Tracking peptide-membrane interactions: insights from in situ coupled confocal-atomic force microscopy imaging of NAP-22 peptide insertion and assembly.
Elucidating the role that charged membrane proteins play in determining cell membrane structure and dynamics is an area of active study. We have applied in situ correlated atomic force and confocal microscopies to characterize the interaction of the NAP-22 peptide with model membranes prepared as supported planar bilayers containing both liquid-ordered and liquid-disordered domains. Our results demonstrated that the NAP-22 peptide interacts with membranes in a concentration-dependent manner, preferentially inserting into DOPC (ld) domains. While at low peptide concentrations, the NAP-22 peptide formed aggregate-like structures within the ld domains, at high peptide concentrations, it appeared to sequester cholesterol into the ld domains and recruited phosphatidyl-myo-inositol 4,5-bisphosphate by inducing a blending effect that homogenizes the phase-segregated domains into one liquid-ordered domain. This study describes a possible mechanism by which the NAP-22 peptide can affect neuronal morphology.


Health Risks Related to Domestic Violence against Roma Women.
Background: Data on Roma women's experience of violence from their male partners are very scarce. We explored the process of actual domestic violence against Roma women, the threat of violence and its health consequences. We further focused on barriers in the availability of specialized support services aimed at eliminating domestic violence. Methods: The sample included 20 Roma women living throughout Slovakia: scattered among the majority (45.0%), in crisis centers and sheltered houses (40.0%), and in segregated Roma settlements (15.0%). Data were obtained through qualitative research by means of semi-structured interviews in 20 individual case studies. All 20 women had experienced a combination of violence: physical, psychological and economic, all of them connected with social isolation. Results: Prevailing gender stereotypes are a precondition of domestic violence against women, regardless of their status. Violence against Roma women resulted in several health consequences, and all of the 20 women suffered from these. Most of them reported general psychological problems (75%), among which anxiety and depression (25%), headache (25%), weight loss (10%) and health problems connected with motor activity (5%). The barriers include lack of awareness among Roma women of any specialised support services and the absence of such services for abused women in the region. Conclusions: Domestic violence results in serious psychological and physical health consequences. Violence elimination is generally set up without a specific ethnic or gender approach. Disregard of these specifics can lead to deepening of the uneven position of Roma women within the family, community and society, and the acceptance of violence against Roma women.


Prenatal phenol and phthalate exposures and birth outcomes.
Many phthalates and phenols are hormonally active and are suspected to alter the course of development. We investigated prenatal exposures to phthalate and phenol metabolites and their associations with body size measures of the infants at birth. We measured 5 phenol and 10 phthalate urinary metabolites in a multiethnic cohort of 404 women in New York City during their third trimester of pregnancy and recorded size of infants at birth. Median urinary concentrations were > 10 microg/L for 2 of 5 phenols and 6 of 10 phthalate monoester metabolites. Concentrations of low-molecular-weight phthalate monoesters (low-MWP) were approximately 5-fold greater than those of high-molecular-weight metabolites. Low-MWP metabolites had a positive association with gestational age [0.97 day gestational age per ln-biomarker; 95% confidence interval (CI), 0.07-1.9 days, multivariate adjusted] and with head circumference. Higher prenatal exposures to 2,5-dichlorophenol (2,5-DCP) predicted lower birth weight in boys (-210 g average birth weight difference between the third tertile and first tertile of 2,5-DCP; 95% CI, 71-348 g). Higher maternal benzophenone-3 (BP3) concentrations were associated with a similar decrease in birth weight among girls but with greater birth weight in boys. We observed a range of phthalate and phenol exposures during pregnancy in our population, but few were associated with birth size. The association of 2,5-DCP and BP3 with reduced or increased birth weight could be important in very early or small-size births. In addition, positive associations of urinary metabolites with some outcomes may be attributable partly to unresolved confounding with maternal anthropometric factors.


Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene.
CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.


Exosome production and its regulation of EGFR during wound healing in renal tubular cells.
Kidney repair following injury involves the reconstitution of a structurally and functionally intact tubular epithelium. Growth factors and their receptors, such as EGFR, are important in the repair of renal tubules. Exosomes are cell-produced small (~100 nm in diameter) vesicles that contain and transfer proteins, lipids, RNAs, and DNAs between cells. In this study, we examined the relationship between exosome production and EGFR activation and the potential role of exosome in wound healing. EGFR activation occurred shortly after scratch wounding in renal tubular cells. Wound repair after scratching was significantly promoted by EGF and suppressed by EGFR inhibitor gefitinib. Interestingly, scratch wounding induced a significant increase of exosome production. The exosome production was decreased by EGF and increased by gefitinib, suggesting a suppressive role of EGFR signaling in exosome production. Conversely, inhibition of exosome release by GW4869 and manumycin A markedly increased EGFR activation and promoted wound healing. Moreover, exosomes derived from scratch-wounding cells could inhibit wound healing. Collectively, the results indicate that wound healing in renal tubular cells is associated with EGFR activation and exosome production. Although EGFR activation promotes wound healing, released exosomes may antagonize EGFR activation and wound healing.


Mother-to-infant transmission of intestinal bifidobacterial strains has an impact on the early development of vaginally delivered infant's microbiota.
Bifidobacterium species are one of the major components of the infant's intestine microbiota. Colonization with bifidobacteria in early infancy is suggested to be important for health in later life. However, information remains limited regarding the source of these microbes. Here, we investigated whether specific strains of bifidobacteria in the maternal intestinal flora are transmitted to their infant's intestine. Fecal samples were collected from healthy 17 mother and infant pairs (Vaginal delivery: 12; Cesarean section delivery: 5). Mother's feces were collected twice before delivery. Infant's feces were collected at 0 (meconium), 3, 7, 30, 90 days after birth. Bifidobacteria isolated from feces were genotyped by multilocus sequencing typing, and the transitions of bifidobacteria counts in infant's feces were analyzed by quantitative real-time PCR. Stains belonging to Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium catenulatum, Bifidobacterium longum subsp. longum, and Bifidobacterium pseudocatenulatum, were identified to be monophyletic between mother's and infant's intestine. Eleven out of 12 vaginal delivered infants carried at least one monophyletic strain. The bifidobacterial counts of the species to which the monophyletic strains belong, increased predominantly in the infant's intestine within 3 days after birth. Among infants delivered by C-section, monophyletic strains were not observed. Moreover, the bifidobacterial counts were significantly lower than the vaginal delivered infants until 7 days of age. Among infants born vaginally, several Bifidobacterium strains transmit from the mother and colonize the infant's intestine shortly after birth. Our data suggest that the mother's intestine is an important source for the vaginal delivered infant's intestinal microbiota.


Autotransplants in multiple myeloma: what have we learned?
Of 496 consecutive patients with multiple myeloma (MM) enrolled in clinical trials of tandem transplants with peripheral blood stem cells support, 470 (95%) completed the first autotransplant with melphalan 200 mg/m2 (MEL 200) and 363 (73%) completed the second transplant with either MEL 200 (40%), MEL 140 mg/m2 (MEL 140) with total-body irradiation (17%), or a combination of alkylating agents (16%), depending on the response status prior to the second transplant; 31 patients up to age 60 years received an allograft as the second transplant. The median interval from first to second transplant was 5 months. Treatment-related mortality during the first year after transplantation was 7%, and complete remission (CR) was obtained in 36%; the median durations of event-free survival (EFS) and overall survival (OS) after transplant were 26 and 41 months, respectively. Low beta 2-microglobulin ([B2M] < or = 2.5 mg/L) and C-reactive protein ([CRP] < or = 0.4 mg/dL) were the most significant standard parameters associated with both prolonged EFS and OS. Median OS exceeded 5.5 years in the one third of patients with both low B2M and CRP. When cytogenetics were included in the analysis, the presence of 11q abnormalities and/or complete or partial deletion of chromosome 13 ("unfavorable karyotype") became a dominant negative feature for both EFS and OS. In addition to these pretransplant parameters, attainment of CR and application of two transplants within 6 months both significantly extended EFS and OS. The group of patients (7%) with high B2M and CRP with either IgA isotype or unfavorable karyotype had the worst prognosis (EFS, < or = 10 months; median OS, < or = 12 months) and will require novel therapy. We conclude that tandem transplants are feasible in the majority of patients up to age 70 years, effecting CR in one third of all patients. Median OS was greater than 5.5 years, regardless of pretransplant features, if the first transplant was applied within 12 months of initial treatment and the second transplant no more than 6 months later.


Novel Cognitive Functions Arise at the Convergence of Macroscale Gradients.
Functions in higher-order brain regions are the source of extensive debate. Past trends have been to describe the brain in terms of a set of functional modules, especially posterior cortical areas, but a new emerging paradigm focuses on interactions between neighboring representations. In this review, we synthesize emerging evidence that a variety of novel functions in the higher-order brain regions are due to convergence. Convergence of macroscale gradients brings feature-rich representations into close proximity, presenting an opportunity for novel functions to arise. Using the TPJ as an example, we demonstrate that convergent areas have three properties, they: (1) are at the peak of the processing hierarchy, (2) combine the most abstracted representations, and (3) are equidistant from other convergent areas. As information moves from primary sensory cortices to higher-order brain regions, it becomes abstracted and hierarchical. Eventually, these processing gradients converge at a point equally and maximally distant from their sensory origins. This convergence, which produces multifaceted cognitive functions, such as mentalizing another person's thoughts or projecting into a future space, parallels evolutionary and developmental characteristics of such regions, resulting in new cognitive and affective faculties.


Subclinical inflammation markers in hyperemesis gravidarum and ketonuria: A case-control study.
Subclinical inflammation markers play a significant role in hyperemesis gravidarum (HEG). Simple hematological markers such as mean platelet volume (MPV), platelet distribution width (PDW), neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW), plateletcrit (PCT), and platelet-to-lymphocyte ratio (PLR) have been shown to reflect inflammatory burden and disease activity in several disorders. Ketonuria is a parameter used in the diagnosis of severe HEG, but its correlation with disease severity remains controversial. The relationship of subclinical inflammation markers with degree of ketonuria has not been examined previously. In this study, we aimed to determine the diagnostic value of these subclinical inflammation markers and the relationship between these markers and grade of ketonuria in patients with HEG. A total of 94 pregnant women with a diagnosis of HEG and 100 gestational age-matched healthy pregnant women were enrolled in this retrospective study. MPV, PDW, NLR, PLR, PCT, and ketonuria were calculated and analyzed from complete blood cell counts and total urine analyses. Lymphocyte count was significantly higher in the control group (P < 0,001); NLR and PLR values were significantly higher in the HEG group (P < 0,001). Among inflammation markers, RDW increased significantly (P = 0,008) with an increase in ketonuria in patients with HEG. A statistically significant correlation was found between white blood cell (WBC) and NLR, PLR, PCT. A moderate uphill relationship was observed between NLR and WBC and a weak uphill linear relationship was observed between WBC and PLR and between WBC and PCT. PLR and NLR can be considered effective markers to aid in the diagnosis of HEG. No marker was found to correlate with ketonuria grade except RDW, although the relationship of the severity of ketonuria with severity of disease is controversial. RDW increases as the degree of ketonuria increases.


In vivo targeted delivery of nanoparticles for theranosis.
Therapy and diagnosis are two major categories in the clinical treatment of disease. Recently, the word "theranosis" has been created, combining the words to describe the implementation of these two distinct pursuits simultaneously. For successful theranosis, the efficient delivery of imaging agents and drugs is critical to provide sufficient imaging signal or drug concentration in the targeted disease site. To achieve this purpose, biomedical researchers have developed various nanoparticles composed of organic or inorganic materials. However, the targeted delivery of these nanoparticles in animal models and patients remains a difficult hurdle for many researchers, even if they show useful properties in cell culture condition. In this Account, we review our strategies for developing theranostic nanoparticles to accomplish in vivo targeted delivery of imaging agents and drugs. By applying these rational strategies, we achieved fine multimodal imaging and successful therapy. Our first strategy involves physicochemical optimization of nanoparticles for long circulation and an enhanced permeation and retention (EPR) effect. We accomplished this result by testing various materials in mouse models and optimizing the physical properties of the materials with imaging techniques. Through these experiments, we developed a glycol chitosan nanoparticle (CNP), which is suitable for angiogenic diseases, such as cancers, even without an additional targeting moiety. The in vivo mechanism of this particle was examined through rationally designed experiments. In addition, we evaluated and compared the biodistribution and target-site accumulation of bare and drug-loaded nanoparticles. We then focus on the targeting moieties that bind to cell surface receptors. Small peptides were selected as targeting moieties because of their stability, low cost, size, and activity per unit mass. Through phage display screening, the interleukin-4 receptor binding peptide was discovered, and we combined it with our nanoparticles. This product accumulated efficiently in atherosclerotic regions or tumors during both imaging and therapy. We also developed hyaluronic acid nanoparticles that can bind efficiently to the CD44 antigen receptors abundant in many tumor cells. Their delivery mechanism is based on both physicochemical optimization for the EPR effect and receptor-mediated endocytosis by their hyaluronic acid backbone. Finally, we introduce the stimuli-responsive system related to the chemical and biological changes in the target disease site. Considering the relatively low pH in tumors and ischemic sites, we applied pH-sensitive micelle to optical imaging, magnetic resonance imaging, anticancer drug delivery, and photodynamic therapy. In addition, we successfully evaluated the in vivo imaging of enzyme activity at the target site with an enzyme-specific peptide sequence and CNPs. On the basis of these strategies, we were able to develop self-assembled nanoparticles for in vivo targeted delivery, and successful results were obtained with them in animal models for both imaging and therapy. We anticipate that these rational strategies, as well as our nanoparticles, will be applied in both the diagnosis and therapy of many human diseases. These theranostic nanoparticles are expected to greatly contribute to optimized therapy for individual patients as personalized medicine, in the near future.


Local environmental variables are key drivers of ant taxonomic and functional beta-diversity in a Mediterranean dryland.
The decomposition of beta-diversity (β-diversity) into its replacement (βrepl) and richness (βrich) components in combination with a taxonomic and functional approach, may help to identify processes driving community composition along environmental gradients. We aimed to understand which abiotic and spatial variables influence ant β-diversity and identify which processes may drive ant β-diversity patterns in Mediterranean drylands by measuring the percentage of variation in ant taxonomic and functional β-diversity explained by local environmental, regional climatic and spatial variables. We found that taxonomic and functional replacement (βrepl) primarily drove patterns in overall β-diversity (βtot). Variation partitioning analysis showed that respectively 16.8%, 12.9% and 21.6% of taxonomic βtot, βrepl and βrich variation were mainly explained by local environmental variables. Local environmental variables were also the main determinants of functional β-diversity, explaining 20.4%, 17.9% and 23.2% of βtot, βrepl and βrich variation, respectively. Findings suggest that niche-based processes drive changes in ant β-diversity, as local environmental variables may act as environmental filters on species and trait composition. While we found that local environmental variables were important predictors of ant β-diversity, further analysis should address the contribution of other mechanisms, e.g. competitive exclusion and resource partitioning, on ant β-diversity.


Development of magnetic molecularly imprinted polymers for selective extraction of Benzoxazolinone-type alkaloids from acanthus plants.
Benzoxazolinone-type alkaloids found in Acanthus ebracteatus and Acanthus ilicifolius Linnaeus possess various beneficial properties, such as antileishmanial, antipyretic, analgesic, antibacterial, and antioxidant effects. In this study, we employed a surface imprinting technique on nanomaterials. We utilized functionalized Fe3O4@SiO2NH2 as a scaffold, with 2-benzoxazolinone and 2H-1,4-benzoxazin-3(4H)-one serving as dual templates, methacrylic acid (MAA) as a functional monomer, ethylene glycol dimethacrylate (EGDMA) as a crosslinker, and 2,2-azodiisobutyric nitrile (AIBN) as the initiator. Prior to polymerization, we screened functional monomers using ultraviolet (UV) spectroscopy. The resulting magnetic surface molecular imprinting polymer (Fe3O4@SiO2@MIP) was thoroughly characterized using Fourier transform infrared spectrometry (FT-IR), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). We also conducted assessments of its adsorption isotherms, dynamics, and selective binding capabilities. Our findings indicate that the MIPs exhibited exceptional selective recognition performance. Through meticulous screening and optimization of extraction and separation conditions, we established an LC‒MS/MS method based on magnetic solid-phase extraction technology. The method exhibited a recovery range of 78.80-106.99 % (RSD, 0.46-3.31 %) for 2-benzoxazolinone, with a limit of detection (LOD) and limit of quantification (LOQ) of 2.85 and 9.00 μg L-1, respectively. For 2H-1,4-benzoxazin-3(4H)-one, the method yielded a recovery range of 84.75-103.53 % (RSD, 0.07-5.96 %), with an LOD and LOQ of 3.60 and 12.60 μg L-1, respectively, in real samples. The resulting Fe3O4@SiO2@MIP demonstrated a high capacity for class-specific adsorption.


Cyclazocine: comparison to hydromorphone and interaction with cocaine.
Kappa-opioid agonists produce neurobiological and behavioral effects opposite to those of cocaine and may be useful for the treatment of cocaine dependence. To evaluate the kappa- and mu-agonist effects of cyclazocine and to test whether cyclazocine pretreatment would attenuate the effects of cocaine, healthy, male and female, experienced opiate and cocaine users (n = 13) were enrolled in a two-phase study. In Phase 1, placebo, cyclazocine (0.2, 0.4 and 0.8 mg) and the mu-agonist hydromorphone (5 and 15 mg) were administered orally in six 4.5-hour sessions separated by at least 72 h. In Phase 2, cocaine (100 mg intranasal) was given 2 h after oral pretreatment with cyclazocine (0, 0.1, 0.2, 0.4, 0.8 and 0 mg, in that order) in each of six sessions conducted daily Monday to Friday and the following Monday. Physiological, subjective and behavioral measures were collected in each session. Nine participants completed Phase 1; eight completed Phase 2. Hydromorphone (15 mg) produced prototypic mu-agonist effects. Cyclazocine exhibited only modest kappa-like effects. Cyclazocine also had only modest, non-dose-related effects on response to cocaine. However, cocaine effects were consistently lower on the last administration (cyclazocine 0 mg pretreatment) following 4 days of cyclazocine pretreatment, compared to the first administration (0 mg pretreatment). This finding is unlikely to be fully attributable to cocaine tolerance and is not accounted for by pharmacokinetic changes; plasma concentrations of cocaine were not altered by cyclazocine. This study is suggestive but not strongly supportive for the use of kappa-opiate drugs to diminish acute effects of cocaine administration or for the use of these kappa agonists in drug abuse treatment applications.


Thrombocytopenia associated with carbamazepine: a case series.
Carbamazepine is increasingly being used in the acute and maintenance treatment of patients with bipolar disorder. Thrombocytopenia represents a serious adverse effect of carbamazepine with which clinicians need to be familiar. The authors describe the course of thrombocytopenia associated with carbamazepine in four patients with bipolar disorder. In all cases, thrombocytopenia appeared 14 to 16 days after the initiation of carbamazepine; also in all cases the platelet count completely recovered within 7 days after the carbamazepine treatment was discontinued. Thrombocytopenia secondary to carbamazepine appears soon after the initiation of treatment and is rapidly followed by recovery after drug discontinuation.


Primary intrathoracic malignant mesenchymal tumours: computed tomography features of a rare group of chest neoplasms.
To describe the computed tomography (CT) features in a case series of primary intrathoracic extracardiac malignant mesenchymal tumours (sarcomas). A 5-year retrospective research was conducted, and 18 patients were selected. CT exams were reviewed by two chest radiologists, blinded to tumour pathological type, origin and grade. Lesions were described in relation to location, size, shape, margins, enhancement, presence of cavitation, calcifications, ground glass component, intratumoural enhanced vessels, pleural effusion, pleural tags, lymphangitis, chest wall/rib involvement and pathological lymph nodes. The readers described five pulmonary, six mediastinal and seven pleural/wall based lesions. Mean largest diameter was 103 mm. The most frequent shape was irregular (n = 12), most predominant margin was smooth (n = 12) and enhancement was mostly heterogeneous (n = 8). Intratumoural vessels and pleural effusion were seen in 11 patients. Pathological lymph nodes were present in four cases and calcifications in two cases. Some frequent radiological features were described independently of tumour location and subtype. A sarcoma should be included as a major differential diagnosis when the radiologist faces an intrathoracic mass of large size (>70 mm) but with well defined smooth or lobulated margins, especially if presenting intratumoural vessels, associated pleural effusion but no significant lymphadenopathy. • Malignant mesenchymal tumours (sarcomas) are rare and can arise from any structure in the chest. • Intrathoracic sarcomas show some frequent radiological features, independent of location and type. • Some CT features may help the radiologist suspect for a sarcoma instead of other more common tumours.


Secondary sex ratio in assisted reproduction: an analysis of 1 376 454 treatment cycles performed in the UK.
Does ART impact the secondary sex ratio (SSR) when compared to natural conception? IVF and ICSI as well as the stage of embryo transfer does impact the overall SSR. The World Health Organization quotes SSR for natural conception to range between 103 and 110 males per 100 female births. A total of 1 376 454 ART cycles were identified, of which 1 002 698 (72.8%) cycles involved IVF or ICSI. Of these, 863 859 (85.2%) were fresh cycles and 124 654 (12.4%) were frozen cycles. Missing data were identified in 14 185 (1.4%) cycles. All cycles recorded in the anonymized UK Human Fertilisation and Embryology Authority (HFEA) registry database between 1991 and 2016 were analysed. All singleton live births were included, and multiple births were excluded to avoid duplication. The overall live birth rate per cycle for all IVF and ICSI treatments was 26.2% (n = 262 961), and the singleton live birth rate per cycle was 17.1% (n = 171 399). The overall SSR for this study was 104.0 males per 100 female births (binomial exact 95% CI: 103.1-105.0) for all IVF and ICSI cycles performed in the UK recorded through the HFEA. This was comparable to the overall SSR for England and Wales at 105.3 males per 100 female births (95% CI: 105.2-105.4) from 1991 to 2016 obtained from the Office of National Statistics database. Male predominance was seen with conventional insemination in fresh IVF treatment cycles (SSR 110.0 males per 100 female births; 95% CI: 108.6-111.5) when compared to micro-injection in fresh ICSI treatment cycles (SSR 97.8 males per 100 female births; 95% CI: 96.5-99.2; odds ratio (OR) 1.16, 95% CI 1.12-1.19, P < 0.0001), as well as with blastocyst stage embryo transfers (SSR 104.8 males per 100 female births; 95% CI: 103.5-106.2) when compared to a cleavage stage embryo transfer (SSR 101.2 males per 100 female births; 95% CI: 99.3-103.1; OR 1.03, 95% CI 1.01-1.06, P = 0.011) for all fertilization methods. The quality of the data relies on the reporting system. Furthermore, success rates through ART have improved since 1991, with an increased number of blastocyst stage embryo transfers. This is the largest study to date evaluating the impact of ART on SSR. The results demonstrate that, overall, ART does have an impact on the SSR when assessed according to the method of fertilization (ICSI increased female births while IVF increased males). However, given the ratio of IVF to ICSI cycles at present with 60% of cycles from IVF and 40% from ICSI, the overall SSR for ART closely reflects the population SSR for, largely, natural conceptions in England and Wales. The study received no funding. C.M.B. is a member of the independent data monitoring group for a clinical endometriosis trial by ObsEva. He is on the scientific advisory board for Myovant and medical advisory board for Flo Health. He has received research grants from Bayer AG, MDNA Life Sciences, Volition Rx and Roche Diagnostics as well as from Wellbeing of Women, Medical Research Council UK, the NIH, the UK National Institute for Health Research and the European Union. He is the current Chair of the Endometriosis Guideline Development Group for ESHRE and was a co-opted member of the Endometriosis Guideline Group by the UK National Institute for Health and Care Excellence (NICE). I.G. has received research grants from Wellbeing of Women, the European Union and Finox. Not applicable.


Acupuncture for low back pain in pregnancy.
Medical doctors are particularly cautious about using acupuncture in pregnancy. This derives from the mostly historical and anecdotal claims that acupuncture can promote abortion, coupled with the fact that spontaneous early pregnancy loss is common, and litigation is increasing. This case report describes the circumstances that lead to the author using deep paraspinal and periosteal acupuncture throughout a patient's pregnancy to help control her low back pain.


Effect of temperature and surfactant on the control release of microencapsulated dye in lecithin liposomes. I.
The objective of our work has been the microencapsulation of dyes with lecithin from soybean, with the formation of liposomes, as a substitute for synthetic auxiliaries so as to improve the quality of the effluent. Current scenarios promote the disintegration and leakage of the liposomes, such as, changes in temperature, pH and the use of surfactants. Since dyeing process is a mix of all these parameters, we pretended to study each one separately. Rhodamine 6G fluorescence is known to be concentration quenched through the formation of non-fluorescent dimmers and, additionally, through the energy transfer from rhodamine monomer to these dimmers (Baptista ALF, Coutinho PJG, Real Oliveira MECD, Gomes JINR. Proceedings of 13th International Symposium of Surfactants, SIS 2000, Gainesville, USA, 2000). The temperature, the surfactant and pH induce a release of the encapsulated dye resulting in rhodamine dilution and consequently alterations in the dimerization/binding equilibrium. The experimental spectra indicate that rhodamine binds almost completely to liposomes. The decomposition of the rhodamine fluorescence spectra allowed us to determine the percentage of released dye during a simulated dyeing process, and allowed us to conclude that the dimerization process occurs mainly at the inner interfaces. The amount of dye released induced by temperature changes was greater in the presence of surfactant.


Do cancer patients tweet? Examining the twitter use of cancer patients in Japan.
Twitter is an interactive, real-time media that could prove useful in health care. Tweets from cancer patients could offer insight into the needs of cancer patients. The objective of this study was to understand cancer patients' social media usage and gain insight into patient needs. A search was conducted of every publicly available user profile on Twitter in Japan for references to the following: breast cancer, leukemia, colon cancer, rectal cancer, colorectal cancer, uterine cancer, cervical cancer, stomach cancer, lung cancer, and ovarian cancer. We then used an application programming interface and a data mining method to conduct a detailed analysis of the tweets from cancer patients. Twitter user profiles included references to breast cancer (n=313), leukemia (n=158), uterine or cervical cancer (n=134), lung cancer (n=87), colon cancer (n=64), and stomach cancer (n=44). A co-occurrence network is seen for all of these cancers, and each cancer has a unique network conformation. Keywords included words about diagnosis, symptoms, and treatments for almost all cancers. Words related to social activities were extracted for breast cancer. Words related to vaccination and support from public insurance were extracted for uterine or cervical cancer. This study demonstrates that cancer patients share information about their underlying disease, including diagnosis, symptoms, and treatments, via Twitter. This information could prove useful to health care providers.


Effects of Lactiplantibacillus plantarum GUANKE on Diphenoxylate-Induced Slow Transit Constipation and Gut Microbiota in Mice.
Slow transit constipation (STC) is a prevalent gastrointestinal condition with slow transit, and some probiotics can effectively relieve constipation, but the exact mechanisms have not been fully understood. In this study, we evaluate the impact of Lactiplantibacillus plantarum GUANKE (GUANKE) on diphenoxylate-induced slow transit constipation and speculate on the underlying mechanisms in a mouse model. Administration of L. plantarum GUANKE alleviated constipation indexes, including defecation time, fecal output and water content, and gastrointestinal transit ratio. In addition, GUANKE restored the protein expression of constipation-related intestinal factors (aquaporins (AQPs) and interstitial Cajal cells (ICCs)) in colon tissues measured using immunofluorescence staining; regulated the neurotransmitters and hormones, such as increased levels of 5-hydroxytryptamine, substance P, and motilin; and decreased levels of vasoactive intestinal peptide and nitric oxide in serum, as measured by an ELISA. 16S rRNA and correlation analysis of feces indicated that GUANKE administration effectively reduced constipation-induced Prevotella enrichment and suggested a potential contribution of Prevotella to diphenoxylate-induced STC in mice. GUANKE had no effect on short-chain fatty acids (SCFAs) in cecum content. This study revealed that GUANKE may alleviate constipation in mice through regulating intestinal neurotransmitter and hormone release and altering specific bacterial taxa, rather than by affecting SCFAs and the diversity of microbiota in the gut. Further research is needed to confirm if the findings observed in this study will be consistent in other animal studies or clinical trials.


In vivo and ex vivo evaluation of a multi-particulate composite construct for sustained transbuccal delivery of carbamazepine.
Carbamazepine (CBZ) is a leading molecule in the management of epilepsy. Surveys have revealed that a sufficient lack of therapeutically efficient CBZ transbuccal formulation exists. Therefore, this investigation was directed toward designing multiparticulate composite construct (MCC) for the transbuccal delivery of CBZ. The MCC was formulated using interphase, coparticulate–cosolvent homogenization technique, and lyophilization. In vitro, ex vivo, and in vivo investigations were performed. The mesoporous (pore width = 80.1233 Å) MCC was mechanically stable (Є(D) = 0.0290 J, M(F) = 8.5490 N/mm) and resilient (M(R) = 5.5040%). It demonstrated distinctive controlled release (9.9800%/h), permeation enhancing (10.8730%/h), drug loading (90.0541%), and bioadhesive (ω(adh) = 0.0034 J, F(det) = 1.0751 N) capacities. In vivo studies on pigs showed the ability of the MCC to effectively initiate and regulate transbuccal permeation of CBZ as visualized by outcomes of the quantitative and qualitative assessments of isolated plasma samples. Furthermore, comparisons of in vitro and in vivo data of MCC with a conventional product highlighted its capability to attain higher bioavailability and more controlled release trends. Histological and cytological investigations confirmed that the MCC is biocompatible. The mathematical model produced relevant pharmacokinetics and in vitro/in vivo correlation information.


Holographic diffraction gratings with enhanced sensitivity based on epoxy-resin photopolymers.
Photopolymers are interesting materials to obtain high-quality performance for the volume holographic data storage with a low noise and high diffraction efficiency. In this paper, the recording of holographic diffraction gratings with a spatial frequency of 1285lines/mm in photopolymerizable epoxy resin materials is experimentally demonstrated. Diffraction efficiency near 92% and an energetic sensitivity of 11.7 x 10-3cm2/J are achieved by designing the proper structure of matrix and also optimizing photopolymer compositions. The effect of photopolymer compositions on the fundamental optical properties is also discussed.


Comparative Genomics Reveals a Remarkable Biosynthetic Potential of the Streptomyces Phylogenetic Lineage Associated with Rugose-Ornamented Spores.
The genus Streptomyces is one of the richest sources of secondary metabolite biosynthetic gene clusters (BGCs). Sequencing of a large number of genomes has provided evidence that this well-known bacterial genus still harbors a large number of cryptic BGCs, and their metabolites are yet to be discovered. When taking a gene-first approach for new natural product discovery, BGC prioritization would be the most crucial step for the discovery of novel chemotypes. We hypothesized that strains with a greater number of BGCs would also contain a greater number of silent unique BGCs due to the presence of complex regulatory systems. Based on this hypothesis, we employed a comparative genomics approach to identify a specific Streptomyces phylogenetic lineage with the highest and yet-uncharacterized biosynthetic potential. A comparison of BGC abundance and genome size across 158 phylogenetically diverse Streptomyces type strains identified that members of the phylogenetic group characterized by the formation of rugose-ornamented spores possess the greatest number of BGCs (average, 50 BGCs) and also the largest genomes (average, 11.5 Mb). The study of genetic and biosynthetic diversities using comparative genomics of 11 sequenced genomes and a genetic similarity network analysis of BGCs suggested that members of this group carry a large number of unique BGCs, the majority of which are cryptic and not associated with any known natural product. We believe that members of this Streptomyces phylogenetic group possess a remarkable biosynthetic potential and thus would be a good target for a metabolite characterization study that could lead to the discovery of novel chemotypes. IMPORTANCE It is now well recognized that members of the genus Streptomyces still harbor a large number of cryptic BGCs in their genomes, which are mostly silent under laboratory culture conditions. Activation of transcriptionally silent BGCs is technically challenging and thus forms a bottleneck when taking a gene-first approach for the discovery of new natural products. Thus, it is important to focus activation efforts on strains with BGCs that have the potential to produce novel metabolites. The clade-level analysis of biosynthetic diversity could provide insights into the relationship between phylogenetic lineage and biosynthetic diversity. By exploring BGC abundance in relation to Streptomyces phylogeny, we identified a specific monophyletic lineage associated with the highest BGC abundance. Then, using a combined analysis of comparative genomics and a genetic network, we demonstrated that members of this lineage are genetically and biosynthetically diverse, contain a large number of cryptic BGCs with novel genotypes, and thus would be a good target for metabolite characterization studies.


The T/t common region of simian virus 40 large T antigen contains a distinct transformation-governing sequence.
Simian virus 40 large T antigen (T) can transform cultured cells, but the mechanisms by which it functions are not entirely understood. Several lines of evidence have suggested that the amino-terminal approximately 130 residues of T may be sufficient to confer the transforming capability. Oligonucleotide-directed mutagenesis was used to generate a series of deletion and substitution mutants within the amino-terminal 82 residues of T, the segment which is shared with simian virus 40 small t antigen (t). Results of stability and transformation assays of these mutants strongly suggest that the 1-to-82 region of T contains sequences which govern T transforming activity and affect in vivo stability. Instability and a defect in transforming activity could be separated from one another genetically. Thus, the 1-to-82 region appears to contain a specific region that contributes to the transforming function of the protein. This segment operates by means other than the simple binding of pRb and/or p107.


The pragmatic randomized optimal platelet and plasma ratios trial: what does it mean for remote damage control resuscitation?
Implications from the pragmatic, randomize, optimal platelet and plasma ratios (PROPPR) trial are critical for remote damage control resuscitation (DCR). Utilizing DCR principals in remote settings can combat early mortality from hemorrhage. Identifying the appropriate transfusion strategy is mandatory prior to adopting prehospital hemostatic resuscitation strategies. The PROPPR study was examined in relation to the following questions: 1) Why is it important to have blood products in the prehospital setting?; 2) Which products should be investigated for prehospital hemostatic resuscitation?; 3) What is the appropriate ratio of blood product transfusion?; and 4) What are the appropriate indications for hemostatic resuscitation? PROPPR demonstrates that early and balanced blood product transfusion ratios reduced mortality in all patients at 3 hours and death from exsanguination at 24 hours (p = 0.03). The median time to death from exsanguination was 2.3 hours, highlighting the need for point-of-injury DCR capabilities. A 1:1:1 transfusion ratio of plasma:platelets:packed red blood cells increased the percentage of patients achieving anatomic hemostasis (p = 0.006). PROPPR used the assessment of blood consumption score to identify patients likely to require ongoing hemostatic resuscitation. The critical administration threshold predicted patient mortality and identified patients likely to require ongoing hemostatic resuscitation. A balanced resuscitation strategy demonstrates an early survival benefit, decreased death from exsanguination at 24 hours and a greater likelihood of achieving hemostasis in critically injured patients receiving a 1:1:1 ratio of plasma:platelets:PRBCs. This finding highlights the need to import DCR principals to remote locations.


Estimating Conditional Transfer Entropy in Time Series Using Mutual Information and Nonlinear Prediction.
We propose a new estimator to measure directed dependencies in time series. The dimensionality of data is first reduced using a new non-uniform embedding technique, where the variables are ranked according to a weighted sum of the amount of new information and improvement of the prediction accuracy provided by the variables. Then, using a greedy approach, the most informative subsets are selected in an iterative way. The algorithm terminates, when the highest ranked variable is not able to significantly improve the accuracy of the prediction as compared to that obtained using the existing selected subsets. In a simulation study, we compare our estimator to existing state-of-the-art methods at different data lengths and directed dependencies strengths. It is demonstrated that the proposed estimator has a significantly higher accuracy than that of existing methods, especially for the difficult case, where the data are highly correlated and coupled. Moreover, we show its false detection of directed dependencies due to instantaneous couplings effect is lower than that of existing measures. We also show applicability of the proposed estimator on real intracranial electroencephalography data.


The effect of steroids on lymphocyte profile in primary chronic glomerulonephritis. Empirical or tailored therapy?
Steroids are still the mainstay of therapy in primary chronic glomerulonephritis (PCGN), regardless of underlying disturbance or pathology. Moreover, relationship between known abnormalities and disease manifestation is stochastic, therefore treatment continues to be empirical. It is not known whether responsiveness is related to immune phenotype. We performed flowcytometric lymphocyte (Ly) phenotyping (CD19, CD3, CD3CD4, CD3CD8, CD56/16) on 16 patients (pts) (12M, 4F), mean age 37.6+/-13 years with primary chronic glomerulonephritis (PCGN): minimal change disease (MCD)--6 pts, focal and segmental glomerulosclerosis (FSGS)--4 pts, mesangial proliferative glomerulonephritis--5 pts, mesangiocapillary glomerulonephritis--1 pt, before and at 7 days of oral Prednisone 1 mg/kg/day (in 2 divided doses). Before steroids: 4/16 pts(25%) had elevated BP; 9/16(56.2) showed nephrotic proteinuria. Serum creatinine was >1.2 mg% in 6/16(37.5%). At 7 days WBC count increased (13,079.37+/-4966.4/microl vs. 8021.25+/-2077.4/microl; p=0.0007), Ly percentage (%) decreased (20.30+/-9% vs. 29.9+/-10.4%; p=0.0095), while absolute (abs.) Ly count remained unchanged. Both CD19 Ly% and CD19 Ly abs. count increased (16.13+/-6.5% vs. 9.52+/-3.7%; p=0.0015, and 410.012+/-29.7/microl vs. 223.56+/-123.8/microl; p=0.0077, respectively). NK (natural killer)% decreased (9.15+/-5.2% vs. 14.19+/-7.1%; p=0.0296). CD3, CD3CD4, CD3CD8 Ly subsets and CD4/CD8 ratio showed no change. Variation in proteinuria (2.88+/-2.1 g/24 h vs. 3.45+/-1.7 g/24 h; p=0.4) did not reach statistical significance (Wilcoxon-Mann-Whitney). In 11 pts we performed an additional analysis at 1 month. Compared to levels before steroids, there was an increase in WBC, CD19 Ly% and CD19 Ly abs. count and a decrease in NK% and NK abs. count. Other Ly subsets and CD4/CD8 ratio remained unchanged. Variation in clinical parameters (proteinuria, serum Creatinine, BP) did not reach statistical significance. Changes in Ly profile precede changes in clinical parameters and thus are divergent. While our patients proved to be early non-responders, further studies to elucidate whether profile changes provide for response specification are warranted.


Anatomy, anatomy, anatomy......
This end of year issue is the usual blend of basic science and medical or surgical treatments, but with a strong anatomical flavour. It would seem there is little new to say about topographical anatomy and yet from a surgical perspective there is still much to be learnt, as evidenced by the in-depth investigation by Liu et al. (1) of the Vidian canal. Although vidian neurectomy is clearly still fashionable in Taiwan, the canal itself has assumed greater importance with the demonstration that this is the principle route for sphenoid invasion by juvenile angiofibroma (JAF) and thus the site of 'recurrence' if not adequately explored (2). Drilling out the canal and the surrounding basi-sphenoid is now recognised as a key determinant in the complete removal of JAF whatever surgical approach is employed. 3-D imaging reconstruction elegantly demonstrates the range of anatomical variation related principally to increased sphenoid pneumatisation and consequent prominence of adjacent structures such as the vidian canal itself and the foramen rotundum (3,4). A better appreciation of this anatomy might even lead to a resurgence of international interest in vidian neurectomy for the treatment of excessive watery rhinorrhoea if the associated complications from the procedure could be minimised (5,6).


Cortical potentiation induced by calcitonin gene-related peptide (CGRP) in the insular cortex of adult mice.
Recent studies demonstrate that calcitonin gene-related peptide (CGRP) plays critical roles in migraine. Immunohistochemistry and in situ hybridization studies have shown that CGRP and its receptors are expressed in cortical areas that are critical for pain perception including the anterior cingulate cortex (ACC) and insular cortex (IC). Recent studies reported that CGRP enhanced excitatory transmission in the ACC. However, little is known about the possible effect of CGRP on excitatory transmission in the IC. In the present study, we investigated the role of CGRP on synaptic transmission in the IC slices of adult male mice. Bath application of CGRP produced dose-dependent potentiation of evoked excitatory postsynaptic currents (eEPSCs). This potentiation was NMDA receptor (NMDAR) independent. After application of CGRP1 receptor antagonist CGRP8-37 or BIBN 4096, CGRP produced potentiation was significantly reduced. Paired-pulse facilitation was significantly decreased by CGRP, suggesting possible presynaptic mechanisms. Consistently, bath application of CGRP significantly increased the frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs). By contrast, amplitudes of sEPSCs and mEPSCs were not significantly affected. Finally, adenylyl cyclase subtype 1 (AC1) and protein kinase A (PKA) are critical for CGRP-produced potentiation, since both selective AC1 inhibitor NB001 and the PKA inhibitor KT5720 completely blocked the potentiation. Our results provide direct evidence that CGRP contributes to synaptic potentiation in the IC, and the AC1 inhibitor NB001 may be beneficial for the treatment of migraine in the future.


Impaired activation of nuclear factor-kappaB in endotoxin-tolerant rats is associated with down-regulation of chemokine gene expression and inhibition of neutrophilic lung inflammation.
We postulated that repeated injections of endotoxin could induce a state of endotoxin tolerance in rats that is mediated at least partially through a nuclear factor (NF)-kappaB-dependent mechanism. We treated rats with four doses of endotoxin (0.06 or 0.6 mg/kg/day) and evaluated the ability of these treatments to modulate activation of the transcription factor NF-kappaB induced by treatment with high dose endotoxin (6 mg/kg). In lung tissue, NF-kappaB activation in response to i.p. injection of high dose endotoxin was blocked by treatment with four daily doses of endotoxin at 0.6 mg/kg/day. Endotoxin tolerance in rats was associated with diminished endotoxin-induced mRNA expression of the NF-kappaB-dependent rat chemokine, cytokine-induced neutrophil chemoattractant. Treatment of rats with four daily doses of 0.6 mg/kg/day of endotoxin almost completely abolished the neutrophilic alveolitis that occurs in rats following i.p. injection of high dose endotoxin. These data indicate that in vivo tolerance to endotoxin challenge is associated with and possibly mediated by inhibition of NF-kappaB activation. Potentially, endotoxin tolerance could be exploited to limit inflammation in disease states whose pathobiology is related to excessive or unregulated inflammation.


Needs of family caregivers in home care for older adults.
to reveal the felt and normative needs of primary family caregivers when providing instrumental support to older adults enrolled in a Home Care Program in a Primary Health Service in the South of Brazil. using Bradshaw's taxonomy of needs to explore the caregiver's felt needs (stated needs) and normative needs (defined by professionals), a mixed exploratory study was conducted in three steps: Descriptive quantitative phase with 39 older adults and their caregiver, using a data sheet based on patient records; Qualitative exploratory phase that included 21 caregiver interviews, analyzed by content analysis; Systematic observation, using an observation guide with 16 caregivers, analyzed by descriptive statistics. the felt needs were related to information about instrumental support activities and subjective aspects of care. Caregivers presented more normative needs related to medications care. understanding caregivers' needs allows nurses to plan interventions based on their particularities.


[Purification and characterization of GM2 synthase, UDP-N-acetylgalactosamine:GM3 beta-N-acetylgalactosaminyl-transferase from rat liver].
A UDP-N-acetylgalactosamine: ganglioside GM3 beta-N-acetylgalactosaminyltransferase which catalyzes the conversion of ganglioside GM3 to GM2 has been purified over 6,000-fold from a Triton X-100 extract of rat liver microsomes by affinity chromatography on UDP-hexanolamine-Sepharose and GM3-acid Sepharose. The purified enzyme is composed of two non-identical subunits with apparent molecular weights of 70,000 and 64,000 on sodium dodecyl sulfate polyacrylamide gel electrophoresis. The enzyme has a pH optimum of pH 6.7-6.9 and requires divalent cations such as Ni2+ or Mn2+. Studies on substrate specificity indicates that GM3 containing N-acetylneuraminic acid and GM3 containing N-glycolylneuraminic acid were both good acceptors. The oligosaccharide of GM3, sialyllactose was also a good acceptor, which indicates that the preferred acceptor substrate has the general structure NeuAc alpha 2- or NeuGc alpha 2-3Gal beta 1-4Glc-O-R, in which the nature of the R moiety has relatively little effect on activity.


Attitudes of medical students regarding legalisation of cannabis and cannabis-education.
Recreational and medicinal use of cannabis is topical in the light of more permissive legislation regarding the substance worldwide. The primary purpose of this study is to determine the attitudes that final-year medical students at the University of Pretoria (UP) hold about recreational and medicinal use of cannabis, as well as determining if they feel they are being adequately trained in this regard. The research was conducted at Weskoppies Psychiatric Hospital, affiliated with the UP. The study follows a cross-sectional, comparative, quantitative design. Data were collected by means of a structured questionnaire. Final-year medical students were identified as participants via a convenience sampling technique. Participation was voluntary and anonymous. A total of 57 valid responses were recorded. The study shows that most medical students had permissive views about cannabis and that the majority feel that they are not being adequately trained to advise patients about medical cannabis in a lecture setting (64.9%, n = 37) or clinical setting (68.4%, n = 38). Results also show that previous personal experience with cannabis led to more permissive views. This study illustrates the need for academic research regarding medicinal cannabis but interestingly shows that medical students want more guidance from their training institution about the topic. This research shows that the conversation surrounding cannabis in medicine is continuous and universities should make a conscious effort to familiarise students with the topic.


Ultraprecise single-molecule localization microscopy enables in situ distance measurements in intact cells.
Single-molecule localization microscopy (SMLM) has the potential to quantify the diversity in spatial arrangements of molecules in intact cells. However, this requires that the single-molecule emitters are localized with ultrahigh precision irrespective of the sample format and the length of the data acquisition. We advance SMLM to enable direct distance measurements between molecules in intact cells on the scale between 1 and 20 nm. Our actively stabilized microscope combines three-dimensional real-time drift corrections and achieves a stabilization of <1 nm and localization precision of ~1 nm. To demonstrate the biological applicability of the new microscope, we show a 4- to 7-nm difference in spatial separations between signaling T cell receptors and phosphatases (CD45) in active and resting T cells. In summary, by overcoming the major bottlenecks in SMLM imaging, it is possible to generate molecular images with nanometer accuracy and conduct distance measurements on the biological relevant length scales.


Inflammatory Cytokine Patterns Associated with Neurological Diseases in Coronavirus Disease 2019.
Patients with coronavirus disease 2019 (COVID-19) can present with distinct neurological manifestations. This study shows that inflammatory neurological diseases were associated with increased levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12, chemokine (C-X-C motif) ligand 8 (CXCL8), and CXCL10 in the cerebrospinal fluid. Conversely, encephalopathy was associated with high serum levels of IL-6, CXCL8, and active tumor growth factor β1. Inflammatory syndromes of the central nervous system in COVID-19 can appear early, as a parainfectious process without significant systemic involvement, or without direct evidence of severe acute respiratory syndrome coronavirus 2 neuroinvasion. At the same time, encephalopathy is mainly influenced by peripheral events, including inflammatory cytokines. ANN NEUROL 2021;89:1041-1045.


Variability in meta-analytic results concerning the value of cholesterol reduction in coronary heart disease: a meta-meta-analysis.
Despite official support for the efficacy of cholesterol reduction, considerable controversy exists, and meta-analyses of this topic have produced conflicting results. The authors assessed the variability of meta-analyses, evaluating the cardiovascular value of cholesterol reduction while attempting to explain the variability. Metaanalyses were identified by electronic search and citation tracking. Included were those conducted prior to 1995 that dealt with cholesterol reduction and total mortality, cardiovascular mortality, or nonfatal cardiovascular disease. In addition to extracting odds ratios for total mortality, cardiovascular mortality, and nonfatal cardiovascular disease, the authors encoded methodological variables, publication variables, and data concerning investigators' backgrounds. Twenty-three meta-analyses were reviewed, and 15 concluded that cholesterol reduction was beneficial. Summary odds ratios for total mortality were heterogeneous, generally failing to support the value of cholesterol reduction. Odds ratios depended on inclusion criteria and investigator variables. Odds ratios for cardiovascular mortality and for nonfatal cardiovascular disease were more homogeneous and supported the value of cholesterol reduction. Methodologically better meta-analyses tended to report more beneficial odds ratios. Although "supportiveness" of the value of cholesterol reduction was associated with inclusion/exclusion criteria and publication variables, the primary outcome variable related to supportiveness was the statistical significance of the odds ratios for cardiovascular mortality.


Immediate Surgical Management of Traumatic Dislocation of the Eye Globe into the Maxillary Sinus: Report of a Rare Case and Literature Review.
We report a case of complete dislocation of the globe into the maxillary sinus, with immediate repositioning of the globe. This report highlights the importance of early surgical repair of orbital fracture and globe repositioning to regain the maximum amount of ocular functions. A review of literature found 19 cases of globe dislocation into the maxillary sinus: One case was enucleated 2 months after misdiagnosis as traumatic enucleation, six cases were documented no vision or no light perception, three cases did not have reported vision (patients did not survive), and nine cases with postoperative vision. We recommend early surgical intervention to restore the cosmetic and visual function of the dislocated eye.


New Treatment Modalities for Neovascular Age-Related Macular Degeneration.
Age-related macular degeneration (AMD) is considered one of the main causes of severe vision loss in older adults. The neovascular form (nAMD) is an advanced stage, which is responsible for the most severe vision loss. Vascular endothelial growth factor (VEGF) is at present the main factor that leads to the development of a neovascular membrane and the increased leakage from the membrane to the retina. At present, anti-VEGF therapy is the only treatment that achieves vision gains in many patients and halts progression in most of them. VEGF blockade can be achieved with several molecules and various treatment regimens, which have been studied with excellent results. Unfortunately, real-world data has shown to be far less efficacious than clinical trials. This gap between clinical trials and real-world results is an unmet medical need that supports the necessity of new treatment modalities for nAMD. Of the various treatments being studied, anti-VEGFs of higher efficacy and longer durability are those more advanced in their development. Brolucizumab and abicipar pegol are 2 new anti-VEGF drugs that had positive results in phase 2 studies and are being tested in phase 3 trials at present. Other promising therapies are antiangiopoietin 2 molecules, which are in phase 2 development. At earlier stages of development but with promising results are squalamine, anti-VEGF-C and -D, and gene therapy. The future will give retina specialists a broad armamentarium with which patients may achieve high visual gains for the long term with a low treatment burden.


Chondrosesamoidean ligament enthesopathy: Prevalence and findings in a population of lame horses imaged with positron emission tomography.
Increased 18 F-Sodium Fluoride (18 F-NaF) uptake at the chondrosesamoidean ligament (ChSL) attachment on the distal phalanx was identified in an exploratory positron emission tomography (PET) study. The prevalence and significance of this lesion has not been previously investigated. The goal of this study was to assess the prevalence of this lesion, its association with other imaging findings and with clinical signs. Retrospective cross-sectional analytical study. All horses with 18 F-NaF PET and computed tomography (CT) imaging of the feet performed between October 2016 and December 2017 were included in the study. All PET scans were independently assessed by two radiologists for increased uptake at the ChSL attachment site and concurrent imaging was reviewed. Clinical findings, treatment and outcome were retrieved from the medical records. Fourteen of 30 horses (20/56 feet) had increased 18 F-NaF uptake in the region of interest. ChSL enthesopathy was the primary lesion in three horses. Other PET abnormalities included navicular bone uptake (13 feet) and ipsilateral palmar process uptake (9 feet). There was no significant association between ChSL enthesopathy and other lesions. ChSL enthesopathy was significantly associated with foot lameness. CT abnormalities at the ChSL attachment were initially identified in one foot, and retrospectively noted in another five following the results of PET imaging. The study is retrospective and there was a limited sample size. PET led to identification of ChSL enthesopathy in a large proportion of horses with foot pain. This finding is most commonly associated with other lesions but may also represent the main abnormality. The axial border of the palmar processes of the distal phalanx should be carefully assessed on cross sectional imaging to identify this lesion. ChSL enthesopathy may be an important but previously not recognised component of foot pathology in horses.


SPIRE: a Searchable, Planetary-scale mIcrobiome REsource.
Meta'omic data on microbial diversity and function accrue exponentially in public repositories, but derived information is often siloed according to data type, study or sampled microbial environment. Here we present SPIRE, a Searchable Planetary-scale mIcrobiome REsource that integrates various consistently processed metagenome-derived microbial data modalities across habitats, geography and phylogeny. SPIRE encompasses 99 146 metagenomic samples from 739 studies covering a wide array of microbial environments and augmented with manually-curated contextual data. Across a total metagenomic assembly of 16 Tbp, SPIRE comprises 35 billion predicted protein sequences and 1.16 million newly constructed metagenome-assembled genomes (MAGs) of medium or high quality. Beyond mapping to the high-quality genome reference provided by proGenomes3 (http://progenomes.embl.de), these novel MAGs form 92 134 novel species-level clusters, the majority of which are unclassified at species level using current tools. SPIRE enables taxonomic profiling of these species clusters via an updated, custom mOTUs database (https://motu-tool.org/) and includes several layers of functional annotation, as well as crosslinks to several (micro-)biological databases. The resource is accessible, searchable and browsable via http://spire.embl.de.


Diagnostic accuracy of urine dipsticks for detecting albuminuria in indigenous and non-indigenous children in a community setting.
Albuminuria predicts cardiovascular and end-stage kidney disease in indigenous populations. Early detection in indigenous children may identify those who could benefit from early treatment. Community-based detection of albuminuria needs to be performed using a reliable, inexpensive, and widely available test, such as a proteinuria dipstick. Dipstick accuracy for detecting albuminuria in a community setting has not been evaluated. We assessed the accuracy of Multistix 10 SG dipsticks to detect baseline albuminuria and predict for persistent albuminuria at a 2-year follow-up in a population-based cohort of Australian Aboriginal and non-Aboriginal elementary-school-aged children. Variability in the accuracy of dipsticks in subgroups of higher risk children was analyzed using the relative diagnostic odds ratio (RDOR). Using Multistix 10 SG dipsticks, index-test-positive cases were defined as >/=0.30 g/L (1+) proteinuria and index-test-negative cases as <0.30 g/L (negative or trace) proteinuria. Referent-test-positive cases were defined as spot albumin:creatinine (ACR) >/=3.4 mg/mmol, and referent-test-negative cases as ACR <3.4 mg/mmol. There were 2,266 children (55.1% Aboriginal, 51.0% boys, mean age 8.9 years) enrolled. At the 2-year follow-up, 1,432 (63.0%) children were retested (54.0% Aboriginal, 50.5% boys, mean age 10.5 years). Prevalence of baseline albuminuria was 7.3%, and persistent albuminuria was 1.5%. Dipsticks had a sensitivity of 62% and specificity of 97% at baseline. In predicting persistent albuminuria, sensitivity was 75% and specificity 93%. Accuracy did not vary with ethnicity, gender, or body mass index. Accuracy was less in younger children (4.0-7.9 years), and in those with hematuria. The performance characteristics of Multistix dipsticks make them suitable for albuminuria detection in Aboriginal and other higher-risk groups of children. More than two thirds of children detected at a single test will have transient rather than persistent albuminuria. Multistix dipsticks are particularly useful for detecting children who will have persistent albuminuria.


Laser-Activatable In Situ Vaccine Enhances Cancer-Immunity Cycle.
The immune response in cancer reflects a series of carefully regulated events; however, current tumor immunotherapies typically address a single key aspect to enhance anti-tumor immunity. In the present study, a nanoplatform (Fe3 O4 @IR820@CpG)-based immunotherapy strategy that targets the multiple key steps in cancer-immunity cycle is developed: 1) promotes the release of tumor-derived proteins (TDPs), including tumor-associated antigens and pro-immunostimulatory factors), in addition to the direct killing effect, by photothermal (PTT) and photodynamic therapy (PDT); 2) captures the released TDPs and delivers them, together with CpG (a Toll-like receptor 9 agonist) to antigen-presenting cells (APCs) to promote antigen presentation and T cell activation; 3) enhances the tumor-killing ability of T cells by combining with anti-programmed death ligand 1 antibody (α-PD-L1), which collectively advances the outstanding of the anti-tumor effects on colorectal, liver and breast cancers. The broad-spectrum anti-tumor activity of Fe3 O4 @IR820@CpG with α-PD-L1 demonstrates that optimally manipulating anti-cancer immunity not singly but as a group provides promising clinical strategies.


Broadening the trans-contextual model of motivation: A study with Spanish adolescents.
The original trans-contextual model of motivation proposed that autonomy support from teachers develops students' autonomous motivation in physical education (PE), and that autonomous motivation is transferred from PE contexts to physical activity leisure-time contexts, and predicts attitudes, perceived behavioral control and subjective norms, and forming intentions to participate in future physical activity behavior. The purpose of this study was to test an extended trans-contextual model of motivation including autonomy support from peers and parents and basic psychological needs in a Spanish sample. School students (n = 400) aged between 12 and 18 years completed measures of perceived autonomy support from three sources, autonomous motivation and constructs from the theory of planned behavior at three different points in time and in two contexts, PE and leisure-time. A path analysis controlling for past physical activity behavior supported the main postulates of the model. Autonomous motivation in a PE context predicted autonomous motivation in a leisure-time physical activity context, perceived autonomy support from teachers predicted satisfaction of basic psychological needs in PE, and perceived autonomy support from peers and parents predicted need satisfaction in leisure-time. This study provides a cross-cultural replication of the trans-contextual model of motivation and broadens it to encompass basic psychological needs.


Peripheral neuropathy in essential mixed cryoglobulinemia.
Sixteen patients with essential mixed cryoglobulinemia were studied and followed up clinically and electrophysiologically for 4.2 years. Peripheral neuropathy was diagnosed in seven cases. Five of these patients had distal symmetrical sensorimotor polyneuropathy. Nerve conduction velocities were normal and therefore indicative of pure axonal neuropathy. Sural nerve biopsy showed moderate loss of myelinated axons in two patients and severe loss in one. This patient also had necrotizing arteritis. The remaining two had both clinical and electrophysiologic signs of overlapping mononeuritis multiplex with severe denervation in the territory of the involved nerves, but normal conduction velocities. Sural nerve biopsy in one of these two patients showed marked loss of myelinated fibers and signs of vasculitis. Two types of neuropathy were noted: (1) a mild distal neuropathy with relatively minor neurologic deficit, probably due to vasa nervorum microcirculation occlusion caused by intravascular deposits of cryoglobulins and (2) a severe distal symmetrical sensorimotor neuropathy or overlapping mononeuritis multiplex, associated with necrotizing vasculitis.


Endolymphatic isotope and BCG in the management of malignant melanoma.
Endolymphatic isotope therapy had such promising early clinical results that the M.R.C. (Medical Research Council) U.K. set up a clinical trial in 1966. This was to compare the effect of endolymphatic isotope therapy with the results of standard methods in the treatment of lower limb malignant melanoma. The interim report had three groups for analysis: Standard Methods (S); Endolymphatic Satisfactory (ES); and Endolymphatic Unsatisfactory (EU). This third group was a subdivision, as a significant number of patients did not have the correct endolymphatic treatment. The five-year survival figures expressed as actuarial percentages were ES=78.8%; S=82.3%; and EU=57.3%. Lymph node recurrence showed a significant difference: ES=2.3%; EU=12%; and S=19%. The conclusions were that endolymphatic isotope therapy was justified in specialized centres where good results could be obtained. Further animal experiments using the VX2 tumour in rabbits indicated that BCG given intracutaneously or intravenously had no therapeutic effect, whereas when applied by intralymphatic injection BCG was successful in treating lymph node metastases. Nineteen patients with poor-prognosis malignant melanoma have received endolymphatic BCG. The clinical results are recorded in this paper and are sufficiently encouraging to warrant its continued use.


Optical pedobarography for assessing neuropathic feet in diabetic patients--a review.
The use of optical pedobarography is presented in this article. The limitations of the analytical methods using peak pressures as a parameter for assessment of foot at risk of plantar ulcers are indicated. A new method, which takes into consideration the actual plantar pressure distribution using the power ratio PR (the ratio of high-frequency power to the total power in the walking foot pressure image distribution)and relates it to 3 levels of sensation loss is described. PR is able to detect early loss of foot sensation characterized by a loss of sensation level of 4.5 gm. The methods available in the literature for management of foot ulcers by proper footwear design, and their limitations, are discussed. A new method of individualized footwear based on matching the softness of the footwear insole with the softness of normal foot sole soft tissue (having durometer reading of 20 degrees Shore) and optimum insole thickness (12 mm) is helpful in the prevention of plantar ulcers.


Intravenous Ringer's lactate versus usual care during labor in nulliparous women: a systematic review and meta-analysis of randomized controlled trials.
Due to limited research on the effectiveness and safety of intravenous (IV) fluids administered during labor, there are no guidelines available. Thus, this meta-analysis aims to evaluate efficacy of IV Ringer's lactate during labor as compared to usual care. Six databases were searched for the randomized controlled trials (RCTs) comparing the effects of IV Ringer's lactate at 125 mL/h or 250 mL/hr during labor in nulliparous women at term as compared to usual care, and the search results were imported to Covidence for screening of the articles. All the concerned outcomes were pooled as risk ratios (RR) or mean difference (MD) with 95% CI in the meta-analysis models using RevMan 5.4. Pooled data from 7 RCTs with 967 nulliparous women showed that the active stage of labor duration (MD -32.16 with 95% CI [40.43 to -23.90], p < 0.00001), need of oxytocin augmentation (RR 0.72 with 95% CI [0.54 to 0.96], p = 0.03) and incidence of prolonged labor (RR 0.57 with 95% CI [0.34 to 0.95], p = 0.03) was significantly lower with IV Ringer's lactate. However, the total duration of labor (p = 0.23), duration of second stage of labor (p = 0.31) and cesarean section rate (p = 0.070) did not differ between the two groups. The test for subgroup analysis based on infusion rate was significant (p = 0.01) for the active stage of labor. IV Ringer's lactate reduced the duration of active labor, the need for oxytocin augmentation and the prolonged labor incidence. However, it did not differ in effect on immediate neonatal health but was found to have more potential for reducing maternal vomiting as compared to usual care with unrestricted oral intake. Further research is needed to explore its effects in the larger and more diverse populations and with different IV fluids for evidence-based guidelines.


Improvement of stone fragmentation during shock-wave lithotripsy using a combined EH/PEAA shock-wave generator-in vitro experiments.
To control the collapse of cavitation bubbles induced during shock-wave lithotripsy (SWL), a piezoelectric annular array (PEAA) shock-wave generator was fabricated and combined with an experimental electrohydraulic (EH) shock-wave lithotripter with a truncated HM-3 reflector. The PEAA generator consists of eight individual transducers of 200-kHz resonant frequency. At a discharge voltage of 15 kV, the PEAA generator produces a shock wave with a peak positive pressure of 8.2 MPa, a positive half cycle duration of 2.9 micros, and a -6-dB beam width of 5 mm. The trigger of the PEAA generator was controlled via fiberoptic link with reference to the spark discharge of the EH generator. Hence, the PEAA-generated shock wave could be used to interact with cavitation bubbles induced by the EH source at various stages of their oscillation. The duration of bubble oscillation during SWL was monitored by a 2.25-MHz focused hydrophone, and this information was used to control the release timing of the PEAA generator. Stone fragmentation tests in vitro were carried out, and demonstrated that stone comminution could be significantly enhanced when the shock wave-bubble interaction occurred during the collapsing phase of the bubbles. A maximum increment of 60% to 80% in stone fragmentation was achieved when the PEAA-generated shock wave arrives near the collapse of the bubbles. Under these conditions, much intensified collapse of the bubbles near the surface of the stone, with strong secondary shock-wave emission and increased stress concentration at the impact site of the solid boundary, was observed using high-speed shadowgraph and photoelastic imaging.


Induction of resistance and expression of defense-related genes in tobacco leaves infiltrated with Ralstonia solanacearum.
Ralstonia solanacearum 8107 (8107) is non-pathogenic to tobacco and elicits the hypersensitive response (HR). In Nicotiana tabacum cv. Samsun NN leaves infiltrated with 8107, acquired resistance to challenging tobacco mosaic virus (TMV) was induced 2-6 d after 8107-infiltration. hsr203J and hin1 genes were expressed only in the 8107-infiltrated area. On the other hand, the expression of PR-1a and PR-1b genes was not detected in the 8107-infiltrated area, but in areas other than that developing the HR. Expression of these PR-1 genes was regulated simultaneously and the kinetics of the expression was dependent on the distance from the infiltration area. Therefore, diffusible signal(s) might be produced in HR-causing cells and transmitted to peripheral cells resulting in expression of PR genes. In NahG10 tobacco infiltrated with 8107, the HR was induced but resistance to TMV was not. Analysis using NahG10 tobacco also showed that the salicylic acid (SA)-dependent signal regulated the expression of hsr203J and PR-1a, but not that of hin1 and PR-1b. These results suggest that resistance of tobacco to 8107 is SA-independent and involves a quite different mechanism from acquired resistance to TMV induced by 8107-infiltration which is SA-dependent.


Adhesion to coral surface as a potential sink for marine microplastics.
Only 1% of plastic entering the ocean is found floating on its surface, with high loads in ocean accumulation zones and semi-enclosed seas, except for the Red Sea, which supports one of the lowest floating plastic loads worldwide. Given the extension of reefs in the Red Sea, we hypothesize a major role of scleractinian corals as sinks, through suspension-feeding, and assessed microplastic removal rates by three Red Sea coral species. Experimental evidence showed removal rates ranging from 0.25 × 10-3 to 14.8 × 10-3 microplastic particles polyp-1 hour-1, among species. However, this was only 2.2 ± 0.6% of the total removal rate, with passive removal through adhesion to the coral surface being 40 times higher than active removal through suspension-feeding. These results point at adhesion of plastic to coral reef structures as a major sink for microplastics suspended in the water column after sinking, helping explain low concentrations in Red Sea surface waters.


Cranial magnetic resonance imaging mistakenly suggests prenatal ischaemia in PEHO-like syndrome.
We describe two sisters with a PEHO-like syndrome. The first-born had early epileptic spasms with hypsarrhythmia, visual inattention with optic atrophy, progressive microcephaly and absence of development. Cranial magnetic resonance imaging revealed periventricular white matter changes. Cerebellar hypoplasia, characteristic of true PEHO syndrome, was absent. The MRI changes were interpreted as periventricular leucomalacia due to prenatal ischaemia, and a low recurrence risk was suggested. Subsequently, the younger sister was born similarly affected. The PEHO syndrome (progressive encephalopathy, hypsarrhythmia and optic atrophy) is a rare, autosomal recessive, encephalopathy of infancy. Diagnosis is clinical but cerebellar hypoplasia on neuroimaging is regarded as an additional necessary criterion. A heterogeneous group of PEHO-like patients, who lack cerebellar hypoplasia but have varying supratentorial abnormalities, have been reported. This is the second report of siblings with a PEHO-like syndrome, and supports the existence of a distinct, autosomal recessive condition in which neuroimaging abnormalities may be misinterpreted.


Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase.
Gluten sensitivity typically presents as celiac disease, a chronic, autoimmune-mediated, small-intestinal disorder. Neurological disorders occur with a frequency of up to 10% in these patients. However, neurological dysfunction can also be the sole presenting feature of gluten sensitivity. Development of autoimmunity directed toward different members of the transglutaminase gene family could offer an explanation for the diversity in manifestations of gluten sensitivity. We have identified a novel neuronal transglutaminase isozyme and investigated whether this enzyme is the target of the immune response in patients with neurological dysfunction. Using recombinant human transglutaminases, we developed enzyme-linked immunosorbent assays and inhibition assays to analyze serum samples of patients with gluten-sensitive gastrointestinal and neurological disorders, and various control groups including unrelated inherited or immune conditions for the presence and specificity of autoantibodies. Whereas the development of anti-transglutaminase 2 IgA is linked with gastrointestinal disease, an anti-transglutaminase 6 IgG and IgA response is prevalent in gluten ataxia, independent of intestinal involvement. Such antibodies are absent in ataxia of defined genetic origin or in healthy individuals. Inhibition studies showed that in those patients with ataxia and enteropathy, separate antibody populations react with the two different transglutaminase isozymes. Furthermore, postmortem analysis of brain tissue showed cerebellar IgA deposits that contained transglutaminase 6. Antibodies against transglutaminase 6 can serve as a marker in addition to human leukocyte antigen type and detection of anti-gliadin and anti-transglutaminase 2 antibodies to identify a subgroup of patients with gluten sensitivity who may be at risk for development of neurological disease.


Electrical autonomic correlates of emotion.
This paper focussed on how electrophysiological autonomic data may contribute to better understand neural substrates of emotional processing. The utility of autonomic electrophysiological markers for assessing emotional and cognitive processes is presented in the context of an important bodily arousal interface. Components of general autonomic control are reviewed and relevant neural modulations of specific autonomic variables were discussed. The role of autonomic feedback on central processes is emphasized and neural influences on autonomic activities as an index of arousal dimension, the electrodermal activity (EDA), are outlined. An overview of brain mechanisms governing generation and control of EDA is presented, and the contribution of electrodermal parameters as indices of emotional activation illustrated by data related to diurnal emotional reactivity and to non consciously subjective emotionality. Conclusions highlight the role of electrical autonomic expressions as tools to explore emotional components of mind-body-mind relationships.


Determining diet from faeces: Selection of metabarcoding primers for the insectivore Pyrenean desman (Galemys pyrenaicus).
Molecular techniques allow non-invasive dietary studies from faeces, providing an invaluable tool to unveil ecological requirements of endangered or elusive species. They contribute to progress on important issues such as genomics, population genetics, dietary studies or reproductive analyses, essential knowledge for conservation biology. Nevertheless, these techniques require general methods to be tailored to the specific research objectives, as well as to substrate- and species-specific constraints. In this pilot study we test a range of available primers to optimise diet analysis from metabarcoding of faeces of a generalist aquatic insectivore, the endangered Pyrenean desman (Galemys pyrenaicus, É. Geoffroy Saint-Hilaire, 1811, Talpidae), as a step to improve the knowledge of the conservation biology of this species. Twenty-four faeces were collected in the field, DNA was extracted from them, and fragments of the standard barcode region (COI) were PCR amplified by using five primer sets (Brandon-Mong, Gillet, Leray, Meusnier and Zeale). PCR outputs were sequenced on the Illumina MiSeq platform, sequences were processed, clustered into OTUs (Operational Taxonomic Units) using UPARSE algorithm and BLASTed against the NCBI database. Although all primer sets successfully amplified their target fragments, they differed considerably in the amounts of sequence reads, rough OTUs, and taxonomically assigned OTUs. Primer sets consistently identified a few abundant prey taxa, probably representing the staple food of the Pyrenean desman. However, they differed in the less common prey groups. Overall, the combination of Gillet and Zeale primer sets were most cost-effective to identify the widest taxonomic range of prey as well as the desman itself, which could be further improved stepwise by adding sequentially the outputs of Leray, Brandon-Mong and Meusnier primers. These results are relevant for the conservation biology of this endangered species as they allow a better characterization of its food and habitat requirements.


Intercalary spacers in the treatment of segmentally destructive diaphyseal humeral lesions in disseminated malignancies.
During a 10-year period, 17 patients with segmentally destructive bone lesions of the humeral diaphysis in disseminated malignancies resulting in impending fracture (8 patients), pathologic fracture (6 patients), or failure of attempted internal fixation techniques (3 patients) were treated with resection of the involved diaphyseal segment and reconstruction with a cemented modular intercalary humeral spacer. Fourteen patients had metastatic cancer, 2 had multiple myeloma, and 1 had lymphoma. Breast and renal carcinoma were the most common pathologic diagnoses. The involved site was within the middle 1/3 in 8 patients, in the proximal-middle junction in 5, in the middle-distal junction in 2, and within the proximal and distal 1/3 in 1 patient each. Early pain relief was successful in 88% of patients. Early in the postoperative hospital course, patients generally were able to use the ipsilateral hand to assist feeding. Radiographic analysis revealed that the limited selection of stem lengths led to 76% of the distal stems and 47% of the proximal stems being shorter than the ideal length. The complication rate independent of disease progression was 29%. The most common complication was temporary radial nerve injury (3 patients). There were 3 implant failures, most commonly due to disengagement of the male-female junction. Two periprosthetic fractures occurred, 1 proximally (due to tumor progression) and 1 distally. Suggestions are given for modification of the implants to improve the major problems of limited versatility in intramedullary stem length and inadequate mating at the junction.


Variation of interferon production during the cell cycle.
The capacity of cells to produce interferon has been found to depend on the phase in the cell cycle at which virus infection took place. Monolayer cultures of L cells were synchronized by the double thymidine-block method. Such synchronously growing cultures were used to study the ability of cells to produce interferon when they were infected with ultraviolet-inactivated Newcastle disease virus (UV-NDV) at different phases of the cell cycle. In all instances, interferon was detected early and reached a maximum at about 16 hr after infection. However, the levels of interferon found in medium of cultures infected at early post-deoxyribonucleic acid (DNA) synthetic (G2) and to some extent at late G2 phases of the cell cycle were comparatively lower than those found in cultures infected at the early DNA synthetic (S) phase. There appeared also in these infected growing cultures a transient period when interferon production was apparently delayed. This period corresponded interestingly with the time of mitotic burst. Infection of thymidine- or 1-beta-d-arabino-furanosylcytosine-inhibited cultures with UV-NDV also led to similar interferon response as that observed in growing cultures infected at early S. However, no transient delay of interferon production was demonstrated in these cultures.


Semen volume and sperm concentration in the ferret (Mustela putorius).
Semen was obtained from 40 of 62 attempted electro-ejaculations of nine anesthetized male ferrets. The ejaculations were performed using a bi-polar rectal electrode and an electrical stimulus of about 4 V and 0.35 mA applied for approximately 4 seconds and repeated at 10-second intervals. The mean number of stimuli required to obtain an ejaculation was 12.3. The spermatozoa concentration per mm3 ranged from 0.07 x 10(6) to 1.98 x 10(6) with a mean of 0.62 x 10(6). The mean number of spermatozoa per ejaculate was 16.35 x 10(6) and the mean volume of semen per ejaculate was 0.026 ml.


Stress sensitivity and the development of affective disorders.
Depressive disorders are the most common form of mental illness in America, affecting females twice as often as males. The great variability of symptoms and responses to therapeutic treatment emphasize the complex underlying neurobiology of disease onset and progression. Evidence from human and animal studies reveals a vital link between individual stress sensitivity and the predisposition toward mood disorders. While the stress response is essential for maintenance of homeostasis and survival, chronic stress and maladaptive responses to stress insults can lead to depression or other affective disorders. A key factor in the mediation of stress responsivity is the neuropeptide corticotropin-releasing factor (CRF). Studies in animal models of heightened stress sensitivity have illustrated the involvement of CRF downstream neurotransmitter targets, including serotonin and norepinephrine, in the profound neurocircuitry failure that may underlie maladaptive coping strategies. Stress sensitivity may also be a risk factor in affective disorder development susceptibility. As females show an increased stress response and recovery time compared to males, they may be at an increased vulnerability for disease. Therefore, examination of sex differences in CRF and downstream targets may aid in the elucidation of the underlying causes of the increased disease presentation in females. While we continue to make progress in our understanding of mood disorder etiology, we still have miles to go before we sleep. As an encouraging number of new animal models of altered stress sensitivity and negative stress coping strategies have been developed, the future looks extremely promising for the possibility of a new generation of drug targets to be developed.


An evaluation of radical prostatectomy at Veterans Affairs Medical Centers: time trends and geographic variation in utilization and outcomes.
To examine temporal trends and geographic variation in utilization of radical prostatectomy (RP) as well as 30-day mortality and complication rates. Administrative data-base study of radical prostatectomy (RP) using the Department of Veterans Affairs Patient Treatment File and Outpatient Clinic File between 1986 to 1996. Logistic regression was used to estimate temporal and geographic effects on the use of RP. All Departments of Veterans Affairs Medical Centers (VAMC) in the contiguous United States. Men aged 45 to 84 years who underwent RP at a VAMC (n = 13,398). Number and utilization of RP, rate of 30-day mortality, major cardiopulmonary or vascular complications, and colorectal injuries requiring surgical repair within 30 days of RP. From 1986 to 1996, the annual number of RP at VAMCs (range, 695-1,545 RP) more than doubled, and the rate of RP at VAMCs per male VA user increased by 40% (range, 48/100,000-66/100,000). After controlling for age and year, the utilization of RP in West North Central, Mountain, West South Central, and Pacific census divisions was 70%, 14%, 10%, and 8% higher, respectively, whereas the utilization of RP in New England, East North Central, and Mid-Atlantic divisions was 38%, 31%, and 25% lower, respectively, than the rest of the nation (P<0.001). Geographic variation in utilization decreased during the period between 1986 and 1996, but a twofold difference in RP utilization in 1996 remained between high- and low-utilization divisions. Major cardiopulmonary complications, vascular complications, and colorectal injuries occurred in 1.7%, 0.2%, and 1.8% of men, respectively. Thirty-day mortality was 0.73%, declined from 1986 to 1996, and was associated with a history of diabetes and congestive heart failure. Utilization of RP at VAMCs increased over time and varied across geographic areas. Thirty-day mortality was less than 1% and decreased with time. Differences in utilization may be caused by uncertainty regarding the effectiveness of early detection and treatment of prostate cancer.


Effects of 1 year of exercise training versus combined exercise training and weight loss on body composition, low-grade inflammation and lipids in overweight patients with coronary artery disease: a randomized trial.
Dyslipidaemia and low-grade inflammation are central in atherogenesis and linked to overweight and physical inactivity. Lifestyle changes are important in secondary prevention of coronary artery disease (CAD). We compared the effects of combined weight loss and interval training with interval training alone on physical fitness, body composition, dyslipidaemia and low-grade inflammation in overweight, sedentary participants with CAD. Seventy CAD patients, BMI 28-40 kg/m2 and age 45-75 years were randomised to (1) 12 weeks' aerobic interval training (AIT) at 90% of peak heart rate three times/week followed by 40 weeks' AIT twice weekly or (2) a low energy diet (LED) (800-1000 kcal/day) for 8-10 weeks followed by 40 weeks' weight maintenance including AIT twice weekly and a high-protein/low-glycaemic load diet. Effects of the intervention were evaluated by physical fitness, body weight and composition. Dyslipidaemia was described using both biochemical analysis of lipid concentrations and lipoprotein particle subclass distribution determined by density profiling. Low-grade inflammation was determined by C-reactive protein, soluble urokinase-type plasminogen activator receptor and tumour necrosis factor α. Effects on continuous outcomes were tested by mixed-models analysis. Twenty-six (74%) AIT and 29 (83%) LED + AIT participants completed the study. At baseline subject included 43 (78%) men; subjects averages were: age 63 years (6.2), body weight 95.9 kg (12.2) and VO2peak 20.7 mL O2/kg/min (4.9). Forty-six (84%) had pre-diabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). LED + AIT reduced body weight by 7.2 kg (- 8.4; - 6.1) and waist circumference by 6.6 cm (- 7.7; - 5.5) compared to 1.7 kg (- 0.7; - 2.6) and 3.3 cm (- 5.1; - 1.5) after AIT (within-group p < 0.001, between-group p < 0.001 and p = 0.018, respectively). Treatments caused similar changes in VO2peak and lowering of total cholesterol, triglycerides, non-HDL cholesterol and low-grade inflammation. A shift toward larger HDL particles was seen following LED + AIT while AIT elicited no change. Both interventions were feasible. Both groups obtained improvements in VO2peak, serum-lipids and inflammation with superior weight loss and greater central fat loss following LED + AIT. Combined LED induced weight loss and exercise can be recommended to CAD patients. Trial registration NCT01724567, November 12, 2012, retrospectively registered (enrolment ended in April 2013).


Volitional control of saccadic adaptation.
Saccadic adaptation is assumed to be driven by an unconscious and automatic mechanism. We wondered if the adaptation process is accessible to volitional control, specifically whether any change in saccade gain can be inhibited. Participants were exposed to post-saccadic error by using the double-step paradigm in which a target is presented in a peripheral location and then stepped during the saccade to another location. In one condition, participants were instructed to follow the target step and look at the final target location. In the other condition they were instructed to inhibit the adjustment of saccade amplitude and look at the initial target location. We conducted two experiments, which differed in the size of the intra-saccadic target step. We found that when told to inhibit amplitude adjustment, gain change was close to zero for outward steps, but some adaptation remained for inward steps. Saccadic latency was not affected by the instruction type for inward steps, but when the target was stepped outward, latencies were longer in the inhibition than in the adaptation condition. The results show that volitional control can be exerted on saccadic adaptation. We suggest that volitional control affects the remapping of the target, thus having a larger impact on outward adaptation.