the overall improvement of patients' objective and subjective conditions before and after the AeroDigestive Team (ADT) program. Among children from 1 month to 18 years of age, patients with complex problems of the airway, breathing, feeding, swallowing, or growth meeting at least two parameters of the inclusion criteria were enrolled. The overall process included referral based on the inclusion criteria, enrollment of ADT program with informed consents, interview and questionnaire for assessing patients' medical condition, prescheduling appointment, multi-specialists' evaluation, monthly team meetings, wrap-up discussion with the patients and family, therapeutic intervention, and follow-up at 6 months with the assessment of outcome measures. The outcome was evaluated objectively and subjectively. The objective outcome measure was divided into surgical or medical intervention, assessment of changes in medical condition, and follow-up study. Both caregiver interviews and questionnaires using a scoring system were used as subjective outcome measures before and after the ADT program. Children were scheduled to be followed-up at 6 months after the interventions or ADT meeting. The aerodigestive program is expected to provide comprehensive and multidisciplinary management of children with complex airway and digestive tract disorders.


[Digital necrosis revealing cold agglutinin disease: Treatment with rituximab].
Digital necrosis is rarer than lower limb necrosis and constitutes a medical or surgical emergency. Etiological evaluation is required. Cold agglutinin disease is a cause of digital necrosis but diagnosis is difficult. Herein we report the case of a 57-year-old man presenting recent paroxysmal acrosyndrome of the left hand subsequently complicated by digital necrosis following occupational exposure to cold in his work as a forklift driver. After etiological evaluation, a diagnosis of primary cold agglutinin disease was made. Intravenous rituximab and topical treatment resulted in complete healing. Cold agglutinin disease is a rare type of auto-immune hemolytic anemia. Following exposure to cold, paroxysmal cutaneous signs are frequent. The disease may be either primary or secondary with B-cell lymphoproliferative disorder, auto-immune disease or infection. A thorough workup is required. To date, the treatment combining the best positive response rate and good safety is rituximab in weekly perfusions over a 1-month period.


Gestation Length is Associated With Early-Life Limb Deformities in Thoroughbred Foals.
Flexural and angular limb deformities (LD) are an important cause of early-life morbidity and mortality/euthanasia in Thoroughbred foals. The majority are congenital in origin but, to date, their precise aetiology is poorly understood. We hypothesized that maternal- and pregnancy-level factors, particularly those with potential to influence in-utero growth and development, could play an important role. The aim of this study was therefore to investigate associations between such factors and early-life LD in Thoroughbred foals. A birth cohort was established on seven farms across the United Kingdom and Ireland and details of veterinary interventions for LD in foals in the first six months of life prospectively recorded. Details of dams' signalment, breeding history and reproductive and veterinary history in the breeding season(s) of interest were retrieved retrospectively from stud farm and veterinary records. Associations between mare- and pregnancy-level factors and LD in offspring were assessed using multivariable logistic regression. Records were available for 275 pregnancies in 235 mares, over two breeding seasons. Pregnancies resulted in the birth of 272 live foals, 21% of which (n = 57/272, 95% CI, 16-26) required veterinary intervention for LD in the first six months of life. Odds of LD decreased by 4% per day increase in gestation length between 314 and 381 days (OR 0.96, 95% CI, 0.93-0.99, P = .01). Longer gestation length appears to reduce the odds of early-life LD, including within the normal range of gestation length for Thoroughbred foals. Further work is required to elucidate biological mechanisms behind this association.


The effects of sleep restriction and altered sleep timing on energy intake and energy expenditure.
Experimental evidence suggests that sleep restriction increases energy intake (EI) and may alter energy expenditure (EE). However, it is unknown whether the timing of a sleep restriction period impacts EI and EE the following day. Hence, we examined the effects of sleep restriction with an advanced wake-time or delayed bedtime on next day EI and EE. Twelve men and 6 women (age: 23±4years, body fat: 18.8±10.1%) participated in 3 randomized crossover sessions: control (habitual bed- and wake-times), 50% sleep restriction with an advanced wake-time and 50% sleep restriction with a delayed bedtime. Outcome variables included sleep architecture (polysomnography), EI (food menu), total EE and activity times (accelerometry). Carbohydrate intake was greater on day 2 in the delayed bedtime vs. control session (1386±513 vs. 1579±571kcal; P=0.03). Relative moderate-intensity physical activity (PA) time was greater in the delayed bedtime session vs. control and advanced wake-time sessions on day 1 (26.6±19.9 vs. 16.1±10.6 and 17.5±11.8%; P=0.01), whereas vigorous-intensity PA time was greater following advanced wake-time vs. delayed bedtime on day 1 (2.7±3.0 vs. 1.3±2.4%; P=0.004). Greater stage 1 sleep (β=110kcal, 95% CI for β=42 to 177kcal; P=0.004), and a trend for lower REM sleep (β=-20kcal, 95% CI for β=-41 to 2kcal; P=0.07), durations were associated with greater EI between sleep restriction sessions. These findings suggest that the timing of a sleep restriction period impacts energy balance parameters. Additional studies are needed to corroborate these findings, given the increasing prevalence of shift workers and incidences of sleep disorders and voluntary sleep restriction.


LC-MS-MS determination of brostallicin in human plasma following automated on-line SPE.
LC-MS-MS method using automated on-line solid-phase extraction (SPE) has been developed and validated for the quantitation of brostallicin (I), a new distamycin derivative, in human plasma. I is a DNA minor groove binder currently under phase I-II clinical evaluation as an anticancer drug. Plasma (0.4 ml) was spiked with 0.2 ml stable label IS solution and placed in a 96-well plate maintained at +4 degrees C. Aliquots of 0.1 ml of prepared samples were loaded into the on-line SPE HySphere Resin SH cartridges (10 mm x 2 mm ID) and the analytes back eluted with the mobile phase into LC-MS-MS system. A Platinum Cyano column (100 mm x 4.6 mm, 3.6 microm) was used to perform the chromatographic analysis. The mobile phase was acetonitrile-ammonium formate buffer (pH 3.5; 20 mM) (70:30, v/v) at a flow rate of 1.0 ml/min. LC flow was split so that 300 microl/min was directed toward the mass spectrometer interface. Retention time of I was 2.6 min and the total cycle time was 8 min. MS detection used an Applied Biosystems/MDS SCIEX API 365 with a TurboIonSpray interface and MRM (m/Z: 725/257 for I and m/Z: 729/257 for IS) operated in positive ion mode. The method was validated over the calibration range 0.124-497 ng/ml. A negligible carry-over effect from the system was observed. In spite of the known instability of I in human plasma (about 20% decrease over 12 h), the ratio analyte/IS peak area showed good stability over the analysis time required for 96 samples. The automated on-line SPE method can be considered as a valid alternative to the off-line manual SPE procedure previously developed.


Biodegradable, elastic shape-memory polymers for potential biomedical applications.
The introduction of biodegradable implant materials as well as minimally invasive surgical procedures in medicine has substantially improved health care within the past few decades. This report describes a group of degradable thermoplastic polymers that are able to change their shape after an increase in temperature. Their shape-memory capability enables bulky implants to be placed in the body through small incisions or to perform complex mechanical deformations automatically. A smart degradable suture was created to illustrate the potential of these shape-memory thermoplastics in biomedical applications.


Clonal analysis of a 5-azacytidine-induced specific increase in growth hormone production by rat pituitary cells.
The nucleoside analog, 5-azacytidine (5-azaCR) which causes genomic hypomethylation in many cell types, increased GH production by GH4C1 rat pituitary cells 3-5 fold. This increased GH production was independent of changes in prolactin (PRL) synthesis by the same cells; it occurred at 10-fold lower 5-azaCR concentrations than those which increased the synthesis of PRL. Elevated GH production persisted for more than 20 population doublings after removal of 5-azaCR from the culture medium, indicating that the induced change was phenotypically stable. GH production remained responsive to stimulation by cortisol in 5-azaCR-treated cells. Clonal analysis demonstrated that the increased GH production was due to a higher incidence of cells in the population which made GH at an enhanced rate.


Brazilian immigrant fathers' perspectives on child's eating and feeding practices: a qualitative study conducted in the United States.
Brazilians comprise a rapidly growing immigrant Latino group in the USA, yet little research has focused on health issues affecting Brazilian children in immigrant families. As increasing evidence is documenting fathers' influential role in their children's eating behaviours and ultimately weight status, the current study sought to explore the Brazilian immigrant fathers' perspectives and practices related to child's feeding practices and their preschool-aged children's eating. Qualitative study using in-depth, semi-structured interviews. Interviews were conducted in Portuguese by native Brazilian research staff using a semi-structured interview guide. Interviews were audio-recorded and transcribed verbatim. Transcripts were analysed thematically using a hybrid approach that incorporated deductive and inductive analytical approaches. Massachusetts. Twenty-one Brazilian immigrant fathers who had at least one child aged 2-5 years. Results revealed fathers' awareness of the importance of healthy eating for their children, their influence as role models and their involvement in feeding routines of their preschool-aged children. Moreover, fathers were receptive to participating in family interventions to promote their children's healthy eating. Nearly all fathers reported wanting to learn more and to do 'what's right' for their children. The current study provides new information about Brazilian immigrant fathers' views about factors influencing their children's healthy eating behaviours and paternal feeding practices. Future research should quantify fathers' feeding styles and practices and solicit fathers' input in the design of culturally appropriate family interventions targeting the home environment of preschool-aged children of Brazilian immigrant families.


[Partial instead of complete splenectomy in children for the pathological staging of Hodgkin disease].
Evaluation of partial splenectomy in children for pathological staging of Hodgkin's disease. Prospective clinical study. University Hospital Groningen. From 1982 to 1988, 12 children with Hodgkin's disease underwent partial splenectomy during laparotomy for pathological staging. A follow-up of these children was conducted up for a median of 6 years (range 4-10) postoperatively. The median hospital stay after the laparotomy was 7 days. There was no postoperative mortality; one patient needed a relaparotomy. During a median follow-up of 6 years, one patient died of secondary leukaemia. All the other children were well. None of the patients developed sepsis and no Howell-Jolly bodies could be found in their blood. Partial splenectomy for pathological staging of Hodgkin's disease is a safe procedure which causes hardly any underestimation of the stage of the disease and which ensures adequate spleen function, depending on the treatment used for Hodgkin's disease.


Efficacy of a substituted methyl benzimidazole carbamate against developing and adult helminth parasites.
The efficacy of a substituted methyl benzimidazole carbamate, methyl 5(6)-[4-N-(2-pyridyl)] piperazino carbamoyl benzimidazole-2-carbamate, was assessed against larval and adult forms of Ancylostoma ceylanicum (hookworm), Nippostrongylus brasiliensis (trichostrongylid), Hymenolepis nana (tapeworm) and Brugia malayi (filariid) in experimentally-infected animals. The compound was found to have high efficacy against the developing stages (L3, L4, L5) of A. ceylanicum in hamsters at a single dose of 12.5 mg kg-1, against larvae of N. brasiliensis at 17.5 mg kg-1 and against cysticercoids of Hymenolepis nana at 100 mg kg-1 daily for 3 days given per os (p.o.) or intraperitoneally (i.p.). All the stages of B. malayi in Mastomys were killed when the compound was given i.p. at a dose of 6.25 mg kg-1 for 5 consecutive days. A dose of 6.25 mg kg-1 eliminated all adult A. ceylanicum from infected hamsters, 100 mg kg-1 resulted in complete removal of Syphacia obvelata adults from 63.6% of infected mice, 25 mg kg-1 X 5 dose eliminated 100% of adult B. malayi from infected Mastomys and a single 50 mg kg-1 dose expelled all H. nana adults from infected rats.


Endorphins mediate overshoot of substance P-induced facilitation of a spinal nociceptive reflex.
In the awake restrained rat the intrathecal administration of substance P to the lumbar spinal cord abruptly but transiently reduces reaction time in the tail-flick test. Interestingly, this hyperalgesic effect is followed by an increased response time, i.e., a hypoalgesia, which lasts less than 10 min. Administration of naloxone reduces the reaction time. It leaves the initial hyperalgesia unaltered but blocks the hypoalgesia. These results are interpreted as indicating that the initial effect of substance P is independent of any direct or indirect action mediated by opiate receptors. On the other hand, however, the antagonism of the hypoalgesia by naloxone suggests that this response is mediated via opiate receptors and, as substance P and opiates appear not to have any direct interaction at the cellular level, the endorphin-mediated hypoalgesia appears to be reflex in nature. Thus, the rebound overshoot of the response to substance P is visualized as an endorphin-mediated reflex activated by the increased transfer of nociceptive information provoked by substance P. The concept is proposed, therefore, that the transfer of nociceptive information is controlled by a servomechanism, or, in physiological terms, this transfer is under homeostatic control. Indeed, as naloxone itself reduces reaction time, it appears that an endogenous opioid is acting tonically to depress this transfer, at least under the conditions of the present experiments.


An efficient method for generation of bi-allelic null mutant mouse embryonic stem cells and its application for investigating epigenetic modifiers.
Mouse embryonic stem (ES) cells are a popular model system to study biological processes, though uncovering recessive phenotypes requires inactivating both alleles. Building upon resources from the International Knockout Mouse Consortium (IKMC), we developed a targeting vector for second allele inactivation in conditional-ready IKMC 'knockout-first' ES cell lines. We applied our technology to several epigenetic regulators, recovering bi-allelic targeted clones with a high efficiency of 60% and used Flp recombinase to restore expression in two null cell lines to demonstrate how our system confirms causality through mutant phenotype reversion. We designed our strategy to select against re-targeting the 'knockout-first' allele and identify essential genes in ES cells, including the histone methyltransferase Setdb1. For confirmation, we exploited the flexibility of our system, enabling tamoxifen inducible conditional gene ablation while controlling for genetic background and tamoxifen effects. Setdb1 ablated ES cells exhibit severe growth inhibition, which is not rescued by exogenous Nanog expression or culturing in naive pluripotency '2i' media, suggesting that the self-renewal defect is mediated through pluripotency network independent pathways. Our strategy to generate null mutant mouse ES cells is applicable to thousands of genes and repurposes existing IKMC Intermediate Vectors.


Krukenberg tumour simulating uterine fibroids and pelvic inflammatory disease.
To report a case of cancer of the colon which presented as secondaries to the ovaries. Case report. The case presented is that of a 39-year-old female who presented with lower abdominal pain and a multinodular pelvic mass which led to an initial diagnosis of multiple uterine fibroids and pelvic inflammatory disease. The presence of a colonic mass was first suggested by ultrasound. Laparotomy revealed carcinoma of the colon with bilateral krukenberg's tumour and an insignificant fibroleiomyoma. This case is reported to alert practitioners that all multinodular pelvic masses should not be assumed to be multiple fibroids.


Itchy body: Topographical difference of itch and scratching and C Nerve fibres.
Itch, also known as pruritus, is an unpleasant sensation that results in an urge to scratch. We can feel itch at any location where itch occurs from the top of the head to the toes. However, there are topographical differences in itch intensity. Itch is mainly conducted by C nerve fibres from the skin where itch emanates to the central nervous system. However, the abundancy of C fibres does not necessarily lead to higher itch intensity. Interestingly, reduction and/or structural changes in C fibres seem to play a role in itch sensation. In addition, C tactile fibres (CT afferents), which are activated by gentle "affective" touch and seem to be associated with scratching pleasurability and the reward system in the brain, can be involved in itch sensation and topographical differences of itch.


Multiple Cerebral Emboli in a Homozygous b-Thalassaemia Patient Due to Factor V 1299 (His-Arg) 4070 A-G Mutation.
Thromboembolic episodes are quite rare in beta thalassemia major patients although there is a tendency for thrombosis in haemolytic anaemias. We report a patient with cerebral thromboembolic episode triggered by a minor blood group incompatibility in which the underlying defect of factor V 1299 (His-Arg) was detected three years after his death.


A universal tool for stability predictions of biotherapeutics, vaccines and in vitro diagnostic products.
It is of particular interest for biopharmaceutical companies developing and distributing fragile biomolecules to warrant the stability and activity of their products during long-term storage and shipment. In accordance with quality by design principles, advanced kinetic modeling (AKM) has been successfully used to predict long-term product shelf-life and relies on data from short-term accelerated stability studies that are used to generate Arrhenius-based kinetic models that can, in turn, be exploited for stability forecasts. The AKM methodology was evaluated through a cross-company perspective on stability modeling for key stability indicating attributes of different types of biotherapeutics, vaccines and biomolecules combined in in vitro diagnostic kits. It is demonstrated that stability predictions up to 3 years for products maintained under recommended storage conditions (2-8 °C) or for products that have experienced temperature excursions outside the cold-chain show excellent agreement with experimental real-time data, thus confirming AKM as a universal and reliable tool for stability predictions for a wide range of product types.


Chromosomal damage induced by maleic hydrazide in mammalian cells in vitro and in vivo.
The induction of sister-chromatid exchanges (SCE) and chromosomal aberrations (Ch.Ab.) by the herbicide maleic hydrazide (MH) has been investigated in Chinese hamster ovary (CHO) cells grown in vitro and in bone marrow cells of mice treated in vivo. MH induces SCE and Ch.Ab. in CHO cells without metabolic activation; however, no induction of SCE was found in the in vivo experiments.


Moderate-to-vigorous physical activity and the risk of stroke recurrence in patients with a history of minor ischemic stroke in Japan: a retrospective analysis.
Physical activity (PA) is beneficial for stroke prevention; in particular, moderate-to-vigorous physical activity (MVPA). However, few studies have investigated its relationship with recurrent ischemic stroke (RIS). To clarify the relationship between MVPA and RIS and the burden of risk factors after a first-ever ischemic stroke. A total of 45 outpatients (mean age 67.1 ± 10.2 years) who had previously experienced a transient ischemic attack or a minor non-cardioembolic ischemic stroke at a single hospital in Japan (mean 6.4 ± 4.2 years previously), were enrolled between March and June 2016. All patients wore an accelerometer around their hips for 10 days, and their percentage body fat (%BF) and visceral fat level (VFL) were measured by bioelectrical impedance. Retrospective information about the history of RIS and risk factors (blood pressure, lipoprotein cholesterol and estimated glomerular filtration rate) were extracted from the clinical records. Binary logistic regression models were used to estimate the relevance of the RIS history to MVPA and potential risk factors such as sociodemographic and clinical variables (obesity, smoking and hypertension). RIS occurred in 9 patients; they had significantly higher VFL (p = 0.007) and %BF (p = 0.007) values and lower MVPA (p = 0.011) values than patients without recurrence. A multivariate analysis of these factors indicated that age, VFL and MVPA were significant independent predictors of RIS. Patients with a history of mild ischemic stroke had low MVPA and high VFL values, which together may be a risk factor for RIS.


Ocular surface area changes after double eyelidplasty.
Double eyelidplasty is one of the most common cosmetic surgeries in Asia. Subjective enlargement of the ocular surface area (OSA) after double eyelidplasty was appreciated by patients. Objective measurement of the OSA provides a more scientific result. We introduce a relatively precise method, using iris as a scale combined with the digital photography and software calculation, to measure the OSA before and after double eyelidplasty. One hundred and nineteen patients (108 females and 11 males) were enrolled in this study. Ninety-two patients received minimally invasive double eyelidplasty without other procedures and 27 patients received medial epicanthoplasty with modified Z-plasty besides double eyelidplasty. Digital photographs of the operative eyes in all patients were obtained preoperatively and postoperatively. The image processing software we used was ImageJ (v1.43, National Institutes of Health, United States). Preoperative and postoperative OSAs were measured. The percentage of difference of the OSA between two eyes in same patient before and after the operation was calculated and compared. The average increase of the OSA among 238 operative eyes was 12.5 ± 8.2%. Preoperative and postoperative OSA differences between two eyes in same patients were significantly decreased after surgery. Digital photography using iris as a scale combined with software calculation is an easy and convenient method to measure the OSA; it provides quantitative information for both preoperative and postoperative evaluation. Our study revealed that double eyelidplasty not only increased OSA but also improved ocular asymmetry after surgery.


Management of aggressive midface and orbital fibrous dysplasia.
To discuss cosmetic and functional implications in the evaluation and treatment planning of large, aggressive midfacial fibrous dysplasias. Eight patients (aged 2-38 years) with large fibrous dysplasias of the maxilla, zygomatic, and ethmoid bones requiring varying degrees of intervention and reconstruction were retrospectively reviewed. Patients with smaller lesions of these regions not requiring resection and reconstruction, as well those requiring sinus surgery alone were excluded from this review. All fibrous dysplasias in this review were monostotic, 6 originating in the maxilla, 1 in the zygoma, and 1 in the ethmoid. Five lesions (4 maxillary, 1 zygomatic) caused cosmetic deformity without functional deficits and required resection and/or contouring only with minimal reconstruction. The remaining lesions were invasive such that function of the eye and/or dentition was affected. These lesions were treated by aggressive resection and various degrees of reconstruction to optimize function. While fibrous dyplasia is classified as a benign process, local expansion can cause significant functional and aesthetic deformities. Each lesion should be thoroughly evaluated and, when vital structures are involved or threatened, total or subtotal resection should be considered. A variety of options should be available to the surgeon for definitive primary reconstruction.


Assessing the impact and resource implications of contrast-enhanced ultrasound on workflow of patients with incidental focal liver lesions on the UK national health service.
Focal liver lesions (FLL) are abnormal growths that require timely identification. Contrast-enhanced ultrasound (CEUS) is a cost-effective imaging modality for characterising FLL with similar sensitivity to computed tomography (CT) and magnetic resonance imaging (MRI). Despite being recommended by NICE, its adoption within the national health service (NHS) is limited due to low clinical demand, limited referral, and lack of knowledge. To evaluate the impact of CEUS on patients with incidental FLL and assess the resource implications of introducing CEUS as a diagnostic service within the NHS. A patient flow review and cost-minimisation analysis were conducted. This involved a targeted literature review, NHS Trust stakeholder consultations, and development of a Microsoft Excel cost-minimisation model to explore potential value of CEUS use versus CT and MRI by episode. A scenario analysis of the base-case explored increasing CEUS use to 50% and 90%. A sensitivity analysis was performed to assess how changes in assumptions impacted the model and the resulting cost estimates. The model, comparing a world with and without CEUS, showed that current use (base-case: 5%) resulted in cost savings of £224,790/year. The sensitivity analysis indicated that regardless of changes to the assumptions, CEUS still resulted in cost savings to the NHS. By increasing CEUS use to 50% and 90%, cost savings of up to £2,247,894/year and £4,046,208/year could be achieved, respectively. By standardising CEUS use for characterising FLL, substantial cost savings could be realised, whilst reducing wait times and expanding diagnostic capacity, thus preserving limited CT and MRI capacity for high-priority cases.


Protein TAU variants present in paired helical filaments (PHFs) of Alzheimer brains.
Polyclonal anti-TAU antisera directed against native Tau protein and the NH2-terminal side of the mouse TAU sequence were used to determine the nature of the TAU variants present in Alzheimer brains and in PHFs. These antibodies labelled specifically neurofibrillary tangles and plaque neurites in Alzheimer brains. On immunoblots of PHF extracts, two entities of 69 and 130 kDa were identified. These TAU-related species were absent from control brains. Protein immunoblot of total Alzheimer and control supernatants were shown to contain the same 4-5 TAU variants but none of the 69 and 130 TAU-related entities found in PHFs. These data suggest that specific TAU species are present in PHFs.


An approach to the diagnosis and treatment of cryofibrinogenemia.
Cryofibrinogenemia is a rarely symptomatic disorder that is underrecognized due to the infrequency with which it causes symptoms. Although completely reversible, this disorder can be life threatening when untreated. In this review, the classification, pathophysiology, and clinical presentation of cryofibrinogenemia are described, based on case reports and prospective observational data. Diagnostic criteria are outlined, and therapies are assessed critically. This information should help clinicians in establishing a diagnosis of cryofibrinogenemia and initiating treatment.


Photodegradation of the herbicide EPTC and the safener dichlormid, alone and in combination.
Photodegradation of the herbicide EPTC (S-ethyl-N, N-dipropylthiocarbamate), and the safener dichlormid (2,2-dichloro-N, N-diallylacetamide) has been examined in methanol and in water solutions. Irradiation of EPTC and dichlormid with UV light at 254 nm caused rapid degradation in both media. Remarkable and gradual changes in color of EPTC irradiated solution was observed from clear to yellow then to intense orange. EPTC half-life of elimination in water was 14.0, and 18.5 min, and in methanol 37.2 and 32.2 min, when irradiated with and without dichlormid, respectively. There was significant difference between rate of EPTC degradation in water and methanol in the presence or in the absence of dichlormid. Negligible degradation of EPTC or dichlormid at > 290 nm was observed. Photoproducts were separated and identified using GC or/and thin-layer chromatography then identified using mass spectrometry. It appeared that some products have high molecular weight that formed as a result of dimerization. This is possibly a result of the coupling of radicals that formed through EPTC degradation. The cleavage of C-S and C-N bonds accounted for the formation of these radicals. Gradual dealkylation of the acid chains of EPTC has also occurred. EPTC-sulfoxide, EPTC-sulfone, Propylamine and dipropylamine were detected as photoproducts of EPTC at 254 nm. Dichlormid pathways of degradation at 254 nm were characterized as dechlorination, dealkylation, and hydrolysis both in water and methanol. The findings showed that dichlormid did not significantly affect EPTC photodegradation either at 254 nm or at > 290 nm. The biological/toxicological properties of the photoproducts need further study, particularly the dimer compounds.


The role of selected metalloproteinases in cheiroarthropathy in children with type 1 diabetes - a pilotage study.
Metalloproteinases of the external matrix play an important role in ethiopatogenesis of diabetic complications especially in microangiopathy and also in fibrosing processes with occurrence the cheiroarthropathy, but clinical data are insufficient. The aim of the study was to assess the influence of metalloproteinases such as gelatinase A (MMP2) and gelatinase B (MMP9), and their tissue inhibitors (TIMP2, TIMP9) in ethiopathogenesis of cheiroatrhopathy in children with diabetes type 1. Forty one children were observed in average age of 14.98 years (±3.03 years), with the average duration of diabetes 6.78 years (±3.21 years), and with average HbA1c within all diabetes duration time 7.1% (6.47-7.5%). In all patients, the occurrence of cheiroarthropathy was checked, and concentration of metalloproteinase's and their inhibitors in serum were measured using ELISA method. Probe was divided into two groups because of presence of cheiroarthropathy. The comparing analysis of these two groups was conducted, and the correlation between metalloproteinase's concentration and their tissue inhibitors with selected parameters was done. When comparing group with cheiroarthropathy (n = 19) with the group without cheiroarthropathy (n = 22), the statistically significant elevated levels of metalloproteinase's were proved such as: MMP2 - 202 ng/ml (193-207) vs. 138 ng/ml (130-158), p < 0.001; MMP9 - 462 ng/ml (426-505) vs. 288 ng/ml (251-313), 0.001; TIMP2 - 182 ng/ml (177-190) vs. 104 ng/ml (88-165), p < 0.001); TIMP9 - 85 ng/ml (68-95) vs. 55 ng/ml (50-60), p < 0.001. There was no correlation between occurrence of cheiroarthropathy and age of the diabetes onset, duration of diabetes, grade of metabolic compensation, insulin dosages, weight and height. In children with long-term diabetes, although relatively metabolic compensation, the cheiroarthropathy has been occurred accompanying by elevated concentrations of metalloproteinase's and their tissue inhibitors. The presence of cheiroarthropathy could be treated as a simple test to identification the patients endangered to develop chronic vascular complication.


The genome of Uukuniemi virus consists of three unique RNA segments.
The three RNA species isolated from virions of Uukuniemi virus, a proposed member of the newly defined Bunyaviridae family, have been characterized by analysis of 32P-labeled ribonuclease T1 oligonucleotides separated on two-dimensional polyacrylamide gels. Each species contains unique oligonucleotides not present in the two others, indicating that the genome of this virus is segmented. Each segment appears to contain a unique primary sequence with little or no overlapping among the segments. The complexities of the RNA segments as calculated from the radioactivity in unique oligonucleotides of defined lengths are about 8000 (L RNA), 3500 (M) and 1900 (S) nucleotides. Since these values are similar to the molecular weights determined by other methods, each size class of RNA corresponds to a single molecular species. The presence of a 5' terminal pppAp ... structure in each RNA segment confirms indications from electron microscopy that the apparently circular RNA segments are not covalently closed. The absence of either a 5' terminal "cap" or 3' terminal poly(A) supports the concept that Uukuniemi virus is a negative strand virus.


Functional acute acquired comitant esotropia: clinical characteristics and efficacy of single Botulinum toxin type A injection.
To examine the clinical features of acute acquired comitant esotropia (AACE) and to evaluate the clinical effectiveness of a single injection of botulinum toxin type A (BTXA) on binocular visual function (BVF). This retrospective, observational case series study enrolled patients with AACE examined from October 2018-May 2019. BTXA was injected into the both medial rectus muscles. The refractive error, best-corrected visual acuity (BCVA), stereoacuity, vergence, accommodation, the horizontal angle of deviation, and the gradient accommodative convergence/accommodation (AC/A) ratio were measured pre- and post-BTXA injection. Data pre- and postinjection were compared by the Wilcoxon signed-rank test. A Spearman correlation coefficient was calculated to explore the relationships between demographic characteristics and BVF. Twenty-two AACE cases were included. Compared with preinjection deviation, the postinjection deviation in the primary position was smaller for near (p < 0.001) and distance (p < 0.001) fixation at 3 months after injection (BTXA). Furthermore, convergence was better for near (p = 0.003) and distance (p < 0.001) fixation, divergence was better for near (p = 0.021) and distance (p < 0.001) fixation, accommodation was better in the right (p = 0.011) and left (p = 0.004) eyes, and the gradient AC/A ratio was better at the third month after injection (p = 0.001). Stereoacuity was improved in 11 (50%), unchanged in 5 (22.73%) and decreased in 6 (27.27%) patients. The preinjection stereoacuity (p = 0.013, r = 0.522) and preinjection deviation for near (p = 0.015 r, = - 0.512) and distance (p = 0.009, r = - 0.541) were significantly associated with patient age. AACE is characterized by a high AC/A ratio and low accommodation. A single injection of BTXA is effective for AACE. Deviation, stereoacuity, and the therapeutic effect of BTXA may be correlated with patient age.


Metabolomics and metabolic pathway networks from human colorectal cancers, adjacent mucosa, and stool.
Colorectal cancers (CRC) are associated with perturbations in cellular amino acids, nucleotides, pentose-phosphate pathway carbohydrates, and glycolytic, gluconeogenic, and tricarboxylic acid intermediates. A non-targeted global metabolome approach was utilized for exploring human CRC, adjacent mucosa, and stool. In this pilot study, we identified metabolite profile differences between CRC and adjacent mucosa from patients undergoing colonic resection. Metabolic pathway analyses further revealed relationships between complex networks of metabolites. Seventeen CRC patients participated in this pilot study and provided CRC, adjacent mucosa ~10 cm proximal to the tumor, and stool. Metabolomes were analyzed by gas chromatography-mass spectrometry (GC/MS) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). All of the library standard identifications were confirmed and further analyzed via MetaboLync(TM) for metabolic network interactions. There were a total of 728 distinct metabolites identified from colonic tissue and stool matrices. Nineteen metabolites significantly distinguished CRC from adjacent mucosa in our patient-matched cohort. Glucose-6-phosphate and fructose-6-phosphate demonstrated 0.64-fold and 0.75-fold lower expression in CRC compared to mucosa, respectively, whereas isobar: betaine aldehyde, N-methyldiethanolamine, and adenylosuccinate had 2.68-fold and 1.88-fold higher relative abundance in CRC. Eleven of the 19 metabolites had not previously been reported for CRC relevance. Metabolic pathway analysis revealed significant perturbations of short-chain fatty acid metabolism, fructose, mannose, and galactose metabolism, and glycolytic, gluconeogenic, and pyruvate metabolism. In comparison to the 500 stool metabolites identified from human CRC patients, only 215 of those stool metabolites were also detected in tissue. This CRC and stool metabolome investigation identified novel metabolites that may serve as key small molecules in CRC pathogenesis, confirmed the results from previously reported CRC metabolome studies, and showed networks for metabolic pathway aberrations. In addition, we found differences between the CRC and stool metabolomes. Stool metabolite profiles were limited for direct associations with CRC and adjacent mucosa, yet metabolic pathways were conserved across both matrices. Larger patient-matched CRC, adjacent non-cancerous colonic mucosa, and stool cohort studies for metabolite profiling are needed to validate these small molecule differences and metabolic pathway aberrations for clinical application to CRC control, treatment, and prevention.


Longitudinal melanonychia in localized scleroderma.
Longitudinal melanonychia associated with scleroderma is rare. This is paradoxical, as increased skin pigmentation is frequent in the latter disease. This article reports 4 cases of longitudinal melanonychia that were found concurrently with various types of localized scleroderma. These 4 cases may be a coincidental finding despite the fact that pigmentation is so frequent a manifestation of scleroderma. In 2 cases, biopsy specimen of the nail matrix showed well-defined melanocytes without cellular atypia. This, in keeping with the pigmentation of scleroderma, appears to result from the functional activation of the matrix melanocytes.


Research Note: Comparison of two methods to measure broiler tibia morphology.
The skeletal integrity of chickens is an important area of research and detailed measures are needed to better understand the influence of experimental manipulation on bone health. The objective of this experiment was to compare 2 methods to measure the superficial tibiotarsus (tibia) morphology of broiler chickens collected in the wet laboratory (WL) or from digital images (DIG). The length, width at 90%, 75%, 50%, 25%, and 10% of the length, proximal and distal head width, medial, lateral, and distal intercondylar groove depth (ID), and proximal head angle were measured on the right and left tibias collected from broilers in 2 experiments (E1, E2). In both experiments, tibias had a greater width at 90% of the length when measured with the WL method compared with the DIG method (P ≤ 0.04), while tibias measured with the DIG method had a greater length, distal ID, and widths at 10%, 25%, 50%, and 75%, of the length compared with the WL method (P < 0.0001). In E1, tibias measured with the DIG method had a greater medial, lateral, and distal ID compared with the WL method (P ≤ 0.04). In E2, compared with the DIG method, tibias measured with the WL method had a greater distal head width and lateral ID, yet a shallower distal ID (P ≤ 0.03). The use of the DIG method provided more precise measures but, due to the limitations of measures from digital images and the opportunity for more accurate measures to be collected with the WL method, the WL method is recommended to measure the superficial morphology of broiler chickens because it was more accessible and practical.


[Sexual self-reflection in patients with atopic dermatitis and psoriasis].
The aim of this study was to evaluate the differences between the Sexual Self-Reflection in patients with atopic dermatitis and psoriasis from a group of healthy controls. Furthermore the influence of coping with the disease and pruritus on the patients' sexuality was studied Patients with atopic dermatitis (n=38), psoriasis (n=31) and healthy controls (n=33) were tested with various psychological questionnaires. The German questionnaire for partnership attributes (PFB), Marburg questionnaire for coping with skin diseases (MHF) and questionnaire for pruritus and cognition (JKF), and sexual self-concept questionnaire (MSSCQ) served as psychometric measures. Patients with atopic dermatitis showed more fears of sex, with pruritus being the main factor, so that controlling pruritus should also improve sexual experience. Patients with psoriasis and sexual problems showed significantly more social fears and avoidance. Appropriate psychosomatic care and educational programs including the therapy of social fears, avoidance and pruritus may also improve sexual life in patients with psoriasis or atopic dermatitis.


AlN Nanowall Structures Grown on Si (111) Substrate by Molecular Beam Epitaxy.
AlN nanowall structures were grown on Si (111) substrate using molecular beam epitaxy at substrate temperature of 700 °C with N/Al flux ratios ranging from 50 to 660. A few types of other AlN nanostructures were also grown under the nitrogen-rich conditions. The AlN nanowalls were ranged typically 60-120 nm in width and from 190 to 470 nm in length by changing N/Al flux ratio. The AlN nanowall structures grown along the c-plane consisted of AlN (0002) crystal with full-width at half maximum of the rocking curve about 5000 arcsec.


Recombinant production of the therapeutic peptide lunasin.
Lunasin is a chemopreventive peptide produced in a number of plant species. It comprises a helical region with homology to a region of chromatin binding proteins, an Arg-Gly-Asp cell adhesion motif and eight aspartic acid residues. In vitro studies indicate that lunasin suppresses chemical and oncogene driven transformation of mammalian cells. We have explored efficient recombinant production of lunasin by exploiting the Clostridium thermocellum CipB cellulose binding domain (CBD) as a fusion partner protein. We used a pET28 vector to express a CBD-lunasin fusion with a hexahistidine tag and Tobacco Etch Virus protease site, to allow protease-mediated release of native lunasin. Autoinduction in E. coli BL21 (DE3) Star cells achieved expression of 3.35 g/L of CBD-lunasin fusion protein. The final yield of lunasin was 210 mg/L corresponding to 32% of the theoretical yield. Purification by cellulose binding and nickel affinity chromatography were tested with the latter proving more satisfactory.The effects of CBD-lunasin expression on growth and morphology of the E. coli cells were examined by light and electron microscopy revealing an altered morphology in a proportion of cells. Cell division appeared to be inhibited in these cells resulting in elongated, non-septated cells. The use of CBD as a fusion partner gave high protein yields by autoinduction, with lunasin release by TEV protease cleavage. With some optimisation this approach could provide a potentially valuable route for production of this therapeutic peptide. Over-expression in the host cells manifest as a cell division defect in a population of the cells, presumably mimicking some aspect of the chemopreventive function observed in mammalian cells.


Artemisia biennis Willd.: Anti-Nociceptive effects and possible mechanisms of action.
Artemisia biennis Willd. (Dermane in Persian) has been used as an antinociceptive remedy in Iranian folkloric medicine. The aim of the present study was to evaluate the anti-nociceptive effects of Artemisia biennis Willd. aerial part essential oil (ABAEO) on male Swiss mice. Nociceptive pain techniques including acetic acid-induced writhing (AAIW), formalin-induced paw licking (FPL), glutamate-induced paw licking (GPL), and tail-flick (TF) models were applied. We assessed opioid and L-arginine-NO-cGMP-KATP pathways to detect the possible anti-nociceptive properties of ABAEO. In addition, neuropathic pain was induced by the cervical spinal cord contusion model. ABAEO (120 mg/kg) had a significant anti-nociceptive activities in comparison to the control animals (p < 0.05) in the AAIW, TF, GPL, and FPL assays. The selective opioid antagonist (naloxonazine) administration in the AAIW test alleviated the anti-nociceptive effect of ABAEO (p < 0.05). L-arginine, methylene blue, and glibenclamide treatment prevented the ABAEO anti-nociceptive effects (p < 0.05); however, sodium nitroprusside could profoundly potentiate the ABAEO-associated antinociception in the FPL (phase II) test (p < 0.05). In nociceptive pain models, Cr (one of the main constituents of ABAEO) showed significant anti-nociceptive effects (p < 0.05). Moreover, the von Frey results indicated that ABAEO could attenuate mechanical allodynia in mice. Our observation revealed the anti-nociceptive effects of ABAEO in male mice. These effects could include, at least in part, modulating glutamatergic mechanisms via opioid systems. Our data output also indicates activating the L-arginine-NO-cGMP-KATP system in ABAEO anti-nociceptive activities.


Investigation of soluble anti-Müllerian hormone receptor type 2 as a biomarker for diagnosis of female fertility disorders.
The ectodomain of the anti-Müllerian hormone (AMH) type 2 receptor is shed by proteases under certain conditions, which makes it measurable in the blood. The aim of this study was to identify correlations of soluble anti-Müllerian hormone receptor type 2 (sAMHR2) with other sex hormone concentrations and to assess whether sAMHR2 may serve as a new biomarker in fertility disorders. In a retrospective cross-sectional study of women (n = 186) with different gynaecological-endocrinological disorders, mixed-effect models were used to analyse the correlation with established diagnostic hormone tests. Receiver operating characteristic curve analysis was performed to assess the diagnostic performance. There was a strong correlation of sAMHR2 with LH (r = 0.898) and FSH (r = 0.846) and a moderate correlation of AMH with testosterone (r = 0.666) and androstenedione (r = 0.696) (all P < 0.001). In diagnoses of polycystic ovary syndrome (PCOS), AMH showed the best performance (area under the curve [AUC] 0.981, cut-off 4 ng/ml) with 96% sensitivity and 94% specificity. sAMHR2 concentrations and sAMHR2/AMH ratios were elevated in women with ovarian insufficiency, compared with all other study groups, including post-menopausal women on hormone replacement therapy. Highest sensitivity and specificity (100% and 98.2%, respectively) were achieved with sAMHR2/AMH ratio for the diagnosis of post-menopausal status (cut-off 68.85). The sAMHR2/AMH ratio (AUC 0.997) had a better performance than sAMHR2 (AUC 0.947), FSH (AUC 0.989) and LH (AUC 0.967). The sAMHR2/AMH ratio may serve as a useful biomarker for infertility diagnostics to identify post-menopausal women.


Fibronectin attachment protein is necessary for efficient attachment and invasion of epithelial cells by Mycobacterium avium subsp. paratuberculosis.
Attachment and ingestion of Mycobacterium avium subsp. paratuberculosis by two epithelial cell lines were enhanced by soluble fibronectin (FN). Peptide blocking of the FN attachment protein (FAP-P) inhibited the internalization of M. avium subsp. paratuberculosis. Disruption of FAP-P expression significantly reduced attachment and ingestion of M. avium subsp. paratuberculosis by T-24 and Caco-2 cells. The results indicate that the interaction between FN and FAP-P facilitates attachment and internalization of M. avium subsp. paratuberculosis by epithelial cells.


Ultrastructural organization of normal and transplanted rat fascia dentata: II. A quantitative analysis of the synaptic organization of intracerebral and intraocular grafts.
As part of an ultrastructural analysis of the normal rat fascia dentata and intracerebral and intraocular dentate transplants the synapses in the dentate molecular layer were quantified. Hippocampal and dentate tissue from 21-day-old rat embryos were grafted into the brain of developing and adult rats and to the anterior eye chamber of adult rats. After 100 or 200 days of survival the recipient rat brains and the recipient eyes were processed for electron microscopy, and the graft dentate molecular layer with the adjacent granule cell layer selected for ultrastructural analysis. Tissue from the dentate molecular layer of normal adult rats served as controls. The dentate synapses were classified as asymmetric (Gray's type 1) or symmetric (Gray's type 2), and according to the postsynaptic element (cell body, dendritic shaft, dendritic spine). The spine synapses were further classified into simple and complex types according to the spine-terminal configuration. Also, the length of synaptic contacts of the individual synaptic types was measured in some grafts, just as the percentage of the cross sectional area of the neuropil covered by blood vessels. The results showed that the synaptic density, expressed as number per unit area of neuropil, to a large extent was the same within the different parts of the normal dentate molecular layer. Compared with this the synaptic density was reduced with 16.4% in dentate molecular layer of the intracerebral graft, primarily because of a 17.6% reduction of simple synapses on dendritic spines and almost halving of the symmetric synapses on dendritic shafts. The synaptic density was independent of the age of the recipient, the intracerebral location of the graft, and the survival time. Although the synaptic length of some of the individual synaptic types increased, this did not compensate for the loss of synapses. In the intraocular grafts the synaptic density was lower than in the intracerebral grafts. Despite the reduced synaptic density, which mainly involved two synaptic types, we conclude that grafted dentate granule cells can develop a remarkably normal, ultrastructural synaptic organization even in the absence of major afferent inputs. This outcome must accordingly be achieved by reorganization of the available intrinsic afferents.


Subjective Evaluation of Voice Characteristics of School Aged Children in a Basket Ball Team.
Voice disorders have been estimated to be present in between 3 and 9% of general population. Sports children have vocal abusive behavior i.e. the extra effort which they put on their voice while playing, leading to voice disorders. It is imperative to find out the voice characteristics of children involved in sports activity. To assess voice characteristics of school aged children, who are active participants in a basket ball team. A group of twenty children (13 males and 7 females) were included in the study. He or she was member of school basket ball team and had participated in many events. The perceptual voice assessment was conducted using GRBAS scale, Buffalo III Voice Profile and Voice Handicap Index (VHI). Findings on GRBAS voice rating scale-In the first parameter i.e. grade 46.7% of the subjects reported slight hoarse component. In the second parameter i.e. Roughness 46.7% of the subjects showed slight roughness component. In another parameter i.e. the asthenia 20% % of the subjects reported slight asthenia component in their voice. In the next parameter i.e. strain in the voice, 26.7% of the subjects showed slight strain component in their voice. Finding on BUFFALO III voice screening profile-In the laryngeal tone, 46.7% of the subjects showed mild hoarse component. Findings on voice handicap index (VHI)-28% of the subjects had functional symptoms of voice problems. 43% of the subjects had some physical symptoms while 28% had affected emotional component. Present study is first of its kind to focus on voice disorders among school going children who are members of a basket ball team. During sport events players tend to scream in order to communicate among their team mates, to show their aggressiveness to their opponents and to show excitement of win or frustration of the lost match leading to various voice problems. There is a high probability of occurrence of voice disorders among children who are active participants of basket ball. Proper counselling of these children is required for preventive measures and to seek voice therapy when required.


Nonpenetrating deep sclerectomy: a 6-year retrospective study.
Nonpenetrating trabeculectomy, also called nonpenetrating deep sclerectomy (NPDS), is a filtering surgery where the internal wall of Schlemm's canal is excised, allowing subconjunctival filtration without actually entering the anterior chamber. This, technique was developed to minimize the complications of trabeculectomy. The authors investigated its safety and efficacy in a retrospective noncomparative study. A total of 258 eyes (179 patients, mean age 61.4 +/- 11.56 years) with uncontrolled open angle glaucoma with prior medical therapy were treated. NPDS with a biocompatible collagen device (157 eyes) sutured to deep scleral bed or with the use of a 5-fluorouracil sponge (90 eyes) were analyzed. The main outcome measure was postoperative intraocular pressure (IOP) with an average follow-up of 54.4 +/- 17.07 months (range 1-85). Efficacy was determined 1 month, 3 months, and every 6 months after the procedure for 6 years. Mean preoperative IOP was 24.47 +/- 5.92 mmHg. Mean postoperative IOP was 14.44 +/- 5.31 mmHg (average lowering of the IOP was 38.94 +/- 23.81%) at 1 month, 15.16 +/- 4.57 mmHg (35.73 +/- 21.35%) at 3 months, 15.87 +/- 4.24 mmHg (32.45 +/- 20.52%) at 6 months, 16.32 +/- 4.53 mmHg (29.96 +/- 23.69%) at 12 months, 17.12 +/- 4.45 mmHg (26.51 +/- 23.93%) at 18 months, 16.77 +/- 4.44 mmHg (28.18 +/- 21.73%) at 24 months, 16.43 +/- 4.15 mmHg (28.89 +/- 23.69%) at 30 months, 16.34 +/- 4.12 mmHg (30.05 +/- 21.61%) at 36 months, 16.16 +/- 4.01 mmHg (30.06 +/- 22.55%) at 42 months, 15.71 +/- 3.74 mmHg (32.49 +/- 19.08%) at 48 months, 15.61 +/- 3.48 mmHg (31.26 +/- 21.01%) after 5 years, and 15.81 +/- 3.79 mmHg (33.73 +/- 20.9%) after 6 years. YAG goniopuncture was performed in 47.3% of cases with a mean follow-up of 12 +/- 13 months. These goniopunctures were effective in lowering IOP after a long-term follow-up (24 months). Additional 5-fluorouracil injections were used in 7% of cases. Visual field (Octopus or Humphrey mean defect and corrected loss variance or loss variance) was not modified (p < 0.01). Number of preoperative glaucoma medications was 2.01 +/- 0.58 and number of postoperative glaucoma medications was 0.85 +/- 0.92. Complications were peroperative microperforations in 27 eyes (10.5%), shallow anterior chamber in 2 eyes, hyphema in 2 eyes (0.8%), cataract in 5 eyes (2%), and dellen in 1 eye (0.4%). No cases of endophthalmitis or choroidal detachment were found. After surgery, 23 eyes (8.9%) required a new filtering surgical procedure, and diode laser cyclophotocoagulation was necessary in 2 eyes (0.8%). The probability success rate, defined as an IOP lower than 21 mmHg, was 66.46% (Kaplan Meier) at 60 months off all glaucoma medications and 80.32% with medical or new surgical treatment. NPDS appears to be an effective and safe filtering procedure for lowering IOP and could be an alternative to trabeculectomy in open angle glaucoma with the advantage of having fewer complications.


Longitudinal follow-up of patients with mild traumatic brain injury by magnetic resonance spectroscopic technique.
To explore the changes in the concentrations of neural markers immediately or several months after mild traumatic brain injury (mTBI). The metabolic markers of neurons in white matter tissues above the lateral ventricle were semi-quantitatively determined by employing 1H magnetic resonance spectroscopic technique (1-H-MRS) in 30 clinically diagnosed cases of mTBI. At the same time, the neurological functions of the subjects, including ability to pay attention, memory, working memory and operational capacity etc were also assessed. The patients were followed up for, on average, 13 days after mTBI and the results showed that Cre, PCre and Glx in the white matter tissues were significantly elevated in mTBI patients. 17 patients (57%) recovered from the injury during the follow-up (median was defined as the 40th post-trauma day). Comparison in terms of intelligence among groups revealed that the levels of neural markers of intelligence development was positively related with intelligence scores). Change in Glx concentrations is most sensitive during trauma or in ensuing repairing processes, and might be different from normal status in the following months and Glx level tends to be accompanied with change in Cre, another energy-related marker.


Lung cancer metastatic to breast: case report and review of the literature.
The incidence of metastases to the breast from nonbreast carcinoma is less than 1% of all breast cancers; of these, adenocarcinoma of the lung to breast is a small proportion (<0.1% of breast carcinomas). The imaging findings of a case of metastatic lung adenocarcinoma to the breast are presented with a review of the literature. Imaging findings including elastography suggesting the breast mass is not a primary breast cancer are highlighted. The importance of notifying the pathologist that nonbreast metastatic disease is in the differential is discussed. The use of appropriate tumor markers is needed; otherwise, the lesion may be interpreted as a triple negative breast cancer.


Further investigations of indomethacin and intestinal ulcers in the rat.
The lower incidence of indomethacin-induced intestinal ulcers in fasted as compared to fed rats must be attributed to factor(s) other than changes in bile flow and composition. Experimental evidence and data in the literature rather suggest that the amount of food present in the gastrointestinal tract at the time indomethacin was given may influence ulcer formation by affecting the duration and degree enterohepatic circulation of this compound.


'The time is now to take action on biodiversity loss'.
Georgina Mills discusses a new report showing a sharp decline in animal populations.


Phosphatidylserine in the Nervous System: Cytoplasmic Regulator of the AKT and PKC Signaling Pathways and Extracellular "Eat-Me" Signal in Microglial Phagocytosis.
Phosphatidylserine (PtdSer) is an important anionic phospholipid found in eukaryotic cells and has been proven to serve as a beneficial factor in the treatment of neurodegenerative diseases. PtdSer resides in the inner leaflet of the plasma membrane, where it is involved in regulating the AKT and PKC signaling pathways; however, it becomes exposed to the extracellular leaflet during neurodevelopmental processes and neurodegenerative diseases, participating in microglia-mediated synaptic and neuronal phagocytosis. In this paper, we review several characteristics of PtdSer, including the synthesis and translocation of PtdSer, the functions of cytoplasmic and exposed PtdSer, and different PtdSer-detection materials used to further understand the role of PtdSer in the nervous system.


The presence of androgen-binding protein in the guinea-pig testis, epididymis and epididymal fluid.
Androgen-binding protein (ABP) is present in the guinea-pig testis, epididymis and epididymal fluid. Guinea-pig ABP sediments as an approx. 4.6S species on sucrose gradients containing 0.01 M KCl. Electrophoresis on non-denaturing polyacrylamide gels indicated that specific androgen binding was present in epididymal cytosol, but not in plasma. Time-course studies indicated that binding equilibrium is approached in about 2.5 h; the dissociation half-time of [3H]5 alpha-DHT from guinea-pig ABP is 5.64 +/- 0.62 h (n = 6) at 4 degrees C. The relative affinities of some steroids for guinea-pig ABP in relation to 5 alpha-DHT = 1 are: testosterone = 0.55 +/- 0.13 (n = 4), estradiol = 0.14 +/- 0.03 (n = 4), the anti-androgen cyproterone acetate = 0.0025 +/- 0.0002 (n = 3). Guinea-pig ABP exhibited an equilibrium dissociation constant of 6.34 +/- 0.52 nM (n = 3) at 4 degrees C and there were 3.43 +/- 0.78 (n = 3) pmoles of binding sites per mg of protein when homogenates of the whole epididymis were assayed. The concentration of ABP was lowest in the caput-corpus region of the epididymis, highest in the proximal cauda, and intermediate in the distal cauda. Essentially all of the ABP present in the distal cauda was intraluminal, as evidenced by the fact that flushing of the duct eliminated most of the [3H]5 alpha-DHT binding activity.


The biogenesis protein PEX14 is an optimal marker for the identification and localization of peroxisomes in different cell types, tissues, and species in morphological studies.
Catalase and ABCD3 are frequently used as markers for the localization of peroxisomes in morphological experiments. Their abundance, however, is highly dependent on metabolic demands, reducing the validity of analyses of peroxisomal abundance and distribution based solely on these proteins. We therefore attempted to find a protein which can be used as an optimal marker for peroxisomes in a variety of species, tissues, cell types and also experimental designs, independently of peroxisomal metabolism. We found that the biogenesis protein peroxin 14 (PEX14) is present in comparable amounts in the membranes of every peroxisome and is optimally suited for immunoblotting, immunohistochemistry, immunofluorescence, and immunoelectron microscopy. Using antibodies against PEX14, we could visualize peroxisomes with almost undetectable catalase content in various mammalian tissue sections (submandibular and adrenal gland, kidney, testis, ovary, brain, and pancreas from mouse, cat, baboon, and human) and cell cultures (primary cells and cell lines). Peroxisome labeling with catalase often showed a similar tissue distribution to the mitochondrial enzyme mitochondrial superoxide dismutase (both responsible for the degradation of reactive oxygen species), whereas ABCD3 exhibited a distinct labeling only in cells involved in lipid metabolism. We increased the sensitivity of our methods by using QuantumDots™, which have higher emission yields compared to classic fluorochromes and are unsusceptible to photobleaching, thereby allowing more exact quantification without artificial mistakes due to heterogeneity of individual peroxisomes. We conclude that PEX14 is indeed the best marker for labeling of peroxisomes in a variety of tissues and cell types in a consistent fashion for comparative morphometry.


GABAergic drugs, morphine and morphine tolerance: a study in relation to nociception and gastrointestinal transit in mice.
Agonists and antagonists of gamma-aminobutyric acid, i.e. GABAergic drugs, such as muscimol, baclofen or bicuculline, alone or in combination, exhibited analgesic effects per se and enhanced the analgesia induced by morphine. The analgesic effects of GABAergic drugs were unaffected by administration of naloxone in a dose which antagonized the analgesia induced by morphine. The ED50 for the antinociceptive effect of muscimol, bicuculline, picrotoxin, gabaculline or aminooxyacetic acid (AOAA) was not affected in the morphine-tolerant group as compared to the control group, in contrast to the increase in the ED50 for morphine under similar conditions; this indicated that there was no development of cross-tolerance between morphine and GABAergic drugs. Muscimol suppressed the abrupt withdrawal-jumping induced by morphine and enhanced the suppression of this phenomenon by morphine. The GABAergic drugs also shared with morphine the property of inhibiting gastrointestinal (GIT) motility. Naloxone reversed the inhibition of motility induced by morphine but failed to influence that induced by GABAergic drugs. In the morphine-tolerant state, the sensitivity of gastrointestinal motility to morphine decreased, whereas, the sensitivity to GABAergic drugs remained unaltered. The results indicate that GABAergic drugs share some of the classical properties of morphine, such as analgesia and inhibition of gastrointestinal motility, but they probably do so by different mechanisms.


Extrahepatic autoimmune diseases in patients with autoimmune hepatitis and their relatives: A Danish nationwide cohort study.
It is widely accepted that patients with autoimmune hepatitis have an increased prevalence of extrahepatic autoimmune diseases. It is believed that the patients' relatives share this trait, but it has not been studied in a satisfactory setting. We conducted a nationwide registry-based cohort study on this issue. From Danish healthcare registries 1994-2015, we included 2745 patients with autoimmune hepatitis, 17 812 of their first- and second-degree relatives and 27 450 general population controls matched with the patients for sex and age. We compared the sex- and age-specific prevalence of extrahepatic autoimmune diseases between the patients with autoimmune hepatitis, their relatives and the controls. We computed the prevalence ratio as a measure of the relative prevalence, using the controls as reference group. In the patients with autoimmune hepatitis, the prevalence ratio of extrahepatic autoimmune diseases ranged from 7 to 10 until age 30 years (prevalence ratio at age 20 = 9.92; 95% confidence interval 6.21-15.83), after which it gradually decreased to about 2 (prevalence ratio at age 80 = 2.37; 95% confidence interval 1.89-3.00). Neither first- nor second-degree relatives had an increased prevalence of extrahepatic autoimmune diseases (prevalence ratio for relatives at age 20 = 1.11; 95% confidence interval 0.72-1.70; prevalence ratio at age 80 = 0.96; 95% confidence interval 0.70-1.31). Danish patients with autoimmune hepatitis were highly prone to extrahepatic autoimmune diseases, but their relatives were not.


Cognitive disorders in patients with chronic kidney disease: Approaches to prevention and treatment.
Cognitive impairment is common in patients with chronic kidney disease (CKD), and early intervention may prevent the progression of this condition. Here, we review interventions for the complications of CKD (anemia, secondary hyperparathyroidism, metabolic acidosis, harmful effects of dialysis, the accumulation of uremic toxins) and for prevention of vascular events, interventions that may potentially be protective against cognitive impairment. Furthermore, we discuss nonpharmacological and pharmacological methods to prevent cognitive impairment and/or minimize the latter's impact on CKD patients' daily lives. A particular attention on kidney function assessment is suggested during work-up for cognitive impairment. Different approaches are promising to reduce cognitive burden in patients with CKD but the availabe dedicated data are scarce. There is a need for studies assessing the effect of interventions on the cognitive function of patients with CKD.


Usefulness of sex steroid hormone levels in predicting coronary artery disease in men.
The relation between sex hormone levels and subsequent risk of a major coronary event was studied in a nested case-control study among 163 men in the Multiple Risk Factor Intervention Trial who later had a major coronary event and in 163 controls. Cases and controls were matched for age, serum cholesterol level, randomization group, randomization date and clinic. Blood samples were collected at baseline before randomization and frozen at -70 degrees C. Follow-up extended over 6 to 8 years. Sixty-one patients had a nonfatal acute myocardial infarction and 102 fatal infarction. Total and free testosterone, total and free estradiol, androstenedione and estrone concentrations were measured. There were no significant differences between cases and controls for any sex hormone level. There was also no difference in the ratio of testosterone to estradiol. Controlling for other cardiovascular risk factors did not change these results. These results do not support previous case-control studies of a relation between sex hormone levels and risk of heart attack among men.


Renal involvement in Mycobacterium leprae infected mice. Histopathological, bacteriological and immunofluorescence study.
Swiss albino mice were inoculated in the footpads with Mycobacterium leprae obtained from untreated lepromatous patient. The kidneys obtained from the animals sacrificed during different periods were processed for histopathology, presence of AFB and immunofluorescence studies. Renal lesions, AFB and immune complex deposits were seen in the infected animals. Such findings have not been studied in great detail in experimental leprosy earlier.


Probiotic characterization of Lactobacillus brevis KU15153 showing antimicrobial and antioxidant effect isolated from kimchi.
Lactobacillus brevis KU15153 was isolated from kimchi and probiotic characterization was performed including analysis of its antimicrobial and antioxidant effects. Lactobacillus rhamnosus GG (LGG) was used as a probiotic control. L. brevis KU15153 survived under artificial gastric conditions and was non-hemolytic, showed antibiotic susceptibility, and did not produce carcinogenic β-glucuronidase. L. brevis KU15153 adhered strongly to HT-29 cells in the direct adherent assay and showed high cell surface hydrophobicity. Particularly, L. brevis KU15153 showed antimicrobial activity against the food-borne pathogens Escherichia coli ATCC 25922, Listeria monocytogenes ATCC 15313, Salmonella Typhimurium P99, and Staphylococcus aureus KCCM 11335. Antioxidant activity was assessed using the DPPH radical scavenging assay and β-carotene and linoleic acid inhibition assay. L. brevis KU15153 showed higher antioxidant activity than LGG. These results suggest that L. brevis KU15153 has potential for use as a probiotic organism.


Abnormal glycosphingolipid metabolism in the nervous system of galactosialidosis.
In an autopsy case of galactosialidosis, GM3, GM2, GM1, and GD1a were accumulated in sympathetic and spinal ganglia and grey matter of the spinal cord. Especially, the accumulations of GM3 and GM2 amounted to 41- and 86-fold increases in sympathetic ganglia, respectively, as compared to normal controls. In addition LacCer, GA2 and GA1 were accumulated in sympathetic and spinal ganglia. The accumulations of GM3 and GD1a are considered to be the result of defective lysosomal sialidase activity and the accumulation of GM1, LacCer and GA1 is also considered to be due to decreased beta-galactosidase activity in this disorder. To better understand the possible mechanism of GM2 accumulation, we determined the activity of GM2 synthesizing enzyme (GM3:UDP-GalNAc transferase), as well as hexosaminidase activity, in sympathetic ganglia, but they did not change. Abnormal ganglioside and neutral glycosphingolipid metabolism, as well as sialyloligosaccharide and sialylglycoprotein metabolism, may be involved in the pathogenesis of this disorder.


Differences in airway remodeling between subjects with severe and moderate asthma.
Airway remodeling in asthma comprises a range of structural changes. Several studies have suggested an association between these changes and disease severity. The relationship between the extent of remodeling and lung function is not well defined. We sought to contrast the structural changes in the airways of well-defined groups of subjects with severe and moderate asthma and to correlate the extent of remodeling with disease severity. Endobronchial biopsy specimens were obtained from 15 subjects with severe and 13 subjects with moderate asthma. Epithelial integrity, cell-layer areas, subepithelial fibrosis, and the distance between epithelial and airway smooth muscle (ASM) layers were measured by means of image analysis. Collagen was identified by using Van Giesen stain, and ASM was defined by using smooth muscle alpha-actin immunostaining. Specific immunostains were performed for the evaluation of RANTES, IL-8, and eotaxin expression as markers of ASM phenotype. ASM area was greater in subjects with severe (0.24+/- 0.03 mm(2)) than in subjects with moderate (0.05+/- 0.01 mm(2)) asthma (P<.001). The distance between the epithelial and ASM layers was less in the severe group (0.12+/- 0.01 mm) than in the moderate group (0.24+/- 0.02, P<.001). A trend toward greater subepithelial fibrosis in subjects with severe asthma did not reach statistical significance. IL-8 and eotaxin expression, but not RANTES expression, were increased in the ASM of subjects with severe asthma compared with in subjects with moderate asthma. Smooth muscle alteration is the key structural change that distinguishes severe from moderate asthma, and phenotypic change in ASM might contribute to the difficulty in obtaining adequate control in some subjects with severe asthma.


Manufacturing Processes of a Purified Microbiome Therapeutic Reduce Risk of Transmission of Potential Bacterial Pathogens in Donor Stool.
Although fecal microbiota transplant has been used to prevent recurrent Clostridioides difficile infection (rCDI), documented pathogen transmissions highlight inherent safety risks of minimally processed stool. We describe manufacturing processes for fecal microbiota spores, live (VOWST; VOS, formerly SER-109), a microbiota-based oral therapeutic of Firmicutes spores. Bacterial inactivation kill curves were obtained after ethanol exposure for 4 model organisms spiked into process intermediates. Bacterial log reduction factors ranged from 6.5 log10 to 7.4 log10 and lysis of spiked organisms occurred rapidly within 30 seconds. These experiments demonstrate substantial and rapid inactivation of representative organisms, supporting the potential benefit of VOS manufacturing processes to mitigate risk.


Monoclonal origin of primary unilateral multifocal pleomorphic adenoma of the parotid gland.
Primary multiple pleomorphic adenomas in a unilateral parotid gland in previously untreated patients is a rare finding, and little is known about the etiology and pathogenesis. Here, a highly unusual case of a primary multifocal pleomorphic adenoma consisting of 15 individual nodules is presented. It is shown that all nodes are clonally related and thus share a common cell of origin excluding an independent multifocal pathogenesis. Most likely, multifocal pleomorphic adenoma represents parasitic nodules that have been detached from a main nodule, which may have been the result of undisclosed trauma.


on-course(®) portal: a tool for in-service training and career development for biomedical scientists.
Successfully navigating through the jungle of biomedical postgraduate courses in Europe has recently been made possible by the release of an Innovative Medicines Initiative (IMI) funded project called on-course(®) (http://www.on-course.eu). on-course(®) lists all master, continued professional development (CPD) and PhD courses in Europe and hosts advanced search options designed by the pharmaceutical industry, academia and regulatory bodies allowing the course seeker to find courses that are most relevant for them. In addition, an IMI cross education and training topic task force has developed a set of quality standards that have been applied to CPD courses. The comprehensive nature of on-course(®) offers a new level of transparency to biomedical course provision in Europe that will help steer future education and training.


Atherosclerotic Cardiovascular Disease or Heart Failure: First Cardiovascular Event in Adults With Prediabetes and Diabetes.
Individuals with prediabetes and diabetes are at increased risk of atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). Whether ASCVD or HF is more likely to occur first in these populations within different race-sex groups is unknown. To determine the competing risk for the first cardiovascular event by subtype in Black and white men and women with prediabetes and diabetes. Individual-level data from adults without ASCVD or HF were pooled from 6 population-based cohorts. We estimated the competing cumulative incidences of ASCVD, HF and noncardiovascular death as the first event in middle-aged (40-59 years) and older (60-79 years) adults, stratified by race and sex, with normal fasting plasma glucose (FPG < 100 mg/dL), prediabetes (FPG 100-125 mg/dL) and diabetes (FPG ≥ 126 mg/dL or on antihyperglycemic agents) at baseline. Within each race-sex group, we estimated risk the adjusted hazard ratio of ASCVD, HF and noncardiovascular death in adults with prediabetes and diabetes relative to adults with normoglycemia after adjusting for cardiovascular risk factors. In 40,117 participants with 638,910 person-years of follow-up, 5781 cases of incident ASCVD and 3179 cases of incident HF occurred. In middle-aged adults with diabetes, competing cumulative incidence of ASCVD as a first event was higher than HF in white men (35.4% vs 11.6%), Black men (31.6% vs 15.1%) and white women (24.3% vs 17.2%) but not in Black women (26.4% vs 28.4%). Within each group, the adjusted hazard ratio of ASCVD and HF was significantly higher in adults with diabetes than in adults with normal FPG levels. Findings were largely similar in middle-aged adults with prediabetes and older adults with prediabetes or diabetes. Black women with diabetes are more likely to develop HF as their first CVD event, whereas individuals with diabetes from other race-sex groups are more likely to present first with ASCVD. These results can inform the tailoring of primary prevention therapies for either HF- or ASCVD-specific pathways based on individual-level risk.


Amino acid induced fractal aggregation of gold nanoparticles: Why and how.
Gold colloids are the object of many studies as they are reported to have potential biological sensing, imaging and drug delivery applications. In the presence of certain amino acids the aggregation of the gold nanoparticles into linear structures is observed, as highlighted by the appearance of a second plasmon band in the UV-Vis spectra of the colloid. The mechanism behind this phenomenon is still under debate. In order to help elucidate this issue, the interaction between gold colloids and different amino acids, modified amino acids and molecules mimicking their side-chain was monitored by UV-Vis absorption, DLS and TEM. The results show that phenomenon can be rationalized in terms of the Diffusion Limited Colloid Aggregation (DLCA) model which gives rise to the fractal aggregation colloids. The global charge of the compound, which influences the ionic strength of the solution, and the ease with which the compound can interact with the GNPs and affect their surface potential, are, the two parameters which control the DLCA regime. Calculations based on the Derjaguin, Landau, Verwey and Overbeek (DLVO) theory confirm all the experimental observations.


Mechanisms of karyotype evolution in the Brazilian scorpions of the subfamily Centruroidinae (Buthidae).
The recently-revised subfamily Centruroidinae is part of the New World clade of buthid scorpions. In this study, we analyzed the cytogenetic characteristics of nine of the 10 Brazilian centruroidines, and one undescribed species of the genus Ischnotelson, using a phylogenetic approach to determine the chromosomal rearrangements responsible for the differentiation of karyotypes among the species. The cytogenetic data recorded in the present study supported the new taxonomic arrangement of the Centruroidinae, with all the species of the same genus sharing the same or similar diploid numbers, i.e., 2n = 20 or 22 in Troglorhopalurus lacrau and T. translucidus, 2n = 25 or 26 in Ischnotelson sp., I. guanambiensis and I. peruassu, and 2n = 28 in Jaguajir agamemnon, J. pintoi and J. rochae. The karyotype modelling in the ChromEvol software indicated 2n = 18 as the ancestral diploid number of the Centruroidinae. The differentiation of karyotypes among the centruroidine genera was based on increasing chromosome numbers resulting from progressive fission events. These changes probably occurred prior to the diversification of the genera Ischnotelson, Jaguajir, Physoctonus and Rhopalurus, and appear to have played a more important role in karyotype evolution at the intergeneric level than the interspecific one. However, the observed increase in diploid numbers was not accompanied by changes in the number or location of ribosomal genes or telomeric sequences. The identification of meiotic cells in female specimens also allowed us to discuss the mechanisms of achiasmatic meiosis in scorpions.


Gestational diabetes mellitus.
Gestational diabetes is an asymptomatic disease of pregnant women, which results in significant morbidity and mortality. However, prompt diagnosis and treatment of this disorder have been found to be effective in decreasing complications. The increased risk for eventual diabetes in the patient and obesity or glucose intolerance in her off-spring suggests that long-term weight control and medical follow-up for both are important.


7,8-Dihydroxyflavone facilitates the action exercise to restore plasticity and functionality: Implications for early brain trauma recovery.
Metabolic dysfunction accompanying traumatic brain injury (TBI) severely impairs the ability of injured neurons to comply with functional demands. This limits the success of rehabilitative strategies by compromising brain plasticity and function, and highlights the need for early interventions to promote energy homeostasis. We sought to examine whether the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) normalizes brain energy deficits and reestablishes more normal patterns of functional connectivity, while enhancing the effects of exercise during post-TBI period. Moderate fluid percussion injury (FPI) was performed and 7,8-DHF (5mg/kg, i.p.) was administered in animals subjected to FPI that either had access to voluntary wheel running for 7days after injury or were sedentary. Compared to sham-injured controls, TBI resulted in reduced hippocampal activation of the BDNF receptor TrkB and associated CREB, reduced levels of plasticity markers GAP-43 and Syn I, as well as impaired memory as indicated by the Barnes maze task. While 7,8-DHF treatment and exercise individually mitigated TBI-induced effects, administration of 7,8-DHF concurrently with exercise facilitated memory performance and augmented levels of markers of cell energy metabolism viz., PGC-1α, COII and AMPK. In parallel to these findings, resting-state functional MRI (fMRI) acquired at 2weeks after injury showed that 7,8-DHF with exercise enhanced hippocampal functional connectivity, and suggests 7,8-DHF and exercise to promote increases in functional connectivity. Together, these findings indicate that post-injury 7,8-DHF treatment promotes enhanced levels of cell metabolism, synaptic plasticity in combination with exercise increases in brain circuit function that facilitates greater physical rehabilitation after TBI.


Proteomic analysis of differential proteins in pancreatic carcinomas: Effects of MBD1 knock-down by stable RNA interference.
Methyl-CpG binding domain protein 1 (MBD1), a suppressor of gene transcription, may be involved in inactivation of tumor suppressor genes during tumorigenesis. Over-expression of MBD1 has been reported in human pancreatic carcinomas. In this study, we established a MBD1-knock-down pancreatic cancer cell line (BxPC-3) using stable RNA interference, to compare the proteomic changes between control and MBD1-knock-down cells using two-dimensional gel electrophoresis and mass spectrometry. We identified five proteins that were up-regulated and nine proteins that were down-regulated. Most of the identified proteins are involved in tumorigenesis, some are prognostic biomarkers for human malignant tumors. Our data suggest that these differential proteins may be associated with the function of MBD1, and provide some insight into the functional mechanism of MBD1 in the development of pancreatic cancer.


Plasma membrane proteoglycans syndecan-2 and syndecan-4 engage with EGFR and RON kinase to sustain carcinoma cell cycle progression.
Epidermal growth factor receptor (EGFR) is a causal factor in carcinoma, yet many carcinoma patients are resistant to EGFR inhibitors. Potential insight into this resistance stems from prior work that showed EGFR in normal epithelial cells docks to the extracellular domain of the plasma membrane proteoglycan syndecan-4 (Sdc4) engaged with α3β1 and α6β4 integrins. We now report that this receptor complex is modified by the recruitment of syndecan-2 (Sdc2), the Recepteur d'Origine Nantais (RON) tyrosine kinase, and the cellular signaling mediator Abelson murine leukemia viral oncogene homolog 1 (ABL1) in triple-negative breast carcinoma and head and neck squamous cell carcinoma, where it contributes to EGFR kinase-independent proliferation. Treatment with a peptide mimetic of the EGFR docking site in the extracellular domain of Sdc4 (called SSTNEGFR) disrupts the entire complex and causes a rapid, global arrest of the cell cycle. Normal epithelial cells do not recruit these additional receptors to the adhesion mechanism and are not arrested by SSTNEGFR. Although EGFR docking with Sdc4 in the tumor cells is required, cell cycle progression does not depend on EGFR kinase. Instead, progression depends on RON kinase, activated by its incorporation into the complex. RON activates ABL1, which suppresses p38 mitogen-activated protein kinase and prevents a p38-mediated signal that would otherwise arrest the cell cycle. These findings add to the growing list of receptor tyrosine kinases that support tumorigenesis when activated by their association with syndecans at sites of matrix adhesion and identify new potential targets for cancer therapy.


A direct role for Wnt8 in ventrolateral mesoderm patterning.
Vertebrate dorsoventral patterning requires both Wnt8 and BMP signaling. Because of their multiple interactions, discerning roles attributable specifically to Wnt8 independent of BMP has been a challenge. For example, Wnt8 represses the dorsal organizer that negatively regulates ventral BMP signals, thus Wnt8 loss-of-function phenotypes may reflect the combined effects of reduced Wnt8 and BMP signaling. We have taken a loss-of-function approach in the zebrafish to generate embryos lacking expression of both Wnt8 and the BMP antagonist Chordin. wnt8;chordin loss-of-function embryos show rescued BMP signaling, thereby allowing us to identify Wnt8-specific requirements. Our analysis shows that Wnt8 is uniquely required to repress prechordal plate specification but not notochord, and that Wnt8 signaling is not essential for specification of tailbud progenitors but is required for normal expansion of posterior mesoderm cell populations. Thus, Wnt8 and BMP signaling have independent roles during vertebrate ventrolateral mesoderm development that can be identified through loss-of-function analysis.


[Primary oxalosis in adulthood. Scintigraphic and radiologic documentation of oxalosis nephropathy, oxalosis arthro-/enthesiopathy and oxalosis cardiomyopathy--review of the literature].
Clinical, radiographic and scintigraphic abnormalities in primary oxalosis of a 52 years old female are demonstrated. Severe oxalosis-nephropathy and oxalosis-arthropathy/enthesiopathy are shown. For the first time an intense myocardial uptake of 99 m Tc-HDP and 99 m Tc-MDP is described in connection with oxalosis. It is suggested that in the appropriate clinical setting this pattern may be suggestive of oxalosis-cardiomyopathy. Review of literature.


Preparation of Eu(III) Complexes Containing Maleopimaric Acid Anhydride with Ultra-narrow and Efficient Fluorescence Emission for High Determination on Gallic Acid in Acetonitrile Solution.
Two novel Eu(III) complexes constructed by maleopimaric acid anhydride (MPA) and 2,2'-bipyridyl (Bpy) / 1, 10-phenanthroline (Phen), named as MPA-Bpy-Eu / MPA-Phen-Eu, have been synthesized by a one-step precipitation method. FTIR, UV, TG, elemental analysis, XPS, and ESI-MS revealed the successful coordination of Eu(III) ions with MPA and Bpy / Phen through Eu-O and Eu-N bonds, respectively. Introducing MPA into coordinate structure increased the electron cloud density in 3d5/2 orbit of Eu(III) ions, enhanced the absolute quantum yields of MPA-Bpy-Eu (89.27%) and MPA-Phen-Eu (94.41%), and decreased the full width at half maxima of 5D0 → 7F2 transitions of MPA-Bpy-Eu (2.23 nm) and MPA-Phen-Eu (2.93 nm), respectively. The fluorescence quenching experiments showed that there was a good linear relationship between the relative fluorescence intensity of MPA-Bpy-Eu and gallic acid (GA) concentration in acetonitrile solution in the range of 0 to 8.41 × 10-2 mM. The results of UV-vis spectra, the fluorescence lifetimes, and the quantum yields demonstrated that the dynamic quenching model played a major role in the quenching process of GA on MPA-Bpy-Eu. The quenching process of GA on MPA-Phen-Eu involved dual fluorescence quenching mechanistic pathways, including static and dynamic models.


Syringe injection pressure: a neglected factor in blood PO2 determination.
The mean arterial blood PO2 values of 20 patients' samples taken into Sarstedt 2 mL Monovette syringes were found to be initially 0.43 kPa higher and after 15 min storage 0.93 kPa higher than the mean values using Corning 3 mL Blood Gas Kit syringes. The Sarstedt syringe allowed entry of small air bubbles and the plunger was noted to be stiff. We speculated that high injection pressures might increase measured PO2. Using each type of syringe, 20 ITU staff injected saline into a Corning 178 pH/blood analyser linked to a pressure transducer via a three-way connector. Mean injection pressures for Sarstedt and Corning syringes were 17.15 and 6.42 kPa, respectively (P less than 0.005). Following injection at pressures between 2.8 and 26.6 kPa, the mean PO2 of equilibrated saline containing an air bubble was 0.80 kPa higher than the mean value obtained at injection pressures of less than 2.8 kPa. However, with no air bubble the mean PO2 of equilibrated saline was still 0.45 kPa higher when injected at pressures between 2.8 and 26.6 kPa than the mean value obtained with injection pressures of 2.8 kPa. We suggest that for optimal PO2 determinations syringes should not only allow minimal air contamination but also have plungers that reduce injection pressure to a minimum.