Design and Development of Small-Molecule Arylaldoxime/5-Nitroimidazole Hybrids as Potent Inhibitors of MARK4: A Promising Approach for Target-Based Cancer Therapy.
Microtubule affinity-regulating kinase 4 (MARK4), a member of the serine/threonine kinase family, is an emerging therapeutic target in anticancer drug discovery paradigm due to its involvement in regulation of microtubule dynamics, cell cycle regulation, and cancer progression. Therefore, to identify the novel chemical architecture for the design and development of novel MARK4 inhibitors with concomitant radical scavenging property, a series of small-molecule arylaldoxime/5-nitroimidazole conjugates were designed and synthesized via multistep chemical reactions following the pharmacophoric hybridization approach. Compound 4h was identified as a promising MARK4 inhibitor with high selectivity toward MARK4 inhibition as compared to the panel of screened 30 kinases pertaining to the serine/threonine family, which was validated by molecular docking and fluorescence binding studies. The comprehensive cell-based examination divulged the promising apoptotic, antiproliferative, and antioxidant potential for the chemotype 4h. The compound 4h was endowed with the K a value of 3.6 × 103 M-1 for human serum albumin, which reflects its remarkable transportation and delivery properties to the target site via blood. The present study impedes that in the future, such compounds may stand as optimized pharmacological lead candidates in drug discovery for targeting cancer via MARK4 inhibition with a remarkable anticancer profile.


Modelling changes in the pharmacokinetics of tacrolimus during pregnancy after kidney transplantation: A retrospective cohort study.
Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole-blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics. The aim of this study was to describe tacrolimus pharmacokinetics throughout pregnancy and explain the changes by investigating covariates in a population pharmacokinetic model. Data of pregnant women using a twice-daily tacrolimus formulation following kidney transplantation were retrospectively collected from 6 months before conception, throughout gestation and up to 6 months postpartum. Pharmacokinetic analysis was performed using nonlinear mixed effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. The final model was evaluated using goodness-of-fit plots, visual predictive checks and a bootstrap analysis. A total of 260 whole-blood tacrolimus predose concentrations from 14 pregnant kidney transplant recipients were included. Clearance increased during pregnancy from 34.5 to 41.7 L/h, by 15, 19 and 21% in the first, second and third trimester, respectively, compared to prior to pregnancy. This indicates a required increase in the tacrolimus dose by the same percentage to maintain the prepregnancy concentration. Haematocrit and gestational age were negatively correlated with tacrolimus clearance (P ≤ 0.01), explaining 18% of interindividual and 85% of interoccasion variability in oral clearance. Tacrolimus clearance increases during pregnancy, resulting in decreased exposure to tacrolimus, which is explained by gestational age and haematocrit. To maintain prepregnancy target whole-blood tacrolimus predose concentrations during pregnancy, increasing the dose is required.


Challenges of New Healthcare Reform Act 2017 and Possible Rise of Defensive Medicine in Nepal.
Hippocratic oath, written 4th or 5th century BC, is still the binding mantra for physicians, which swears to fulfill to the best of one's ability and judgement, and treat sick human beings not just illness. But with changing health trends in southeast Asia region, there is a dramatic shift in patients and patients' party expectations regarding treatment, recovery, complications, and death. Such expectations havelead to violence against physicians and shift towards alternative medical practice. This article explores the possible rise of defensive medicine and its broader implications in health care system in Nepal with regard to the new 'Muluki Aparadh Samhita Ain 2074/Criminal (Code) Act 2017'. Keywords: Changing health; criminal act; defensive medicine; muluki ain, Nepal.


Sample size planning for statistical power and accuracy in parameter estimation.
This review examines recent advances in sample size planning, not only from the perspective of an individual researcher, but also with regard to the goal of developing cumulative knowledge. Psychologists have traditionally thought of sample size planning in terms of power analysis. Although we review recent advances in power analysis, our main focus is the desirability of achieving accurate parameter estimates, either instead of or in addition to obtaining sufficient power. Accuracy in parameter estimation (AIPE) has taken on increasing importance in light of recent emphasis on effect size estimation and formation of confidence intervals. The review provides an overview of the logic behind sample size planning for AIPE and summarizes recent advances in implementing this approach in designs commonly used in psychological research.


[The Lemierre syndrome: a complicated oropharyngeal infection].
The Lemierre syndrome or 'necrobacillosis' is a post angina sepsis caused by an acute oropharyngeal infection with a secondary thrombophlebitis of the internal jugular vein. There are often septic emboli in the lungs, although intestinal organs can also be affected. This syndrome is caused by the strictly anaerobic gram-negative pathogen Fusobacterium necrophorum, sometimes in combination with other pathogens. The patient typically presents with high fever, pain in the neck, malaise and dyspnoea one week after the start of an angina. Plain chest radiograph shows bilateral nodular infiltrates, ultrasound reveals a thrombophlebitis of the internal jugular vein. CT scan can be useful to confirm the diagnosis and possible complications. In the beginning there is often a transient hyperbilirubinemia with toxic inflammatory blood results. Under the correct antibiotic regime complete recovery can be obtained.


Hydroxyurea-associated dermatomyositis-like eruption demonstrating abnormal epidermal p53 expression: a potential premalignant manifestation of chronic hydroxyurea and UV radiation exposure.
Chronic hydroxyurea therapy is associated with numerous cutaneous adverse effects. While hydroxyurea-associated nonmelanoma skin cancers are known to be associated with significant morbidity and occasional mortality, to date, dermatomyositis-like eruption has been considered a benign entity, other than its ability to mimic true dermatomyositis leading to inappropriate immunosuppression. More recently, hydroxyurea-associated squamous dysplasia has been characterized as a premalignant precursor to hydroxyurea-associated nonmelanoma skin cancers and shown to manifest abnormal p53 expression. An elderly woman receiving chronic hydroxyurea therapy for myelodysplasia developed a dermatomyositis-like eruption that was misdiagnosed as true dermatomyositis, leading to continuation of hydroxyurea. Years later she developed severe hydroxyurea-associated nonmelanoma skin cancers resulting in discontinuation of hydroxyurea, poor control of her myelodysplasia, and death. Re-evaluation with immunohistochemical analysis of tissue from her original dermatomyositis-like eruption revealed focal confluent nuclear expression of p53 along the lower layers of the epidermis, suggestive of a premalignant state. We suggest that dermatomyositis-like eruption and hydroxyurea-associated squamous dysplasia represent similar clinical manifestations of a common underlying chronic phototoxic process involving aberrant keratinocyte p53 expression mediated by hydroxyurea's antimetabolite properties and UV radiation exposure. Accordingly, we suggest that dermatomyositis-like eruption, previously considered a benign entity, may represent a premalignant precursor of hydroxyurea-associated nonmelanoma skin cancers warranting discontinuation of hydroxyurea therapy.


Suppression of damping-off disease in host plants by the rhizoplane bacterium Lysobacter sp. strain SB-K88 is linked to plant colonization and antibiosis against soilborne Peronosporomycetes.
We previously demonstrated that xanthobaccin A from the rhizoplane bacterium Lysobacter sp. strain SB-K88 suppresses damping-off disease caused by Pythium sp. in sugar beet. In this study we focused on modes of Lysobacter sp. strain SB-K88 root colonization and antibiosis of the bacterium against Aphanomyces cochlioides, a pathogen of damping-off disease. Scanning electron microscopic analysis of 2-week-old sugar beet seedlings from seeds previously inoculated with SB-K88 revealed dense colonization on the root surfaces and a characteristic perpendicular pattern of Lysobacter colonization possibly generated via development of polar, brush-like fimbriae. In colonized regions a semitransparent film apparently enveloping the root and microcolonies were observed on the root surface. This Lysobacter strain also efficiently colonized the roots of several plants, including spinach, tomato, Arabidopsis thaliana, and Amaranthus gangeticus. Plants grown from both sugar beet and spinach seeds that were previously treated with Lysobacter sp. strain SB-K88 displayed significant resistance to the damping-off disease triggered by A. cochlioides. Interestingly, zoospores of A. cochlioides became immotile within 1 min after exposure to a SB-K88 cell suspension, a cell-free supernatant of SB-K88, or pure xanthobaccin A (MIC, 0.01 microg/ml). In all cases, lysis followed within 30 min in the presence of the inhibiting factor(s). Our data indicate that Lysobacter sp. strain SB-K88 has a direct inhibitory effect on A. cochlioides, suppressing damping-off disease. Furthermore, this inhibitory effect of Lysobacter sp. strain SB-K88 is likely due to a combination of antibiosis and characteristic biofilm formation at the rhizoplane of the host plant.


NDVI changes in the Arctic: Functional significance in the moist acidic tundra of Northern Alaska.
The Normalized Difference Vegetation Index (NDVI), derived from reflected visible and infrared radiation, has been critical to understanding change across the Arctic, but relatively few ground truthing efforts have directly linked NDVI to structural and functional properties of Arctic tundra ecosystems. To improve the interpretation of changing NDVI within moist acidic tundra (MAT), a common Arctic ecosystem, we coupled measurements of NDVI, vegetation structure, and CO2 flux in seventy MAT plots, chosen to represent the full range of typical MAT vegetation conditions, over two growing seasons. Light-saturated photosynthesis, ecosystem respiration, and net ecosystem CO2 exchange were well predicted by NDVI, but not by vertically-projected leaf area, our nondestructive proxy for leaf area index (LAI). Further, our data indicate that NDVI in this ecosystem is driven primarily by the biochemical properties of the canopy leaves of the dominant plant functional types, rather than purely the amount of leaf area; NDVI was more strongly correlated with top cover and repeated cover of deciduous shrubs than other plant functional types, a finding supported by our data from separate "monotypic" plots. In these pure stands of a plant functional type, deciduous shrubs exhibited higher NDVI than any other plant functional type. Likewise, leaves from the two most common deciduous shrubs, Betula nana and Salix pulchra, exhibited higher leaf-level NDVI than those from the codominant graminoid, Eriophorum vaginatum. Our findings suggest that recent increases in NDVI in MAT in the North American Arctic are largely driven by expanding deciduous shrub canopies, with substantial implications for MAT ecosystem function, especially net carbon uptake.


Scaling Exponents of Time Series Data: A Machine Learning Approach.
In this study, we present a novel approach to estimating the Hurst exponent of time series data using a variety of machine learning algorithms. The Hurst exponent is a crucial parameter in characterizing long-range dependence in time series, and traditional methods such as Rescaled Range (R/S) analysis and Detrended Fluctuation Analysis (DFA) have been widely used for its estimation. However, these methods have certain limitations, which we sought to address by modifying the R/S approach to distinguish between fractional Lévy and fractional Brownian motion, and by demonstrating the inadequacy of DFA and similar methods for data that resembles fractional Lévy motion. This inspired us to utilize machine learning techniques to improve the estimation process. In an unprecedented step, we train various machine learning models, including LightGBM, MLP, and AdaBoost, on synthetic data generated from random walks, namely fractional Brownian motion and fractional Lévy motion, where the ground truth Hurst exponent is known. This means that we can initialize and create these stochastic processes with a scaling Hurst/scaling exponent, which is then used as the ground truth for training. Furthermore, we perform the continuous estimation of the scaling exponent directly from the time series, without resorting to the calculation of the power spectrum or other sophisticated preprocessing steps, as done in past approaches. Our experiments reveal that the machine learning-based estimators outperform traditional R/S analysis and DFA methods in estimating the Hurst exponent, particularly for data akin to fractional Lévy motion. Validating our approach on real-world financial data, we observe a divergence between the estimated Hurst/scaling exponents and results reported in the literature. Nevertheless, the confirmation provided by known ground truths reinforces the superiority of our approach in terms of accuracy. This work highlights the potential of machine learning algorithms for accurately estimating the Hurst exponent, paving new paths for time series analysis. By marrying traditional finance methods with the capabilities of machine learning, our study provides a novel contribution towards the future of time series data analysis.


Neurobehavioural profile of low-birthweight infants with cystic periventricular leukomalacia.
Twenty-three low-birthweight infants (17 males, six females) diagnosed with cystic periventricular leukomalacia (PVL; median gestational age 30 wks, postmenstrual age range 25 to 36 wks; median birthweight 1365 g, range 680 to 2010 g) were evaluated and compared with 209 comparison infants (117 males, 92 females; median gestational age 33 wks, postmenstrual age range 25 to 39 wks; birthweight 1771 g, range 670 to 2460 g). There were three assessment times: 36 to 38 weeks (preterm), 40 to 42 weeks (term), and 44 to 46 weeks (post-term); the Neonatal Behavioral Assessment Scale (NBAS) was used for assessment. Outcome at 2 years was assessed on the basis of a neurological examination, magnetic resonance imaging, computerized tomography, electroencephalography, and the Mental and Psychomotor Development Indices of the Bayley Scales of Infant Development. All infants in the PVL group were found to have evidence of cerebral palsy, whereas all infants in the comparison group were normally developing. Infants with PVL performed more poorly on all elements of the NBAS examination at all three assessment times compared with the comparison group. They demonstrated poorer motor control, less responsiveness to environmental stimuli, less regulatory capacity, and more abnormal reflexes compared with the comparison group. These results suggest that LBW infants with PVL show dysfunction and/or disorganization in their neurobehavioural systems in the neonatal period. Assessment of neonatal neurobehavioural characteristics using the NBAS may assist clinicians in identifying LBW infants with PVL, and in formulating plans for the developmental care of these infants.


Correspondence programs for smoking cessation and weight control: a comparison of two strategies in the Minnesota Heart Health Program.
Mailed invitations to participate in weight loss and/or smoking cessation correspondence programs to 31,400 households in a suburban community. Two programs were offered to randomized subsets of households, a 6-month correspondence program costing +5 and the same program for free but requiring a +60 deposit to be refunded based on success in weight loss or smoking cessation. Overall, sign-up included 1,304 people for weight loss and 142 for smoking cessation. The +5 program was about 5 times as popular as the incentive program. Validated weight change after 6 months averaged about 4 lb for the +5 program and 8 lb for the incentive program. Corresponding rates of smoking cessation were about 9% and 20%, respectively. We conclude that correspondence programs for the promotion of weight control and smoking cessation are potentially cost-effective methods for reaching individuals in the community at large, many of whom would not be interested in clinic-based programs. Issues meriting further research include recruitment, especially of smokers, and evaluation of the relative trade-offs in recruitment success versus efficacy of differing treatment approaches.


Three case reports of the metabolic and electroencephalographic changes during advanced Buddhist meditation techniques.
To examine the extent to which advanced meditative practices might alter body metabolism and the electroencephalogram (EEG), we investigated three Tibetan Buddhist monks living in the Rumtek monastery in Sikkim, India. In a study carried out in February 1988, we found that during the practice of several different meditative practices, resting metabolism (VO2) could be both raised (up to 61%) and lowered (down to 64%). The reduction from rest is the largest ever reported. On the EEG, marked asymmetry in alpha and beta activity between the hemispheres and increased beta activity were present. From these three case reports, we conclude that advanced meditative practices may yield different alterations in metabolism (there are also forms of meditation that increase metabolism) and that the decreases in metabolism can be striking.


The Present and Future of Yellow Fever Vaccines.
The disease yellow fever (YF) is prevented by a live-attenuated vaccine, termed 17D, which has been in use since the 1930s. One dose of the vaccine is thought to give lifelong (35+ years) protective immunity, and neutralizing antibodies are the correlate of protection. Despite being a vaccine-preventable disease, YF remains a major public health burden, causing an estimated 109,000 severe infections and 51,000 deaths annually. There are issues of supply and demand for the vaccine, and outbreaks in 2016 and 2018 resulted in fractional dosing of the vaccine to meet demand. The World Health Organization (WHO) has established the "Eliminate Yellow Fever Epidemics" (EYE) initiative to reduce the burden of YF over the next 10 years. As with most vaccines, the WHO has recommendations to assure the quality, safety, and efficacy of the YF vaccine. These require the use of live 17D vaccine only produced in embryonated chicken eggs, and safety evaluated in non-human primates only. Thus, any second-generation vaccines would require modification of WHO recommendations if they were to be used in endemic countries. There are multiple second-generation YF vaccine candidates in various stages of development that must be shown to be non-inferior to the current 17D vaccine in terms of safety and immunogenicity to progress through clinical trials to potential licensing. The historic 17D vaccine continues to shape the global vaccine landscape in its use in the generation of multiple licensed recombinant chimeric live vaccines and vaccine candidates, in which its structural protein genes are replaced with those of other viruses, such as dengue and Japanese encephalitis. There is no doubt that the YF 17D live-attenuated vaccine will continue to play a role in the development of new vaccines for YF, as well as potentially for many other pathogens.


[Ways to improve the health of the population of Ukraine].
An analysis was performed of the health status of the population of Ukraine with reference to social-and-economic, ecological, and medical factors affecting it. Especial emphasis is placed on prophylaxis within the whole health system. It is pointed out that positive results are to be achieved through pursuing the scientifically substantiated policy of administering prophylaxis. Such a policy is deemed warranted at both regional and national levels. It is emphasized that the existing health system of Ukraine requires adaptation under present-day conditions in the state, financing of certain programmes to ensure improvement of health in the best way possible.


Complete tracheal rings and hypoplastic left heart variant: a rare and fatal association.
Congenital complete tracheal rings are usually associated with pulmonary slings. We report a rare association of congenital complete tracheal rings with hypoplastic left heart variant. A term infant with diagnosis of a mildly hypoplastic mitral valve, unicuspid aortic valve, and moderately hypoplastic aortic arch with severe coarctation underwent a hybrid procedure initially. Upon failing extubation attempts, complete tracheal rings were seen on direct laryngoscopy. The combination of the lesions resulted in a poor outcome. In patients with failure of extubation post-cardiac surgery, a diagnosis of complete tracheal rings should be included in the differential and a direct laryngoscopy should be considered.


Performance evaluation of the zero-multipole summation method in modern molecular dynamics software.
The zero-multiple summation method (ZMM) is a cutoff-based method for calculating electrostatic interactions in molecular dynamics simulations, utilizing an electrostatic neutralization principle as a physical basis. Since the accuracies of the ZMM have been revealed to be sufficient in previous studies, it is highly desirable to clarify its practical performance. In this paper, the performance of the ZMM is compared with that of the smooth particle mesh Ewald method (SPME), where the both methods are implemented in molecular dynamics software package GROMACS. Extensive performance comparisons against a highly optimized, parameter-tuned SPME implementation are performed for various-sized water systems and two protein-water systems. We analyze in detail the dependence of the performance on the potential parameters and the number of CPU cores. Even though the ZMM uses a larger cutoff distance than the SPME does, the performance of the ZMM is comparable to or better than that of the SPME. This is because the ZMM does not require a time-consuming electrostatic convolution and because the ZMM gains short neighbor-list distances due to the smooth damping feature of the pairwise potential function near the cutoff length. We found, in particular, that the ZMM with quadrupole or octupole cancellation and no damping factor is an excellent candidate for the fast calculation of electrostatic interactions. © 2018 Wiley Periodicals, Inc.


Additivity of Diene Substituent Gibbs Free Energy Contributions for Diels-Alder Reactions between Me2C=CMe2 and Substituted Cyclopentadienes.
Systematic computational studies of pericyclic Diels-Alder reactions between (H3C)2C=C(CH3)2, 1, and all permutations of substituted cyclopentadienes c-C5R1R2R3R4R5aR5b (R = H, CH3, CF3, F) allowed isolation of substitutional effects on Gibbs free energy barrier heights and reaction Gibbs free energies. "Average Substitution Gibbs Free Energy Correction" ΔG ASC# ‡/ΔG ASC# values for each substituent in each position appeared to be additive. Substituent effects on barriers showed interesting contrasts. Methyl substitution at positions 5a and 5b increased barriers significantly, while substitution at all other positions had essentially no impact. In contrast, fluoro substitution at positions 5a and 5b lowered barriers more than substitution at other positions. Trifluoromethyl substitution mixed these effects, in that substitution at positions 5a and 5b increased barriers, but substitution at other positions lowered them. Despite the variances, ΔG ASC# ‡/ΔG ASC# values allowed reliable prediction of barriers and exergonicities for reactions between 1 and highly substituted cyclopentadienes, and between 1 and cyclopentadienes with random mixtures of CH3/CF3/F substituents. ΔG ASC# ‡/ΔG ASC# values were correlated with steric considerations and quantum theory of atoms in molecules (QTAIM) calculations. Overall, the ASC values provide a resource for predicting which Diels-Alder reactions of this type should occur at rapid rates and/or give stable bicyclic products.


EXPERIMENTAL TRANSMISSION OF INFLUENZA VIRUS INFECTION IN MICE. I. THE PERIOD OF TRANSMISSIBILITY.
An experimental model has been developed for the reproducible transmission of influenza virus infection from experimentally infected mice to uninfected cage mates. Infector mice transmit influenza virus infection most readily during the period 24 to 48 hours after initiation of their infection. This restricted period of transmission is not due to declining titers of infective virus in the nose, trachea, or lungs of infector mice after 48 hours of infection, since peak titers in these tissues are maintained for another 48 hours. A mouse-adapted strain of A2 virus was found to be more readily transmitted than the mouse-adapted CAM strain of influenza A1 virus, although the CAM strain induced higher pulmonary virus titers and more extensive lung lesions.


Change in disease activity is associated with TNF-α inhibitor serum levels in patients with axial spondyloarthritis in daily clinical practice.
To investigate, in daily clinical practice, TNF-α inhibitor serum trough levels in patients experiencing an increase in axial spondyloarthritis (ax-SpA) related symptoms. Secondly, to explore if these serum trough levels are associated with disease activity (DA) and/or change in DA. Patients from the GLAS cohort treated with TNF-α inhibitors who had a serum trough level measurement during follow-up because of an increase in ax-SpA related symptoms between June 2015 and June 2018 were included. Serum trough levels were stratified in a therapeutic and below therapeutic range, based on published reference values of Sanquin in 2019. DA was assessed by ASDAS and BASDAI and change in DA (i.e. ΔASDAS or BASDAI compared to the visit before increasing symptoms). 31 patients had a serum trough level measurement because of increasing symptoms. These patients had a median treatment duration of 4.8 years (IQR 0.9-8.6). 22 (71%) had active disease according to ASDAS (score ≥2.1) and 15 (47%) had therapeutic drug levels. The increase in DA was significantly larger in patients with below therapeutic drug levels compared to patients with therapeutic levels (ΔASDAS: 0.94±0.81 vs. -0.07±1.26, p<0.05; ΔBASDAI: 1.72±1.73 vs. -0.53±1.8, p<0.005). No significant differences were found in absolute DA scores between patients with or without therapeutic drug levels. In this observational study in daily clinical practice, approximately half of ax-SpA patients who experienced an increase in symptoms had below therapeutic TNF-α inhibitor serum trough levels. Change in DA and not absolute DA scores was significantly associated with drug levels.


The safety of obstetrical ultrasound: a review.
Ultrasound is a commonly employed imaging modality in obstetrics and is generally regarded as safe to the fetus. Current ultrasound technology, however, has significantly higher output potential than older machines used in most clinical studies, and the safety profile for the increasing use of Doppler, 3-dimensional (D) and 4-D ultrasound with modern machines is unknown. This article reviews the current status of ultrasound safety within obstetrics, including proposed mechanisms of harm, existing scientific and clinical evidence regarding those mechanisms, and considerations of safety for the clinical user.


Elective caesarean section in a tertiary hospital in Sokoto, north western Nigeria.
Elective caesarean sections have been considered safer for both mother and the fetus compared to their emergency counterpart. However, emergency caesarean sections have continued to form bulk of caesarean deliveries in our facility. The objective of this study was to determine the caesarean section rate together with the trend, indications, and maternal mortality associated with elective caesarean operation. A retrospective analysis of clinical records of all the patients that had caesarean section between January 2002 and December 2010 (9 years) at Usmanu Danfodiyo University Teaching Hospital (UDUTH) Sokoto, Nigeria was conducted. During the 9 year study period, 2284 caesarean sections were performed out of 22,985 total deliveries at UDUTH Sokoto, thus giving a caesarean section rate of 9.9%. Emergency and elective operations accounted for 1784 (78.2%) and 498 (21.8%) of the cases respectively. The rate of elective caesarean section increased from 1.7% in 2002 to 3.2% in 2007. Thereafter it declined gradually to 1.8% in 2010. Repeat caesarean section (30.7%) and malpresentation (17.1%) were the most common indications for elective caesarean operation. There were 18 maternal deaths from caesarean section and only one from the elective caesarean procedure. The rising trend in the elective caesarean section rate in this study underscores the need for better and improved patient selection together with counseling on its benefits and risks. This is because despite the fact that it is safer than emergency caesarean operation, it is not entirely devoid of complications. Routine use of spinal anesthesia in performing the procedure should be encouraged.


New haptophyte lineages and multiple independent colonizations of freshwater ecosystems.
The diversity and ecological relevance of small haptophytes in marine systems is increasingly recognized. Similar investigations in freshwater remain scarce, despite some recent studies showing the existence of divergent haptophyte lineages and indicating that these microalgae can occur at high abundance in lakes. We studied the diversity of haptophytes in a wide variety of marine, salty continental and, most particularly, freshwater environments by amplifying, cloning and sequencing 18S rRNA genes. For this purpose, we designed two sets of primers specific for the two recognized haptophyte classes, Prymnesiophyceae and Pavlovophyceae. We detected pavlovophyte sequences only in freshwater systems as well as several novel prymnesiophyte phylotypes in both freshwater and marine environments. In addition, we retrieved a cluster of sequences (HAP-3) from the Marmara Sea branching deeply in the haptophyte tree with no clear affiliation to either of the two recognized classes. Five of the freshwater prymnesiophyte phylotypes detected formed a divergent monophyletic group (EV) without close described representatives that branched within the Isochrysidales, a group of generally marine and most often calcifying coccolithophorids. The presence of several sequences of freshwater haptophytes scattered among marine taxa in phylogenetic trees confirms the occurrence of several independent haptophyte transitions between marine and freshwater environments.


Prognostic value of tumor-associated macrophages count in human non-muscle-invasive bladder cancer treated by BCG immunotherapy.
Tumor-associated macrophages can regulate the growth of various cancers positively or negatively. Intravesical bacillus Calmette-Guerin instillation is now the gold standard treatment for bladder carcinoma in situ. The authors investigated the correlation between tumor-associated macrophages infiltrating bladder carcinoma in situ and the response to intravesical bacillus Calmette-Guerin therapy. The authors examined paraffin-embedded tissues from 41 patients with bladder carcinoma in situ who received intravesical bacillus Calmette-Guerin therapy. Tumor-associated macrophages were immunohistochemically stained by anti-CD68 monoclonal antibody. The median number of tumor-associated macrophages infiltrating among cancer cells and the number in the lamina propria were 4 and 24, respectively. Recurrent carcinoma in situ was found in 4.8% of cases with a lower cancer cell tumor-associated macrophage count but in 47.6% of those with a higher cancer cell tumor-associated macrophage count (less than 4 vs. 4 or greater). Recurrence was found in 31.8% of patients with a lower lamina propria tumor-associated macrophage count but in 21.1% of those with a higher lamina propria tumor-associated macrophage count (less than 25 vs. 25 or greater). The median ratio of tumor-associated macrophages among cancer cells vs. in the lamina propria was 0.2. Recurrence-free survival was significantly better in patients with a lower cancer cell tumor-associated macrophage count (p = .0002). Those with a lower cancer cell-to-lamina propria tumor-associated macrophage ratio had a higher recurrence-free rate (p < .0001). Multivariate analysis revealed that the cancer cell tumor-associated macrophage count and the cancer cell-to-lamina propria tumor-associated macrophage ratio can be prognostic factors for bladder carcinoma in situ. The count of tumor-associated macrophages infiltrating the cancer area is useful for predicting the response of bladder carcinoma in situ to intravesical bacillus Calmette-Guerin instillation before treatment initiation. Although on univariate analysis TAMs are associated with other poor prognosticators, on multivariate analysis, TAMs appear only to be associated with MI and VI. TAMs may play a significant role in the biology of tumor progression of endometrial adenocarcinoma, but do not appear to be independent prognostic indicators of patient's survival.


Behavioural intervention trials for HIV/STD prevention in schools: are they feasible?
To assess the feasibility of conducting a large randomised controlled trial (RCT) of peer led intervention in schools to reduce the risk of HIV/STD and promote sexual health. Four secondary schools in Greater London were randomly assigned to receive peer led intervention (two experimental schools) or to act as control schools. In the experimental schools, trained volunteers aged 16-17 years (year 12) delivered the peer led intervention to 13-14 year old pupils (year 9). In the control schools, year 9 pupils received the usual teacher led sex education. Questionnaire data collected from year 9 pupils at baseline included views on the quality of sex education/intervention received, and knowledge and attitudes about HIV/AIDS and other sexual matters. Focus groups were also conducted with peer educators and year 9 pupils. Data on the process of delivering sex education/intervention and on attitudes to the RCT were collected for each of the schools. Analysis focused on the acceptability of a randomised trial to schools, parents, and pupils. Nearly 500 parents were informed about the research and invited to examine the study questionnaire; only nine raised questions and only one pupil was withdrawn from the study. Questionnaire completion rates were around 90% in all schools. At baseline, the majority of year 9 pupils wanted more information about a wide range of sexual matters. Focus group work indicated considerable enthusiasm for peer led education, among peer educators and year 9 pupils. Class discipline was the most frequently noted problem with the delivery of the peer led intervention. Evaluation of a peer led behavioural intervention through an RCT can be acceptable to schools, pupils, and parents and is feasible in practice. In general, pupils who received the peer led intervention responded more positively than those in control schools. A large RCT of the long term (5-7 year) effects of this novel intervention on sexual health outcomes is now under way.


The dietary management of patients with diabetes and renal disease: challenges and practicalities.
Diabetes mellitus is one of the major causes of chronic kidney disease and end-stage renal disease. Diet and lifestyle modification are vital components of optimal treatment for both conditions. This paper will address appropriate and often diverse treatment for each individual, understanding that advising changes which positively impact both conditions is a major challenge for health care professionals working within either speciality. It will also highlight where overlap can be contradictory rather than complementary, and offers practical guidance to support patients in making the necessary lifestyle changes to have maximal positive impact upon both conditions and their overall health.


The Tides of Enceladus' Porous Core.
The inferred density of Enceladus' core, together with evidence of hydrothermal activity within the moon, suggests that the core is porous. Tidal dissipation in an unconsolidated core has been proposed as the main source of Enceladus' geological activity. However, the tidal response of its core has generally been modeled assuming it behaves viscoelastically rather than poroviscoelastically. In this work, we analyze the poroviscoelastic response to better constrain the distribution of tidal dissipation within Enceladus. A poroviscoelastic body has a different tidal response than a viscoelastic one; pressure within the pores alters the stress field and induces a Darcian porous flow. This flow represents an additional pathway for energy dissipation. Using Biot's theory of poroviscoelasticity, we develop a new framework to obtain the tidal response of a spherically symmetric, self-gravitating moon with porous layers and apply it to Enceladus. We show that the boundary conditions at the interface of the core and overlying ocean play a key role in the tidal response. The ocean hinders the development of a large-amplitude Darcian flow, making negligible the Darcian contribution to the dissipation budget. We therefore infer that Enceladus' core can be the source of its geological activity only if it has a low rigidity and a very low viscosity. A future mission to Enceladus could test this hypothesis by measuring the phase lags of tidally induced changes of gravitational potential and surface displacements.


Addressing the need for staff support among nurses caring for the AIDS population.
More and more nurses are caring for individuals with AIDS-spectrum disorders. When nurses become involved in hospital-based AIDS treatment, major psychosocial issues can arise. In settings where nursing personnel have limited or no experience working with patients with AIDS, fear of contagion is a major issue. This fear has both rational and irrational components. In general, providing up-to-date information in a small group setting can effectively reduce irrational fears. Rational fears, which are not as easily dealt with, should be a stimulus for behavior change (e.g., adoption of precautionary guidelines for reducing the possibility of accidental infection). Different issues arise among nurses specializing in AIDS care and include burnout, a sense of professional isolation, and the need to establish personal boundaries in dealing with patients. Guidelines are offered for establishing a group approach to address these concerns and to handle the sensitive issues that may arise.


Normative models of health technology assessment and the social production of evidence about telehealth care.
Telehealthcare is a rapidly growing field of clinical activity and technical development. These new technologies have caught the attention of clinicians and policy makers because they seem to offer more rapid access to specialist care, and the potential to solve structural problems around inequalities of service provision and distribution. However, as a field of clinical practice, telehealthcare has consistently been criticised because of the poor quality of the clinical and technical evidence that its proponents have marshalled. The problem of "evidence" is not a local one. In this paper, we undertake two tasks: first, we critically contrast the normative expectations of the wider field of Health Technology Assessment (HTA) with those configured within debates about Telehealthcare Evaluation; and second, we critically review models that provide structures within which the production of evidence about telehealthcare can take place. Our analysis focuses on the political projects configured within a literature aimed at stabilising evaluative knowledge production about telehealthcare in the face of substantial political and methodological problems.


How general practitioners manage patients with irritable bowel syndrome. Data from a German urban area.
Irritable bowel syndrome (IBS) is a common functional disorder in the general Western population. The majority of patients with IBS are managed by general practitioners (GP). Therefore, it is very important that GP are well trained in the approach to functional gastrointestinal disorders. There is the impression that the knowledge of diagnostic IBS criteria may be deficient in GPs. The present study is a survey of the knowledge and management of general practitioners in Germany regarding IBS. All general practitioners (n=260) of an urban area with about 600,000 inhibitants were asked by mail to complete a multiple choice questionnaire concerning their knowledge on IBS and their management of IBS patients. A completed questionnaire was returned by 121 of the general practitioners (46.5% response rate). The majority of the responders were male (61%) and had an experience exceeding 10 years (75%). IBS was regarded as a functional disorder by 55% (49% as a motility disorder and 66% as a psychic disorder). The diagnosis of IBS was mainly based on the patient's history, a colonoscopy was considered by 57%. Diagnostic criteria for IBS were used only by 22 GPs (18%). Referral to gastroenterologists was initiated by 26% of the GPs in all patients with suspected IBS. The majority referred patients only in case of unclear diagnosis or insufficient therapeutic results. Medical therapy was prescribed by 96% of the GPs. Psychotherapy and alternative therapies were additionally performed by 55% and 61%, respectively. The majority of the GPs (66%) estimated the percentage of IBS patients in their daily routine between 1 and 10% and stated that they have seen 1 to 5 patients during the past week. Diagnostic IBS criteria such as Rome criteria are largely unknown among GPs in our area. Pathogenetic models of IBS are deficiently known in GPs. It is likely that the minority of patients who are referred to gastroenterologists have special problems. Their management should probably be different from that of the unreferred majority. Many therapeutic modalities in primary care have no medical evidence. Further studies on therapy options in IBS should also be made in primary care.


Linking social drivers of marine debris with actual marine debris on beaches.
The drivers (social) and pressures (physical) of marine debris have typically been examined separately. We redress this by using social and beach surveys at nine Tasmanian beaches, across three coastlines and within three categories of urbanisation, to examine whether people acknowledge that their actions contribute to the issue of marine debris, and whether these social drivers are reflected in the amount of marine debris detected on beaches. A large proportion (75%) of survey participants do not litter at beaches; with age, gender, income and residency influencing littering behaviour. Thus, participants recognise that littering at beaches is a problem. This social trend was reflected in the small amounts of debris that were detected. Furthermore, the amount of debris was not statistically influenced by the degree of beach urbanisation, the coastline sampled, or the proximity to beach access points. By linking social and physical aspects of this issue, management outcomes can be improved.


Increased phosphatidylcholine concentration in saliva reduces surface tension and improves airway patency in obstructive sleep apnoea.
Surface tension may have important role for maintaining upper airway patency in patients with obstructive sleep apnoea. It has been demonstrated that elevated surface tension increases the pharyngeal pressures required to reopen the upper airway following collapse. The aim of the study was to evaluate the associations between the concentrations of endogenous surfactants in saliva with indices of upper airway patency in obstructive sleep apnoea. We studied 20 male patients with obstructive sleep apnoea (age: 60·3 ± 10·3 years; BMI: 25·9 ± 4·6 kg m(-2); AHI: 41·5 ± 18·6 events h(-1)). We obtained 100-μL samples of saliva prior to overnight polysomnographic sleep study. The surface tension was determined using the pull-off force technique. The concentration of phosphatidylcholine (PC) was evaluated by liquid chromatography-mass spectrometry (LC-MS/MS). Regression analysis between apnoea, hypopnoea and apnoea/hypopnoea indices and the ratio of hypopnoea time/total disordered breathing time (HT/DBT) with surface tension and PC were performed. P < 0·05 was considered significant. The mean saliva surface tension was 48·8 ± 8·0 mN m(-1) and PC concentration was 15·7 ± 11·1 nM. The surface tension was negatively correlated with the PC concentration (r = -0·48, P = 0·03). There was a significant positive correlation between surface tension with hypopnoea index (r = 0·50, P = 0·03) and HT/DBT (r = 0·6, P = 0·006), but not apnoea or apnoea/hypopnoea index (P > 0·11). Similarly, PC concentration negatively correlated with hypopnoea index (r = -0·45, P = 0·04) and HT/DBT (r = -0·6, P = 0·004), but not with apnoea index or AHI (P > 0·08). An increase in salivary PC concentration may increase upper airway patency in obstructive sleep apnoea through a reduction in surface tension.


Macrolide use and the risk of vascular disease in HIV-infected men in the Multicenter AIDS Cohort Study.
There has been increasing concern that HIV-infected individuals may be more at risk for cardiovascular events in the highly-active antiretroviral therapy (HAART) era. This study examined the risk of thromboembolic events in HIV-infected and non-infected individuals and the effect of macrolide prophylaxis on those outcomes. A subcohort analysis was undertaken using data collected in the Multicenter AIDS Cohort Study to examine the relative risk of vascular events (myocardial infarction, unstable angina and ischaemic stroke). Cox proportional hazard model using age as the time scale with time varying cofactors obtained at each semi-annual visit were used to assess the independent effect of macrolide use. Controlling for other significant effects including race and smoking, HIV-infection was not independently associated with vascular events. Increased risk was observed among those who used HAART (relative hazard 1.09, 95% confidence intervals 1.00-1.19 in multivariate model), antihypertensive treatment (1.81 [1.26-2.60]), lipid-lowering medication (1.65 [1.12-2.42]), and antibiotics (1.72 [1.25-2.36]). The protective association of macrolide use for a vascular event in the HAART era was also significant (0.10 [0.01-0.75]). Traditional risk factors are important in the pathogenesis of vascular events in HIV-infected individuals. Macrolide antibiotics may have a protective effect in the HIV-infected individuals in the HAART era.


Three-dimensional Pattern of Inflammatory Periapical Lesion Extension in the Premolar's Region: An Application of K-means Clustering.
Cone-Beam Computed Tomography (CBCT) provides a better diagnosis of endodontic lesions. The present study would assess the pattern of periapical lesion extension in premolar teeth using CBCT. In this descriptive study' 330 roots in the regions of maxillary and mandibular premolars have been evaluated. Maximum periapical lesion extensions in the three orthogonal planes (axial, coronal, and sagittal) were measured and recorded in millimeters. Measurements were compared based on gender' dental arch, tooth type, and root. Statistical analysis was performed using repeated measure ANOVA, Bonferroni, Chi-square tests, and clustering data analysis (K-means method). The significant level was set at 0.05. There were significant differences between the lesion expansions in the three-dimensional planes (p-value<0.001). The highest average of lesion extension in the premolar regions of the examined population was reported in the vertical dimension (4.1± 1.3), followed by horizontal buccolingual dimension (3.4±1.1) and horizontal mesiodistal dimension (3.1±1.0), respectively. According to independent variables, in the premolar region, only tooth roots showed significant differences in the lesion extension (p-value=0.002). Clustering data analysis showed that the majority of the participants were categorized in a cluster with lower lesion extension. Based on clustering data analysis, the small lesions were significantly observed in the first premolar and buccal roots. Since the periapical lesion extension in the buccolingual dimension, which could not be detected in the 2-D imaging techniques, was rather high in the region of premolar teeth, and CBCT, as a 3-D imaging technique, is a suitable option for the precise evaluation of periapical lesion extension. Also, the majority of the lesions in this tooth area are small and located in the buccal roots.


Clinical effectiveness of a Bayesian algorithm for the diagnosis and management of heparin-induced thrombocytopenia.
Essentials We previously published a diagnostic algorithm for heparin-induced thrombocytopenia (HIT). In this study, we validated the algorithm in an independent large healthcare system. The accuracy was 98%, sensitivity 82% and specificity 99%. The algorithm has potential to improve accuracy and efficiency in the diagnosis of HIT. Background Heparin-induced thrombocytopenia (HIT) is a life-threatening drug reaction caused by antiplatelet factor 4/heparin (anti-PF4/H) antibodies. Commercial tests to detect these antibodies have suboptimal operating characteristics. We previously developed a diagnostic algorithm for HIT that incorporated 'four Ts' (4Ts) scoring and a stratified interpretation of an anti-PF4/H enzyme-linked immunosorbent assay (ELISA) and yielded a discriminant accuracy of 0.97 (95% confidence interval [CI], 0.93-1.00). Objectives The purpose of this study was to validate the algorithm in an independent patient population and quantitate effects that algorithm adherence could have on clinical care. Methods A retrospective cohort comprised patients who had undergone anti-PF4/H ELISA and serotonin release assay (SRA) testing in our healthcare system from 2010 to 2014. We determined the algorithm recommendation for each patient, compared recommendations with the clinical care received, and enumerated consequences of discrepancies. Operating characteristics were calculated for algorithm recommendations using SRA as the reference standard. Results Analysis was performed on 181 patients, 10 of whom were ruled in for HIT. The algorithm accurately stratified 98% of patients (95% CI, 95-99%), ruling out HIT in 158, ruling in HIT in 10 and recommending an SRA in 13 patients. Algorithm adherence would have obviated 165 SRAs and prevented 30 courses of unnecessary antithrombotic therapy for HIT. Diagnostic sensitivity was 0.82 (95% CI, 0.48-0.98), specificity 0.99 (95% CI, 0.97-1.00), PPV 0.90 (95% CI, 0.56-0.99) and NPV 0.99 (95% CI, 0.96-1.00). Conclusions An algorithm incorporating 4Ts scoring and a stratified interpretation of the anti-PF4/H ELISA has good operating characteristics and the potential to improve management of suspected HIT patients.


The challenges of ageism in Brazil.
The material and symbolic resource flows and obligations between generations leave an indelible imprint on family members. These intergenerational exchanges have increased in recent years with growing human longevity and they thus have become important to current academic and policy agendas. Concurrently, ageism and age discrimination have emerged as important subjects. The main goal of this article is to call attention to these issues and their relationship with the current policy debate on resource allocation by age groups. We argue that ageism and the practice of age discrimination in Brazil should be viewed as part of the multiple forms of discrimination experienced by individuals. While noticing someone's age is not inherently offensive, acting on age-based stereotypes clearly works against the individual and often goes unchallenged by mainstream society. A central assumption in this paper is that the way we frame ageism and intergenerational relations significantly affects perceived age discrimination and support for age-based social programs.


The pcnB gene of Escherichia coli, which is required for ColE1 copy number maintenance, is dispensable.
The pcnB gene product of Escherchia coli is required for copy number maintenance of plasmids related to ColE1 and also for that of the IncFII plasmid R1. Because PcnB is similar to the tRNA-binding protein tRNA nucleotidyltransferase, we have suggested that the protein would be required only for processes in which an RNA is a prominent regulatory component. This appears to be so; strains deleted for pcnB, although defective in ColE1 and R1 plasmid maintenance, maintain the iteron-regulated plasmids F and P1 normally. We also find that strains deleted for pcnB grow normally, demonstrating that PcnB has no essential cellular role under the conditions tested and suggesting that regulation by antisense RNAs similar to RNAI has no critical role in any essential host process. We confirm by immunological tests that PcnB is likely to be the commercially available enzyme poly(A) polymerase.


BIM-46174 fragments as potential ligands of G proteins.
The 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine derivative BIM-46174 has received attention as Gαq inhibitor. We conducted structural reductions to monocyclic and bicyclic substructures to explore the chemical space of BIM fragments and to gain insights into the pharmacophore of BIM-type Gαq inhibitors. Two piperazin-2-one-containing fragments and a small library of bicyclic lactams featuring fused pyrazine and diazepine rings were synthesized and evaluated. The results of a second messenger-based cellular assay indicate that the entire BIM structure is required for efficient Gαq inhibition.


Effect of phenolic acids on the rheological properties and proteins of hard wheat flour dough and bread.
The effects of different phenolic acids on the rheological properties and gluten proteins of hard wheat flour dough and bread were investigated. Caffeic, ferulic, syringic and gallic acids were each blended with hard wheat flour at a concentration of 4.44 µmol L(-1) g(-1) flour. Mixing time and tolerance were reduced with the addition of phenolic acids. The phenolic acids reduced the maximum resistance to extension (R(max)) and increased the extensibility of dough, with effects in the following order: gallic < syringic < ferulic < caffeic acid. The effect on R(max) was more pronounced in overmixed dough. Loaf volume was most significantly decreased with the addition of caffeic acid. Extraction of sodium dodecyl sulfate-soluble high-molecular-weight proteins was increased in both mixed and fermented doughs by the addition of ferulic and caffeic acids. The order of influence of the phenolic acids on the rheological properties and protein structure of dough and bread was consistent with that of their antioxidant activity. The addition of caffeic and ferulic acids reduced R(max) and increased the extensibility of hard wheat flour dough by modifying the high-molecular-weight gluten, which resulted in decreased bread volume.


Prevalence of antibodies against proteins derived from leukemia cells in patients with chronic myeloid leukemia.
Although various studies supported the notion that leukemia cells in chronic myeloid leukemia (CML) may be recognized by the immune system, direct evidence showing the immunogenicity in vivo of proteins derived from the leukemia cells is lacking. In this study, we have constructed an expression cDNA library from the leukemia cells of a patient with CML and used the autologous serum to screen for high-titer IgG antibodies directed at the leukemia-derived proteins. We isolated eight distinct clones from the library, suggesting that multiple immune responses were elicited in the autologous host. Sequence analysis showed high degrees of homology to known gene sequences in six of the eight clones. Neither bcr-abl nor proteinase 3 sequences were isolated. Using Northern blot analysis, seven of the eight clones showed ubiquitous expression in normal bone marrow, leukemia cell lines, fresh leukemia cells, and normal tissues. However, clone no. 4 showed restricted mRNA expression, being only detected in some fresh leukemia cells, K562 cells, and normal testicular RNA. Using bacterial lysates in dot blot analysis, a panel of sera from normal individuals and patients with CML and other hematological malignancies were screened for high-titer antibodies against these eight clones. There were, among the CML patients, signficantly higher prevalence of antibodies against seven of the eight clones. They were observed even after omitting from the analysis patients with multiple myeloma whose associated immune paresis may impair immune responses to these proteins. Interestingly, antibodies against these proteins were also detected in a small number of normal individuals. Although the precise clinical significance of our findings remains to be determined, this study provides evidence in support of the potential immunogenicity of leukemia-derived proteins in the autologous host. It also provides basis for further investigations to characterize these proteins, especially clone no. 4, and determine their potential for immune targeting in CML.


Genetic associations with brain microbleeds: Systematic review and meta-analyses.
We performed a systematic review and meta-analyses to assess the evidence for genetic associations with brain microbleeds (BMBs). We sought all published studies of the association between any genetic polymorphism and BMBs studied in a total of >100 people. We critically appraised studies, and calculated pooled odds ratios (ORs) using the generic inverse variance fixed effects method. We used I² and χ² statistics to assess heterogeneity, and fail-safe N estimates to assess the robustness of our results. Only the APOE ε2/3/4 polymorphism had been studied in >100 people (10 studies, 7,351 participants). Compared with people with the ε3/ε3 genotype, carriers of the ε4 allele (ε4+) were statistically significantly more likely to have BMBs in any location (ε4+ vs ε3/ε3: pooled OR 1.22, 95% confidence interval [CI] 1.05-1.41, p = 0.01). For strictly lobar BMBs, this association appeared slightly stronger (ε4+ vs ε3/ε3: pooled OR 1.35, 95% CI 1.10-1.66, p = 0.005). The association of ε4+ genotypes with strictly lobar BMBs was reasonably robust to potential publication and reporting biases. Given the known associations of APOE alleles with lobar intracerebral hemorrhage and cerebral amyloid angiopathy, these findings support the concept that strictly lobar BMBs may be an imaging biomarker of cerebral amyloid angiopathy.


The context of human genetic evolution.
The debate on modern human origins has often focused on the relationship between genes and fossils. Although more and more genetic evidence has been accumulating in favor of a recent African origin for modern humans, it has been assumed by many that the fossil evidence remains ambiguous. On the contrary, it has been clear for some time that the fossil evidence does not support the multiregional model: Fossils and archeology indicate a pattern of multiple dispersals from and beyond Africa, against which the genetic data can be compared. The continuing value of paleobiology is in complementing genetic information by revealing the context of human evolution: locating the dispersals and extinctions of populations in time and space, correlating these events with the environmental forces that shaped them, and providing an increasingly detailed understanding of the morphology and technology of early humans.


Oxidation-reduction potential and sperm DNA fragmentation, and their associations with sperm morphological anomalies amongst fertile and infertile men.
To assess seminal oxidation-reduction potential (ORP) and sperm DNA fragmentation (SDF) in male infertility and their relationships with sperm morphology in fertile and infertile men. Prospective case-control study comparing the findings of infertile men (n = 1168) to those of men with confirmed fertility (n = 100) regarding demographics and semen characteristics (conventional and advanced semen tests). Spearman rank correlation assessed the correlation between ORP, SDF, and different morphological indices. Means of ORP and SDF were assessed in variable levels of normal sperm morphology amongst all participants. Infertile patients had a significantly lower mean sperm count (32.7 vs 58.7 × 106 sperm/mL), total motility (50.1% vs 60.4%), and normal morphology (5.7% vs 9.9%). Conversely, infertile patients had significantly higher mean head defects (54% vs 48%), and higher ORP and SDF values than fertile controls. ORP and SDF showed significant positive correlations and significant negative correlations with sperm head defects and normal morphology in infertile patients, respectively. ORP and SDF were significantly inversely associated with the level of normal sperm morphology. Using receiver operating characteristic curve analysis, ORP and SDF threshold values of 1.73 mV/106 sperm/mL and 25.5%, respectively, were associated with 76% and 56% sensitivity and 72% and 72.2% specificity, respectively, in differentiating <4% from ≥4% normal morphology. A direct inverse relationship exists between seminal ORP and SDF with various levels of normal sperm morphology. Using ORP and SDF measures in conjunction with standard semen morphology analysis could validate the result of the fertility status of patients.


Necrosis of Pedunculated Lipofibroma by Nab-Paclitaxel.
We present a rare phenomenon of a soft tumor hanging on the woman's left upper arm that underwent necrosis from the distal aspect during chemotherapy for pancreatic cancer. The benign tumor, pedunculated lipofibroma, originally had normal color for 10 years and then became necrotic when she was treated with gemcitabine and nab-paclitaxel. Necrosis stopped in conjunction with chemotherapy cessation. Dermatologists must remember that nab-paclitaxel could develop necrosis of a skin tumor.


Firing of Replication Origins Is Disturbed by a CDK4/6 Inhibitor in a pRb-Independent Manner.
Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, underlining a need to characterize the effects of CDK4/6 inhibitors beyond pRb. Our study demonstrates how palbociclib impairs origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA while showing no cell cycle arrest. Furthermore, this CDK4/6 inhibitor treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of the Pre-initiation complex (Pre-IC) proteins on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and of its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib in combination with other drugs to target genomic instability in pRB-deficient cancers.


Disrupted Neuroglial Metabolic Coupling after Peripheral Surgery.
Immune-related events in the periphery can remotely affect brain function, contributing to neurodegenerative processes and cognitive decline. In mice, peripheral surgery induces a systemic inflammatory response associated with changes in hippocampal synaptic plasticity and transient cognitive decline, however, the underlying mechanisms remain unknown. Here we investigated the effect of peripheral surgery on neuronal-glial function within hippocampal neuronal circuits of relevance to cognitive processing in male mice at 6, 24, and 72 h postsurgery. At 6 h we detect the proinflammatory cytokine IL-6 in the hippocampus, followed up by alterations in the mRNA and protein expression of astrocytic and neuronal proteins necessary for optimal energy supply to the brain and for the reuptake and recycling of glutamate in the synapse. Similarly, at 24 h postsurgery the mRNA expression of structural proteins (GFAP and AQP4) was compromised. At this time point, functional analysis in astrocytes revealed a decrease in resting calcium signaling. Examination of neuronal activity by whole-cell patch-clamp shows elevated levels of glutamatergic transmission and changes in AMPA receptor subunit composition at 72 h postsurgery. Finally, lactate, an essential energy substrate produced by astrocytes and critical for memory formation, decreases at 6 and 72 h after surgery. Based on temporal parallels with our previous studies, we propose that the previously reported cognitive decline observed at 72 h postsurgery in mice might be the consequence of temporal hippocampal metabolic, structural, and functional changes in astrocytes that lead to a disruption of the neuroglial metabolic coupling and consequently to a neuronal dysfunction.SIGNIFICANCE STATEMENT A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that reaches the brain and associates with immune activation and cognitive decline. Understanding the mechanisms by which immune-related events in the periphery can influence brain processes is essential for the development of therapies to prevent or treat postoperative cognitive dysfunction and other forms of cognitive decline related to immune-to-brain communication, such as Alzheimer's and Parkinson's diseases. Here we describe the temporal orchestration of a series of metabolic, structural, and functional changes after aseptic trauma in mice related to astrocytes and later in neurons that emphasize the role of astrocytes as key intermediaries between peripheral immune events, neuronal processing, and potentially cognition.


Tumor-dependent Effects of Proteoglycans and Various Glycosaminoglycan Synthesizing Enzymes and Sulfotransferases on Patients' Outcome.
The small leucine-rich proteoglycans (SLRPs) biglycan (BGN) and decorin (DCN) linked with sulfated glycosaminoglycan (GAG) chains exhibit oncogenic or tumor suppressive potentials depending on the cellular context and association with GAGs. We hypothesized that structural alterations and expression levels of BGN, DCN and their associated chondroitin sulfate (CS) polymerizing enzymes, dermatan sulfate (DS) epimerases and various sulfatases might be correlated with the tumor (sub)type and patients' survival. We acquired breast cancer (BC) and glioma patients' datasets from cBioPortal and R2 Genomics. Structural alterations and the expression pattern of CS polymerizing enzymes, DS epimerases and carbohydrate sulfotransferases (CHST) were compared to that of BGN and DCN and correlated to their clinical relevance. In BC, no mutations, but amplifications (0.2 - 2.1 %) and deletions (0.05 - 0.4 %) were found in BGN, DCN and CS/DS enzymes. In contrast, missense and/or truncated mutations (0.1 - 0.5 %), but a reduced amplification rate (0 - 1.5 %) were found in glioma. When compared to BC, the structural abnormalities caused altered mRNA expression levels of BGN, DCN, GAG synthesizing enzymes and CHST. Mutations in SLPRs, CHSY1, CHST4 and CHSY3 were correlated with a poor prognosis in glioma, while lack of mutations and copy number variations in the SLRPs, CHSY3, CHST15 and DSE displayed an increased survival in BC. A distinct association of BGN and DCN with CHST, CS polymerizing enzymes and DS epimerases was found in BC and glioma. Thus, a unique pattern of structural alterations and expression, which has clinical relevance, was found for PGs and GAG synthesizing enzymes and CHST in BC and glioma, which might help to identify high-risk patients and to develop personalized therapeutics.


Students' perceptions of belonging in the School of Nursing at a regional university in Australia.
Attrition in pre-registration nursing degrees is a global issue. Students' perceptions of belonging is a factor that influences attrition. The objective of this study was to evaluate students' perception of belonging to a School of Nursing, as well as their intention to complete the pre-registration Bachelor of Nursing (BN) program following implementation of the Initiatives for Retention (IR) intervention. A prospective cross-sectional survey of student nurses was undertaken using an online questionnaire. A large regional university in Australia. Pre-registration nursing students. Perceptions of Belonging were evaluated using the 24-item Belonging questionnaire comprising three subscales. Data were analysed using SPSS version 25. Pearson's correlation, Student's t-tests and one way ANOVA were used to assess associations and differences in belonging scores and student demographics, study status and participation in the Initiatives for Retention (IR) intervention. A total of 201 students responded to the voluntary questionnaire. The mean score for overall Belonging was 70.5 (maximum obtainable 96), mean Scores for University affiliation, University support and acceptance, and staff relations with students were 34.7, 24.1 and 11.8 respectively. Female students, those who were studying at the university for less than a year and those who participated in the IR intervention activities reported significantly higher University Belonging scores compared to their contemporaries. Logistic regression revealed that students studying the BN course for more than 3 years (OR: 0.43 95% CI 0.20-0.93, p = 0.031), and those employed (OR: 0.435, 95% CI 0.16-0.16, p = 0.022) were significant predictors of not attending the IR sessions. There were no significant differences in overall University Belonging scores based on other demographic characteristics and, study status. The majority of the students (84%) stated that they plan to continue and complete the BN program. Measures designed to develop student involvement may positively contribute a successful relationship between the institution and the student, increasing the students' sense of belonging and decreasing attrition among student nurses. Initiatives for Retention (IR) facilitate a greater sense of belonging in nursing students hence Schools of Nursing should consider embedding such strategies.


Receptor-Interacting Protein 140 Orchestrates the Dynamics of Macrophage M1/M2 Polarization.
Macrophage classical (M1) versus alternative (M2) polarization is critical for the homeostatic control of innate immunity. Uncontrolled macrophage polarization is frequently implicated in diseases. This study reports a new functional role for receptor-interacting protein 140 (RIP140) in regulating this phenotypic switch. RIP140 is required for M1 activation, and its degradation is critical to LPS-induced endotoxin tolerance (ET). Here, we found that failure to establish RIP140 degradation-mediated ET prevents M2 polarization, and reducing RIP140 level facilitates an M1/M2 switch, resulting in more efficient wound healing in animal models generated with either transgenic or bone marrow transplant procedures. The M2-suppressive effect is elicited by a new function of RIP140 that, in macrophages exposed to M2 cues, is exported to cytosol, forming complexes with CAPNS1 (calpain regulatory subunit) to activate calpain 1/2, that activates PTP1B phosphatase. The activated PTP1B then reduces STAT6 phosphorylation, thereby suppressing the efficiency of M2 polarization. It is concluded that RIP140 plays dual roles in regulating the M1-M2 phenotype switch: the first, in the nucleus, is an M1 enhancer and the second, in the cytosol, is an M2 suppressor. Modulating the level and/or subcellular distribution of RIP140 can be a new therapeutic strategy for diseases where inflammatory/anti-inflammatory responses are critical.


Standardization of serological assays for parasitic diseases with schistosomiasis and toxocariasis as prototypes.
A standardized microtest plate enzyme-linked immunosorbent assay (ELISA) was developed using the microsomal fraction of adult worms of Schistosoma mansoni (MAMA) as antigen. A standard reference serum pool was prepared and arbitrarily designated as having 100 activity units per microliter. The precision of the test, the suitability as a standard of the reference serum pool, and the J index as a method of determining the significant level of reactivity were evaluated. The predictability of the assay for patients with S. mansoni infections and for non-schistosomiasis patients was 95%. Preliminary studies with the truly quantitative microtest plate kinetic ELISA indicate that this assay is suitable for standardization for schistosomiasis and toxoplasmosis. The need for WHO International Reference Sera with designated International Units and for well-defined batteries of sera for evaluating the specificity and sensitivity of assays was emphasized.


The mechanical basis of cell rearrangement. I. Epithelial morphogenesis during Fundulus epiboly.
Many morphogenetic processes are accomplished by coordinated cell rearrangements. These rearrangements are accompanied by substantial shifts in the neighbor relationships between cells. Here we propose a model for studying morphogenesis in epithelial sheets by directed cell neighbor change. Our model describes cell rearrangements by accounting for the balance of forces between neighboring cells within an epithelium. Cell rearrangement and cell shape changes occur when these forces are not in mechanical equilibrium. We will show that cell rearrangement within the epidermal enveloping layer (EVL) of the teleost fish Fundulus during epiboly can be explained solely in terms of the balance of forces generated among constituent epithelial cells. Within a cell, we account for circumferential elastic forces and the force generated by hydrostatic and osmotic pressure. The model treats epithelial cells as two-dimensional polygons where the mechanical forces are applied to the polygonal nodes. A cell node protrudes or contracts when the nodal forces are not in mechanical equilibrium. In an epithelial sheet, adjacent cells share common boundary nodes; in this way, mechanical force is transmitted from cell to cell, mimicking junctional coupling. These junctional nodes can slide, and nodes may appear or disappear, so that the number of polygonal sides is variable. Computer graphics allows us to compare numerical simulations of the model with time-lapse cinemicroscopy of cell rearrangements in the living embryo, and data obtained from fixed and silver stained embryos. By manipulating the mechanical properties of the model cells we can study the conditions necessary to reproduce normal cell behavior during Fundulus epiboly. We find that simple stress relaxation is sufficient to account for cell rearrangements among interior cells of the EVL when they are isotropically contractile. Experimental observations show that the number of EVL marginal cells continuously decreases throughout epiboly. In order for the simulation to reproduce this behavior, cells at the EVL boundary must generate protrusive forces rather than contractile tension forces. Therefore, the simulation results suggest that the mechanical properties of EVL marginal cells at their leading edge must be quite different from EVL interior cells.


Hospitalizations for Cardiovascular Disease After Liver Transplantation in the United States.
Cardiovascular disease (CVD) is a leading cause of post-liver transplant death, and variable care patterns may affect outcomes. We aimed to describe epidemiology and outcomes of inpatient CVD care across US hospitals. Using a merged data set from the 2002-2011 Nationwide Inpatient Sample and the American Hospital Association Annual Survey, we evaluated liver transplant patients admitted primarily with myocardial infarction (MI), stroke (cerebrovascular accident [CVA]), congestive heart failure (CHF), dysrhythmias, cardiac arrest (CA), or malignant hypertension. Patient-level data include demographics, Charlson comorbidity index, and CVD diagnoses. Facility-level variables included ownership status, payer-mix, hospital resources, teaching status, and physician/nursing-to-bed ratios. We used generalized estimating equations to evaluate patient- and hospital-level factors associated with mortality. There were 4763 hospitalizations that occurred in 153 facilities (transplant hospitals, n = 80). CVD hospitalizations increased overall by 115% over the decade (P < 0.01). CVA and MI declined over time (both P < 0.05), but CHF and dysrhythmia grew significantly (both P < 0.03); a total of 19% of hospitalizations were for multiple CVD diagnoses. Transplant hospitals had lower comorbidity patients (P < 0.001) and greater resource intensity including presence of cardiac intensive care unit, interventional radiology, operating rooms, teaching status, and nursing density (all P < 0.01). Transplant and nontransplant hospitals had similar unadjusted mortality (overall, 3.9%, P = 0.55; by diagnosis, all P > 0.07). Transplant hospitals had significantly longer overall length of stay, higher total costs, and more high-cost hospitalizations (all P < 0.05). After risk adjustment, transplant hospitals were associated with higher mortality and high-cost hospitalizations. In conclusion, CVD after liver transplant is evolving and responsible for growing rates of inpatient care. Transplant hospitals are associated with poor outcomes, even after risk adjustment for patient and hospital characteristics, which may be attributable to selective referral of certain patient phenotypes but could also be related to differences in quality of care. Further study is warranted.


[Chronic recurrent abdominal pain in school children].
The diagnostic approach of children with recurrent abdominal pain (RAP) was investigated by means of a standard protocol. The protocol consisted of recently developed laboratory techniques and 'routine' investigations. In addition, all patients were subjected to an extensive psychological investigation. The main results show that in a high percentage (42%) of patients organic abnormalities could be found. Particularly the small bowel seemed to be involved in the pathogenesis of the complaints. Furthermore, gastro-esophageal reflux appeared to be present in as many as 50% of the patients investigated and there might be a relationship with the abdominal pain complaints. Helicobacter pylori did not appear to play an important role in these patients. Comparing the results of the psychologic investigation with a pain-free control group, we did not find clear evidence that psychological factors play a role in the pathogenesis of these patients' complaints. Children with RAP, particularly when complaints exist longer than 6 months, need to be investigated for the presence of organic abnormalities that might provide an explanation for the complaints.


Canadian Patients' Preferences in Topical Psoriasis Care: Insights From the PROPEL Surveys.
Patients with psoriasis of all severities employ topical treatment, either alone or in combination. Promoting Patient Engagement at the Leading Edge of Topical Psoriasis Treatment (PROPEL) surveyed Canadian dermatologists and their patients about their attitudes toward topical care. To identify gaps between patients and dermatologists regarding the burden of psoriasis, the burden of treatment, and priorities for topical care to Canadian patients with psoriasis. Two parallel surveys explored patient attitudes toward psoriasis and their experience with topical care, as expressed by patients or as perceived by their dermatologists. A third survey, addressed to patients, included additional questions regarding treatment adherence to current topical treatment regimens. PROPEL dermatologists underestimated the burden associated with psoriatic itch. Otherwise, they were well aligned with patients' views, including their preference for maintaining topical care of their psoriasis over other treatment modalities, the nature of good psoriasis control, and desirable features of topical medications. Despite holding generally positive views of topical therapy, many patients self-identified as poorly adherent. Long-term adherence to psoriasis topical care remains a challenge. Formulations with improved acceptability might help patients maintain good adherence.


Evaluation of Ultrasound-Guided Fine-Needle Aspiration Cytology of Ovarian Masses with Histopathological Correlation.
Preoperative cytodiagnosis of ovarian masses is a difficult process, and sampling of pelvic masses is quite easier after the improvement of imaging techniques. Though histopathology is the gold standard, fine-needle aspiration cytology (FNAC) under ultrasound (US) guidance can be a valuable tool for pre-operative diagnosis of ovarian lesions, especially in the hands of an experienced pathologist. The present study was performed to evaluate the role of US-guided FNAC in pre-operative cytological diagnosis of ovarian masses in comparison with histopathology, and to assess the pitfalls and limitations of cytological interpretation. This study was conducted over a 2-year period on 70 cases of ovarian masses, which were evaluated by US-guided FNAC. Sensitivity, specificity and diagnostic efficacy were calculated using histopathology as gold standard. On cytological evaluation, non-neoplastic cysts, and benign and malignant ovarian tumours were diagnosed in 8, 18 and 40 cases, respectively. On histopathology, 62 cases were concordant with cytology. Sensitivity and specificity were 95.23 and 95.83%, respectively, in the present study. Diagnostic accuracy was 93.94% in respect to the correct diagnosis. Cytohistological discrepancies and limitations of the study are discussed. US-guided FNAC has proved as a quick, economic and safe procedure in diagnosing ovarian masses with brilliant accuracy.


Effect of clavulanic acid on activity of beta-lactam antibiotics in Serratia marcescens isolates producing both a TEM beta-lactamase and a chromosomal cephalosporinase.
An isolate of Serratia marcescens that produced both an inducible chromosomal and a plasmid-mediated TEM-1 beta-lactamase was resistant to ampicillin and amoxicillin and also demonstrated decreased susceptibility to extended-spectrum beta-lactam antibiotics (ESBAs). Clavulanic acid did not lower the MICs of the ESBAs, but it decreased the MICs of the penicillins. The TEM-1-producing plasmid was transferred to a more susceptible S. marcescens strain that produced a well-characterized inducible chromosomal beta-lactamase. The MICs of the ESBAs remained at a low level for the transconjugant. Ampicillin and amoxicillin which were good substrates for the plasmid-mediated enzyme, were not well hydrolyzed by the chromosomal enzymes; the ESBAs were hydrolyzed slowly by all the enzymes. When each of the S. marcescens strains was grown with these beta-lactam antibiotics, at least modest increases in chromosomal beta-lactamase activity were observed. When organisms were grown in the presence of clavulanic acid and an ESBA, no enhanced induction was observed. The increases in the MICs of the ESBAs observed for the initial clinical isolate may have been due to a combination of low inducibility, slow hydrolysis, and differences in permeability between the S. marcescens isolates. When clavulanic acid and a penicillin were added to strains that produced both a plasmid-mediated TEM and a chromosomal beta-lactamase, much higher levels of chromosomal beta-lactamase activity were present than were observed in cultures induced by the penicillin alone. This was due to the higher levels of penicillin that were available for induction as a result of inhibition of the TEM enzyme by clavulanate.


Arsenic Accumulation and Physiological Response of Three Leafy Vegetable Varieties to As Stress.
Arsenic (As) in leafy vegetables may harm humans. Herein, we assessed As accumulation in leafy vegetables and the associated physiological resistance mechanisms using soil pot and hydroponic experiments. Garland chrysanthemum (Chrysanthemum coronarium L.), spinach (Spinacia oleracea L.), and lettuce (Lactuca sativa L.) were tested, and the soil As safety threshold values of the tested leafy vegetables were 91.7, 76.2, and 80.7 mg kg−1, respectively, i.e., higher than the soil environmental quality standard of China. According to growth indicators and oxidative stress markers (malondialdehyde, the ratio of reduced glutathione to oxidized glutathione, and soluble protein), the order of As tolerance was: GC > SP > LE. The high tolerance of GC was due to the low transport factor of As from the roots to the shoots; the high activity of superoxide dismutase, glutathione peroxidase, and catalase; and the high content of phytochelatin in the roots. Results of this work shed light on the use of As-contaminated soils and plant tolerance of As stress.


Significance of abdominal ultrasound in inflammatory bowel disease.
Transabdominal ultrasound is most commonly used to examine the liver, hepatobiliary-pancreatic and urogenital tract. Its use for imaging the intestinal tract is less well established and has been considered more difficult in the past. Improvements in technology and increasing experience with sonographic findings in a variety of intestinal diseases including inflammatory bowel disease (IBD), however, have contributed to firmly establishing the role of ultrasound as a clinically important, non-invasive and widely available imaging modality. In addition, newer techniques such as harmonic imaging and contrast-enhanced ultrasound have recently gained attention. Transabdominal ultrasound is clinically useful in the initial diagnosis of IBD by evaluating bowel wall thickness and surrounding structures including peri-intestinal inflammatory reaction, extent and localization of involved bowel segments and detection of extraluminal complications such as fistula, abscesses, carcinoma and ileus. Transabdominal ultrasound is currently accepted as a clinically important first-line tool in assessing patients with Crohn's disease irrespective of their clinical symptoms and/or disease activity. It helps to better characterize the course of the disease in individual patients and can guide therapeutic decisions. The topic of this review is to provide an updated overview of the role of transabdominal ultrasound in IBD including Crohn's disease, ulcerative colitis, tuberculosis and neutropenic colitis while summarizing the results of recent studies with special reference to sensitivity/specificity in detecting the disease and sonomorphologic features to evaluate disease activity and its luminal and extraluminal complications.


Noninvasive assessment of language dominance in children and adolescents with functional MRI: a preliminary study.
Assessment of language organization is crucial in patients considered for epilepsy surgery. In children, the current techniques, intra-carotid amobarbital test (IAT) for language dominance, and cortical electrostimulation mapping (ESM), are invasive and risky. Functional magnetic resonance imaging (fMRI) is an alternative method for noninvasive functional mapping, through the detection of the hemodynamic changes associated with neuronal activation. We used fMRI, to assess language dominance in children with partial epilepsy. Eleven right handed children and adolescents performed a word generation task during fMRI acquisition focused on the frontal lobes. Areas where the signal time course correlated with the test paradigm (r = 0.7) were considered activated. Extent and magnitude of signal changes were used to calculate asymmetry indices. Seven patients had IAT, ESM, or surgery outcome available for comparison. fMRI language dominance always agreed with IAT (6 cases) and ESM (1 case), showing left dominance in six and bilateral language in one. fMRI demonstrated left dominance in three additional children, and right dominance in one with early onset of left temporal epilepsy. Four children whose initial studies were equivocal due to noncompliance or motion artifacts were restudied successfully. fMRI can be used to assess language lateralization noninvasively in children. It has the potential to replace current functional mapping techniques in patients, and to provide important data on brain development.


Autosomal recessive inheritance in the Setleis bitemporal 'forceps marks' syndrome.
We present the clinical findings in two children with the Setleis bitemporal "forceps marks" syndrome. The striking features include the following: (1) bitemporal scarring, an anomaly that resembles forceps marks; (2) periorbital puffiness with wrinkling of the skin; (3) abnormalities of the eyebrows; (4) anomalies of the eyelashes; (5) flattening of the nasal bridge with a bulbous nasal tip; (6) increased mobility of the skin, associated with severely redundant facial soft tissue; and (7) normal growth and development. The evidence that suggests that this unusual syndrome is inherited in an autosomal recessive fashion includes the following: (1) seven of the patients have come from the relatively isolated towns of San Sebastian and Aguadilla in Puerto Rico; (2) two sets of affected siblings have been described, and, in both cases, the siblings' parents were normal; and (3) one of the children described herein is the product of a consanguineous mating. Although the pathogenetic mechanism is unknown, Setleis syndrome is clearly inherited as an autosomal recessive trait.


Dipyridinoarsole: a new class of stable and modifiable heteroatom-bridged bipyridines.
Herein, we report our experimental and computational investigations on a stable and modifiable As-bridged dipyridinoheterole, dipyridinoarsole. Oxidation of the arsenic atom changes the frontier orbital energies and quaternization of nitrogen atoms produces electrochromic materials. Dipyridinoarsole is suitable for practical applications due to its superior stability compared to its phosphole analogues.


Impact of rifampicin dose in bone and joint prosthetic device infections due to Staphylococcus spp: a retrospective single-center study in France.
Prosthetic joint infections (PJI) are a major cause of morbidity and mortality burden worldwide. While surgical management is well defined, rifampicin (RIF) dose remains controversial. The aim of our study was to determine whether Rifampicin dose impact infection outcomes in PJI due to Staphylococcus spp. single-center retrospective study including 411 patients with PJI due to Rifampicin-sensitive Staphylococcus spp. Rifampicine dose was categorized as follow: < 10 mg/kg/day, 10-20 mg/kg/day or > 20 mg/kg/day. The primary endpoint was patient recovery, defined as being free of infection during 12 months after the end of the initial antibiotic course. 321 (78%) received RIF for the full antibiotic course. RIF dose didn't affect patients recovery rate with 67, 76 and 69% in the < 10, 10-20 and > 20 mg/kg/day groups, respectively (p = 0.083). In univariate analysis, recovery rate was significantly associated with gender (p = 0.012) but not to RIF dose, or Staphylococcus phenotype (aureus or coagulase-negative). In multivariate analysis, age (p = 0.01) and treatment duration (p < 0.01) were significantly associated with recovery rate. These data suggest that lower doses of RIF are as efficient and safe as the recommended high-dose French regimen in the treatment of PJI.


Ameliorative effect of black grape juice on systemic alterations and mandibular osteoradionecrosis induced by whole brain irradiation in rats.
Whole brain irradiation (WBI) causes a variety of secondary side-effects including anorexia and bone necrosis. We evaluated the radiomodifying effect of black grape juice (BGJ) on WBI alterations in rats measuring food and water intake, body weight, hemogram, and morphological and histological mandibular parameters. Forty male rats (200-250 g) were exposed to eight sessions of cranial X-ray irradiation. The total dose absorbed was 32 Gy delivered over 2 weeks. Four groups were defined: (i) NG: non-irradiated, glucose and fructose solution-supplemented (GFS); (ii) NJ: non-irradiated, BGJ-supplemented; (iii) RG: irradiated, GFS-supplemented; and (iv) RJ: irradiated, BGJ-supplemented. Rats received daily BGJ or GFS dosing by gavage starting 4 days before, continuing during, and ending 4 days after WBI. RJ rats ingested more food and water and showed less body weight loss than RG rats during the irradiation period. Forty days after WBI, irradiated animals started losing weight again compared with controls as a consequence of masticatory hypofunction by mandibular osteoradionecrosis (ORN). Osteoclastic activity and inflammation were apparent in RG rat mandibles. BGJ was able to attenuate the severity of ORN as well as to improve white and red blood cell counts. Fractionated whole brain irradiation induces mandibular changes that interfere with normal feeding. BGJ can be used to mitigate systemic side-effects of brain irradiation and ORN.


Translational cognitive endocrinology: designing rodent experiments with the goal to ultimately enhance cognitive health in women.
Understanding the cognitive impact of endogenously derived, and exogenously administered, hormone alterations is necessary for developing hormone treatments to support healthy brain function in women, especially during aging. The increasing number of studies in the burgeoning area of translational cognitive neuroendocrinology has revealed numerous factors that influence the extent and direction of female steroid effects on cognition. Here, we discuss the decision processes underlying the design of rodent hormone manipulation experiments evaluating learning and memory. It is noted that even when beginning with a clear hypothesis-driven question, there are numerous factors to consider in order to solidify a sound experimental design that will yield clean, interpretable results. Decisions and considerations include: age of animals at hormone administration and test, ovariectomy implementation, when to administer hormones relative to ovarian hormone loss, how and whether to monitor the estrous cycle if animals are ovary-intact, dose of hormone, administration route of hormone, hormone treatment confirmation protocols, handling procedures required for hormone administration and treatment confirmation, cognitive domains to be tested and which mazes should be utilized to test these cognitive domains, and control measures to be used. A balanced view of optimal design and realistic experimental practice and protocol is presented. The emerging results from translational cognitive neuroendocrinology studies have been diverse, but also enlightening and exciting as we realize the broad scope and powerful nature of ovarian hormone effects on the brain and its function. We must design, implement, and interpret hormone and cognition experiments with sensitivity to these tenets, acknowledging and respecting the breadth and depth of the impact gonadal hormones have on brain functioning and its rich plasticity. This article is part of a Special Issue entitled Hormone Therapy.


Preferences of Transgender and Gender-Nonconforming Persons in Gender-Confirming Surgical Care: A Cross-Sectional Study.
Increased awareness for transgender and gender-nonconforming individuals may lead to increased demand for surgical interventions in gender-confirming care. However, limited literature exists regarding transgender and gender-nonconforming preferences and experiences with medical or surgical care. The authors aim to characterize the medical and surgical care sought by this population, as well as their surgical preferences, motivations, and barriers to care. An online questionnaire about opinions and personal experiences with medical and surgical care during gender transition was publicized via regional online social networking forums in Connecticut and surrounding areas catering to transgender communities. Responses were received from 313 participants. Participants were 97% male gender at birth and 92% white with an average (SD) age of 51.6 (13.5) years. Fifty-nine percent identified as male-to-female transgender and 20% as gender nonconforming. Respondents were aware of their gender identity at a mean (SD) age of 9.6 (9.0) years, but did not begin transitioning until a mean (SD) age of 38.9 (20.8) years, with gender-nonconforming respondents choosing to transition at a significantly younger age as compared with transgender respondents (29.8 vs 41.4 years; P = 0.0061, unpaired t test). Only 42% of all respondents, with a significantly greater number of transgender as opposed to gender-nonconforming individuals, had previously met with a physician to discuss transitioning (49% vs 21%, P = 0.002, χ test). Eight percent of the study population had undergone gender confirmation surgery (GCS), 52% were interested in GCS, and 40% were not interested in GCS. Primary motivation for GCS included discomfort in one's current body (28%), and barriers to GCS included cost (40%) and reactions of family (40%), partners (32%), and friends (25%). Transgender and gender-nonconforming individuals lack medical support for gender transition, with fewer than half of survey respondents reporting a prior meeting with a physician to discuss transitioning. The reported perspectives offer important insight into transgender preferences that should act as the basis of future efforts to improve the efficacy of gender-confirming care.