Real-time detection of metal ions using conjugated polymer composite papers.
Cellulose, a natural polymeric material, has widespread technical applications because of its inherent structural rigidity and high surface area. As a conjugated polymer, polypyrrole shows practical potential for a diverse and promising range of future technologies. Here, we demonstrate a strategy for the real-time detection and removal of metal ions with polypyrrole/cellulose (PPCL) composite papers in solution. Simply, the conjugated polymer papers had different chemical/physical properties by applying different potentials to them, which resulted in differentiable response patterns and adsorption efficiencies for individual metal ions. First, large-area PPCL papers with a diameter of 5 cm were readily obtained via vapor deposition polymerization. The papers exhibited both mechanical flexibility and robustness, in which polypyrrole retained its redox property perfectly. The ability of the PPCL papers to recognize metal ions was examined in static and flow cells, in which real-time current change was monitored at five different applied potentials (+1, +0.5, 0, -0.5, and -1 V vs. Ag/AgCl). Distinguishable signals in the PPCL paper responses were observed for individual metal ions through principal component analysis. Particularly, the PPCL papers yielded unique signatures for three metal ions, Hg(ii), Ag(i), and Cr(iii), even in a real sample, groundwater. The sorption of metal ions by PPCL papers was examined in the flow system. The PPCL papers had a greatly superior adsorption efficiency for Hg(ii) compared to that of the other metal ions. With the strong demand for the development of inexpensive, flexible, light-weight, and environmentally friendly devices, the fascinating characteristics of these PPCL papers are likely to provide good opportunities for low-cost paper-based flexible or wearable devices.


[The active state of cross-striated muscle cell sarcomere (an imitation model)].
An index of the sarcomere active state is introduced. It reflects the most important processes of sarcomere contraction, such as calcium diffusion taking into account permeability of calcium channels and its binding with troponin, formation of energy supplies and interaction of sarcomere contractile proteins. The effect of changes of the values of diffusion coefficients and chemical reactions rates was studied theoretically.


Hypoxic hepatitis: clinical and hemodynamic study in 142 consecutive cases.
The centrilobular liver cell necrosis observed in hypoxic hepatitis is generally attributed to failure of hepatic blood perfusion. Accordingly, this injury of the liver is commonly recognized under the terms "shock liver" or "ischemic hepatitis." During a 10-year period, 142 episodes of hypoxic hepatitis were consecutively identified in the intensive care unit of a general hospital, and the clinical, biological, and hemodynamic parameters were prospectively collected on individual files. We conducted the current study to assess retrospectively the role of the hemodynamic mechanisms of tissue hypoxia: ischemia, passive venous congestion, and hypoxemia. Among the 142 episodes of hypoxic hepatitis, 138 were separated in 4 main groups based on clinical features: decompensated congestive heart failure (80 cases), acute cardiac failure (20 cases), exacerbated chronic respiratory failure (19 cases), and toxic/septic shock (19 cases). An elementary hemodynamic evaluation, including blood pressure, central venous pressure, and arterial blood gas analysis, was carried out in every episode and a more complete hemodynamic assessment through pulmonary artery catheterization was performed in 61 episodes. The hemodynamic mechanisms responsible for hypoxic hepatitis were different in the 4 groups. In congestive heart failure and acute heart failure, the hypoxia of the liver resulted from decreased hepatic blood flow (ischemia) due to left-sided heart failure and from venous congestion secondary to right-sided heart failure. In chronic respiratory failure, liver hypoxia was mainly due to profound hypoxemia. In toxic/septic shock, oxygen delivery to the liver was not decreased but oxygen needs were increased, while the liver was unable to use oxygen properly. In all conditions underlying hypoxic hepatitis, except toxic/septic shock, a shock state was observed in only about 50% of the cases. Therefore, the expressions "shock liver" or "ischemic hepatitis" are misleading and should be replaced by the more general term "hypoxic hepatitis."


Availability and quality of mobile health app privacy policies.
Mobile health (mHealth) customers shopping for applications (apps) should be aware of app privacy practices so they can make informed decisions about purchase and use. We sought to assess the availability, scope, and transparency of mHealth app privacy policies on iOS and Android. Over 35,000 mHealth apps are available for iOS and Android. Of the 600 most commonly used apps, only 183 (30.5%) had privacy policies. Average policy length was 1755 (SD 1301) words with a reading grade level of 16 (SD 2.9). Two thirds (66.1%) of privacy policies did not specifically address the app itself. Our findings show that currently mHealth developers often fail to provide app privacy policies. The privacy policies that are available do not make information privacy practices transparent to users, require college-level literacy, and are often not focused on the app itself. Further research is warranted to address why privacy policies are often absent, opaque, or irrelevant, and to find a remedy.


Candidate lethal haplotypes and causal mutations in Angus cattle.
If unmanaged, high rates of inbreeding in livestock populations adversely impact their reproductive fitness. In beef cattle, historical selection strategies have increased the frequency of several segregating fatal autosomal recessive polymorphisms. Selective breeding has also decreased the extent of haplotypic diversity genome-wide. By identifying haplotypes for which homozygotes are not observed but would be expected based on their frequency, candidates for developmentally lethal recessive loci can be localized. This analysis comes without the need for observation of the loss-associated phenotype (e.g., failure to implant, first trimester abortion, deformity at birth). In this study, haplotypes were estimated for 3961 registered Angus individuals using 52,545 SNP loci using findhap v2, which exploited the complex pedigree among the individuals in this population. Seven loci were detected to possess haplotypes that were not observed in homozygous form despite a sufficiently high frequency and pedigree-based expectation of homozygote occurrence. These haplotypes were identified as candidates for harboring autosomal recessive lethal alleles. Of the genotyped individuals, 109 were resequenced to an average 27X depth of coverage to identify putative loss-of-function alleles genome-wide and had variants called using a custom in-house developed pipeline. For the candidate lethal-harboring haplotypes present in these bulls, sequence-called genotypes were used to identify concordant variants. In addition, whole-genome sequence imputation of variants was performed into the set of 3961 genotyped animals using the 109 resequenced animals to identify candidate lethal recessive variants at the seven loci. Following the imputation, no variants were identified that were fully concordant with the marker-based diplotypes. Selective breeding programs could utilize the predicted lethal haplotypes associated with SNP genotypes. Sequencing and other methods for identifying the causal variants underlying these haplotypes can allow for more efficient methods of management such as gene editing. These two methods in total will reduce the negative impacts of inbreeding on fertility and maximize overall genetic gains.


Privacy and Biobanking in China: A Case of Policy in Transition.
Disease-based biobanks have operated in hospitals and research institutes in China for decades, and China has recently embarked on a plan to establish further biobank networks with the aim of promoting data sharing among the existing biobanks. Although the Chinese Constitution has only recently begun to recognize individual privacy as a distinct and independent constitutional right, biobanking in China has been loosely regulated under a patchwork of sometimes overlapping laws (such as the Interim Measures for the Administration of Human Genetic Resources) and regulatory instruments, as well as and the policies of individual biobanks and networks of biobanks (such as the Shanghai Biobank Network Guidelines). A Draft Ordinance on Human Genetics Resources is currently being developed that will deal in more detail than previous laws with issues such as management measures, legal liability, and punishment for violations. International data sharing will be tightly regulated under this new law, and individual biobanks' policies such as the Shanghai Guidelines may choose to regulate such sharing even more. In contrast with national regulatory instruments, the Shanghai Guidelines also contain detailed de-identification policies, and explicitly endorse broad consent.


Ciprofloxacin and ceftriaxone alter cytokine responses, but not Toll-like receptors, to Salmonella infection in vitro.
Antibiotics that enhance host natural defences to infection offer an alternative approach to treating infections. However, mechanisms underlying such processes are poorly understood. The aim of this study was to investigate the effects of clinically relevant concentrations of two antibiotics on bacterial interactions with murine macrophages. Adhesion of Salmonella Typhimurium SL1344 to and invasion by Salmonella Typhimurium SL1344 of antibiotic-treated or untreated J774 murine macrophages were measured using a tissue culture infection model. Expression of genes central to the Toll-like receptor (TLR) signalling pathway of macrophages infected with Salmonella was analysed using the RT(2) Profiler PCR Array. Cytokine production was measured by ELISA. Adhesion of Salmonella Typhimurium SL1344 to J774 macrophage monolayers was increased when macrophages were exposed to ciprofloxacin and ceftriaxone, while invasion was decreased by ciprofloxacin. Expression of IL-1β and TNF-α mRNA was greater in SL1344-infected macrophages that had been treated with ciprofloxacin or ceftriaxone than in macrophages exposed to antibiotics alone or SL1344 alone. TLR mRNA was down-regulated by SL1344 infection, a response that was not altered by antibiotic pretreatment. Clinically relevant concentrations of two antibiotics differentially enhanced the response of immune cells and their interaction with bacteria, increasing bacterial adhesion to macrophages and increasing cytokine production. As increased expression of IL-1β fosters apoptosis of Salmonella-infected macrophages and clearance by neutrophils, the immunomodulatory potential of these antibiotics may explain, in part, why these two drugs continue to be used to treat salmonellosis successfully.


The morphological and histological characters of the male external genitalia of the house musk shrew, Suncus murinus.
External genitalia are the reproductive organs necessary for efficient copulation and internal fertilization in various mammalian species. Their morphogeneses display significant morphological and developmental differences among species. The house musk shrew, Suncus murinus (hereafter described as suncus) is a species of the order Insectivora, which has been considered as primitive and one of the earliest eutheria phylogenetically. Comparative anatomical analyses of phylogenetically different mammals will contribute to the better understanding of morphological diversity of external genitalia. This study performed various anatomical and histological analyses concerning the organization of the external genitalia of male suncus. It was shown that the external genitalia of suncus possessed a muscular structure, which we proposed as musculus ischiocavernosus dorsalis of suncus. The musculus ischiocavernosus dorsalis is originated from the inner surface of the tuber ischiadicum and was allocated adjacent to the corpus cavernosum penis. In addition, a pair of alpha-smooth muscle actin positive muscles was located bilaterally to the urethra. This unique morphology of the external genitalia of suncus males may provide a unique model system to investigate genital morphogenesis.


Stretchable Electronic Wearable Motion Sensors Delineate Signatures of Human Motion Tasks.
Digital tracking of human motion offers the potential to monitor a wide range of activities detecting normal versus abnormal performance of tasks. We examined the ability of a wearable, conformal sensor system, fabricated from stretchable electronics with contained accelerometers and gyroscopes, to specifically detect, monitor, and define motion signals and "signatures," associated with tasks of daily living activities. The sensor system was affixed to the dominant hand of healthy volunteers (n = 4) who then completed four tasks. For all tasks examined, motion data could be captured, monitored continuously, uploaded to the digital cloud, and stored for further analysis. Acceleration and gyroscope data were collected in the x-, y-, and z-axes, yielding unique patterns of component motion signals for each task studied. Upon analysis, low-frequency (<10 Hz) tasks (walking, drinking from a mug, and opening a pill bottle) showed low intersubject variability (<0.3g difference) and low interrepetition variability (<0.1g difference) when comparing the acceleration of each axis for a single task. High-frequency (≥10 Hz) activity (brushing teeth) yielded low intersubject variability of peak frequencies in acceleration of each axis. Each motion task was readily distinguishable and identifiable (with ≥70% accuracy) by independent observers from motion signatures alone, without the need for direct visual observation. Stretchable electronic technologies offer the potential to provide wireless capture, tracking, and analysis of detailed directional components of motion for a wide range of individual activities and functional status.


Cognitive-Driven Activities of Daily Living Impairment as a Predictor for Dementia in Parkinson Disease: A Longitudinal Cohort Study.
One-third of Parkinson's disease (PD) patients with mild cognitive impairment (PD-MCI) convert to dementia within a few years. Markers with a high prognostic value for dementia conversion are needed. Loss of everyday function primarily caused by cognitive dysfunction is the core criterion for the diagnosis of PD dementia, with an onset of more complex instrumental activities of daily living (IADL) dysfunction in the prodromal stage. This study evaluated the phenotype associated with cognitive IADL impairment and its predictive value for defining a high-risk group for PD dementia. An observational longitudinal study using cognitive and clinical scores in addition to genetic and CSF biomarkers was conducted. The Functional Activities Questionnaire (FAQ) quotient (cut-off ≥1), indicating more cognitive than motor-driven IADL impairment, defined cognitive IADL impairment status at baseline. Hazard ratios (HR) were used to compare the impact of baseline classifications on dementia conversion. Of 268 patients with PD assessed at baseline, 108 (40.3%) had PD-MCI. After a period of 3.78±0.84 years, 164 (61.2%) patients were re-assessed. At follow-up, 93 (56.7%) patients had no cognitive impairment, 54 (32.9%) fulfilled PD-MCI criteria, and 17 (10.4%) had developed dementia. The HR of baseline cognitive IADL impairment (n=37) for dementia conversion was descriptively higher than for PD-MCI, but highest in patients with both markers (HR=12.01, 95%-CI 4.47-32.22, p<0.001). In the follow-up sample, nearly half of patients (n=10, 47.6%) with baseline classification of cognitive IADL impairment and PD-MCI converted to dementia. Baseline status of cognitive IADL impairment was associated with higher non-motor burden, worse cognitive performance, and more severe IADL progression over the study period. The importance of differentiating between cognitive and motor aspects on ADL function in PD and monitoring cognitive ADL impairment in the prodromal stage of dementia is paramount. Patients with PD-MCI and cognitive IADL impairment may be a valuable target group for clinical trials aiming to slow down development of dementia. ClinicalTrials.gov NCT03687203. This study provides Class II evidence that impairment of cognitive activities of daily living is associated with progression from mild cognitive impairment to dementia among patients with Parkinson's disease.


[Normalization of the dimensions of the left ventricle as measured by echocardiography].
An M mode echocardiographic study was performed, of left ventricular dimensions and wall thickness in two series of normal (N1, N2) and pathological (P1, P2) subjects. In the more recent series (N2 = 40, P2 = 17) data acquisition was facilitated by tests deduced from the technique of ultrasound transit time. The parameters compared were based on: 1) the proportionality between fractional shortening and fractional thickening (N1: not significant; N2: p less than 0.001), 2) the relationship between systolic radius and wall thickness (linear correlation, r = 0.95, between N2 and P2). The slope seemed to be related to the initial condition of contraction, the ratio of end diastolic wall thickness/radius (N1: p less than 0.01). There are several ways of normalising myocardial surface of section in adults and children; the normal surface is related to body surface area (r = 0.87; p less than 0.001 between calculated and predicted values for a N2 mean of 9.3 +/- 0.06 cm2/m2). The end diastolic diameters and wall thicknesses correlated with body surface area but the coefficients were not as statistically significant due to physiological variations in chamber filling. The indexed myocardial surface was increased (p less than 0.001) in the pathological series. The introduction of these tests improves the reliability of echocardiographic data. The use of several measurements simultaneously allows normalisation of body surface area and increases the diagnostic efficacy.


A systematic review of complementary and alternative medicine in oncology: Psychological and physical effects of manipulative and body-based practices.
Complementary and Alternative Medicines (CAM) are widely used by cancer patients, despite limited evidence of efficacy. Manipulative and body-based practices are some of the most commonly used CAM. This systematic review evaluates their benefits in oncology. A systematic literature review was carried out with no restriction of language, time, cancer location or type. PubMed, CENTRAL, PsycArticle, PsychInfo, Psychology and Behavioral Sciences Collection and SOCindex were queried. Inclusion criteria were adult cancer patients and randomized controlled trials (RCT) assessing manipulative and body-based complementary practices on psychological and symptom outcomes. Effect size was calculated when applicable. Of 1624 articles retrieved, 41 articles were included: massage (24), reflexology (11), acupressure (6). Overall, 25 studies showed positive and significant effects on symptom outcomes (versus 9 that did not), especially pain and fatigue. Mixed outcomes were found for quality of life (8 papers finding a significant effect vs. 10 which did not) and mood (14 papers vs. 13). In most studies, there was a high risk of bias with a mean Jadad score of 2, making interpretation of results difficult. These results seem to indicate that manipulative CAM may be effective on symptom management in cancer. However, more robust methodologies are needed. The methodological requirements of randomized controlled trials are challenging, and more informative results may be provided by more pragmatic study design.


[Educational nutritional intervention as an effective tool for changing eating habits and body weight among those who practice physical activities].
The scope of this study was to evaluate the effectiveness of two methods of educational nutritional intervention together with women who practice regular physical activities by fostering the adoption of healthy eating habits. The study population consisted of 52 women aged between 19 and 59 who frequented the Academia da Cidade Program in Aracaju in the State of Sergipe. The study was a randomized comparison of two intervention groups and was of the pre-test/post-test variety. The educational activities were based on two protocols - one less intensive (P1 Group) and one more intensive (P2 Group) - over a period of two months. The variables analyzed were nutritional knowledge, anthropometric measurements and changes in eating habits. The changes identified were improvement in eating habits and reduction in weight and Body Mass Index for the P2 group. The modifications identified referred mainly to increased consumption of fruit and vegetables, reduction of fat in cooking, reduction in the volume of food eaten per meal and increased meal frequency. In relation to nutritional knowledge, only 2 of the 12 questions showed significant changes. The most intensive method proved effective in changing dietary habits leading to weight loss.


The immunologic Warburg effect: Evidence and therapeutic opportunities in autoimmunity.
Pro-inflammatory signals induce metabolic reprogramming in innate and adaptive immune cells of both myeloid and lymphoid lineage, characterized by a shift to aerobic glycolysis akin to the Warburg effect first described in cancer. Blocking the switch to aerobic glycolysis impairs the survival, differentiation, and effector functions of pro-inflammatory cell types while favoring anti-inflammatory and regulatory phenotypes. Glycolytic reprogramming may therefore represent a selective vulnerability of inflammatory immune cells, providing an opportunity to modulate immune responses in autoimmune disease without broad toxicity in other tissues of the body. The mechanisms by which aerobic glycolysis and the balance between glycolysis and oxidative phosphorylation regulate immune responses have only begun to be understood, with many additional insights expected in the years to come. Immunometabolic therapies targeting aerobic glycolysis include both pharmacologic inhibitors of key enzymes and glucose-restricted diets, such as the ketogenic diet. Animal studies support a role for these pharmacologic and dietary therapies for the treatment of autoimmune diseases, and in a few cases proof of concept has been demonstrated in human disease. Nonetheless, much more work is needed to establish the clinical safety and efficacy of these treatments. This article is categorized under: Biological Mechanisms > Metabolism Translational, Genomic, and Systems Medicine > Translational Medicine Biological Mechanisms > Cell Signaling.


Non-HLA-antibodies targeting Angiotensin type 1 receptor and antibody mediated rejection.
Antibody-mediated mechanisms directed against non-HLA related targets may exert negative impact on allograft function and survival. Angiotensin type 1 receptor (AT(1)R) emerges as a functional target for non-HLA allo- and autoantibodies (AT(1)R-Abs) comprising of IgG1 and IgG3 subclasses. Proof of concept for pathophysiologic relevance of AT(1)R-Abs in antibody mediated rejection (AMR) in renal transplants was provided by passive transfer studies in animal model and therapeutic rescue of patients. Although AT(1)R-Abs may belong to complement fixing IgG subclasses, C4d positivity in renal transplant biopsies was not frequently detected implicating complement independent mechanisms of injury. AT(1)R-Abs exert direct effects on endothelial and vascular smooth muscle cells by induction of Erk1/2 signaling and increased DNA binding of transcription factors associated with pro-inflammatory and pro-coagulatory responses. Establishment of enzyme-linked immunosorbent assay employing extracts of cells overexpressing AT(1)R in its native conformation was instrumental for recent studies in independent cohorts. Assessing the AT(1)R-Ab-status along with the HLA-antibodies may help to identify patients at particular risk for irreversible acute or chronic allograft injuries and improve overall outcomes. This review summarizes the current state of research in AT(1)R biology, development in diagnostic strategies, discusses recent clinical studies, and provides perspectives on further refinements in understanding AT(1)R-Ab-actions.


GLP-1 based therapeutics: simultaneously combating T2DM and obesity.
Glucagon-like peptide-1 (GLP-1) enhances meal-related insulin secretion, which lowers blood glucose excursions. In addition to its incretin action, GLP-1 acts on the GLP-1 receptor (GLP-1R) in the brain to suppress feeding. These combined actions of GLP-1R signaling cause improvements in glycemic control as well as weight loss in type II diabetes (T2DM) patients treated with GLP-1R agonists. This is a superior advantage of GLP-1R pharmaceuticals as many other drugs used to treat T2DM are weight neutral or actual cause weight gain. This review summarizes GLP-1R action on energy and glucose metabolism, the effectiveness of current GLP-1R agonists on weight loss in T2DM patients, as well as GLP-1R combination therapies.


Targeting MPS1 Enhances Radiosensitization of Human Glioblastoma by Modulating DNA Repair Proteins.
To ensure faithful chromosome segregation, cells use the spindle assembly checkpoint (SAC), which can be activated in aneuploid cancer cells. Targeting the components of SAC machinery required for the growth of aneuploid cells may offer a cancer cell-specific therapeutic approach. In this study, the effects of inhibiting Monopolar spindle 1, MPS1 (TTK), an essential SAC kinase, on the radiosensitization of glioblastoma (GBM) cells were analyzed. Clonogenic survival was used to determine the effects of the MPS1 inhibitor NMS-P715 on radiosensitivity in multiple model systems, including GBM cell lines, a normal astrocyte, and a normal fibroblast cell line. DNA double-strand breaks (DSB) were evaluated using γH2AX foci, and cell death was measured by mitotic catastrophe evaluation. Transcriptome analysis was performed via unbiased microarray expression profiling. Tumor xenografts grown from GBM cells were used in tumor growth delay studies. Inhibition of MPS1 activity resulted in reduced GBM cell proliferation. Furthermore, NMS-P715 enhanced the radiosensitivity of GBM cells by decreased repair of DSBs and induction of postradiation mitotic catastrophe. NMS-P715 in combination with fractionated doses of radiation significantly enhanced the tumor growth delay. Molecular profiling of MPS1-silenced GBM cells showed an altered expression of transcripts associated with DNA damage, repair, and replication, including the DNA-dependent protein kinase (PRKDC/DNAPK). Next, inhibition of MPS1 blocked two important DNA repair pathways. In conclusion, these results not only highlight a role for MPS1 kinase in DNA repair and as prognostic marker but also indicate it as a viable option in glioblastoma therapy. Inhibition of MPS1 kinase in combination with radiation represents a promising new approach for glioblastoma and for other cancer therapies.


Coma due to malplaced external ventricular drain.
Ventriculostomy or external ventricular drain (EVD) placement by free-hand technique has a high malplacement rate. It is a blind procedure that often requires multiple attempts and revisions. To date, no neurological complication due to EVD malplacement has been reported in the literature. In this report, we present the first case of coma induced by a malplaced EVD and the patient regained consciousness after the drain was adjusted. Our discussion focused on various techniques that can improve the accuracy of EVD insertion. EVD insertion under image guidance provides better accuracy with limited disadvantages. We hypothesized that the patient's coma was due to the mass effect and irritation of the malplaced EVD exerted onto the ventral periaqueductal grey matter and the ascending neurons from upper brainstem.


Negligible effect of ions on the hydrogen-bond structure in liquid water.
The effects of ions on bulk properties of liquid water, such as viscosity, have suggested that ions alter water's hydrogen-bonding network. We measured the orientational correlation time of water molecules in Mg(ClO4)2, NaClO4, and Na2SO4 solutions by means of femtosecond pump-probe spectroscopy. The addition of ions had no influence on the rotational dynamics of water molecules outside the first solvation shells of the ions. This result shows that the presence of ions does not lead to an enhancement or a breakdown of the hydrogen-bond network in liquid water.


Chimpanzee-red colobus encounter rates show a red colobus population decline associated with predation by chimpanzees at Ngogo.
Chimpanzees (Pan troglodytes) hunt various primates, but concentrate on red colobus monkeys (Piliocolobus spp.) wherever the two species are sympatric. The extraordinarily large Ngogo chimpanzee community in Kibale National Park, Uganda, preys heavily on the local population of red colobus (P. tephrosceles). Census data showed a steep decline in this population in the center of the chimpanzees' home range between 1975 and 2007 [Lwanga et al., 2011; Teelen, 2007b]. Given no obvious change in food availability, predation by chimpanzees was the most likely cause [ibid.; Teelen, 2008]. However, census data from other parts of the home range raised the possibility that the decline was restricted to this central area [Teelen, 2007a] We present data from 1998 to 2012 on the rate of encounters between chimpanzees and red colobus that provide a chimpanzee-centered estimate of red colobus density, thus of predation opportunities, throughout the home range. These corroborate census data by showing a long-term decline in encounters near the center. They also show that encounters become relatively more common at increasing distances from the center, but encounter rates have decreased even in peripheral areas and, by implication, the red colobus population has declined throughout the study area. These data corroborate Teelen's [2008] conclusion that chimpanzee predation on red colobus during the 1990s and early 2000s was unsustainable. Hunting rates and prey offtake rates have also declined markedly; whether this will allow the red colobus population to recover is unknown. In contrast, rates at which chimpanzees encountered redtail monkeys (Cercopithecus ascanius) and grey-cheeked mangabeys (Lophocebus albigena) did not decrease. Neither did they increase, however, contrary to long-term census data from the center of the study area [Lwanga et al., 2011].


Organ-Specific Toxicities Due to Radiation Therapy in Cancer Patients With or Without HIV Infection: A Systematic Review of the Literature.
Background: To synthesize published literature on the association between human immunodeficiency virus (HIV) infection and radiation therapy (RT)-related toxicities. Methods: Two electronic databases, MEDLINE and Embase, were searched to identify studies published before November 2016 comparing RT-related toxicities between HIV-infected and HIV-uninfected patients receiving RT or chemoradiation therapy (CRT) for cancer. A qualitative synthesis of included articles and organ-specific toxicities was then performed. Results: Of the 21 studies included in this review, 15 reported on anal cancer treatment, three on cervical cancer, two on Kaposi sarcoma, and one on prostate cancer. Reports in the pre-antiretroviral therapy (ART) or early ART era tended to identify increased morbidity and mortality with HIV infection. However, modern series incorporating more concurrent chemotherapy, conformal RT techniques, and ART administration result in fewer studies reporting toxicity differences in patients treated for anal and cervical cancers. When statistically significant, HIV-infected patients had higher rates of gastrointestinal toxicity with anal cancer CRT (up to 50%) and higher rates of hematologic toxicity with cervical cancer CRT (up to 31%). Of the 17 studies reporting treatment outcomes, nine suggest HIV-infected patients may have reduced local control and/or survival rates. Conclusions: Overall, RT is likely similarly tolerated between HIV-infected and HIV-uninfected patients, especially with modern RT techniques. HIV-infected patients should continue to receive established standard of care RT and CRT dosing.


Compromised frontocerebellar circuitry contributes to nonplanning impulsivity in recovering alcoholics.
Degradation of frontocerebellar circuitry is a principal neural mechanism of alcoholism-related executive dysfunctions affecting impulse control and cognitive planning. We tested the hypothesis that alcoholic patients would demonstrate compromised dorsal anterior cingulate cortex (dACC) -cerebellar functional connectivity when adjusting their strategies to accommodate uncertain conditions and would recruit compensatory brain regions to overcome ineffective response patterns. Twenty-six alcoholics and 26 healthy participants underwent functional MRI in two sequential runs while performing a decision-making task. The first run required a response regardless of level of ambiguity of the stimuli; the second run allowed a PASS option (i.e., no response choice), which was useful on ambiguous trials. Healthy controls demonstrated strong synchronous activity between the dACC and cerebellum while planning and executing a behavioral strategy. By contrast, alcoholics showed synchronous activity between the dACC and the premotor cortex, perhaps enabling successful compensation for accuracy and reaction time in certain conditions; however, a negative outcome of this strategy was rigidity in modifying response strategy to accommodate uncertain conditions. Compared with the alcoholic group, the control group had lower nonplanning impulsiveness, which correlated with using the option PASS to respond in uncertain conditions. These findings suggest that compromised dACC-cerebellar functional circuitry contributes to recruitment of an alternative network-dACC-premotor cortex- to perform well under low-risk, unambiguous conditions. This compensatory network, however, was inadequate to enable the alcoholics to avert making poor choices in planning and executing an effective behavioral strategy in high-risk, uncertain conditions.


Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice.
HER2 overexpression and/or amplification have been reported in endometrial serous carcinoma, suggesting that HER2 may be a promising therapeutic target. However, there is considerable variation in the reported rates of HER2 overexpression and amplification, likely--at least in part--resulting from variability in the testing methods, interpretation, and scoring criteria used. Unlike in breast and gastric cancer, currently there are no established guidelines for HER2 testing in endometrial carcinoma. A total of 108 endometrial carcinoma cases--85 pure serous carcinomas and 23 mixed endometrial carcinomas with serous component--were identified over a 4-year period. All H&E and HER2 immunohistochemical slides were reviewed and HER2 FISH results (available on 52 cases) were retrieved from pathology reports. HER2 immunohistochemical scores were assigned according to the FDA criteria and the current breast ASCO/CAP scoring criteria. Clinical information was retrieved from the patients' medical records. Thirty-eight cases (35%) showed HER2 overexpression and/or gene amplification, 20 of which (53%) had significant heterogeneity of protein expression by immunohistochemistry. Lack of apical membrane staining resulting in a lateral/basolateral staining pattern was observed in the majority of HER2-positive tumors. Five of the HER2-positive cases (13%) demonstrated discrepant immunohistochemical scores when using the FDA versus ASCO/CAP scoring system. The overall concordance rate between HER2 immunohistochemistry and FISH was 75% (39/52) when using the FDA criteria, compared with 81% (42/52) by the ASCO/CAP scoring system. In conclusion, in this largest comprehensive study, 35% of endometrial serous carcinoma harbors HER2 protein overexpression and/or gene amplification, over half of which demonstrate significant heterogeneity of protein expression. The current breast ASCO/CAP scoring criteria provide the highest concordance between immunohistochemistry and FISH. Assessment of HER2 immunohistochemistry on multiple tumor sections or sections with large tumor areas is recommended, due to the significant heterogeneity of HER2 protein expression.


RNA-interference-directed chromatin modification coupled to RNA polymerase II transcription.
RNA interference (RNAi) acts on long double-stranded RNAs (dsRNAs) in a variety of eukaryotes to generate small interfering RNAs that target homologous messenger RNA, resulting in their destruction. This process is widely used to 'knock-down' the expression of genes of interest to explore phenotypes. In plants, fission yeast, ciliates, flies and mammalian cells, short interfering RNAs (siRNAs) also induce DNA or chromatin modifications at the homologous genomic locus, which can result in transcriptional silencing or sequence elimination. siRNAs may direct DNA or chromatin modification by siRNA-DNA interactions at the homologous locus. Alternatively, they may act by interactions between siRNA and nascent transcript. Here we show that in fission yeast (Schizosaccharomyces pombe), chromatin modifications are only directed by RNAi if the homologous DNA sequences are transcribed. Furthermore, transcription by exogenous T7 polymerase is not sufficient. Ago1, a component of the RNAi effector RISC/RITS complex, associates with target transcripts and RNA polymerase II. Truncation of the regulatory carboxy-terminal domain (CTD) of RNA pol II disrupts transcriptional silencing, indicating that, like other RNA processing events, RNAi-directed chromatin modification is coupled to transcription.


The DNA helicase activity of BLM is necessary for the correction of the genomic instability of bloom syndrome cells.
Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by growth deficiency, immunodeficiency, genomic instability, and the early development of cancers of many types. BLM, the protein encoded by BLM, the gene mutated in BS, is localized in nuclear foci and absent from BS cells. BLM encodes a DNA helicase, and proteins from three missense alleles lack displacement activity. BLM transfected into BS cells reduces the frequency of sister chromatid exchanges and restores BLM in the nucleus. Missense alleles fail to reduce the sister chromatid exchanges in transfected BS cells or restore the normal nuclear pattern. BLM complements a phenotype of a Saccharomyces cerevisiae sgs1 top3 strain, and the missense alleles do not. This work demonstrates the importance of the enzymatic activity of BLM for its function and nuclear localization pattern.


Addition of Androgens Improves Survival in Elderly Patients With Acute Myeloid Leukemia: A GOELAMS Study.
Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m2 on days 1 to 5, cytarabine 100 mg/m2 on days 1 to 7, and lomustine 200 mg/m2 on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m2 on day 1, cytarabine 100 mg/m2 on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 109/L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.


Densitometry in glucocorticoid-induced osteoporosis.
The technique of choice for the measurement of bone mineral density (BMD) in patients with glucocorticoid-induced osteoporosis (GIOP) is dual X-ray absorptiometry (DXA), which has been demonstrated to be reliable in diagnosing osteoporosis and monitoring bone mass variations over time in GIOP. However, in patients with both exogenous (i.e. due to glucocorticoid therapy) and endogenous cortisol excess, the BMD decrease does not fully explain the high risk of fractures. Therefore, the BMD thresholds in guidelines for the prevention of GC-related fractures are different and debated. Quantitative computed tomography (QCT), which is useful to separately study cortical and trabecular bone and to measure true "volumetric" BMD, has been suggested to be a better predictor of vertebral fractures than DXA. However, QCT has the limit of the possible underestimation of bone mass and QCT T-scores may be lower as compared to DXA T-score values for the same skeletal site. Quantitative ultrasound, which is considered to reflect both BMD and structural properties of bone such as connectivity and elasticity, is able to diagnose low BMD in GIOP, but its role in monitoring BMD changes and in predicting fracture's risk remains unknown. Low BMD and high rate of bone loss have been suggested to be possible complications even of subclinical hypercortisolism regardless for gender and gonadal status. On the other hand, low BMD and vertebral fractures may be the initial presentation of an otherwise asymptomatic cortisol excess.


The relative importance of suboperations of prospective memory.
An event-based and a time-based prospective memory (PM) task, a script generation task, several working memory tasks, an incidental retrospective memory task, and a screen clock were implemented on the computer in one integrated procedure lasting between one and two hours. The procedure was designed to simulate four working days and four nights for a white-collar employee. Sixty-eight normal participants completed the task. Time-based prospective memory (self-injecting and going to bed at preordained times of day) shared unique variance with clock checking, but hardly at all with incidental retrospective memory. On the other hand, event-based prospective memory (answering a faint telephone cue as quickly as possible) shared unique variance with incidental retrospective memory of formally task irrelevant context and less with clock checking. The latter correlational dissociation of event-based versus time-based PM by retrospective memory reached significance, inspiring the idea that administrative versus clerical work might each impose its own type of PM demands. In both types of PM, low-level abilities (use of external aids and incidental encoding of context, respectively) seem to be critical for good performance, more so than for high-order executive functions. Our software is offered to the readership to explicitate these findings further or for other research pursuits.


Structure-activity studies of fluoroalkyl-substituted gamma-butyrolactone and gamma-thiobutyrolactone modulators of GABA(A) receptor function.
Dihydro-2(3H)-furanones (gamma-butyrolactones) and dihydro-2(3H)-thiophenones (gamma-thiobutyrolactones) containing fluoroalkyl groups at positions C-3, C-4, and C-5 of the heterocyclic rings were prepared. The anticonvulsant/convulsant activities of the compounds were evaluated in mice. Brain concentrations of the compounds were determined and the effects of the compounds on [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) binding to the picrotoxin site on GABAA receptors were investigated. The effects of the compounds on GABAA receptor function were studied using electrophysiological methods and cultured rat hippocampal neurons. Fluorination at C-3 results in either subtle or pronounced effects on the pharmacological activity of the compounds. When hydrogens are replaced with fluorines at the methylene carbon of an ethyl group, as in 3-(1,1-difluoroethyl)dihydro-3-methyl-2(3H)-furanone (1), the anticonvulsant actions of the compound are not much changed from those found for the corresponding alkyl-substituted analogue. In marked contrast, fluorination at the methyl carbon of the ethyl group, as in dihydro-3-methyl-3-(2,2,2-trifluoroethyl)-2(3H)-furanone (3), produces a compound having convulsant activity. This convulsant activity seems to be due to an increased affinity of the compound for the picrotoxin site on GABAA receptors caused by an interaction that involves the trifluoromethyl group. Results obtained with gamma-butyrolactones containing either a 3-(1-trifluoromethyl)ethyl or a 3-(1-methyl-1-trifluoromethyl)ethyl substituent indicate that the interactions of the trifluoromethyl group with the picrotoxin binding site are subject to both stereochemical and steric constraints. Sulfur for oxygen heteroatom substitution, as in the corresponding gamma-thiobutyrolactones, affects the type (competitive, non-competitive, etc.) of binding interactions that these compounds have with the picrotoxin site in a complex manner. Fluorination of alkyl groups at the C-4 and C-5 positions of gamma-butyrolactones having convulsant activity increases convulsant potency.


The treatment of the asthmatic mother during pregnancy and lactation.
In summary, the management of asthma in the pregnant patient does not differ much from the management of asthma in a patient who is not pregnant. An awareness of how asthma medications affect the fetus is important since it is rare to reach the ideal management where no medication at all is given. The benefit to risk ratio must be considered for both mother and her fetus should be medication be required. Since hypoxemia is the greatest single danger to both the mother and fetus important medications should not be withheld and the physician should not wait too long. The mother should be counseled about avoiding medications that include tetracycline, iodine products, aspirin or non-steroidal anti-inflammatory agents, tartrazine, sedatives, and beta-adrenergic blocking agents. It is just as important to remember that alcohol and cigarettes are potent drugs or interact with other medications. Inapropriate exercise, irritants or allergens might also require counseling so that the pregnant mother can avoid them. A good common sense and caring approach of a physician to a well informed patient represents the most appropriate management of asthma in the pregnant patient and nursing mother.


An ultrastructural investigation of afferent connections of the red nucleus in the rat.
The pattern and mode of termination of afferents to the red nucleus of the rat were investigated with the electron microscope. Lesions were placed by electrocautery in the sensorimotor cortex or were placed electrolytically in the deep cerebellar nuclei and brachium conjunctivum using a stereotaxic approach. With both types of lesion, degenerating fibres of passage, preterminal axons, and synaptic terminals were observed in greatest numbers on the third post-operative day. Following cerebellar lesions, degenerating terminals occurred on the cell bodies and proximal dendrites of large, multipolar neurons in the magnocellular portion of the red nucleus, and on intermediate and small dendrites in the parvocellular portion. It is concluded that the former are interpositus terminals while the latter are dentate (lateralis) terminals ending on rubrospinal and rubrobulbar neurons respectively. Following lesions of the sensorimotor cortex, small degenerating terminals were observed on the distal dendrites and dendritic spines of parvocellular, rubrobulbar neurons. Large terminals containing round vesicles did not undergo degeneration following either type of lesion. These findings suggest the existence of an interpositorubro-spinal pathway in which the interpositus terminals exert a strong influence on the large, caudally placed rubrospinal neurons. The background excitability of the rostrally located rubrobulbar neurons is probably regulated by the distal cortical input while the more proximally located dentate terminals probably exert a stronger discrete influence over their activity.


Effects of triiodothyronine administration on the adenylyl cyclase system in brown adipose tissue of rat.
This study was undertaken to investigate the effect of triiodothyronine (T3) administration to euthyroid rats on beta 3-adrenoceptor (beta 3-AR) expression and on the different components of the adenylyl cyclase (AC) system in brown adipose tissue (BAT). In rats treated with T3, the beta 3-AR density (assessed by the binding of [3H]CGP-12177) showed a decrease of 50%, as did their mRNA, as analyzed by reverse transcriptase-polymerase chain reaction. In hyperthyroid rats, compared with control rats, there was a 40% increase in G alpha s activity (stimulated by NaF or GTP gamma S) and a fourfold increase in the protein concentration (Western blotting). In contrast, the level of the pertussis toxin substrate Gi declined by 35% in response to T3. Analysis of dose-response curves for isoproterenol and CGP-12177 revealed that neither basal nor stimulated AC activities nor 50% stimulatory concentration for these agonists was changed by T3 administration. In conclusion, these results suggest that downregulation of the beta 3-AR by T3 was counter-balanced by changes in other components of the AC cascade (i.e., Gs and Gi), so no change occurred in the capacity of BAT to generate adenosine 3',5'-cyclic monophosphate.


Automated CT perfusion analysis reveals medial temporal perfusion abnormalities during transient global amnesia.
The underlying pathophysiology of Transient global amnesia (TGA) remains elusive. Reports of perfusion abnormalities in TGA were inconsistent, but semi-automated analysis of perfusion CT (CTP) may improve reliability and precision of perfusion deficit detection. Per institutional protocol, all TGA patients undergo multiphasic contrast-CT with arch to vertex CT angiography, intracranial CT venography, MRI, and EEG upon admission. During the study period consecutive patients diagnosed with TGA underwent CTP during the early acute amnestic phase. We retrospectively reviewed the clinical and radiological findings. Five patients (3 female. median age 71, range 47-74) fulfilled entry criteria. Automated CTP analysis revealed the absence of an ischemic core (defined by CBF < 30%) or conventionally defined clinically relevant hypoperfusion area (defined by Time-to-maximum (Tmax) >6 s) in any of the patients. However, four of the five patients demonstrated territories of benign oligemia defined as Tmax>4 s in areas supplied by the Posterior Cerebral Artery. Three of these four patients had clear involvement of the bilateral medial temporal lobes. None of the patients had epileptic activity on their EEG. Both CTA and MRI were normal apart for small foci of restricted diffusion in the hippocampus of four patients. Deficits in perfusion were found in the hippocampi of 60% of patients in the acute phase of TGA using automated image analysis software. This method may provide a quick and simple method to detect these abnormalities. These perfusion abnormalities could help solidify the diagnosis at an early stage and may advance our understanding of this elusive syndrome.


Regional ion channel gene expression heterogeneity and ventricular fibrillation dynamics in human hearts.
Structural differences between ventricular regions may not be the sole determinant of local ventricular fibrillation (VF) dynamics and molecular remodeling may play a role. To define regional ion channel expression in myopathic hearts compared to normal hearts, and correlate expression to regional VF dynamics. High throughput real-time RT-PCR was used to quantify the expression patterns of 84 ion-channel, calcium cycling, connexin and related gene transcripts from sites in the LV, septum, and RV in 8 patients undergoing transplantation. An additional eight non-diseased donor human hearts served as controls. To relate local ion channel expression change to VF dynamics localized VF mapping was performed on the explanted myopathic hearts right adjacent to sampled regions. Compared to non-diseased ventricles, significant differences (p<0.05) were identified in the expression of 23 genes in the myopathic LV and 32 genes in the myopathic RV. Within the myopathic hearts significant regional (LV vs septum vs RV) expression differences were observed for 13 subunits: Nav1.1, Cx43, Ca3.1, Cavα2δ2, Cavβ2, HCN2, Na/K ATPase-1, CASQ1, CASQ2, RYR2, Kir2.3, Kir3.4, SUR2 (p<0.05). In a subset of genes we demonstrated differences in protein expression between control and myopathic hearts, which were concordant with the mRNA expression profiles for these genes. Variability in the expression of Cx43, hERG, Na(+)/K(+) ATPase ß1 and Kir2.1 correlated to variability in local VF dynamics (p<0.001). To better understand the contribution of multiple ion channel changes on VF frequency, simulations of a human myocyte model were conducted. These simulations demonstrated the complex nature by which VF dynamics are regulated when multi-channel changes are occurring simultaneously, compared to known linear relationships. Ion channel expression profile in myopathic human hearts is significantly altered compared to normal hearts. Multi-channel ion changes influence VF dynamic in a complex manner not predicted by known single channel linear relationships.


Multi-exposure diffraction pattern fusion applied to enable wider-angle transmission Kikuchi diffraction with direct electron detectors.
Diffraction pattern analysis can be used to reveal the crystalline structure of materials, and this information is used to nano- and micro-structure of advanced engineering materials that enable modern life. For nano-structured materials typically diffraction pattern analysis is performed in the transmission electron microscope (TEM) and TEM diffraction patterns typically have a limited angular range (less than a few degrees) due to the long camera length, and this requires analysis of multiple patterns to probe a unit cell. As a different approach, wide angle Kikuchi patterns can be captured using an on-axis detector in the scanning electron microscope (SEM) with a shorter camera length. These 'transmission Kikuchi diffraction' (TKD) patterns present a direct projection of the unit cell and can be routinely analysed using EBSD-based methods and dynamical diffraction theory. In the present work, we enhance this analysis significantly and present a multi-exposure diffraction pattern fusion method that increases the dynamic range of the detected patterns captured with a Timepix3-based direct electron detector (DED). This method uses an easy-to-apply exposure fusion routine to collect data and extend the dynamic range, as well as normalise the intensity distribution within these very wide (>95°) angle patterns. The potential of this method is demonstrated with full diffraction sphere reprojection and highlight potential of the approach to rapidly probe the structure of nano-structured materials in the scanning electron microscope.


Extracting fuzzy control rules from experimental human operator data.
This paper proposes an approach where the interpretation of manual control strategies is carried out by modeling the human operator as a fuzzy logic controller. The linguistic rules thus obtained can provide a better insight into the operator's actions, allowing mistakes to be more easily pinpointed and corrected. Instead of extracting the control rules directly from raw experimental data, an intermediary ARMA model for the operator is employed to improve the data consistency. For illustration, this method is applied to the problem of supervising an apprentice operator, with basis on rules extracted from the actions of an experienced manual operator.


Clinical Comparison of High-resolution and Standard Refractions and Prescriptions.
Recently, novel refraction technology allows subjective refractions to be performed with a higher-resolution. It is unclear, however, if these benefits are noticed and appreciated by the patient during the examination and after dispensing. This study investigated benefits and drawbacks of high-resolution refraction technology over standard, specifically in terms of the refraction, glasses prescription, and participant's perceptions of the technology. Sixty progressive-addition-lens wearers (aged 35 to 70 years) and 60 single-vision wearers (18 years or older) were randomized to a high-resolution refraction (Vision-R 800; Essilor Instruments, Dallas, TX; essilorinstrumentsusa.com ) and standard refraction in a 2-week crossover dispensing design. Refractive results were converted to M, J0, and J45 and analyzed using multivariate t tests. Bayesian estimation was used to analyze differences between refraction type and age group for subjective outcomes. Differences in refractive error between the two refractions were small, and none differed statistically ( P > .05) or clinically (e.g., <0.25 D) in either subgroup. Visual acuities at distance and near were better than 0.00 logMAR; none of the mean differences between the refractions reached statistical or clinical (e.g., <0.10 D) significance. Participants significantly preferred the high-resolution refraction for its quickness and efficiency, improved comfort, and less stress. Bayesian analysis indicated a 76% probability that participants had higher confidence in the high-resolution refraction, 93% probability that they would seek it out for their care, and 94% probability that they would recommend an optometrist using this technology. Refractive and acuity endpoints were similar with the high-resolution and standard refraction. Participants, however, perceived several key benefits of the high-resolution refraction and prescription for their care, the care of their friends/family, and the practice itself.


Near-perfect elastoplasticity in pure nanocrystalline copper.
Ductile metals and alloys undergo plastic yielding at room temperature, during which they exhibit work-hardening and the generation of surface instabilities that lead to necking and failure. We show that pure nanocrystalline copper behaves differently, displaying near-perfect elastoplastic behavior characterized by Newtonian flow and the absence of both work-hardening and neck formation. We observed this behavior in tensile tests on fully dense large-scale bulk nanocrystalline samples. The experimental results further our understanding of the unique mechanical properties of nanocrystalline materials and also provide a basis for commercial technologies for the plastic (and superplastic) formation of such materials.


Quantification of Cervical Cord Cross-Sectional Area: Which Acquisition, Vertebra Level, and Analysis Software? A Multicenter Repeatability Study on a Traveling Healthy Volunteer.
Background: Considerable spinal cord (SC) atrophy occurs in multiple sclerosis (MS). While MRI-based techniques for SC cross-sectional area (CSA) quantification have improved over time, there is no common agreement on whether to measure at single vertebral levels or across larger regions and whether upper SC CSA can be reliably measured from brain images. Aim: To compare in a multicenter setting three CSA measurement methods in terms of repeatability at different anatomical levels. To analyze the agreement between measurements performed on the cervical cord and on brain MRI. Method: One healthy volunteer was scanned three times on the same day in six sites (three scanner vendors) using a 3T MRI protocol including sagittal 3D T1-weighted imaging of the brain (covering the upper cervical cord) and of the SC. Images were analyzed using two semiautomated methods [NeuroQLab (NQL) and the Active Surface Model (ASM)] and the fully automated Spinal Cord Toolbox (SCT) on different vertebral levels (C1-C2; C2/3) on SC and brain images and the entire cervical cord (C1-C7) on SC images only. Results: CSA estimates were significantly smaller using SCT compared to NQL and ASM (p < 0.001), regardless of the cord level. Inter-scanner repeatability was best in C1-C7: coefficients of variation for NQL, ASM, and SCT: 0.4, 0.6, and 1.0%, respectively. CSAs estimated in brain MRI were slightly lower than in SC MRI (all p ≤ 0.006 at the C1-C2 level). Despite protocol harmonization between the centers with regard to image resolution and use of high-contrast 3D T1-weighted sequences, the variability of CSA was partly scanner dependent probably due to differences in scanner geometry, coil design, and details of the MRI parameter settings. Conclusion: For CSA quantification, dedicated isotropic SC MRI should be acquired, which yielded best repeatability in the entire cervical cord. In the upper part of the cervical cord, use of brain MRI scans entailed only a minor loss of CSA repeatability compared to SC MRI. Due to systematic differences between scanners and the CSA quantification software, both should be kept constant within a study. The MRI dataset of this study is available publicly to test new analysis approaches.


Pharmacological characterization of alpha-adrenoreceptor subtypes in rat isolated thoracic aorta.
The subtype of alpha-adrenoreceptor mediating contraction in rat isolated thoracic aorta was classified pharmacologically using preferential agonists and antagonists, and by utilizing mixed agonist and antagonist interactions. Noradrenaline was 8 to 10-times more potent at contracting the aorta than phenylephrine and both agonists were about 1000 and 10,000-fold respectively more potent than azepexole (a preferential alpha 2-agonist). Prazosin (a preferential alpha 1-antagonist) inhibited the dose-response curves to noradrenaline and phenylephrine 100 and 1000-times respectively more effectively than either phentolamine or rauwolscine (a preferential alpha 2-antagonist). Furthermore, prazosin (5 x 10(-9) M) completely abolished contractions elicited by a single concentration of azepexole (3 x 10(-4) M). In mixed antagonist studies, rauwolscine (5 x 10(-7) M) failed to shift the dose-response curves to noradrenaline and phenylephrine obtained in the presence of prazosin (5 x 10(-9) M). In mixed agonist experiments, azepexole (3 x 10(-4) M) acted as a partial antagonist toward phenylephrine-induced contractions. The results suggest that the alpha-adrenoreceptor of the rat thoracic aorta is predominantly, if not exclusively, of the alpha 1-subtype.


Low Oxygen Storage Improves Tomato Postharvest Cold Tolerance, Especially for Tomatoes Cultivated with Far-Red LED Light.
We investigated the effects of low oxygen storage on chilling injury development, colour development, respiration and H2O2 levels of 'Merlice' tomatoes cultivated with and without far red (FR) LED lighting during 20 days of shelf-life. Mature green (MG) and red (R) tomatoes were stored at 2 °C in combination with 0.5, 2.5, 5 and 21 kPa O2 for 15 days (experiment 1). MG tomatoes cultivated under either white LED or white LED light with FR LED light were stored at 2 °C in combination with 1, 5 and 21 O2 kPa for 14 days (experiment 2). Chilled MG and R tomatoes from experiment 1 showed decay, firmness loss and higher weight loss during shelf-life which were reduced under low oxygen conditions. FR during cultivation improved chilling tolerance of MG tomatoes. Fastest colour development and lowest respiration rate during shelf-life were observed for MG fruit cultivated with FR lighting prior to storage at 1 kPa O2/0 kPa CO2. H2O2 levels during the shelf-life were not affected during cold storage. The improved cold tolerance of MG tomatoes cultivated with FR lighting is likely due to lower oxygen uptake that led to both higher lycopene synthesis and less softening.


[Endovascular laser irradiation of blood in the comprehensive treatment of stomach cancer].
The data on the treatment of 35 patients with gastric cancer (two groups) are presented. In group I, surgery and chemotherapy were given; in group II--intravenous helium-neon laser therapy as a component of complex treatment. Dynamic changes in hematological and immunological indices were investigated. The immunological and hemopoietic indices improved after laser therapy.


In vitro activity of mecillinam and nitroxoline against Neisseria gonorrhoeae - re-purposing old antibiotics in the multi-drug resistance era.
In 2018, the European Centre for Disease Prevention and Control reported the first cases of extensively drug-resistant Neisseria gonorrhoeae infections in Europe. Seeking new options for antimicrobial therapy we investigated the susceptibility of N. gonorrhoeae to nitroxoline (NIT) and mecillinam (MCM), both of which are currently only indicated to treat uncomplicated urinary tract infections. Clinical N. gonorrhoeae isolates with non-susceptibility to penicillin from two German medical centres were included (n =27). Most isolates were also non-susceptible to a range of other anti-gonococcal antimicrobials (cefotaxime, ciprofloxacin, azithromycin, tetracycline). All isolates were further characterized by multi-locus sequence typing. MICs of penicillin and cefotaxime were determined by agar gradient diffusion. Production of penicillinase was tested by cefinase disk test. Susceptibility of MCM was investigated by agar dilution, NIT by agar dilution and disk diffusion. Penicillin MICs ranged from 0.125 to 64 mg l-1 and MICs of cefotaxime ranged from < 0.016 to 1 mg l-1 . Five isolates were penicillinase-producers. MICs of MCM ranged from 16 to > 128 mg l-1 whereas MICs of NIT ranged from 0.125 to 2 mg l-1 . NIT disk diffusion (median zone diameter 32 mm) correlated well with results from agar dilution. We demonstrated excellent in vitro activity of NIT against clinical N. gonorrhoeae isolates with non-susceptibility to standard anti-gonococcal antibiotics. MCM activity was unsatisfactory. Correlation of agar dilution and disk diffusion in NIT susceptibility testing is an important aspect with potential clinical implications.


Transpericardial 3D Echocardiography in the Sheep Model, Facilitating Real Time Anatomical Assessment for Planning and Guiding Transcatheter Mitral Valve Replacement and Repair.
Symptomatic mitral regurgitation (MR) is associated with high morbidity and mortality which can be ameliorated by surgical valve replacement or repair. Despite this, many patients are excluded from surgery. Transcatheter mitral repair and replacement has emerged as a promising therapeutic option for the treatment of severe MR. The majority of these procedures rely on high definition three dimensional (3D) transesophageal echocardiographic (TEE) real time imaging. The sheep model is the model of choice for preclinical studies of transcatheter mitral valve (MV) replacement and repair. However due to the thoracic conformation TEE studies in those animals are suboptimal. In this study we tested and compared the feasibility of conventional TEE and newly described transpericardial 3D echocardiography (TPE) for assessment of the MV as a tool to plan and possibly guide transcatheter/transapical procedures in the sheep model. The conventional TEE was challenging and produced incomplete data in all of the animals. In contrast, the TPE method clearly depicted the left atria and ventricle, MV apparatus, LVOT, aortic valve and proximal ascending aorta facilitating high resolution 3D rendering in all of the animals. The value of TEE in the sheep model is limited and could not be reliable for complete assessment of the LV and mitral valve apparatus. Whereas, TPE produce reliable and similar imaging to TEE in the human patients which could allow animal testing of devices designed to be delivered in humans.


Emerging therapeutic targets for narcolepsy.
Narcolepsy type 1 (NT1) and type 2 (NT2) are chronic sleep disorders primarily characterized by excessive daytime sleepiness (EDS), disturbed sleep-wake regulation, and reduced quality of life. The precise disease mechanism is unclear, but it is certain that in NT1 the hypocretin/orexin (Hcrt) system is affected. Current treatment options are symptomatic - they improve EDS and/or reduce cataplexy. Complete symptom control is relatively rare - particularly problematic is residual daytime sleepiness. This review discusses various emerging treatment targets for narcolepsy. The focus is on the Hcrt receptors but included are also wake-promoting pathways, and sleep-stabilization through GABAergic mechanisms. Additionally, we discuss the potential of targeting the likely autoimmune basis of narcolepsy. PubMed and ClinicalTrials.gov was searched through June 2021 for relevant information. Targeting Hcrt receptors has the potential to alleviate narcolepsy symptoms. Results from ongoing drug development programs are promising, but care needs to be taken when evaluating potential side effects. It is still largely unknown what roles Hcrt receptors play in the periphery and how these might be affected by treatment. Immunotherapies could potentially target the core pathophysiology of narcolepsy, but more work is needed to identify the best therapeutic target for this approach.


Gender difference in body mass index in West New Britain Province, Papua New Guinea: A sub-analysis of a cross-sectional questionnaire study.
Globally, more women are likely to be obese than men, and the need for a gender-specific strategy concerning related health issues is important. Our study aimed to clarify gender difference related to obesity in Papua New Guinea by a sub-analysis of our previous questionnaire-based cross-sectional study. We used demographic and anthropometric data (body mass index) from a convenient sample of 558 community-dwelling healthy people (mean age 34.8 14.0 years, 48.2% women). To clarify gender differences, we conducted an unpaired t-test and Chi-square test between males and females. Obesity was twice as common in females than males (20.5% vs. 10.4%) and over half of the women had abnormal body mass index (51.3% vs. 39.1%) compared to their male counterparts.


[The modulatory role of neurokinins in affective behaviors].
Neurokinins (NK) are peptide molecules with modulatory actions on other neurotransmitter systems, notably the monoaminergic ones, within the central nervous system and peripheral tissues. A great deal of evidence supports a role for these substances, mainly for substance P and its main receptor NK1, in a number of physiologic and pathologic conditions, including affective and behavioral responses to stress. NK1 receptor antagonists have shown preclinical activity in several paradigms of anxiety and depression. Mutant mice lacking the NK1 receptor gene have an increased firing rate of dorsal raphe serotonergic neurons, an effect that can also be seen after the administration of substance P antagonists. When given chronically, NK1 antagonists promote an enhancement of serotonergic transmission in the hippocampus that seems to be mediated by interaction with other neurotransmission systems. Clinical efficacy of such drugs has also been demonstrated among patients with major depression, although the results have been inconclusive. More research is needed to elucidate the precise role these drugs could play in the treatment of affective disorders in the future.


[Neuroimmunoendocrinology of the fat tissue].
Recent information concerning the white fat tissue allows considering it as endocrine system involved in the neuro-immune-endocrine interactions in regulating various aspects of homeostasis. The contribution presented sums up the latest evidence of adipocyte secreting hormones (leptine and resistine), cytokine (TNF alpha), as well as shedlight on mechanisms, involved in control of energy metabolism, immune reactions and food intake monitoring.


Magnetic resonance imaging of the normal feline abdomen: an anatomic reference.
Magnetic resonance images of two adult domestic short-haired cats were obtained with a whole body scanner. Images of the abdomen were compared with cross-sectional anatomy cadaver specimens from the same two cats. Anatomic structures were first identified on the cadaver specimens with the aid of anatomy texts and references and were then identified and labeled on the magnetic resonance images. Results from this project provide an atlas of normal cross-sectional MRI anatomy of the feline abdomen.


[Some viral zoonoses transmitted by pets (author's transl)].
Besides dogs and cats, various other animals are more or less popular as pets in the Netherlands. It is importance to the veterinary practitioner to know which diseases may be transmitted to man by these animals. Of the viral zoonoses. rabies constitutes a menace to man, in which dogs and, to a less extent, cats supply a link between man and free-living wild animals. Another viral zoonosis in which interest was centered in recent years, is lymphocytic choriomeningitis (LCM) caused by a virus which often is latent in mice but which may also be detected in young hamsters. A human disease caused by a pathogenic agent which should not be classified with the viruses, is chlamydiosis (psittacosis, ornithosis), which disease is usually transmitted to man by psittacine birds or pigeons. Of the above disease, the pathogenic agents, the clinical pictures in man and animals, the mode of transmission and possible preventive and therapeutic measures are discussed. Finally, the risk of transmission of viral zoonoses by less current "pets" is stressed.


Characterization of recombinant Autographa californica nuclear polyhedrosis virus (NPV) expressing the beta-galactosidase gene in both Sf21 and Bm5 cells by Bombyx mori NPV p143 helicase gene.
Genomic DNA of recombinant AcNPV expressing beta-galactosidase was cotransfected with p143 helicase gene of BmNPV into Sf21 cells. Ac-Bm hybrid viruses capable of replicating in both Bm5 and Sf21 cells were isolated. Ac-Bm hybrid viruses expressing beta-galactosidase either at the highest (Ac-Bm hybrid virus-HE) or lowest (Ac-Bm hybrid virus-LE) level were chosen for the characterization of beta-galactosidase expression in Bm5 and Sf21 cells. Expression level of beta-galactosidase and replication of Ac-Bm hybrid virus-HE in Sf21 cells were nearly identical to those of recombinant AcNPV. Furthermore, replication of Ac-Bm hybrid virus-HE in Bm5 cells was similar to that of wild-type BmNPV, and Ac-Bm hybrid virus-HE clearly expressed beta-galactosidase in Bm5 cells. However, expression of beta-galactosidase by Ac-Bm hybrid virus-HE in Bm5 cells was significantly lower than that expressed in Sf21 cells. The titer of Ac-Bm hybrid virus-HE determined by plaque assays in Bm5 cells was similar to that determined in Sf21 cells, but the plaque size formed by Ac-Bm hybrid virus-HE in Bm5 cells was apparently smaller than that formed in Sf21 cells. In addition, expression levels and virus titers of Ac-Bm hybrid virus-LE in Sf21 and Bm5 were significantly lower than those of Ac-Bm hybrid virus-HE. Therefore, DNA sequences were determined for the region of the p143 gene controlling the host range in Ac-Bm hybrid viruses. The results showed that the deduced amino acid sequences of Ac-Bm hybrid virus-HE were almost identical to those of BmNPV. There were differences only in amino acids at positions 461 and 470, whereas those of Ac-Bm hybrid virus-LE were different at position 461, 470, 514, and 528 from those of BmNPV. In conclusion, our results clearly demonstrated that Ac-Bm hybrid virus-HE has an additional advantage of expanded host range for producing recombinant proteins.


[Dynamic radionuclide ventriculography in the diagnosis of heart and lung diseases].
The authors have provided a comparative analysis of various modifications of radionuclide ventriculography and assessment of their potentialities for clinical use. A total of 120 patients with chronic nonspecific lung diseases, coronary heart disease and rheumatic heart disease were examined. It was established that the most accurate information to assess myocardial contractility was obtained by a method of the determination of the ejection fraction by the "activity-time" curve with a fixed zone of interest, and the universal patient's position was the left front oblique projection. The right ventricular ejection fraction was determined in parallel with the study of the left ventricular ejection fraction characterizing myocardial contractility in cardiovascular pathology. The study of the former extended significantly the potentialities of radionuclide ventriculography, allowed the assessment of the hemodynamic state of the lesser circulation and compensatory potentialities of the right ventricle of the heart in cardiopulmonary pathology.


Corneal Dystrophy Mutations Drive Pathogenesis by Targeting TGFBIp Stability and Solubility in a Latent Amyloid-forming Domain.
Numerous mutations in the corneal protein TGFBIp lead to opaque extracellular deposits and corneal dystrophies (CDs). Here we elucidate the molecular origins underlying TGFBIp's mutation-induced increase in aggregation propensity through comprehensive biophysical and bioinformatic analyses of mutations associated with every major subtype of TGFBIp-linked CDs including lattice corneal dystrophy (LCD) and three subtypes of granular corneal dystrophy (GCD 1-3). LCD mutations at buried positions in the C-terminal Fas1-4 domain lead to decreased stability. GCD variants show biophysical profiles distinct from those of LCD mutations. GCD 1 and 3 mutations reduce solubility rather than stability. Half of the 50 positions within Fas1-4 most sensitive to mutation are associated with at least one known disease-causing mutation, including 10 of the top 11 positions. Thus, TGFBIp aggregation is driven by mutations that despite their physico-chemical diversity target either the stability or solubility of Fas1-4 in predictable ways, suggesting straightforward general therapeutic strategies.


Genetic deletion of Trb3, the mammalian Drosophila tribbles homolog, displays normal hepatic insulin signaling and glucose homeostasis.
Trb3, a mammalian homolog of Drosophila tribbles, was proposed as a suppressor of Akt activity, predominantly in conditions of fasting and diabetes. Given these prior studies, we sought to determine whether Trb3 plays a major role in modulating hepatic insulin sensitivity. To answer this question, we produced mice in which a lacZ reporter was knocked into the locus containing the gene Trib3, resulting in a Trib3 null animal. Trib3 expression analyses demonstrated that the Trib3 is expressed in liver, adipose tissues, heart, kidney, lung, skin, small intestine, stomach, and denervated, but not normal, skeletal muscle. Trib3(-/-) mice are essentially identical to their wild-type littermates in overall appearance and body composition. Phenotypic analysis of Trib3(-/-) mice did not detect any alteration in serum glucose, insulin, or lipid levels; glucose or insulin tolerance; or energy metabolism. Studies in Trib3(-/-) hepatocytes revealed normal Akt and glycogen synthase kinase- 3beta phosphorylation patterns, glycogen levels, and expressions of key regulatory gluconeogenic and glycolytic genes. These data demonstrate that deletion of Trib3 has minimal effect on insulin-induced Akt activation in hepatic tissue, and, as such, they question any nonredundant role for Trb3 in the maintenance of glucose and energy homeostasis in mice.


Signalling of the BCR is regulated by a lipid rafts-localised transcription factor, Bright.
Regulation of BCR signalling strength is crucial for B-cell development and function. Bright is a B-cell-restricted factor that complexes with Bruton's tyrosine kinase (Btk) and its substrate, transcription initiation factor-I (TFII-I), to activate immunoglobulin heavy chain gene transcription in the nucleus. Here we show that a palmitoylated pool of Bright is diverted to lipid rafts of resting B cells where it associates with signalosome components. After BCR ligation, Bright transiently interacts with sumoylation enzymes, blocks calcium flux and phosphorylation of Btk and TFII-I and is then discharged from lipid rafts as a Sumo-I-modified form. The resulting lipid raft concentration of Bright contributes to the signalling threshold of B cells, as their sensitivity to BCR stimulation decreases as the levels of Bright increase. Bright regulates signalling independent of its role in IgH transcription, as shown by specific dominant-negative titration of rafts-specific forms. This study identifies a BCR tuning mechanism in lipid rafts that is regulated by differential post-translational modification of a transcription factor with implications for B-cell tolerance and autoimmunity.


Liposomes-coated hydroxyapatite and tricalcium phosphate implanted in the mandibular bony defect of miniature swine.
Hydroxyapatite and tricalcium phosphate have been used as bone implants for some period of time. Now unfortunately, these materials have failed to become the nucleation sites for bone regeneration. We hypothesized that coating hydroxyapatite and tricalcium phosphate with negatively charged liposomes may improve the nucleation process for new bone formation. The present study was designed to test this hypothesis. Experiments were carried out in 15 miniature swines' mandibular angle with artificial bony defects. In each of the swine, the bony defects on one side were implanted with either liposomes coated with hydroxyapatite or liposomes coated with tricalcium phosphate, while the other side served as control. At the end of the third and sixth weeks following the operation, we observed result, took histology and radiographs of the operated area. The results showed that liposomes-coated materials were biocompatible and their clinical endpoint was enhanced. At the end of the third week, the implant material was surrounded by dense connective tissues. At the end of the sixth week, there were new bone formations near the implanted material. In addition, liposomes which were immobilized in agarose gel and implanted in the defects showed new bony bridge formation. These observations suggest that liposomes have the ability in promoting repair of osseous deficiencies.


Uterotrophic action of the insecticide methoxychlor.
Dusting of rats and mice, as well as oral treatment with the insecticide methoxychlor, produced uterine weight increase in these rodents. Ablation of the ovaries, adrenals, or pituitary did not alter this effect, thus indicating a direct trophic action of this agent on the uterus. It is apparent that the application of this insecticide to animals used for hormonal experiments introduces an additional variable.


[Effect of preliminary adaptation to short-term stress exposure on the resistance of the spontaneously contracting myocardium to a lipid peroxidation inducer].
Contractile function of the isolated right atrium was studied in male Wistar rats adapted to short-term stressor exposures at varying times after adaptation was completed. Adaptation to short-term stressor exposures induced a limited decrease in myocardial contractility immediately after adaptation was over. On the 3d day an additional reduction in the characteristics of contractile function was still observed. However, by the 5th day the characteristics recovered to the control level. At the same time adaptation completely prevented the derangement of myocardial contractility, induced by exposure to a prolonged stress. That protective effect was observed as early as adaptation was completed, on days 3 and 5 after adaptation, and became lessened on the 10th day. It is assumed that on the 5th day after adaptation the animals are in a postadaptation state where the untoward effect of adaptation disappears whereas the protective effect is demonstrable to a full extent. As a result all the characteristics of myocardial contractility following a prolonged stress on the 5th day after completion of short-term stressor exposures differed in no way from the control parameters.


Is there a dose-response relationship of metformin treatment in patients with polycystic ovary syndrome? Results from a multicentric study.
Do different dosages of metformin account for different clinical and biochemical outcomes in women with polycystic ovary syndrome (PCOS) and do basal anthropometric and metabolic characteristics of the patients provide any indications regarding the dose required to reach the target effect? Different doses of metformin exerted the same effects on clinical, biochemical and metabolic parameters in patients affected by PCOS. Since the insulin-sensitizing agents came into use in the management of PCOS, metformin has shown a positive benefits-risks ratio. Nonetheless, therapeutic schedules are not well standardized. This is the first study which systematically analyses the effect of different doses of metformin on clinical, hormonal and metabolic features of PCOS. On the basis of our results, higher doses are no more effective than lower doses. A multicentric cohort prospective study. A total of 250 PCOS women were enrolled, 49 lost to follow-up. Menstrual cyclicity, hormonal assays, oral glucose tolerance test, lipid profile and ultrasonographic pelvic examination were evaluated at the baseline and after 6 months of metformin treatment at different doses (1000, 1500 and 1700 mg). A total of 201 PCOS patients completed the study without protocol violations in three university hospitals: seventy-three patients from Centre A (treated with metformin 500 mg twice a day), 60 patients from Centre B (treated with metformin 500 mg three times a day) and 68 patients from Centre C (treated with metformin 850 mg twice a day). Metformin exerted an overall positive effect on the clinical and endocrine-metabolic features of PCOS. The degree of these effects was independent of the administered dosage in every range of basal body mass index (BMI). When patients were stratified according to their insulinaemic status, scattered inter-doses differences were found in some of the outcome measures. Patients who exhibited an increase of >2 menstrual cycles/year were considered as responders to treatment. Responders had a higher basal BMI than non-responders and showed a greater reduction in plasma testosterone levels after metformin treatment, but other outcome measures did not differ significantly. Total insulin secretion in the 180 min following the glucose tolerance test before metformin treatment (basal AUC-I) was significantly correlated with the decrease in insulin secretion induced by metformin in both the whole group and in responders, but only correlated with the variation in the number of cycles in responders. The different doses were administered in different centres, and between-centre variation is a potential confounding factor. The paradigm of using the minimum effective dose of metformin could be pursued in other pathological conditions characterized by insulin resistance. No funding or competing interests to declare.


Nidogen-1 and nidogen-2 are found in basement membranes during human embryonic development.
The recently identified nidogen-2 is a matrix protein showing homology to the well-known basement membrane molecule nidogen-1. Nidogen-1 might well serve as a link between laminin-1 and collagen type IV and thus stabilise certain basement membranes in vivo and play a major role in embryogenesis. However, the exact tissue distribution of nidogen-1 and nidogen-2 during human embryogenesis is still unclear. As a first step towards the elucidation of their possible cell biological functions during human development, we compared the distribution of both nidogens during human organogenesis at the light microscope level. Nidogen-2 and nidogen-1 were found to be ubiquitous components of basement membrane zones underneath developing epithelia of most of the major organ systems. However, in the developing intestine and the pancreas anlage, only nidogen-1 was present in the epithelial basement membrane zones of all developmental stages investigated. Our data suggest that nidogen-2 and nidogen-1, as is known for mouse development, could well participate in cell biological functions during human development. These two proteins might well be able to fulfil identical functions during human organogenesis.


Gastrointestinal imaging in AIDS--luminal gastrointestinal tract.
Barium radiography of the gastrointestinal tract in patients with AIDS can assist in the evaluation of numerous problems including dysphagia, odynophagia, diarrhea, abdominal pain, symptoms of intermittent obstruction, and/or gastrointestinal bleeding. It can localize disease, evaluate complications, guide endoscopic biopsy, and monitor the progress of therapy.


Functional parcellation using time courses of instantaneous connectivity.
Functional neuroimaging studies have led to understanding the brain as a collection of spatially segregated functional networks. It is thought that each of these networks is in turn composed of a set of distinct sub-regions that together support each network's function. Considering the sub-regions to be an essential part of the brain's functional architecture, several strategies have been put forward that aim at identifying the functional sub-units of the brain by means of functional parcellations. Current parcellation strategies typically employ a bottom-up strategy, creating a parcellation by clustering smaller units. We propose a novel top-down parcellation strategy, using time courses of instantaneous connectivity to subdivide an initial region of interest into sub-regions. We use split-half reproducibility to choose the optimal number of sub-regions. We apply our Instantaneous Connectivity Parcellation (ICP) strategy on high-quality resting-state FMRI data, and demonstrate the ability to generate parcellations for thalamus, entorhinal cortex, motor cortex, and subcortex including brainstem and striatum. We evaluate the subdivisions against available cytoarchitecture maps to show that our parcellation strategy recovers biologically valid subdivisions that adhere to known cytoarchitectural features.


The Role of Adjuvant Radiotherapy for a Case of Primary Breast Sarcoma: A Plan Comparison between Three Modern Techniques and a Review of the Literature.
A 65-year-old woman, affected by a malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma) of the left breast, presented to our department to receive the postoperative radiotherapy. In the absence of prospective and randomized trials and investigations on breast sarcoma irradiation in literature, due to the rarity of this pathology, the role of adjuvant radiotherapy remains unclear. To identify the best radiotherapy technique for this patient, three methods were compared: 3D conformal radiotherapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and volumetric arc therapy (VMAT) or RapidArc® (RA). 50 Gy was prescribed to the chest wall and 66 Gy to the tumor bed. Three plans were designed, and target coverage, organs-at-risk sparing, and treatment efficiency were compared. IMRT and RA improved both target coverage and dose uniformity/homogeneity. Planning objective for the lung is always satisfied comparing the different techniques, but the volume receiving 20 Gy drops to 17% by RA compared to 3D-CRT. The heart volume receiving 30 Gy was 10% by IMRT, against 13% and 16% by RA and 3D-CRT. The monitor unit (MU) required by 3D-CRT was 527 MU, followed by RA and IMRT. Treatment time was similar with 3D-CRT and RA but doubled using IMRT. Although all three radiotherapy techniques offered a satisfactory solution, RA and IMRT offer some improvement on target coverage, dose homogeneity, and conformity for this particular case of breast sarcoma.


Is ostension any more than attention?
According to natural pedagogy theory, infants are sensitive to particular ostensive cues that communicate to them that they are being addressed and that they can expect to learn referential information. We demonstrate that 6-month-old infants follow others' gaze direction in situations that are highly attention-grabbing. This occurs irrespective of whether these situations include communicative intent and ostensive cues (a model looks directly into the child's eyes prior to shifting gaze to an object) or not (a model shivers while looking down prior to shifting gaze to an object). In contrast, in less attention-grabbing contexts in which the model simply looks down prior to shifting gaze to an object, no effect is found. These findings demonstrate that one of the central pillars of natural pedagogy is false. Sensitivity to gaze following in infancy is not restricted to contexts in which ostensive cues are conveyed.


How does knee pain affect trunk and knee motion during badminton forehand lunges?
Badminton requires extensive lower extremity movement and a precise coordination of the upper extremity and trunk movements. Accordingly, this study investigated motions of the trunk and the knee, control of dynamic stability and muscle activation patterns of individuals with and without knee pain. Seventeen participants with chronic knee pain and 17 healthy participants participated in the study and performed forehand forward and backward diagonal lunges. This study showed that those with knee pain exhibited smaller knee motions in frontal and horizontal planes during forward lunge but greater knee motions in sagittal plane during backward lunge. By contrast, in both tasks, the injured group showed a smaller value on the activation level of the paraspinal muscles in pre-impact phase, hip-shoulder separation angle, trunk forward inclination range and peak centre of mass (COM) velocity. Badminton players with knee pain adopt a more conservative movement pattern of the knee to minimise recurrence of knee pain. The healthy group exhibit better weight-shifting ability due to a greater control of the trunk and knee muscles. Training programmes for badminton players with knee pain should be designed to improve both the neuromuscular control and muscle strength of the core muscles and the knee extensor with focus on the backward lunge motion.


Antibiotics and Host-Tailored Probiotics Similarly Modulate Effects on the Developing Avian Microbiome, Mycobiome, and Host Gene Expression.
The microbiome is important to all animals, including poultry, playing a critical role in health and performance. Low-dose antibiotics have historically been used to modulate food production animals and their microbiome. Identifying alternatives to antibiotics conferring similar modulatory properties has been elusive. The purpose of this study was to determine if a host-tailored probiotic could recapitulate effects of a low-dose antibiotic on host response and the developing microbiome. Over 13 days of life, turkey poults were supplemented continuously with a low-dose antibiotic or oral supplementation of a prebiotic with or without two different probiotics (8 cage units, n = 80 per group). Gastrointestinal bacterial and fungal communities of poults were characterized by 16S rRNA gene and ITS2 amplicon sequencing. Localized and systemic host gene expression was assessed using transcriptome sequencing (RNA-Seq), kinase activity was assessed by avian-specific kinome peptide arrays, and performance parameters were assessed. We found that development of the early-life microbiome of turkey poults was tightly ordered in a tissue- and time-specific manner. Low-dose antibiotic and turkey-tailored probiotic supplementation, but not nontailored probiotic supplementation, elicited similar shifts in overall microbiome composition during development compared to controls. Treatment-induced bacterial changes were accompanied by parallel shifts in the fungal community and host gene expression and enhanced performance metrics. These results were validated in pen trials that identified further additive effects of the turkey-tailored probiotic combined with different prebiotics. Alternative approaches to low-dose antibiotic use in poultry are feasible and can be optimized utilizing the indigenous poultry microbiome. Similar approaches may also be beneficial for humans.IMPORTANCE Alternative approaches are greatly needed to reduce the need for antibiotic use in food animal production. This study utilized a pipeline for the development of a host-tailored probiotic to enhance performance in commercial turkeys and modulate their microbiota, similar to the effects of low-dose antibiotic administration. We determined that a host-tailored probiotic, developed in the context of the commercial turkey gut microbiome, was more effective at modulating these parameters than a nontailored probiotic cocktail. Furthermore, the host-tailored probiotic mimicked many of the effects of a low-dose antibiotic growth promoter. Surprisingly, the effects of the antibiotic growth promoter and host-tailored probiotic were observed across kingdoms, illustrating the coordinated interkingdom effects of these approaches. This work suggests that tailored approaches to probiotic development hold promise for modulating the avian host and its microbiota.


Hypocholesterolemic activity of beta-sitosterol in cholesterol fed sea quail.
Male SEA quail were fed a 0.5% cholesterol supplemented diet, to which was added 0%, 1%, and 2% beta-sitosterol, for a period of seven days. Dietarily administered beta-sitosterol reduced total serum cholesterol levels by 62% and 72% at the 1% and 2% treatment doses, respectively. This hypocholesterolemic activity of sitosterol in cholesterol fed SEA quail was anticipated on the basis of the numerous earlier studies demonstrating similar activity in cholesterol fed chickens. Beta-sitosterol was tested in SEA quail to experimentally confirm its expected serum cholesterol lowering effects and to expand further the utility of the SEA quail model in cholesterol and atherosclerosis research.