Association of Dual LRRK2 G2019S and GBA Variations With Parkinson Disease Progression.
Despite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual LRRK2 and GBA variations Parkinson disease (PD) than in GBA variation PD alone. To evaluate the association of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in PD. This longitudinal cohort study of continuous measures in LRRK2 PD, GBA PD, LRRK2/GBA PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-LRRK2-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for GBA and LRRK2 variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020. The associations of LRRK2 G2019S and GBA genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale-Part III scores were examined using linear mixed effects models with PD duration as the time scale. Among 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had GBA PD, 155 (13.0%) had LRRK2 PD, 21 (1.8%) had LRRK2/GBA PD, and 889 (74.5%) had idiopathic PD. Patients with GBA PD had faster decline in MoCA than those with LRRK2/GBA PD (B [SE], -0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], -0.33 [0.09] points/y; P < .001), or idiopathic PD (B [SE], -0.23 [0.08] points/y; P = .005). There was a LRRK2 G2019S × GBA interaction in MoCA decline (B [SE], 0.22 [0.11] points/y; P = .04), but not after excluding severe GBA variations (B [SE], 0.12 [0.11] points/y; P = .28). Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004). These findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD. This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe GBA variation is warranted.


Groundwater sustainability: Developing a non-cooperative optimal management scenario in shared groundwater resources under water bankruptcy conditions.
Groundwater level drawdown changes the hydrological cycle and poses challenges such as land subsidence and reduction of the groundwater quality. In this study, a new approach using a simulation-optimization framework was developed for shared groundwater management under water bankruptcy conditions (where water demand is greater than the allowable discharge capacity of water resources). The novelty of this study lies in using bankruptcy rules and a game model to manage a bankrupted shared groundwater resource considering aquifer sustainability. Accordingly, groundwater flow in the aquifer was numerically simulated by a finite-differences model (MODFLOW). Then, the repeated performance code of the finite-differences model was run for different discharge scenarios, and the results were applied to develop an MLP-ANN meta-model. By coupling the meta-model with a non-dominated sorting genetic algorithm II (NSGA-II)-based multi-objective optimization model, an optimized cultivation pattern under water bankruptcy conditions was achieved. Then, six different bankruptcy methods were utilized to specify groundwater allocation between three stakeholders. To manage the water bankruptcy conditions, different scenarios considering various groundwater extraction rates and cultivation areas were defined, and the optimization model was recoded for each scenario to find the corresponding optimized cultivation pattern. To consider the competition between stakeholders for groundwater extraction, a non-cooperative 3-player game was applied to achieve a compromise for different combinations of management strategies, which maximizes the profit and yields the best cultivation scenario. Applicability of the proposed methodology was investigated in an aquifer system located in Golestan Province, Iran, including three regions (Minudasht, Azadshahr, and Gonbade-kavus). Results show that the proposed method is capable of managing the bankruptcy conditions by generating greater agricultural profit and reducing groundwater drawdowns.


Diagnosis of cerebral amyloid angiopathy by enzyme-linked immunosorbent assay of cystatin C in cerebrospinal fluid.
An abnormally low level of cystatin C in the cerebrospinal fluid is a diagnostic marker for the hereditary form of brain hemorrhage associated with amyloidosis that was first identified in Iceland. We developed an assay for cystatin C to use in the diagnosis of patients with cerebral amyloid angiopathy and brain hemorrhage. This test consists of a sandwich enzyme-linked immunosorbent assay using monoclonal mouse anticystatin C and polyclonal rabbit anticystatin C antibodies. The cystatin C level was assayed in cerebrospinal fluid samples from 29 patients with brain hemorrhage and 45 control patients with other neurological diseases. Fifteen patients with brain hemorrhage showed low cystatin C levels (less than or equal to 70 ng/ml) in a clinical setting in which the positive and negative findings were compatible with a diagnosis of cerebral amyloid angiopathy. Immunohistological examination of brain tissue obtained by biopsy from two of the 15 patients confirmed the diagnosis of cerebral amyloid angiopathy and identified the deposition of cystatin C and beta-protein. This enzyme-linked immunosorbent assay is simple to perform and may be useful for investigating patients suspected of having cerebral amyloid angiopathy with brain hemorrhage and the deposition of cystatin C.


Discovery and Development of the Aryl O-Sulfamate Pharmacophore for Oncology and Women's Health.
In 1994, following work from this laboratory, it was reported that estrone-3-O-sulfamate irreversibly inhibits a new potential hormone-dependent cancer target steroid sulfatase (STS). Subsequent drug discovery projects were initiated to develop the core aryl O-sulfamate pharmacophore that, over some 20 years, have led to steroidal and nonsteroidal drugs in numerous preclinical and clinical trials, with promising results in oncology and women's health, including endometriosis. Drugs have been designed to inhibit STS, e.g., Irosustat, as innovative dual-targeting aromatase-steroid sulfatase inhibitors (DASIs) and as multitargeting agents for hormone-independent tumors, such as the steroidal STX140 and nonsteroidal counterparts, acting inter alia through microtubule disruption. The aryl sulfamate pharmacophore is highly versatile, operating via three distinct mechanisms of action, and imbues attractive pharmaceutical properties. This Perspective gives a personal view of the work leading both to the therapeutic concepts and these drugs, their current status, and how they might develop in the future.


Exploring the role of water in molecular recognition: predicting protein ligandability using a combinatorial search of surface hydration sites.
The interaction between any two biological molecules must compete with their interaction with water molecules. This makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. A small molecule binding to a protein is able to recognize a unique binding site on a protein by displacing bound water molecules from specific hydration sites. Quantifying the interactions of these water molecules allows us to estimate the potential of the protein to bind a small molecule. This is referred to as ligandability. In the study, we describe a method to predict ligandability by performing a search of all possible combinations of hydration sites on protein surfaces. We predict ligandability as the summed binding free energy for each of the constituent hydration sites, computed using inhomogeneous fluid solvation theory. We compared the predicted ligandability with the maximum observed binding affinity for 20 proteins in the human bromodomain family. Based on this comparison, it was determined that effective inhibitors have been developed for the majority of bromodomains, in the range from 10 to 100 nM. However, we predict that more potent inhibitors can be developed for the bromodomains BPTF and BRD7 with relative ease, but that further efforts to develop inhibitors for ATAD2 will be extremely challenging. We have also made predictions for the 14 bromodomains with no reported small molecule K d values by isothermal titration calorimetry. The calculations predict that PBRM1(1) will be a challenging target, while others such as TAF1L(2), PBRM1(4) and TAF1(2), should be highly ligandable. As an outcome of this work, we assembled a database of experimental maximal K d that can serve as a community resource assisting medicinal chemistry efforts focused on BRDs. Effective prediction of ligandability would be a very useful tool in the drug discovery process.


Combined Imaging Markers Dissociate Alzheimer's Disease and Frontotemporal Lobar Degeneration - An ALE Meta-Analysis.
To compare and dissociate the neural correlates of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), we combine and synthesize here recent comprehensive meta-analyses. Systematic and quantitative meta-analyses were conducted according to the QUOROM statement by calculating anatomical likelihood estimates (ALE). AD (n = 578) and the three subtypes of FTLD, frontotemporal dementia, semantic dementia (SD), and progressive non-fluent aphasia (n = 229), were compared in conjunction analyses, separately for atrophy and reductions in glucose metabolism. Atrophy coincided in the amygdala and hippocampal head in AD and the FTLD subtype SD. The other brain regions did not show any overlap between AD and FTLD subtypes for both atrophy and changes in glucose metabolism. For AD alone (n = 826), another conjunction analysis revealed a regional dissociation between atrophy and hypoperfusion/hypometabolism, whereby hypoperfusion and hypometabolism coincided in the angular/supramarginal gyrus and inferior precuneus/posterior cingulate gyrus. Our data together with other imaging studies suggest a specific dissociation of AD and FTLD if, beside atrophy, additional imaging markers in AD such as abnormally low parietal glucose utilization and perfusion are taken into account. Results support the incorporation of standardized imaging inclusion criteria into future diagnostic systems, which is crucial for early individual diagnosis and treatment in the future.


Development of functional hydrogels for heart failure.
Although some advanced treatments of heart failure (HF) have experienced great development in recent decades, morbidity and mortality associated with HF have not improved significantly. Hydrogels have some unique advantages for the delivery and controlled release of bioactive molecules, drugs, and cells, which can directly affect the heart locally. Many studies have shown that hydrogels represent a new approach for the treatment of HF. In this review, we present a current perspective of hydrogel-based approaches for cardiac tissue engineering and myocardial regeneration in ischemia-induced HF, with an emphasis on functional studies, translation, and clinical advancements.


Opisthotonic posturing with neuromuscular irritability attributable to 4-aminopyridine ingestion by a healthy pediatric patient.
4-Aminopyridine (4-AP) is a potassium channel blocker used to increase muscle strength in the treatment of demyelinating diseases such as multiple sclerosis. We describe a case of ingestion by an 8-month-old child that resulted in severe but transient symptoms. An 8-month-old boy was found with greenish saliva, and a capsule with green 4-AP powder was missing. On arrival to an emergency department, he was jittery, tachycardic, and tachypneic. Activated charcoal, a cathartic, and midazolam (0.5 mg/kg) were administered before transfer to a tertiary pediatric hospital. On arrival, the infant remained tachycardic and tachypneic. His eyes deviated upward and he was noted to have 3+ deep tendon reflexes bilaterally. He was administered 0.9% normal saline (20 mL/kg) for a wide pulse pressure with low diastolic blood pressure. The patient developed dramatic opisthotonic posturing and vermiform tongue fasciculations. The symptoms responded well to repeated intravenous doses of benzodiazepines. In this case, we used 2 doses of lorazepam (0.05 mg/kg each). During opisthotonic posturing, an electroencephalogram performed in the intensive care unit revealed no evidence of seizure activity. Within 20 hours after admission, the patient became asymptomatic. This case is, to our knowledge, the first documented pediatric 4-AP ingestion. Clinical signs and symptoms are described as well as the response to therapy with benzodiazepines. The electroencephalogram performed while the patient was symptomatic was negative for seizures.


Rapid diagnosis of extrapulmonary tuberculosis with Xpert Mycobacterium tuberculosis/rifampicin assay.
XpertMycobacterium tuberculosis/rifampicin (Xpert MTB/RIF) assay has been endorsed by the World Health Organization (WHO) for diagnosis of extrapulmonary tuberculosis (EPTB), while the sensitivity and specificity have not been fully evaluated. We aimed to evaluate the performance of Xpert MTB/RIF assay in the detection of different extrapulmonary specimens. A total of 420 nonrespiratory specimens were detected with acid-fast bacilli (AFB) smear microscopy, solid culture, conventional drug susceptibility testing (DST) and Xpert MTB/RIF assay. Using solid culture and conventional DST as the gold standard, we assessed the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of the Xpert MTB/RIF assay for detecting MTB and rifampin resistance, respectively. When setting the solid culture results as the gold standard, the sensitivity, specificity, PPV, NPV and Kappa value of Xpert MTB/RIF assay and AFB smear results were 70.6 % (48/68), 91.96 % (318/346), 63.2 % (48/76), 94.1 % (318/338), 0.60, respectively. In addition, when compared with conventional DST results, the sensitivity, specificity, PPV, NPV and Kappa of the Xpert MTB/RIF assay for detecting rifampin resistance were 91.7 % (11/12), 100.0 % (47/47), 100.0 % (11/11), 97.9 % (47/48) and 0.95, respectively. Compared with AFB smear and solid culture, Xpert MTB/RIF assay has high sensitivities and short detection time, so could be used as an alternative for the rapid diagnosis of EPTB and rifampin resistance in clinical practice.


Free-standing supercapacitors from Kraft lignin nanofibers with remarkable volumetric energy density.
We have discovered a very simple method to address the challenge associated with the low volumetric energy density of free-standing carbon nanofiber electrodes for supercapacitors by electrospinning Kraft lignin in the presence of an oxidizing salt (NaNO3) and subsequent carbonization in a reducing atmosphere. The presence of the oxidative salt decreases the diameter of the resulting carbon nanofibers doubling their packing density from 0.51 to 1.03 mg cm-2 and hence doubling the volumetric energy density. At the same time, the oxidative NaNO3 salt eletrospun and carbonized together with lignin dissolved in NaOH acts as a template to increase the microporosity, thus contributing to a good gravimetric energy density. By simply adjusting the process parameters (amount of oxidizing/reducing agent), the gravimetric and volumetric energy density of the resulting lignin free-standing carbon nanofiber electrodes can be carefully tailored to fit specific power to energy demands. The areal capacitance increased from 147 mF cm-2 in the absence of NaNO3 to 350 mF cm-2 with NaNO3 translating into a volumetric energy density increase from 949 μW h cm-3 without NaNO3 to 2245 μW h cm-3 with NaNO3. Meanwhile, the gravimetric capacitance also increased from 151 F g-1 without to 192 F g-1 with NaNO3.


Raising the priority of preventing chronic diseases: a political process.
Chronic diseases, especially cardiovascular diseases, diabetes, cancer, and chronic obstructive respiratory diseases,are neglected globally despite growing awareness of the serious burden that they cause. Global and national policies have failed to stop, and in many cases have contributed to, the chronic disease pandemic. Low-cost and highly effective solutions for the prevention of chronic diseases are readily available; the failure to respond is now a political, rather than a technical issue. We seek to understand this failure and to position chronic disease centrally on the global health and development agendas. To identify strategies for generation of increased political priority for chronic diseases and to further the involvement of development agencies, we use an adapted political process model. This model has previously been used to assess the success and failure of social movements. On the basis of this analysis,we recommend three strategies: reframe the debate to emphasise the societal determinants of disease and the interrelation between chronic disease, poverty, and development; mobilise resources through a cooperative and inclusive approach to development and by equitably distributing resources on the basis of avoidable mortality; and build one merging strategic and political opportunities, such as the World Health Assembly 2008–13 Action Plan and the high level meeting of the UN General Assembly in 2011 on chronic disease. Until the full set of threats—which include chronic disease—that trap poor households in cycles of debt and illness are addressed, progress towards equitable human development will remain inadequate.


Tissue damage markers after a spinal manipulation in healthy subjects: a preliminary report of a randomized controlled trial.
Spinal manipulation (SM) is a manual therapy technique frequently applied to treat musculoskeletal disorders because of its analgesic effects. It is defined by a manual procedure involving a directed impulse to move a joint past its physiologic range of movement (ROM). In this sense, to exceed the physiologic ROM of a joint could trigger tissue damage, which might represent an adverse effect associated with spinal manipulation. The present work tries to explore the presence of tissue damage associated with SM through the damage markers analysis. Thirty healthy subjects recruited at the University of Jaén were submitted to a placebo SM (control group; n = 10), a single lower cervical manipulation (cervical group; n = 10), and a thoracic manipulation (n = 10). Before the intervention, blood samples were extracted and centrifuged to obtain plasma and serum. The procedure was repeated right after the intervention and two hours after the intervention. Tissue damage markers creatine phosphokinase (CPK), lactate dehydrogenase (LDH), C-reactive protein (CRP), troponin-I, myoglobin, neuron-specific enolase (NSE), and aldolase were determined in samples. Statistical analysis was performed through a 3 × 3 mixed-model ANOVA. Neither cervical manipulation nor thoracic manipulation did produce significant changes in the CPK, LDH, CRP, troponin-I, myoglobin, NSE, or aldolase blood levels. Our data suggest that the mechanical strain produced by SM seems to be innocuous to the joints and surrounding tissues in healthy subjects.


A neural signature of contextually mediated intentional forgetting.
The mental context in which we experience an event plays a fundamental role in how we organize our memories of an event (e.g. in relation to other events) and, in turn, how we retrieve those memories later. Because we use contextual representations to retrieve information pertaining to our past, processes that alter our representations of context can enhance or diminish our capacity to retrieve particular memories. We designed a functional magnetic resonance imaging (fMRI) experiment to test the hypothesis that people can intentionally forget previously experienced events by changing their mental representations of contextual information associated with those events. We had human participants study two lists of words, manipulating whether they were told to forget (or remember) the first list prior to studying the second list. We used pattern classifiers to track neural patterns that reflected contextual information associated with the first list and found that, consistent with the notion of contextual change, the activation of the first-list contextual representation was lower following a forget instruction than a remember instruction. Further, the magnitude of this neural signature of contextual change was negatively correlated with participants' abilities to later recall items from the first list.


64Cu- and 68Ga-labelled [Nle(14),Lys(40)(Ahx-NODAGA)NH2]-exendin-4 for pancreatic beta cell imaging in rats.
Glucagon-like peptide-1 receptor (GLP-1R) is a molecular target for imaging of pancreatic beta cells. We compared the ability of [Nle(14),Lys(40)(Ahx-NODAGA-(64)Cu)NH2]-exendin-4 ([(64)Cu]NODAGA-exendin-4) and [Nle(14),Lys(40)(Ahx-NODAGA-(68)Ga)NH2]-exendin-4 ([(68)Ga]NODAGA-exendin-4) to detect native pancreatic islets in rodents. The stability, lipophilicity and affinity of the radiotracers to the GLP-1R were determined in vitro. The biodistribution of the tracers was assessed using autoradiography, ex vivo biodistribution and PET imaging. Estimates for human radiation dosimetry were calculated. We found GLP-1R-specific labelling of pancreatic islets. However, the pancreas could not be visualised in PET images. The highest uptake of the tracers was observed in the kidneys. Effective dose estimates for [(64)Cu]NODAGA-exendin-4 and [(68)Ga]NODAGA-exendin-4 were 0.144 and 0.012 mSv/MBq, respectively. [(64)Cu]NODAGA-exendin-4 might be more effective for labelling islets than [(68)Ga]NODAGA-exendin-4. This is probably due to the lower specific radioactivity of [(68)Ga]NODAGA-exendin-4 compared to [(64)Cu]NODAGA-exendin-4. The radiation dose in the kidneys may limit the use of [(64)Cu]NODAGA-exendin-4 as a clinical tracer.


Oseltamivir use in low-birth weight infants during the 2009 nH1N1 influenza a outbreak in the Western Cape, South Africa.
Before vaccination against nH1N1 influenza was available in South Africa our hospital experienced an outbreak of nH1N1 infection on the maternal and neonatal platform. Oseltamivir was administered to nine low birth weight infants, five for therapy and four for prophylaxis. The median gestational age was 31 (27-37) weeks and the birth weight was 1660 (720-2360) g. Respiratory function improved in those with confirmed disease and none receiving prophylaxis developed worsening respiratory symptoms. One neonate receiving prophylaxis developed self-limiting conjunctivitis; another succumbed from necrotizing enterocolitis (NEC) three days post completion of oseltamivir treatment. A causal relationship between oseltamivir and NEC, although unlikely, cannot be confirmed or excluded.


Structures of thermophilic and mesophilic adenylate kinases from the genus Methanococcus.
The crystal structures of adenylate kinases from the thermophile Methanococcus thermolithotrophicus and the mesophile Methanococcus voltae have been solved to resolutions of 2.8A and 2.5A, respectively. The structures of the enzymes are similar to that of the adenylate kinase from archaeal Sulfolobus acidocaldarius in many respects such as the extended central beta-sheets, the short LID domain, and the trimeric state. The analysis of unligated and AMP-bound subunits of M.voltae suggests that movements of two mobile domains are not independent of each other. The methanococcal structures are examined with respect to their lack of the "invariant" Lys residue within the phosphate-binding loop, and two Arg residues in the LID domain are proposed as substituting residues based on their conservation among archaeal adenylate kinases and mobility within the structures. Since S.acidocaldarius adenylate kinase has the invariant Lys residue as well as the two Arg residues, its phosphate-binding loop is examined and compared with those of other adenylate kinases. On the basis of the comparison and other available biochemical data, the unusual conformation of the Lys residue in S.acidocaldarius adenylate kinase is explained. Despite possessing 78% sequence identity, the methanococcal enzymes exhibit significantly different thermal stabilities. To study the determinants of thermostability, several structural features including salt-links, hydrogen bonds, packing density, surface to volume ratio and buried surface area are compared between the enzymes. From their difference in apolar buried surface area, hydrophobic interaction is proposed to be a basis for the disparate thermostabilities, and the corresponding free energy difference is also estimated. Results of previous mutational studies are interpreted in terms of the crystal structures, and support the importance of hydrophobic interactions in thermostability.


Nutrition in the age-related disablement process.
The transition from independence to disability in older adults is characterized by detectable changes in body composition and physical function. Epidemiologic studies have shown that weight loss, reduced caloric intake and the reduced intake of specific nutrients are associated with such changes. The mechanisms underlying these associations remain unclear, and different hypotheses have been suggested, including the reduction of the antioxidant effects of some nutrients. Changes in muscle mass and quality might play a central role in the pathway linking malnutrition, its biological and molecular consequences, and function. A different approach aims at assessing diets by dietary patterns, which capture intercorrelations of nutrients within a diet, rather than by selective foods or nutrients: epidemiologic evidence suggests that some types of diet, such as the Mediterranean diet, might prevent negative functional outcomes in older adults. However, despite a theoretical and empirical basis, intervention studies using nutritional supplementation have shown inconclusive results in preventing functional impairment and disability. The present work is the result of a review and consensus effort of a European task force on nutrition in the elderly, promoted by the International Association of Gerontology and Geriatrics (IAGG) European Region. After the critical review of different aspects related to the role of nutrition in the transition from independence to disability, we propose future lines for research, including the determination of levels of inadequacy and target doses of supplements, the study of interactions (between nutrients within a diet and with other lifestyle aspects), and the association with functional outcomes.


Thrombocytopenia in liver disease.
To evaluate recent findings in the multifaceted pathophysiological mechanisms underlying thrombocytopenia in patients with chronic liver disease and to assess its therapeutic management. Antiplatelet antibodies, despite being observed rather frequently in patients with chronic viral liver disease, have minimal relevance in the determinism of thrombocytopenia, and antiviral treatment of the underlying liver disease does not seem to significantly affect their prevalence. Translational application of the results of studies evaluating coagulation disorders associated with liver disease seems to suggest that these may be improved by treating thrombocytopenia. Both splenectomy and partial splenic embolization are still part of the therapeutic approach to thrombocytopenia. As far as this latter technique is concerned, patient selection is fundamental, and its success likely depends upon thrombopoietin-mediated mechanisms. Eltrombopag is a promising thrombopoietic drug that proved to be able to safely increase platelet counts in patients with viral liver disease and allows the initiation of antiviral treatment. New insights into the pathophysiological mechanisms of thrombocytopenia in patients with liver disease have provided interesting clinical reflex. In these patients, novel therapies for treating thrombocytopenia seem promising, although it remains to be established whether treating thrombocytopenia may help improve liver disease-associated coagulopathy.


Absence of colony-stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice results in male fertility defects.
Previous studies have shown that the mononuclear phagocyte growth factor, colony-stimulating factor-1 (CSF-1), has an important role in female reproduction. Mating experiments with osteopetrotic (csfmop/csfmop) mice, which possess an inactivating mutation in the CSF-1 gene, suggested that there are male, as well as female, reproductive defects. In the present study, we have shown that male csfmop/csfmop mice have a sevenfold lower concentration of circulating testosterone (T) and a significantly lower intratesticular T concentration than wild-type mice. These lowered T concentrations were associated with a reduction in mating capability and a reduction in the number of viable sperm. Reconstitution of male csfmop/csfmop mice with either circulating T in the adult or circulating CSF-1 throughout the postnatal period completely restored viable sperm numbers and significantly restored sexual behavior. These observations, coupled with the close association of Leydig cells with testicular macrophages and the proposed function of these macrophages in the regulation of Leydig cell steroidogenesis, suggest that CSF-1-regulated testicular macrophages play an important role in male reproduction.


Improved color coordinates of green monochromatic pc-LED capped with a band-pass filter.
This study introduces a "greener" green monochromatic phosphor-converted light-emitting diode (pc-LED) using a band-pass filter (BPF) combined with a long-pass dichroic filter (LPDF) and a short-pass dichroic filter (SPDF) to improve the color quality of our previously developed LPDF-capped green pc-LED. This can also address the drawbacks of III-V semiconductor-type green LEDs, which show a low luminous efficacy and a poor current dependence of the efficacy and color coordinates compared to blue semiconductor-type LEDs. The optical properties of green monochromatic pc-LEDs using a BPF are compared with those of LPDF-capped green pc-LEDs, which have a broad band spectrum, and III-V semiconductor-type green LEDs by changing the transmittance wavelength range of the BPF and the peak wavelength of the green phosphors. BPF-capped green monochromatic pc-LEDs provide a high luminous efficacy (134 lm/W at 60 mA), and "greener" 1931 Commission Internationale d'Eclairage (CIE; CIEx, CIEy) color coordinates (0.24, 0.66) owing to the narrowed emission spectrum. We also propose a two-dimensional (2D) polystyrene (PS) microbead (2-μm diameter) monolayer as a scattering layer to overcome the poor angular dependence of the color coordinates of the transmitted light through a nano-multilayered dichroic filter such as an LPDF or BPF. The 2D PS scattering layer improves the angular dependence of the green color emitted from a BPF-capped green pc-LED with only 3% loss of luminous efficacy.


Acupuncture for overactive bladder: a randomized controlled trial.
To compare acupuncture treatment for overactive bladder with urge incontinence with a placebo acupuncture treatment. Eighty-five women enrolled in this randomized, placebo-controlled trial. Women were randomly assigned to either receive an acupuncture treatment expected to improve their bladder symptoms, or a placebo acupuncture treatment designed to promote relaxation. They underwent cystometric testing, completed a 3-day voiding diary, and completed the urinary distress inventory and incontinence impact questionnaire, validated quality-of-life inventories, before and after 4 weekly acupuncture treatments. The primary endpoint was number of incontinent episodes over 3 days. Secondary endpoints included voiding frequency and urgency, cystometric bladder capacity, maximum voided volume, and the urinary distress inventory and incontinence impact questionnaire symptom scores. Seventy-four women completed all aspects of the study. Women in both treatment and placebo groups had significant decreases in number of incontinent episodes (59% for treatment, 40% for placebo) without a significant difference in the change between the groups. Women in the treatment group had a 14% reduction in urinary frequency (P = .013), a 30% reduction in the proportion of voids associated with urgency (P = .016), and a 13% increase in both maximum voided volume and maximum cystometric capacity (P = .01). Both groups also had an improvement in the urinary distress inventory and incontinence impact questionnaire scores (54% decrease for treatment, 30% decrease for placebo, P < .001 for the difference in change between the groups). Women who received 4 weekly bladder-specific acupuncture treatments had significant improvements in bladder capacity, urgency, frequency, and quality-of-life scores as compared with women who received placebo acupuncture treatments. I.


Semi-viviparous embryo development and dehydrin expression in the mangrove Rhizophora mucronata Lam.
Rhizophora mucronata Lam. is a tropical mangrove with semi-viviparous (cotyledon body protrusion before shedding), non-quiescent and non-desiccating (recalcitrant) seeds. As recalcitrance has been thought to relate to the absence of desiccation-related proteins such as dehydrins, we for the first time systematically described and classified embryogenesis in R. mucronata and assessed the presence of dehydrin-like proteins. Embryogenesis largely follows the classic pattern till stage eight, the torpedo stage, with the formation of a cotyledonary body. Ovule and embryo express radical adaptations to semi-vivipary in the saline environment: (1) A large, highly vacuolated and persistent endosperm without noticeable food reserves that envelopes the developing embryo. (2) Absence of vascular tissue connections between embryo and maternal tissue, but, instead, transfer layers in between endosperm and integument and endosperm and embryo. Dehydrin-like proteins (55-65 kDa) were detected by the Western analysis, in the ovules till stage 10 when the integuments are dehisced. An additional 50 kDa band was detected at stages 6-8. Together these results suggest a continuous flow of water with nutrients from the integument via the endosperm to the embryo, circumventing the vascular route and probably suppressing the initially induced dehydrin expression.


Effects of Post-administration of β-Carotene on Diet-induced Atopic Dermatitis in Hairless Mice.
Atopic dermatitis (AD) is a cutaneous condition characterized by itchy, swollen, and dry skin, which is mediated by T helper cell-related cytokines. β-Carotene, a natural red pigment found in plants, exhibits antioxidant activity that has been shown to promote an inflammatory response. Because it is not clear whether β-carotene suppresses inflammation in AD skin tissues, we examined the effects of oral administration of β-carotene in mice induced by a low zinc/magnesium diet (HR-AD diet). Our studies found that AD-like inflammation was remarkably reduced by β-carotene. In addition, β-carotene significantly suppressed protein expression of TNF-α, IL-1β, and MCP-1 and mRNA expression of TSLP, IL-6, IL-1β, IL-4, IL-5, and Par-2 in AD-like skin tissues. It was also found that mRNA and protein expression of filaggrin (a major structural protein in epidermis) in AD-like skin was significantly elevated by β-carotene administration. Furthermore, β-carotene treatment significantly reduced the activity and/or mRNA expression of matrix metalloproteinases (MMPs), degradation of the extracellular matrix and regulation of chemokines. These results suggest that β-carotene reduces skin inflammation through the suppressed expression of inflammatory factors or the activity of MMPs as well as the promotion of filaggrin expression in AD-like skin. β-Carotene is a potent anti-inflammatory agent, which improves AD-like skin by enhancing the skin barrier function.


Pre and probiotics in the prevention and treatment of food allergy.
Recent studies on the pathogenesis of allergy in both man and experimental animals continue to show the importance of commensal bacteria in the gastrointestinal tract in stimulating and directing the immune system. The interest in modulating commensal bacterial flora with prebiotics and probiotics to prevent and treat food allergy has multiplied in recent years. Studies on prevention suggest that probiotic supplementation reduces IgE-associated eczema. It seems that prenatal administration is of importance. Colonization seems to be readily achieved, so there is proof of concept. However, after cessation of the administration, a rapid decline in colonization is evident. IgE sensitization in atopic eczema is a risk factor for allergic airways disease, and the reduced IgE-associated atopic eczema demonstrated may be an indication of less respiratory allergic disease later. Administration of probiotics to children with allergy or at risk of allergy seems to stimulate a low-grade inflammation by activating the innate immune system and further production of IL-10. Modulation of commensal bacteria of the gut with probiotics has been shown to modulate the immune system and to have an effect on both the prevention and treatment of food allergy. The effects have been highly variable depending on the mode of treatment and the optimal treatment remains unsettled at present.


Exploring critical uncertainties in pathway assessments of human-assisted introductions of alien forest species in Canada.
Long-distance introductions of alien species are often driven by socioeconomic factors, such that conventional "biological" invasion models may not be capable of estimating spread fully and reliably. In this study, we demonstrate a new technique for assessing and reconstructing human-mediated pathways of alien forest species entries to major settlements in Canada via commercial road transportation and domestic trade. We undertook our analysis in three steps. First, we used existing data on movement of commodities associated with bark- and wood-boring forest pests to build a probabilistic model of how the organisms may be moved from one location to another through a transportation network. We then used this model to generate multiple sets of predictions of species arrival rates at every location in the transportation network, and to identify the locations with the highest likelihood of new incursions. Finally, we evaluated the sensitivity of the species arrival rates to uncertainty in key model assumptions by testing the impact of additive and multiplicative errors (by respectively adding a uniform random variate or symmetric variation bounds to the arrival rate values) on the probabilities of pest transmission from one location to another, as well as the impact of the removal of one or more nodes and all connecting links to other nodes from the underlying transportation network. Overall, the identification of potential pest arrival hotspots is moderately robust to uncertainties in key modeling assumptions. Large urban areas and major border crossings that have the highest predicted species arrival rates have the lowest sensitivities to uncertainty in the pest transmission potential and to random changes in the structure of the transportation network. The roadside survey data appears to be sufficient to delineate major hubs and hotspots where pests are likely to arrive from other locations in the network via commercial truck transport. However, "pass-through" locations with few incoming and outgoing routes can be identified with lower precision. The arrival rates of alien forest pests appear to be highly sensitive to additive errors. Surprisingly, the impact of random changes in the structure of the transportation network was relatively low.


A community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol.
The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety. A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals. The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm. This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence.


Dielectric pads and low- B1+ adiabatic pulses: complementary techniques to optimize structural T1 w whole-brain MP2RAGE scans at 7 tesla.
To evaluate the combination of low-B1 (+) adiabatic pulses and high permittivity (εr ≈ 165) dielectric pads effectiveness to reproducibly improve the inversion efficiency for whole-brain MP2RAGE scans, at ultra-high field. Two low-B1 (+) adiabatic pulses, HS8 and TR-FOCI, were compared with the conventional HS1 adiabatic pulse in MP2RAGE acquisitions of four subjects at 7 Tesla. The uniform MP2RAGE images were qualitatively assessed for poor inversion artifacts by trained observers. Each subject was rescanned using dielectric pads. Eight further subjects underwent two MP2RAGE scan sessions using dielectric pads and the TR-FOCI adiabatic pulse. The HS8 and TR-FOCI pulses improved inversion coverage in all subjects compared with the HS1 pulse. However, in subjects whose head lengths are large (≥136 mm) relative to the coil's z-coverage, the B1 (+) field over the cerebellum was insufficient to cause inversion. Dielectric pads increase the B1 (+) field, by ∼50%, over the cerebellum, which in conjunction with the TR-FOCI pulse, reproducibly improves the inversion efficiency over the whole brain for subjects with head lengths ≤155 mm. Minor residual inversion artifacts were present in three of eight subjects (head lengths ≥155 mm). The complementary techniques of low-B1 (+) adiabatic RF pulses and high permittivity dielectric pads allow whole-brain structural T1 w images to be reliably acquired at ultra-high field. J. Magn. Reson. Imaging 2014;40:804-812. © 2013 Wiley Periodicals, Inc.


Jellyfish distribute vertically according to irradiance.
We tested the hypothesis that the coronate jellyfish Periphylla periphylla distributes vertically according to a preferential range of absolute light intensities. The study was carried out in Lurefjorden, Norway, a fjord characterized by mass occurrences of this jellyfish. We collected data on the vertical distribution of P. periphylla medusa during day, dusk and night periods from video observations by a remotely operated vehicle in relation to estimated ambient light levels. Our results suggest that large P. periphylla (average size in catches ~9 cm diameter) avoided total irradiance levels above 5×10-3 µmol quanta m-2 s-1. Nearly two-thirds of the population stayed above irradiance of 10-7 µmol quanta m-2 s-1 during daytime, while some individuals occupied much darker water. Thus, part of the population appeared to distribute vertically and undertake diel vertical migration (DVM) according to a preferential range of light intensities.


Human DNA polymerase alpha catalytic polypeptide binds ConA and RCA and contains a specific labile site in the N-terminus.
The catalytic polypeptide of DNA polymerase alpha is often observed in vitro as a family of phosphopolypeptides predominantly of 180 and 165 kDa derived from a single primary structure. The estimated Mr of this polypeptide deduced from the full-length cDNA is 165 kDa. Immunoblot analysis with polyclonal antibodies against peptides of the N- and C-termini of the deduced primary sequence indicates that the observed family of polypeptides from 180 kDa to lower molecular weight results from proteolytic cleavage from the N-terminus. Antibodies against the N-terminal peptide detect only the 180 kDa species suggesting that this higher molecular weight polypeptide may be the result of posttranslational modification of the 165 kDa primary translation product. The catalytic polypeptide is not only phosphorylated but is also found to react with lectins ConA and RCA. N-terminal sequencing of the isolated catalytic polypeptide from human cells and of the recombinant fusion proteins indicates that the often observed 165 kDa polypeptide is the in vitro proteolytic cleavage product of the modified 180 kDa protein at the specific site between lys123 and lys124 within the sequence -RNVKKLAVTKPNN-.


Effects of different forms of dietary hydrogenated fats on serum lipoprotein cholesterol levels.
Metabolic studies suggest that fatty acids containing at least one double bond in the trans configuration, which are found in hydrogenated fat, have a detrimental effect on serum lipoprotein cholesterol levels as compared with unsaturated fatty acids containing double bonds only in the cis configuration. We compared the effects of diets with a broad range of trans fatty acids on serum lipoprotein cholesterol levels. Eighteen women and 18 men consumed each of six diets in random order for 35-day periods. The foods were identical in each diet, and each diet provided 30 percent of calories as fat, with two thirds of the fat contributed as soybean oil (<0.5 g of trans fatty acid per 100 g of fat), semiliquid margarine (<0.5 g per 100 g), soft margarine (7.4 g per 100 g), shortening (9.9 g per 100 g), or stick margarine (20.1 g per 100 g). The effects of those diets on serum lipoprotein cholesterol, triglyceride, and apolipoprotein levels were compared with those of a diet enriched with butter, which has a high content of saturated fat. The mean (+/-SD) serum low-density lipoprotein (LDL) cholesterol level was 177+/-32 mg per deciliter (4.58+/-0.85 mmol per liter) and the mean high-density lipoprotein (HDL) cholesterol level was 45+/-10 mg per deciliter (1.2+/-0.26 mmol per liter) after subjects consumed the butter-enriched diet. The LDL cholesterol level was reduced on average by 12 percent, 11 percent, 9 percent, 7 percent, and 5 percent, respectively, after subjects consumed the diets enriched with soybean oil, semiliquid margarine, soft margarine, shortening, and stick margarine; the HDL cholesterol level was reduced by 3 percent, 4 percent, 4 percent, 4 percent, and 6 percent, respectively. Ratios of total cholesterol to HDL cholesterol were lowest after the consumption of the soybean-oil diet and semiliquid-margarine diet and highest after the stick-margarine diet. Our findings indicate that the consumption of products that are low in trans fatty acids and saturated fat has beneficial effects on serum lipoprotein cholesterol levels.


Prevalence and Risk Factors of Prostate Cancer in Chinese Men with PSA 4-10 ng/mL Who Underwent TRUS-Guided Prostate Biopsy: The Utilization of PAMD Score.
To elucidate the characteristics and risk factors for positive biopsy outcomes in Chinese patients with prostate specific antigen (PSA) 4-10 ng/mL and develop a risk-stratification score model. The data of 345 patients who underwent transrectal ultrasound-guided prostate biopsy between 2011 and 2013 was retrospectively analyzed. Digital rectal examination (DRE), prostate volume (PV), magnetic resonance imaging (MRI), and smoking status were also collected. Positive biopsy outcomes were defined as prostate cancer (PCa) and high grade PCa (HGPCa, Gleason Score ≥ 7). The median PSA was 7.15 (IQR 5.91-8.45) ng/mL. Overall 138 patients (40.0%) were shown to have PCa, including 100 patients (29.0%) with HGPCa. Smaller PV, elder age, MRI results, and positive DRE were proved to be predictive factors for positive biopsy outcomes in both univariate and multivariate analysis. We developed a "PAMD" score which combined the four factors to categorize patients into three risk groups, and the model performed good predictive sensitivity and specificity. The prevalence of prostate cancer in Chinese patients with PSA 4-10 ng/mL was 40%, including 29% patients with high grade disease. DRE, age, MRI, and PV were predictive factors for positive biopsy outcomes, and the PAMD score model could be utilized for risk-stratification and decision-making.


ZIPK is critical for the motility and contractility of VSMCs through the regulation of nonmuscle myosin II isoforms.
Migration of medial vascular smooth muscle cells (VSMCs) into the intimal layer contributes to pathological remodeling of the blood vessel in arterial hypertension and atherosclerosis. It is well established that reorganization of cytoskeletal networks is an essential component of cellular motile events. However, there is currently a lack of insight into the cellular characteristics of VSMC migration under three-dimensional environments. Here, we investigated the mechanisms of VSMC migration and remodeling using two different collagen matrix assays as in vitro models: migration of VSMCs within a collagen matrix for VSMC invasion and contraction of a collagen gel by VSMCs for VSMC remodeling and contraction. We found that nonmuscle myosin IIA (NMIIA) and nonmuscle myosin IIB (NMIIB) differentially contribute to the migratory capacity of VSMCs via NMII isoform-dependent cytoskeletal reorganization. Depletion of NMIIA by short hairpin RNA revealed a unique interplay between actomyosin and microtubules during VSMC migration. On the other hand, NMIIB was required for the structural maintenance of migrating VSMC. Interestingly, there was a significant difference between NMIIA and NMIIB knockdown in the VSMC migration but not in the VSMC-mediated collagen gel contraction. Furthermore, depletion of zipper-interacting protein kinase by short hairpin RNA resulted in an impairment of VSMC migration and a substantial decrease of VSMC-mediated collagen gel contraction. These results suggest that NMIIA and NMIIB uniquely control VSMC migration and may contribute to vascular remodeling, which are both regulated by zipper-interacting protein kinase.


Impact of maternal pulmonary insufficiency on fetal growth in pregnancy.
Rationale: It is known that fetal growth is usually proportional to left-sided cardiac output (CO), which parallels the right-sided CO and that congenital right-sided lesions are usually associated with better perinatal outcomes than left-sided lesions.Objective: Our objective was to document whether newborns from mothers with severe residual pulmonary valve insufficiency (PI) after surgical tetralogy of Fallot (TOF) or pulmonary valve stenosis (PS) correction have lower birth weight (BW) than newborns from mothers with absent, mild, or moderate PI.Methods: This is a retrospective cohort study of women affected with repaired TOF and corrected PS with varied severity of residual PI. Exclusion criteria were: left ventricular dysfunction, left-sided valvular heart disease, other right-sided structural heart disease, chronic hypertension, substance addiction, and incomplete follow-up. Pregnancies were divided into three groups: absent or mild PI, moderate PI, and severe PI. A generalized linear model with normal dependent variable distribution was built and the parameter estimation made with Generalized Estimation Equations (GEE) to take into account repeated mother in data. Variables such as gestational age at birth, maternal age, smoking, and body mass index were tested with bivariate analyses to assess their effect on BW. Only gestational age remained in the adjusted model.Results: A total of 45 patients were included (33 TOF and 12 PS) and 97 pregnancies were reported: 22 miscarriages (22.7%) (15 TOF, 7 PS) and 75 successful pregnancies (57 TOF, 18 PS). The patients were divided into three groups: 1) absent or mild PI, 2) moderate PI, and 3) severe PI groups, which comprised, respectively, 29 (15 TOF, 4 PS), 20 (10 TOF, 1 PS), and 26 successful pregnancies (8 TOF, 7 PS). Using three levels of PI (absent or mild, moderate, and severe), the unadjusted model showed a significant effect of level of PI on BW (p = .0118), as well as the adjusted model (p = .0263) with gestational age as a covariate. The estimated mean newborn's BW was 3055.8 g in the severe PI group, 3151.0 g in the moderate PI group, and 3376.4 g in the absent or mild group when adjusted for gestational age. Hence, we estimated that the mean newborn's BW is 321 g lower in the severe PI group compared with absent or mild PI group ((CI: 572.3; -68.9), p = .0087).Conclusions: Pregnancy is usually well tolerated in repaired TOF and corrected PS. Severe PI either from repaired TOF or PS is at higher risk of lower newborn's BW. Special attention must be paid to the severity of PI. Fetal growth surveillance in the third trimester is warranted.


Alcohol consumption, life satisfaction and mental health among Norwegian college and university students.
High-level alcohol consumption is common in, and central to, the student community. Among adults, high-level alcohol consumption, and sometimes also low, has been associated with poorer social integration and mental health. We aimed to investigate how alcohol consumption relates to life satisfaction and mental health among students in higher education. Data from the Norwegian study of students' health and well-being (SHoT, 2014, n = 9632) were used. Associations between alcohol consumption (AUDIT; abstainers, low risk, risky and hazardous consumption) and life satisfaction and mental health complaints, as well as number of close friends, and social and emotional loneliness were investigated using linear regression models. Crude models and models adjusted for age, gender and relationship status were conducted. Students reporting hazardous consumption reported lower life satisfaction, more mental health complaints, and more emotional and social loneliness than students with low risk consumption. Students reporting risky consumption reported slightly reduced life satisfaction and more mental health complaints, but more close friends and less social loneliness. Abstainers did not report reduced life satisfaction or more mental health complaints, despite reporting fewer close friends and more social loneliness. High-level alcohol consumption among students might indicate increased risk of several problems in the future - but also currently. Our findings further imply that the quality of friendships might be more important for life satisfaction and mental health than the number of friends, but also that social integration in student communities might be more difficult for students who do not drink.


Spatial memory for vertical locations.
Most studies on spatial memory refer to the horizontal plane, leaving an open question as to whether findings generalize to vertical spaces where gravity and the visual upright of our surrounding space are salient orientation cues. In three experiments, we examined which reference frame is used to organize memory for vertical locations: the one based on the body vertical, the visual-room vertical, or the direction of gravity. Participants judged interobject spatial relationships learned from a vertical layout in a virtual room. During learning and testing, we varied the orientation of the participant's body (upright vs. lying sideways) and the visually presented room relative to gravity (e.g., rotated by 90° along the frontal plane). Across all experiments, participants made quicker or more accurate judgments when the room was oriented in the same way as during learning with respect to their body, irrespective of their orientations relative to gravity. This suggests that participants employed an egocentric body-based reference frame for representing vertical object locations. Our study also revealed an effect of body-gravity alignment during testing. Participants recalled spatial relations more accurately when upright, regardless of the body and visual-room orientation during learning. This finding is consistent with a hypothesis of selection conflict between different reference frames. Overall, our results suggest that a body-based reference frame is preferred over salient allocentric reference frames in memory for vertical locations perceived from a single view. Further, memory of vertical space seems to be tuned to work best in the default upright body orientation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


[Childhood prevalence of cardiovascular risk factors].
Cardiovascular risk factors were investigated in 356 children 5 to 9 years of age who were treated at a primary care center located in a low-income area in Greater Metropolitan Rio de Janeiro, Brazil. Lipid profile, nutritional status, food intake, and lifestyle were evaluated. 10.7% of the children were overweight, 68.4% had some type of dyslipidemia, and 18.6% showed high LDL-c. To describe the food intake pattern, the answers to the qualitative food questionnaire were submitted to multivariate cluster analysis, producing six basic groups: traditional Brazilian cooking; "modern" food (including diet and light products); fried food; sweets and soft drinks (mixed with other groups); and other poorly defined groups. The high prevalence of cardiovascular risk factors (beginning in childhood) and the evidence of inadequate dietary habits indicate that a preventive family-focused strategy is needed to change the dietary pattern of low-income groups towards healthier eating.


A strong quantitative trait locus for wing length on chromosome 2 in a wild population of great reed warblers.
Wing length is a key character for essential behaviours related to bird flight such as migration and foraging. In the present study, we initiate the search for the genes underlying wing length in birds by studying a long-distance migrant, the great reed warbler (Acrocephalus arundinaceus). In this species wing length is an evolutionary interesting trait with pronounced latitudinal gradient and sex-specific selection regimes in local populations. We performed a quantitative trait locus (QTL) scan for wing length in great reed warblers using phenotypic, genotypic, pedigree and linkage map data from our long-term study population in Sweden. We applied the linkage analysis mapping method implemented in GridQTL (a new web-based software) and detected a genome-wide significant QTL for wing length on chromosome 2, to our knowledge, the first detected QTL in wild birds. The QTL extended over 25 cM and accounted for a substantial part (37%) of the phenotypic variance of the trait. A genome scan for tarsus length (a body-size-related trait) did not show any signal, implying that the wing-length QTL on chromosome 2 was not associated with body size. Our results provide a first important step into understanding the genetic architecture of avian wing length, and give opportunities to study the evolutionary dynamics of wing length at the locus level.


Evaluation of relationships between results of electrocardiography and echocardiography in 341 chimpanzees (Pan troglodytes).
To examine potential relationships between ECG characteristics and echocardiographic measures of cardiac structure in chimpanzees (Pan troglodytes). 341 chimpanzees (175 males and 166 females) from 5 sanctuaries and 2 zoological collections. Chimpanzees were anesthetized for routine health examinations between May 2011 and July 2017 as part of the International Primate Heart Project and, during the same anesthetic events, underwent 12-lead ECG and transthoracic echocardiographic assessments. Relationships between results for ECG and those for echocardiographic measures of atrial areas, left ventricular internal diameter in diastole (LVIDd), and mean left ventricular wall thicknesses (MLVWT) were assessed with correlational analysis, then multiple linear regression analyses were used to create hierarchical models to predict cardiac structure from ECG findings. Findings indicated correlations (r = -0.231 to 0.310) between results for ECG variables and echocardiographic measures. The duration and amplitude of P waves in lead II had the strongest correlations with atrial areas. The Sokolow-Lyon criteria, QRS-complex duration, and R-wave amplitude in leads V6 and II had the strongest correlations with MLVWT, whereas the Sokolow-Lyon criteria, QRS-complex duration, and S-wave amplitude in leads V2 and V1 had the strongest correlations with LVIDd. However, the ECG predictive models that were generated only accounted for 17%, 7%, 11%, and 8% of the variance in the right atrial end-systolic area, left atrial end-systolic area, MLVWT, and LVIDd, respectively. Results indicated that relationships existed between ECG findings and cardiac morphology in the chimpanzees of the present study; however, further research is required to examine whether the predictive models generated can be modified to improve their clinical utility.


Early Intervention Services for First Episode of Psychosis in South London and the Maudsley (SLaM): 20 Years of Care and Research for Young People.
Introduction: Early Intervention for a first episode of Psychosis (EI) is essential to improve outcomes. There is limited research describing real-world implementation of EI services. Method: Analysis of service characteristics, outcomes (described through a retrospective 2007-2017 Electronic Health Record (EHR) cohort study) and clinical research relating to the first 20 years of implementation of EI services in South London and Maudsley (SLaM) Trust. Results: SLaM EI are standalone services serving 443,050 young individuals in South-London, where (2017) incidence of psychosis (58.3-71.9 cases per 100,000 person-years) is greater than the national average. From 2007-2017 (when the EHR was established), 1,200 individuals (62.67% male, mean age 24.38 years, 88.17% single; two-thirds of non-white ethnicity) received NICE-compliant EI care. Pathways to EI services came mainly (75.26%) through inpatient (39.83%) or community (19.33%) mental health services or Accident and Emergency departments (A&E) (16%). At 6 year follow-up 34.92% of patients were still being prescribed antipsychotics. The 3 month and 6 year cumulative proportions of those receiving clozapine were 0.75 and 7.33%; those compulsorily admitted to psychiatric hospitals 26.92 and 57.25%; those admitted to physical health hospitals 6.83 and 31.17%, respectively. Average 3 months and 6 year days spent in hospital were 0.82 and 1.85, respectively; mean 6 year attendance at A&E was 3.01. SLaM EI clinical research attracted £58 million grant income and numerous high-impact scientific publications. Conclusions: SLaM EI services represent one of the largest, most established services of its kind, and are a leading model for development of similar services in the UK and worldwide.


Molecular exploration of the first-century Tomb of the Shroud in Akeldama, Jerusalem.
The Tomb of the Shroud is a first-century C.E. tomb discovered in Akeldama, Jerusalem, Israel that had been illegally entered and looted. The investigation of this tomb by an interdisciplinary team of researchers began in 2000. More than twenty stone ossuaries for collecting human bones were found, along with textiles from a burial shroud, hair and skeletal remains. The research presented here focuses on genetic analysis of the bioarchaeological remains from the tomb using mitochondrial DNA to examine familial relationships of the individuals within the tomb and molecular screening for the presence of disease. There are three mitochondrial haplotypes shared between a number of the remains analyzed suggesting a possible family tomb. There were two pathogens genetically detected within the collection of osteological samples, these were Mycobacterium tuberculosis and Mycobacterium leprae. The Tomb of the Shroud is one of very few examples of a preserved shrouded human burial and the only example of a plaster sealed loculus with remains genetically confirmed to have belonged to a shrouded male individual that suffered from tuberculosis and leprosy dating to the first-century C.E. This is the earliest case of leprosy with a confirmed date in which M. leprae DNA was detected.


Rapid spread of Vibrio cholerae O1 throughout Kenya, 2005.
Between January and June 2005, 5 distinct cholera outbreaks occurred in Kenya. Overall, 990 cases and 25 deaths (2.5%) were reported. Four outbreaks occurred in towns along major highways, and 1 occurred in a refugee camp near the Sudanese border, accessible to Nairobi by daily flights. Matched case-control studies from 2 outbreaks showed that failure to treat drinking water and storing drinking water in wide-mouthed containers were significantly associated with disease. Isolates from all 5 outbreaks were Vibrio cholerae O1, Inaba serotype, and had genetically similar PFGE patterns of SfiI-digested chromosomal DNA. Linkage of the outbreak locations by major transportation routes, their temporal proximity, and similar PFGE patterns of isolates suggests the outbreaks might have been linked epidemiologically, showing the speed and distance of cholera spread in countries like Kenya with pockets of susceptible populations connected by modern transportation. Prevention measures remain implementation of point-of-use safe water systems and case finding and referral.


Effects of gender-transformative relationships and sexuality education to reduce adolescent pregnancy (the JACK trial): a cluster-randomised trial.
The need to engage boys in gender-transformative relationships and sexuality education (RSE) to reduce adolescent pregnancy is endorsed by WHO. We aimed to test an intervention which used a gender-transformative approach to engage adolescents in RSE to prevent unprotected sex. This cluster-randomised trial with process and economic evaluations tested a school-based intervention entitled If I Were Jack versus standard RSE (control) for students (aged 14-15 years) in UK schools. Schools were randomly allocated (1:1) and masked to allocation at baseline. The primary outcome was self-reported avoidance of unprotected sex (sexual abstinence or use of reliable contraception at last sex) after 12-14-months. We analysed the data using intention-to-treat mixed effects regression models. Of 803 schools assessed for eligibility, 263 schools were invited by letter, of which 66 schools agreed to be randomly assigned, of which 62 schools completed follow-up. The trial was done between Feb 1, 2018, and March 6, 2020. 8216 students participated at baseline in 2018; 6561 (79·85%) provided 12-14 months follow-up. There was no significant difference in the primary outcome of avoidance of unprotected sex: 2648 (86·62) of 3057 in the intervention group avoided unprotected sex versus 2768 (86·41%) of 3203 in the control group (adjusted odds ratio [aOR] 0·85 [95% CI 0·58-1·26], p=0·42). Exploratory post-hoc analysis of the two components of the primary outcome showed that significantly more intervention students used reliable contraception at last sex compared with control students and there was no significant difference between the groups for sexual abstinence. No adverse events were reported. The intervention had a null effect on the primary outcome of preventing unprotected sex (increasing sexual abstinence or use of reliable contraception) in the whole student population. However, the results showed significant increases in use of reliable contraceptives for sexually active students. Engaging all young people early through RSE is important so that as they become sexually active, rates of unprotected sex are reduced. National Institute for Health Research.


The conservation and uniqueness of the caspase family in the basal chordate, amphioxus.
The caspase family, which plays a central role in apoptosis in metazoans, has undergone an expansion in amphioxus, increasing to 45 members through domain recombination and shuffling. In order to shed light on the conservation and uniqueness of this family in amphioxus, we cloned three representative caspase genes, designated as bbtCaspase-8, bbtCaspase-1/2 and bbtCaspase3-like, from the amphioxus Branchiostoma belcheri tsingtauense. We found that bbtCaspase-8 with conserved protein architecture is involved in the Fas-associated death domain-Caspase-8 mediated pro-apoptotic extrinsic pathway, while bbtCaspase3-like may mediate a nuclear apoptotic pathway in amphioxus. Also, bbtCaspase-1/2 can co-localize with bbtFADD2 in the nucleus, and be recruited to the cytoplasm by amphioxus apoptosis associated speck-like proteins containing a caspase recruitment domain, indicating that bbtCaspase-1/2 may serve as a switch between apoptosis and caspase-dependent innate immune response in invertebrates. Finally, amphioxus extrinsic apoptotic pathway related caspases played important roles in early embryogenesis. Our study not only demonstrates the conservation of bbtCaspase-8 in apoptosis, but also reveals the unique features of several amphioxus caspases with novel domain architectures arose some 500 million years ago.


Microfluidic-based vascularized microphysiological systems.
Microphysiological systems have emerged in the last decade to provide an alternative to in vivo models in basic science and pharmaceutical research. In the field of vascular biology, in particular, there has been a lack of a suitable in vitro model exhibiting a three-dimensional structure and the physiological function of vasculature integrated with organ-on-a-chip models. The rapid development of organ-on-a-chip technology is well positioned to fulfill unmet needs. Recently, functional integration of vasculature with diverse microphysiological systems has been increasing. This recent trend corresponds to emerging research interest in how the vascular system contributes to various physiological and pathological conditions. This innovative platform has undergone significant development, but adoption of this technology by end-users and researchers in biology is still a work in progress. Therefore, it is critical to focus on simplification and standardization to promote the distribution and acceptance of this technology by the end-users. In this review, we will introduce the latest developments in vascularized microphysiological systems and summarize their outlook in basic research and drug screening applications.


The effects of physiologic amounts of simple sugars on lipoprotein, glucose, and insulin levels in normal subjects.
Using a crossover design, eight healthy volunteers randomly received physiologic amounts (1/3 of each subject's total carbohydrate intake) of either fructose or sucrose as the primary source of simple sugar, incorporated into isocaloric diets comprised of typical American foods. After 7 and 14 days of consuming either of the two sugars, no change occurred in fasting glucose or insulin levels. In addition, total triglyceride, total cholesterol, low-density-lipoprotein (LDL) cholesterol, and high-density-lipoprotein (HDL) cholesterol concentrations were unaltered. Since our study used conventional foods in normal eating patterns rather than contrived formulas or excessive amounts of simple sugar, our data indicate that there is no difference between sucrose or fructose on various lipid components or glucose and fasting insulin levels in the "real world" in normal subjects.


Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition.
Metastatic melanoma is characterized by extremely poor survival rates and hence novel therapies are urgently required. The ability of many anticancer drugs to activate autophagy, a lysosomal-mediated catabolic process which usually promotes cell survival, suggests targeting the autophagy pathway may be a novel means to augment therapy. Autophagy and apoptosis were assessed in vitro in human melanoma cell lines in response to clinically achievable concentrations of the endoplasmic reticulum (ER) stress-inducing drugs fenretinide or bortezomib, and in vivo using a s.c. xenograft model. Autophagy was activated in response to fenretinide or bortezomib in B-RAF wild-type cells, shown by increased conversion of LC3 to the autophagic vesicle-associated form (LC3-II) and redistribution to autophagosomes and autolysosomes, increased acidic vesicular organelle formation and autophagic vacuolization. In contrast, autophagy was significantly reduced in B-RAF-mutated melanoma cells, an effect attributed partly to oncogenic B-RAF. Rapamycin treatment was unable to stimulate LC3-II accumulation or redistribution in the presence of mutated B-RAF, indicative of de-regulated mTORC1-dependent autophagy. Knockdown of Beclin-1 or ATG7 sensitized B-RAF wild-type cells to fenretinide- or bortezomib-induced cell death, demonstrating a pro-survival function of autophagy. In addition, autophagy was partially reactivated in B-RAF-mutated cells treated with the BH3 mimetic ABT737 in combination with fenretinide or bortezomib, suggesting autophagy resistance is partly mediated by abrogated Beclin-1 function. Our findings suggest inhibition of autophagy in combination with ER stress-inducing agents may represent a means by which to harness autophagy for the therapeutic benefit of B-RAF wild-type melanoma.


Charge stabilizing tris(triphenylamine)-zinc porphyrin-carbon nanotube hybrids: synthesis, characterization and excited state charge transfer studies.
Functionalization of single-walled (SWCNTs) and double-walled carbon nanotubes (DWCNTs) with a charge stabilizing zinc porphyrin functionalized with triphenylamine entities has been accomplished. The synthetic approach involved the reaction of tris-(triphenylamine)porphyrinato zinc(ii) with iodobenzene functionalized nanotubes through a Sonogashira C-C cross coupling reaction under microwave irradiation conditions. Evidence of covalent functionalization and the extent of functionalization was obtained from systematic studies carried out by AFM, TGA, XPS and Raman spectroscopy techniques. The porphyrin-nanotube interactions in the SWCNT-porphyrin hybrid were probed by studies involving optical absorbance, Raman spectroscopy, steady-state and time resolved emission and electrochemical studies. The fluorescence of porphyrin in this hybrid was found to be quenched due to interactions with the CNTs. Femtosecond transient absorption spectral studies covering both the visible and near-infrared regions were supportive of excited state charge transfer interactions in the zinc porphyrin-SWCNT. The charge separated state was persistent for about 1 ns. Electron pooling experiments suggested that this donor-acceptor nanohybrid could be a useful photocatalyst.


Addressing anal health in the HIV primary care setting: a disappointing reality.
The increased risk of anal cancer among individuals living with HIV suggests that anal health (e.g., anal symptoms, anal practices, examination of the anus) should be an issue of priority for HIV care providers to discuss with their HIV-infected patients. We investigated the prevalence of HIV-infected individuals discussing anal health with their HIV primary care provider and factors associated with this discussion. We surveyed 518 adult patients from 5 HIV primary care clinics in Miami, Florida, from May 2004 to May 2005. Overall, only 22% of women, 32% of heterosexual men, and 54% of men who have sex with men (MSM) reported discussing anal health with their HIV providers in the prior 12 months. In a multivariable logistic regression, when adjusting for other factors, heterosexual men and MSM were 2.31 and 5.56 times, respectively, more likely to discuss anal health with their HIV providers compared to their women counterparts. Other factors associated with anal health discussion were the patients' better perception of engagement with HIV providers and having had a sexually transmitted disease exam in the past 12 months. Reporting of unprotected sex with HIV-negative or unknown HIV status was inversely related to discussion of anal health with primary care providers (odds ratio [OR] = 0.53). Efforts are greatly needed to increase the focus on anal health in the HIV primary care setting for both men and women.


Blastocyst transfer is not associated with increased rates of monozygotic twins when controlling for embryo cohort quality.
To compare monozygotic twinning (MZT) rates in patients undergoing blastocyst or cleavage-stage ET. Retrospective cohort. Academic research center. Autologous, fresh IVF cycles resulting in a clinical pregnancy from 1999 to 2014. None. Monozygotic twin pregnancy in blastocyst-stage transfer vs. cleavage-stage transfer when controlling for patient prognosis and embryo cohort quality factors. There were a total of 9,969 fresh transfer cycles resulting in a pregnancy during the study period. Of these pregnancies, 234 monozygotic twin pregnancies were identified (2.4%). Of all transfers, 5,191 were cleavage-stage and 4,778 were blastocyst-stage transfers. There were a total of 99 MZT identified in the cleavage-stage group (1.9%) and 135 MZT in the blastocyst ET group (2.4%), which was significant. Multivariable logistic regression revealed that increasing age was associated with a significant reduction in MZT, regardless of transfer order. Embryo cohort quality factors, including the number and proportion of six- to eight-cell embryos and availability of supernumerary embryos, were also significant. When controlling for patient age, time period during which the cycle took place, the number and proportion of six- to eight-cell embryos, and availability of supernumerary embryos, there was no longer a difference in MZT rate between blastocyst and cleavage transfer. Patient prognosis and embryo cohort quality seem to be major factors in MZT rate in women undergoing blastocyst transfer. Although technology-based effects cannot be excluded, patient and embryo characteristics play an important role.


Insulin responses to varying profiles of subcutaneous insulin infusion: kinetic modelling studies.
Refinement of continuous subcutaneous insulin infusion for diabetes therapy requires improved knowledge of subcutaneous insulin absorption kinetics. We have used kinetic modelling to quantitate systemic insulin delivery produced by subcutaneously-infused insulin (i.e. simulated meal and basal delivery). Profiles were studied in normal subjects, with endogenous insulin suppressed. Paired studies of intravenous insulin infusion enabled systemic insulin delivery to be quantitated. High rate subcutaneous delivery (10 U in 5 min) resulted in a systemic delivery of approximately 8 U in 4 h. Increasing infused insulin concentration delayed systemic delivery (p less than 0.025). Both continuous and pulsatile low-rate infusions (2.4 U/h) gave similar slow increases in systemic delivery to 1 U after 4 h. Computer fitting to a two-pool model of the subcutaneous space suggested a low rate of insulin degradation for all profiles (rate constant less than 10%/h). We conclude that: systemic insulin delivery following subcutaneous infusion conforms reasonably to a two-pool model, subcutaneous insulin degradation is low regardless of input profile, a long delay in basal systemic delivery should be taken into account when initiating or resuming interrupted subcutaneous insulin infusion. Kinetic modelling of subcutaneous insulin absorption should be useful to predict the impact of programming strategies for continuous subcutaneous insulin infusion therapy.


BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction.
Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival, differentiation and synaptic plasticity. The BDNF pro-peptide is a post-processing product of the precursor BDNF. Using surface plasmon resonance and biochemical experiments, we first demonstrated that the BDNF pro-peptide binds to mature BDNF with high affinity, but not other neurotrophins. This interaction was more enhanced at acidic pH than at neutral pH, suggesting that the binding is significant in intracellular compartments such as trafficking vesicles rather than the extracellular space. The common Val66Met BDNF polymorphism results in a valine instead of a methionine in the pro-domain, which affects human brain functions and the activity-dependent secretion of BDNF. We investigated the influence of this variation on the interaction between BDNF and the pro-peptide. Interestingly, the Val66Met polymorphism stabilized the heterodimeric complex of BDNF and its pro-peptide. Furthermore, compared with the Val-containing pro-peptide, the complex with the Met-type pro-peptide was more stable at both acidic and neutral pH, suggesting that the Val66Met BDNF polymorphism forms a more stable complex. A computational modeling provided an interpretation to the role of the Val66Met mutation in the interaction of BDNF and its pro-peptide. Lastly, we performed electrophysiological experiments, which indicated that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal long-term depression (LTD), suggesting a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. It was previously reported that the BDNF pro-domain exerts a chaperone-like function and assists the folding of the BDNF protein. However, our results suggest a new role for the BDNF pro-domain (or pro-peptide) following proteolytic cleave of precursor BDNF, and provide insight into the Val66Met polymorphism.


Intronic microRNAs: a crossroad in gene regulation.
Most human genes transcribed by RNA Pol II (polymerase II) contain short exons separated by long tracts of non-coding intronic sequences. In addition to their role in generating proteomic diversity through the process of alternative splicing, intronic sequences host many ncRNAs (non-coding RNAs), involved in various gene regulation processes. miRNAs (microRNAs) are short ncRNAs that mediate either mRNA transcript translational repression and/or degradation. Between 50 and 80% of miRNAs are encoded within introns of host mRNA genes. This observation suggests that there is co-regulation between the miRNA biogenesis and pre-mRNA splicing processes. The present review summarizes current advances in this field and discusses possible roles for intronic co-transcriptional cleavage events in the regulation of human gene expression.


Is There Enough Evidence for Osteosarcopenic Obesity as a Distinct Entity? A Critical Literature Review.
The co-existence of impaired bone health (osteopenia/osteoporosis), reduced muscle mass and strength (sarcopenia), and increased adiposity (obesity) in middle-aged and older people has been identified in recent studies, leading to a proposal for the existence of "osteosarcopenic obesity" as a distinct entity. Evidence for the pathophysiological overlap of these conditions is mounting, although a causal relationship is yet to be established. Each component condition occurs frequently with increasing age, and with shared risk factors in many instances, thus, an overlap of these three conditions is not surprising. However, whether the concurrent existence of sarcopenia, osteoporosis and obesity leads to an increased risk of adverse musculoskeletal outcomes and mortality above and beyond the risks associated with the sum of the component parts remains to be proven and is a question of research interest. In this article, we review evidence for the existence of osteosarcopenic obesity including the current operational definition of osteosarcopenic obesity, prevalence, pathophysiology, outcomes and exploratory approaches to the management of components. We conclude that, there is insufficient evidence to support a discrete clinical entity of osteosarcopenic obesity at this time. To expand knowledge and understanding in this area, there is a need for consensus on a definition of osteosarcopenic obesity which will allow for identification, further epidemiological studies and comparisons between studies. Additionally, studies should assess whether the clinical outcomes associated with osteosarcopenic obesity are worse than the mere addition of those linked with its components. This will help to determine whether defining a person as having this triad will eventually result in a more effective treatment than addressing each of the three conditions separately.


Self-recovering stimuli-responsive macrocycle-equipped supramolecular ionogels with unusual mechanical properties.
A chiral, crown-ether-functionalized bisurea gelator forms supramolecular gels in ionic liquids. The resulting ionogels show a remarkably high thermal stability with gel-sol transition temperatures (T(gs)) reaching more than 100 °C. The mechanical strength of these ionogels is surprisingly high and even comparable to that of cross-linked protein fibres. Furthermore, the ionogels exhibit rapid self-recovery properties after structural damage caused by deformation. Pseudorotaxanes form from the gelators' benzo[21]crown-7 ethers as the wheels and secondary ammonium ions as the axles despite the competition between that cation and the imidazolium ions of the ionic liquid for crown ether binding. Pseudorotaxane formation as an external chemical stimulus triggers the gel-sol transition of the ionogels.


Internet cognitive testing of large samples needed in genetic research.
Quantitative and molecular genetic research requires large samples to provide adequate statistical power, but it is expensive to test large samples in person, especially when the participants are widely distributed geographically. Increasing access to inexpensive and fast Internet connections makes it possible to test large samples efficiently and economically online. Reliability and validity of Internet testing for cognitive ability have not been previously reported; these issues are especially pertinent for testing children. We developed Internet versions of reading, language, mathematics and general cognitive ability tests and investigated their reliability and validity for 10- and 12-year-old children. We tested online more than 2500 pairs of 10-year-old twins and compared their scores to similar internet-based measures administered online to a subsample of the children when they were 12 years old (> 759 pairs). Within 3 months of the online testing at 12 years, we administered standard paper and pencil versions of the reading and mathematics tests in person to 30 children (15 pairs of twins). Scores on Internet-based measures at 10 and 12 years correlated .63 on average across the two years, suggesting substantial stability and high reliability. Correlations of about .80 between Internet measures and in-person testing suggest excellent validity. In addition, the comparison of the internet-based measures to ratings from teachers based on criteria from the UK National Curriculum suggests good concurrent validity for these tests. We conclude that Internet testing can be reliable and valid for collecting cognitive test data on large samples even for children as young as 10 years.


Image-Guided Interventions: We've come a long way, but are we there?
While the term "image-guided surgery" has gained popularity fairly recently, the use of imaging for medical interventions dates as far back as the beginning of the 20th century. Dr. George H. Gray of Lynn, Massachusetts, reported in his 1908 article "X-rays in Surgical Work," published in volume 2 of the Journal of Therapeutics and Dietetics, that "the one great stride in the handling of difficult cases was the accurate diagnosis made possible by the use of the X-rays." His story points to the day when a seamstress presented to his office with a broken sewing needle embedded in her hand. Thanks to the use of the recently discovered X-rays by Wilhelm Conrad Roentgen, the father of diagnostic radiology, Gray was able not only to confirm that the needle was indeed embedded in her hand but also to locate its parts, saving "an hour's hunting as some had previously done and then often failed."


Multisession CyberKnife radiosurgery for intramedullary spinal cord arteriovenous malformations.
Intramedullary spinal cord arteriovenous malformations (AVMs) have an unfavorable natural history that characteristically involves myelopathy secondary to progressive ischemia and/or recurrent hemorrhage. Although some lesions can be managed successfully with embolization and surgery, AVM size, location, and angioarchitecture precludes treatment in many circumstances. Given the poor outlook for such patients, and building on the successful experience with radiosurgical ablation of cerebral AVMs, our group at Stanford University has used CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery (SRS) to treat selected spinal cord AVMs since 1997. In this article, we retrospectively analyze our preliminary experience with this technique. Fifteen patients with intramedullary spinal cord AVMs (nine cervical, three thoracic, and three conus medullaris) were treated by image-guided SRS between 1997 and 2005. SRS was delivered in two to five sessions with an average marginal dose of 20.5 Gy. The biologically effective dose used in individual patients was escalated gradually over the course of this study. Clinical and magnetic resonance imaging follow-up were carried out annually, and spinal angiography was repeated at 3 years. After a mean follow-up period of 27.9 months (range, 3-59 mo), six of the seven patients who were more than 3 years from SRS had significant reductions in AVM volumes on interim magnetic resonance imaging examinations. In four of the five patients who underwent postoperative spinal angiography, persistent AVM was confirmed, albeit reduced in size. One patient demonstrated complete angiographic obliteration of a conus medullaris AVM 26 months after radiosurgery. There was no evidence of further hemorrhage after CyberKnife treatment or neurological deterioration attributable to SRS. This description of CyberKnife radiosurgical ablation demonstrates its feasibility and apparent safety for selected intramedullary spinal cord AVMs. Additional experience is necessary to ascertain the optimal radiosurgical dose and ultimate efficacy of this technique.


The permeability of the skin of the aquatic anuran Xenopus laevis (Pipidae).
The undirectional transcutaneous fluxes of Na, Cl, water and urea were measured, in vitro, in the pipoid anuran Xenopus laevis. An active uptake (outside to inside) of Na was observed but Cl movements appeared to be passive. The effluxes of Na and Cl were low compared to those measured in other species of amphibians. The active Na transport was less than that of more terrestrial species and, although it could be stimulated by vasotocin, aldosterone was ineffective. The permeability of the skin to water was also low and although it was increased in the presence of vasotocin the magnitude of the response was much less than seen in more terrestrial anurans. The skin was permeable to urea but the movement of this solute was not remarkable when compared to that in other amphibians. These properties of the skin are discussed in relation to the animal's aquatic manner of life.


Craniocervical arterial dissections as sequelae of chiropractic manipulation: patterns of injury and management.
Chiropractic manipulation of the cervical spine is a known cause of craniocervical arterial dissections. In this paper, the authors describe the patterns of arterial injury after chiropractic manipulation and their management in the modern endovascular era. A prospectively maintained endovascular database was reviewed to identify patients presenting with craniocervical arterial dissections after chiropractic manipulation. Factors assessed included time to symptomatic presentation, location of the injured arterial segment, neurological symptoms, endovascular treatment, surgical treatment, clinical outcome, and radiographic follow-up. Thirteen patients (8 women and 5 men, mean age 44 years, range 30-73 years) presented with neurological deficits, head and neck pain, or both, typically within hours or days of chiropractic manipulation. Arterial dissections were identified along the entire course of the vertebral artery, including the origin through the V(4) segment. Three patients had vertebral artery dissections that continued rostrally to involve the basilar artery. Two patients had dissections of the internal carotid artery (ICA): 1 involved the cervical ICA and 1 involved the petrocavernous ICA. Stenting was performed in 5 cases, and thrombolysis of the basilar artery was performed in 1 case. Three patients underwent emergency cerebellar decompression because of impending herniation. Six patients were treated with medication alone, including either anticoagulation or antiplatelet therapy. Clinical follow-up was obtained in all patients (mean 19 months). Three patients had permanent neurological deficits, and 1 died of a massive cerebellar stroke. The remaining 9 patients recovered completely. Of the 12 patients who survived, radiographic follow-up was obtained in all but 1 of the most recently treated patients (mean 12 months). All stents were widely patent at follow-up. Chiropractic manipulation of the cervical spine can produce dissections involving the cervical and cranial segments of the vertebral and carotid arteries. These injuries can be severe, requiring endovascular stenting and cranial surgery. In this patient series, a significant percentage (31%, 4/13) of patients were left permanently disabled or died as a result of their arterial injuries.


Midlife sexuality among Thai adults: Adjustment to aging in the Thai family context.
The objective of the study is to assess views of age related changes in sexual behavior among married Thai adults age 53 to 57. Results are viewed in the context of life course theory. In-depth interviews were conducted with 44 Thai adults in Bangkok and the four regions of Thailand. Topics covered include changing sexual behavior with age, adjustment to this change, gender differences in behavior, attitudes toward commercial sex and other non-marital sexual partners, and condom use. Most respondents were aware of this change and saw a decrease in sexual activity and desire more often among women compared to men. At the same time, many respondents viewed sexuality as important to a marriage. Some respondents accepted the decrease in sexual activity and focused more on work, family and temple activities. Thai Buddhism was seen as an important resource for people who were dealing with changes due to aging. Other persons turned to other partners including both commercial and non-commercial partners. The influence of the HIV epidemic that began in the 1990s was seen in concerns about disease transmission with extramarital partners and consequent attitudes toward condom use. The acceptability of extramarital partners in the family and community ranged from acceptance to strong disapproval of extramarital relationships.


Semaphorin 3A induces mesenchymal-stem-like properties in human periodontal ligament cells.
Periodontal ligament stem cells (PDLSCs) have recently been proposed as a novel option in periodontal regenerative therapy. However, one of the issues is the difficulty of stably generating PDLSCs because of the variation of stem cell potential between donors. Here, we show that Semaphorin 3A (Sema3A) can induce mesenchymal-stem-like properties in human periodontal ligament (PDL) cells. Sema3A expression was specifically observed in the dental follicle during tooth development and in parts of mature PDL tissue in rodent tooth and periodontal tissue. Sema3A expression levels were found to be higher in multipotential human PDL cell clones compared with low-differentiation potential clones. Sema3A-overexpressing PDL cells exhibited an enhanced capacity to differentiate into both functional osteoblasts and adipocytes. Moreover, PDL cells treated with Sema3A only at the initiation of culture stimulated osteogenesis, while Sema3A treatment throughout the culture had no effect on osteogenic differentiation. Finally, Sema3A-overexpressing PDL cells upregulated the expression of embryonic stem cell markers (NANOG, OCT4, and E-cadherin) and mesenchymal stem cell markers (CD73, CD90, CD105, CD146, and CD166), and Sema3A promoted cell division activity of PDL cells. These results suggest that Sema3A may possess the function to convert PDL cells into mesenchymal-stem-like cells.