Multiple cranial neuropathies.
Patients presenting with multiple cranial neuropathies are not uncommon in neurologic clinical practice. The evaluation of these patients can often be overwhelming due to the vast and complicated etiologies as well as the potential for devastating neurologic outcomes. Dysfunction of the cranial nerves can occur anywhere in their course from intrinsic brainstem dysfunction to their peripheral courses. The focus of this review will be on the extramedullary causes of multiple cranial neuropathies as discussion of the brainstem syndromes is more relevant when considering intrinsic disorders of the brainstem. The goals are to provide the reader with an overview of those extramedullary conditions that have a predilection for causing multiple cranial nerve palsies. In turn, this will serve to provide a practical and systematic approach to allow for a more targeted diagnostic evaluation of this, often cumbersome, presentation.


The value of an elastic tissue stain in detecting venous invasion in colorectal cancer.
Venous invasion by tumour is an independent prognostic indicator of both prognosis and risk of development of distant metastases in colorectal carcinoma. The use of special stains to aid its detection in pathology specimens is not currently universally recommended. To determine whether an elastica stain significantly increases the incidence of detection of vascular invasion compared with routinely stained sections. Serial sections from the 75 cases of colorectal carcinoma were stained by haematoxylin and eosin (H&E) only and elastica counterstained with H&E. The incidence of both intramural and extramural venous invasion was recorded and compared with that seen when the tumours were originally reported. Extramural venous invasion had been noted in 14 of the pathology reports and was seen in 18 cases when only the H&E sections were viewed in the study. It was present in 32 cases when elastica stained sections were analysed. Intramural venous invasion was seen in eight cases on H&E sections and 30 cases on elastica stained sections. The use of elastica stained serial sections to detect venous invasion in tumours should be recommended in guidelines for the reporting of colorectal carcinomas.


[Relation between temperature and processes of spontaneous quantum and non-quantum mediator release from motor nerve endings of the mouse].
The spontaneous quantal and nonquantal acetylcholine release was investigated at the temperature range from 10 to 35 degrees C in white mouse semidiaphragm. The quantal release was evaluated by calculation of miniature end-plate potentials frequency, while the nonquantal one--from the H-effect value. The spontaneous quantal release increased exponentially with the temperature growth. The temperature dependence of the nonquantal release showed two relative maxima: at 20 degrees and 35 degrees C. At 10 degrees C the nonquantal release was absent. The value of calculated effective energy of activation of the quantal release was 57.0 kJ/mol in the investigated temperature range. The effective energy of activation for the nonquantal release process in intervals 15-20 degrees C and 25-35 degrees C was 45.5 and 38.2 kJ/mol, relatively. It is suggested that the nonquantal release is rather due to active transport processes than to simple diffusion of acetylcholine molecules.


Lumbar back and posterior pelvic pain during pregnancy: a 3-year follow-up.
This study is a prospective, consecutive, 3-year cohort study of women with back pain in an index pregnancy. The aim was to describe the physical status and disability among women with back pain 3 years after delivery. Pain was identified as lumbar back pain, posterior pelvic pain or combined lumbar as well as posterior pelvic pain. Previous studies have established that all three types of pain can be reduced by structured physiotherapy during pregnancy, and the beneficial effect may last for several years. Though it is known that some women have residual pain for a long time, the relative incidence of the three pain types and their degree of disability associated with each have never been reported. Neither has any study presented findings of a physical examination of women 3 years post partum with a focus on the type of pain. All women who were registered as having experienced back pain during an index pregnancy were interviewed by mail 3 years post partum. Women who had residual back pain filled in an additional questionnaire and were physically examined. Out of 799 pregnant women, 231 had some type of back pain during the index pregnancy, and 41 women had pain 3 years later. Women with combined lumbar and posterior pelvic pain were significantly more disabled ( P<0.05) and had significantly lower endurance in the lumbar back and hip abduction muscles ( P<0.01). Some 5% of all pregnant women, or 20% of all women with back pain during pregnancy, had pain 3 years later. The key problem may be poor muscle function in the back and pelvis.


Biogenesis of the mycobacterial cell wall and the site of action of ethambutol.
The effect of ethambutol (EMB) is primarily on polymerization steps in the biosynthesis of the arabinan component of cell wall arabinogalactan (AG) of Mycobacterium smegmatis. Inhibition of the synthesis of the arabinan of lipoarabinomannan (LAM) occurred later, and thus in the cases of AG and LAM, the polymerization of D-arabinofuranose apparently involves separate pathways. While the synthesis of these arabinans was normal in an EMB-resistant isogeneic strain, the addition of EMB to the resistant strain resulted in partial inhibition of the synthesis of the arabinan of LAM and the emergence of a novel, truncated form of LAM, indicating partial susceptibility of the resistant gene(s) and providing a new intermediate in the LAM biosynthetic sequence. A consequence of inhibition of AG arabinan biosynthesis is the lack of new sites for mycolate attachment and thus the channeling of mycolate residues into a variety of free lipids which then accumulate. The primary biochemical effects of EMB can be explained by postulating separate AG and LAM pathways catalyzed by a variety of extramembranous arabinosyl transferases with various degrees of sensitivity to EMB.


Efficacy and toxicity of rectal cancer reirradiation using IMRT for patients who have received prior pelvic radiation therapy.
Locally recurrent rectal cancer may cause significant morbidity. Prior reports of rectal cancer reirradiation following local recurrence suggest treatment efficacy, with variable rates of late toxicity. Modern techniques including intensity modulated radiation therapy (IMRT) may improve the therapeutic index. We report outcomes for pelvic reirradiation as treatment for rectal cancer using IMRT. The records of 31 patients undergoing reirradiation for rectal cancer between 2004 and 2013 were reviewed. All patients underwent IMRT using an accelerated hyperfractionation (39 Gy in 1.5-Gy fractions delivered twice daily, n=15) or once-daily fractionation technique (median dose, 30.4 Gy; range, 27-40 Gy in 15-22 fractions; n = 16). The median cumulative dose was 77 Gy (range, 59-113), and the median interval from prior pelvic radiation therapy was 39.8 months (range, 10.1-307.6). Treatment intent was palliative in 20 patients and neoadjuvant or adjuvant in 11 patients. Surgery was generally reserved for patients with an isolated local recurrence. Concurrent chemotherapy was administered for 25/31 patients, most frequently capecitabine (n=11) or continuous infusion 5-fluorouracil (n=10). Median follow-up was 11.3 months. The prescribed treatment was completed in 29/31 patients (93.5%). Among 18 patients with symptoms attributable to recurrent disease, successful palliation was achieved in 10/18 (55.6%). The rate of grade 2 and grade 3 acute toxicities was 32.3% and 3.2%, respectively. Local control rates at 1 and 2 years were 61.3% and 47.3%, respectively. Median overall survival was 21.9 months, and 1-year survival was 66.7% for patients who had surgical resection versus 58.7% for those who did not (P = .0802). Rectal cancer reirradiation using IMRT is well-tolerated in the setting of prior pelvic radiation therapy. Given significant risk of local progression, further dose escalation may be warranted for patients with life expectancy exceeding 1 year.


Rapid Evolution of Genes Involved in Learning and Energy Metabolism for Domestication of the Laboratory Rat.
The laboratory rat, widely used in biomedical research, is domesticated from wild brown rat. The origin and genetic mechanism underlying domestication of the laboratory rat remain largely elusive. In the present study, large scale genomes supported a single origin for the laboratory rat, possibly from a sister group to wild rats from Europe/Africa/Middle East. Genomic and transcriptomic analyses uncovered many artificially selected genes (e.g., FOXP2, B3GAT1, and CLOCK) involved in the nervous system. These genes associate with learning ability and regulation of circadian rhythm, which likely enabled the successful domestication of the laboratory rat. Particularly, many genes, including mitochondrial genes responsible for energy metabolism, displayed a substantially increased expression in the brain of laboratory rats compared with wild rats. Our findings demystify the origin and evolution of this model animal, and provide insight into the process of its domestication.


The many places of frequency: evidence for a novel locus of the lexical frequency effect in word production.
The effect of lexical frequency on language-processing tasks is exceptionally reliable. For example, pictures with higher frequency names are named faster and more accurately than those with lower frequency names. Experiments with normal participants and patients strongly suggest that this production effect arises at the level of lexical access. Further work has suggested that within lexical access this effect arises at the level of lexical representations. Here we present patient E.C. who shows an effect of lexical frequency on his nonword error rate. The best explanation of his performance is that there is an additional locus of frequency at the interface of lexical and segmental representational levels. We confirm this hypothesis by showing that only computational models with frequency at this new locus can produce a similar error pattern to that of patient E.C. Finally, in an analysis of a large group of Italian patients, we show that there exist patients who replicate E.C.'s pattern of results and others who show the complementary pattern of frequency effects on semantic error rates. Our results combined with previous findings suggest that frequency plays a role throughout the process of lexical access.


Chronic suppurative osteomyelitis of maxilla mimicking actinimycotic osteomyelitis: A rare case report.
Osteomyelitis is a disease which is heterogeneous in its pathophysiology, clinical presentation and management. It is considered to be one of the most difficult-to-treat infectious diseases. Progressive bony destruction and the formation of sequestra are hallmarks of osteomyelitis. We hereby report a rare case of maxillary osteomyelitis, which had actinomycotic osteomyelitis like presentation but was histopathologically diagnosed as a severe form of chronic suppurative osteomyelitis.


Work and lifestyle factors associated with morbidity of electronic women workers in Selangor, Malaysia.
The objective of this study was to identify sociodemographic, work, living arrangement and lifestyle factors associated with morbidity of electronics women workers in selected factories in Selangor, Malaysia. The research design was a cross-sectional questionnaire-based survey. Most of the 401 respondents were young single Malay women. Morbidity was high as 85.5% of the women reported experiencing at least one chronic health problem, and 25.7% said that an illness or injury prevented them from carrying out normal activities within the last two weeks. Major acute illness symptoms were the common cold, backache, and diarrhoea while chronic health problems such as persistent headache, eye problems, menstrual problems, and persistent backache were also reported. After logistic regression, chronic health problems was significantly associated with room sharing; while illness that prevented normal activities within the last two weeks was significantly associated with overtime work and exercise. Further research is recommended to understand the complex inter-relationship between morbidity and working and living conditions.


Temperature (de)activated patchy colloidal particles.
We present a new model of patchy particles in which the interaction sites can be activated or deactivated by varying the temperature of the system. We study the thermodynamics of the system by means of Wertheim's first order perturbation theory, and use Flory-Stockmayer theory of polymerization to analyse the percolation threshold. We find a very rich phase behaviour including lower critical points and reentrant percolation.


Integrated omics profiling of dextran sodium sulfate-induced colitic mice supplemented with Wolfberry (Lycium barbarum).
We used a multi-omics profiling approach to investigate the suppressive effects of 2% Wolfberry (WOL)-enriched diets on dextran sodium sulfate (DSS)-induced colitis in mice. It was observed that in mice fed the WOL diet, the disease activity index, colon shortening, plasma concentrations of matrix metalloproteinase-3 and relative mesenteric fat weight were significantly improved as compared to the DSS group. Results from colon transcriptome and proteome profiles showed that WOL supplementation significantly ameliorated the expression of genes and proteins associated with the integrity of the colonic mucosal wall and colonic inflammation. Based on the hepatic transcriptome, proteome and metabolome data, genes involved in fatty acid metabolism, proteins involved in inflammation and metabolites related to glycolysis were downregulated in WOL mice, leading to lowered inflammation and changes in these molecules may have led to improvement in body weight loss. The integrated nutrigenomic approach thus revealed the molecular mechanisms underlying the ameliorative effect of whole WOL fruit consumption on inflammatory bowel disease.


Integral three-dimensional television with video system using pixel-offset method.
Integral three-dimensional (3D) television based on integral imaging requires huge amounts of information. Previously, we constructed an Integral 3D television using Super Hi-Vision (SHV) technology, with 7680 pixels horizontally and 4320 pixels vertically. We report on improved image quality through the development of video system with an equivalent of 8000 scan lines for use with Integral 3D television. We conducted experiments to evaluate the resolution of 3D images using an experimental setup and were able to show that by using the pixel-offset method we have eliminated aliasing produced by full-resolution SHV video equipment. We confirmed that the application of the pixel-offset method to integral 3D television is effective in increasing the resolution of reconstructed images.


Design of a randomized controlled double-blind crossover clinical trial to assess the effects of saliva substitutes on bovine enamel and dentin in situ.
Hyposalivation is caused by various syndromes, diabetes, drugs, inflammation, infection, or radiotherapy of the salivary glands. Patients with hyposalivation often show an increased caries incidence. Moreover, hyposalivation is frequently accompanied by oral discomfort and impaired oral functions, and saliva substitutes are widely used to alleviate oral symptoms. However, preference of saliva substitutes due to taste, handling, and relief of oral symptoms has been discussed controversially. Some of the marketed products have shown demineralizing effects on dental hard tissues in vitro. This demineralizing potential is attributed to the undersaturation with respect to calcium phosphates. Therefore, it is important to modify the mineralizing potential of saliva substitutes to prevent carious lesions. Thus, the aim of the present study was to evaluate the effects of a possible remineralizing saliva substitute (SN; modified Saliva natura) compared to a demineralizing one (G; Glandosane) on mineral parameters of sound bovine dentin and enamel as well as on artificially demineralized enamel specimens in situ. Moreover, oral well-being after use of each saliva substitute was recorded. Using a randomized, double-blind, crossover, phase II/III in situ trial, volunteers with hyposalivation utilize removable dentures containing bovine specimens during the experimental period. The volunteers are divided into two groups, and are required to apply both saliva substitutes for seven weeks each. After both test periods, differences in mineral loss and lesion depth between values before and after exposure are evaluated based on microradiographs. The oral well-being of the volunteers before and after therapy is determined using questionnaires. With respect to the microradiographic analysis, equal mineral losses and lesion depths of enamel and dentin specimens during treatment with SN and G, and no differences in patients' experienced oral comfort after SN compared to G usage are expected (H0). Up to now, 14 patients have been included in the study, and no reasons for early termination of the trial have been identified. The design seems suitable for determining the effects of saliva substitutes on dental hard tissues in situ, and should provide detailed information on the oral well-being after use of different saliva substitutes in patients with hyposalivation. ClinicalTrials.gov ID. NCT01165970.


Genome-Based Analyses of Six Hexacorallian Species Reject the "Naked Coral" Hypothesis.
Scleractinian corals are the foundation species of the coral-reef ecosystem. Their calcium carbonate skeletons form extensive structures that are home to millions of species, making coral reefs one of the most diverse ecosystems of our planet. However, our understanding of how reef-building corals have evolved the ability to calcify and become the ecosystem builders they are today is hampered by uncertain relationships within their subclass Hexacorallia. Corallimorpharians have been proposed to originate from a complex scleractinian ancestor that lost the ability to calcify in response to increasing ocean acidification, suggesting the possibility for corals to lose and gain the ability to calcify in response to increasing ocean acidification. Here, we employed a phylogenomic approach using whole-genome data from six hexacorallian species to resolve the evolutionary relationship between reef-building corals and their noncalcifying relatives. Phylogenetic analysis based on 1,421 single-copy orthologs, as well as gene presence/absence and synteny information, converged on the same topologies, showing strong support for scleractinian monophyly and a corallimorpharian sister clade. Our broad phylogenomic approach using sequence-based and sequence-independent analyses provides unambiguous evidence for the monophyly of scleractinian corals and the rejection of corallimorpharians as descendants of a complex coral ancestor.


Steroid-induced glaucoma after laser in situ keratomileusis associated with interface fluid.
To report the ocular manifestations and clinical course of eyes developing interface fluid after laser in situ keratomileusis (LASIK) surgery from a steroid-induced rise in intraocular pressure. Retrospective, noncomparative interventional case series. We examined six eyes of four patients who had diffuse lamellar keratitis develop after uneventful myopic LASIK surgery and were treated with topical corticosteroids. PRINCIPAL OUTCOME MEASURE: Slit-lamp findings, intraocular pressure measurements, and visual field loss. All eyes had a pocket of fluid develop in the lamellar interface between the flap and the stromal bed associated with a corticosteroid-induced rise in intraocular pressure. However, because of the interface fluid, intraocular pressure was normal or low by central corneal Goldmann applanation tonometry in all eyes. The elevated intraocular pressure was diagnosed by peripheral measurement in several cases after months of elevated pressure. All six eyes had visual field defects develop. Three eyes of two patients had severe glaucomatous optic neuropathy and decreased visual acuity develop as a result of undiagnosed steroid-induced elevated intraocular pressure. A steroid-induced rise in intraocular pressure after LASIK can cause transudation of aqueous fluid across the endothelium that collects in the flap interface. The interface fluid leads to inaccurately low central applanation tonometry measurements that obscure the diagnosis of steroid-induced glaucoma. Serious visual loss may result.


Oligomerization of indole derivatives with incorporation of thiols.
Two molecules of indole derivative, e.g. indole-5-carboxylic acid, reacted with one molecule of thiol, e.g. 1,2-ethanedithiol, in the presence of trifluoroacetic acid to yield adducts such as 3-[2-(2-amino-5-carboxyphenyl)-1-(2-mercaptoethylthio)ethyl]-1Hindole-5-carboxylic acid. Parallel formation of dimers, such as 2,3-dihydro-1H,1'H-2,3'-biindole-5,5'-dicarboxylic acid and trimers, such as 3,3'-[2-(2-amino-5-carboxyphenyl) ethane-1,1-diyl]bis(1H-indole-5-carboxylic acid) of the indole derivatives was also observed. Reaction of a mixture of indole and indole-5-carboxylic acid with 2-phenylethanethiol proceeded in a regioselective way, affording 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H-indole-5-carboxylic acid. An additional product of this reaction was 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-2,3-dihydro-1H,1'H-2,3'-biindole-5'-carboxylic acid, which upon standing in DMSO-d6 solution gave 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H,1'H-2,3'-biindole-5'-carboxylic acid. Structures of all compounds were elucidated by NMR, and a mechanism for their formation was suggested.


The detection of spermine and spermidine in human in vitro fertilization supernatants and their relation to early embryo-associated suppressor activity.
Suppressor activity in human IVF supernatants is dependent on the activity of monoamine oxidase present in nonheat-treated FBS and is therefore likely a polyamine. Pooled suppressive growth phase IVF supernatants were concentrated and subjected to HPLC fractionation. The inhibitory peak in the 1,000 to 2,000 d range was neutralized by antibody reactive with spermine and spermidine, and the presence of both polyamines was confirmed by TLC and by ELISA. These data suggest that IVF supernatant polyamines (spermine and spermidine) are responsible for the early embryo-associated suppressor activity correlating with pregnancy success.


Phylogeography of West Nile virus: from the cradle of evolution in Africa to Eurasia, Australia, and the Americas.
West Nile virus (WNV) is the most widely distributed of the encephalitic flaviviruses and is a major cause of encephalitis, with isolates obtained from all continents, apart from Antarctica. Subsequent to its divergence from the other members of the Japanese encephalitis virus complex, presumably in Africa, WNV has diverged into individual lineages that mostly correspond with geographic distribution. Here we elucidate the phylogeography and evolutionary history of isolates from lineage 1 of WNV. Interestingly, there are many examples of the same amino acid having evolved independently on multiple occasions. In Africa, WNV exists in an endemic cycle, whereas it is epidemic in Europe, being reintroduced regularly from Africa either directly (in western Europe) or via the Middle East (in eastern Europe). Significantly, introduction into other geographic areas has occurred on one occasion only in each region, leading to subsequent establishment and expansion of the virus in these areas. Only one endemic genotype each is present in India and Australia, suggesting that WNV was successfully introduced into these locations once only. Each introduction occurred many centuries ago, probably due to trade and exploration during the 19th century. Likewise, in the Americas, WNV was successfully introduced in 1999 and subsequently became endemic across most temperate regions of North America (NA). In contrast to previous suggestions, an isolate from the epidemic in Israel in 1998 was not the direct progenitor of the NA epidemic; rather, both epidemics originated from the same (unknown) location.


Infant BMI peak, breastfeeding, and body composition at age 3 y.
With the increasing focus on obesity, growth patterns in infancy and early childhood have gained much attention. Although the adiposity rebound has been in focus because of a shown association with adult obesity, not much has been published about the infant peak in body mass index (BMI). This study links age and BMI at infant peak to duration of breastfeeding and body composition at 3 y of age. Frequent weight and height measurements for 311 Danish children in the SKOT (Complementary and Young Child Feeding - Impact on Short and Long Term Development and Health; in Danish) cohort were used to estimate BMI growth curves for the age span from 14 d to 19 mo by using a nonlinear mixed-effects model. BMI growth velocity before peak and age and BMI at peak were derived from the subject-specific models. Information about pregnancy and breastfeeding was assessed from background questionnaires. Assessment of body composition at age 3 y was made based on bioelectrical impedance, weight, and height. A longer duration of exclusive breastfeeding was associated with an earlier peak in infant BMI (P = 0.0003) and a lower prepeak velocity (P < 0.0001). BMI level at peak and prepeak velocity was positively associated with fat and fat-free mass at age 3 y (all P < 0.0001), whereas a later age at peak was associated with a lower fat mass, fat mass index, and fat-free mass index at age 3 y (all P < 0.001). BMI peak characteristics are strongly associated with both duration of exclusive breastfeeding and body composition at 3 y of age. Thus, a better knowledge of characteristics and determinants of the early BMI peak is likely to improve our understanding of early development of obesity.


Enhanced optical imaging of human gliomas and tumor margins.
One of the potential variables affecting the overall survival and quality of life of patients with intracranial gliomas is the extent of tumor resection that results in the smallest volume of residual disease. A technique involving enhanced optical imaging of human gliomas has the potential to localize tumors, identify tumor remaining at the resection margins, and determine the grade of the tumor. In a preliminary study involving nine patients undergoing surgery for the removal of intrinsic brain tumors, enhanced optical imaging was performed using indocyanine green as an intravenous contrast-enhancement agent. Optical images were obtained before and after injection of the indocyanine green. The studies in the nine patients showed differences in the dynamic optical signals among normal brain, low-grade astrocytomas, and malignant astrocytomas. Optical imaging of the resection margins in malignant tumors showed differences between adjacent normal tissue and remaining tumor tissue. Enhanced optical imaging of human gliomas using a contrast-enhancing dye, indocyanine green, provides a potential means to differentiate between normal brain and tumor tissue at the cortical surface and the depths of the resection margins. Having the ability to obtain real-time information and feedback in the operating room may allow neurosurgeons to maximize the extent of tumor resection while sparing normal brain and increasing the diagnostic accuracy of intraoperative biopsies. Enhanced optical imaging potentially could facilitate the accuracy and safety of surgery when tumors are removed at sites even outside the central nervous system.


Using endoscopic procedures for AN-DRG (Australian National Diagnosis Related Groups) assignment: Australia leads the way.
The study reported in this article sought to develop Australian National Diagnosis Related Groups (AN-DRGs) using endoscopic procedures in Major Diagnostic Category (MDC) 6 (Digestive System) and MDC 7 (Hepatobiliary System and Pancreas) through statistical analysis of the Australian Casemix Clinical Committee's recommendations. Five ANOVA were undertaken on final recommendations for gastroscopy and colonoscopy in MDC 6. The Reduction in Variance (RIV) for the AN-DRGs in version 3 relative to version 2 increased by up to 14.6%, representing RIV of between 25.28% to 32.30%. For all ANOVAs, F > 100, alpha < .0001, Coefficient of Variation (CV) was generally lower in version 3 by between 0.4% to 22.9%, except for AN-DRGs for other gastroscopy for major gastro-intestinal disease, which increased by 8.7%. Two ANOVA for Endoscopic Retrograde Cholangio-pancreatography Procedures (ERCP) recommendations resulted in RIV of up to 18.67%, F > 100, alpha < .0001 and CV up to 0.8091. MDC 6, in AN-DRG versions 3 and 3.1, has 11 AN-DRGs following the surgical hierarchy involving gastroscopy and colonoscopy. Patients assigned will not have an operating room procedure; they will have a non-operating room procedure that is either a complex therapeutic or other (diagnostic or therapeutic) procedure. Similar AN-DRGs are in MDC 7 for ERCP. Version 3.1 has expanded the definition of Common Bile Duct Exploration (CDE) to include ERCP. There is no separate AN-DRG for laparoscopy cholecystectomy.


[The specific features of diagnosis of breast diseases accompanied by the retracted nipple syndrome].
By examining 201 patents by currently available radiation (X-ray, ultrasound, and radionuclide) and pathomorphological techniques, the authors consider that benign diseases (nonspecific mastitis, focal fibrosclerosis, pathological secretion appearing as ductal cysts or papillomas, fibroadenomas, gynecomastia, oleogranulomas) and different histological forms of breast cancer (Paget's disease, infiltrating ductal carcinoma, infiltrating and non-infiltrating lobular carcinoma) result in the retracted nipple syndrome. The sensitivity, accuracy, and specificity of various diagnostic techniques used alone or in combination have been calculated. A monitoring system and indications for surgical treatment have been developed. The pathomorphological mechanisms of nipple retraction have been defined.


Compatible observable decompositions for coarse-grained representations of real molecular systems.
Coarse-grained (CG) observable expressions, such as pressure or potential energy, are generally different than their fine-grained (FG, e.g., atomistic) counterparts. Recently, we analyzed this so-called "representability problem" in Wagner et al. [J. Chem. Phys. 145, 044108 (2016)]. While the issue of representability was clearly and mathematically stated in that work, it was not made clear how to actually determine CG observable expressions from the underlying FG systems that can only be simulated numerically. In this work, we propose minimization targets for the CG observables of such systems. These CG observables are compatible with each other and with structural observables. Also, these CG observables are systematically improvable since they are variationally minimized. Our methods are local and data efficient because we decompose the observable contributions. Hence, our approaches are called the multiscale compatible observable decomposition (MS-CODE) and the relative entropy compatible observable decomposition (RE-CODE), which reflect two main approaches to the "bottom-up" coarse-graining of real FG systems. The parameterization of these CG observable expressions requires the introduction of new, symmetric basis sets and one-body terms. We apply MS-CODE and RE-CODE to 1-site and 2-site CG models of methanol for the case of pressure, as well as to 1-site methanol and acetonitrile models for potential energy.


Descriptive study on neural tube defects in Argentina.
Neural tube defects (NTDs) are the most common congenital anomalies of the central nervous system. Prevalence of NTDs varies depending on geographic region and folic acid fortification. The main objectives of this study are to analyze the prevalences of NTDs reported to the National Registry of Congenital Anomalies of Argentina (RENAC) during the period 2009 to 2013, to compare them with data from other selected surveillance systems of the Americas, and to evaluate the impact of folic acid fortification on the prevalence of NTDs in Argentina. We analyzed changes in prevalence between 2009 and 2013 for the RENAC, and differences in prevalence between RENAC and other surveillance systems. We evaluated changes for the pre and postfortification time periods in Argentina. In Argentina, anencephaly and spina bifida showed no statistically significant variation between 2009 and 2013, and encephalocele showed a statistically significant decline. The RENAC showed a statistically significant higher prevalence for all three defects when compared with surveillance systems from Chile, Colombia, and Costa Rica, and a statistically significant lower birth prevalence than Cuba for anencephaly. No differences were observed when comparing it to the Atlanta-USA and Mexico systems. A significant decrease in prevalence was observed for all three anomalies for the postfortification period in Argentina. The characteristics of cases reported to the RENAC are similar to those already reported in the literature. The differences in prevalence between the RENAC and other surveillance systems could be artifactual or real. We confirmed the decrease of prevalence of NTDs after folic acid fortification.


Kinetic Detection of Apoptosis Events Via Caspase 3/7 Activation in a Tumor-Immune Microenvironment on a Chip.
The development of advanced biological models like microphysiological systems, able to rebuild the complexity of the physiological and/or pathological environments at a single-cell detail level in an in-vivo-like approach, is proving to be a promising tool to understand the mechanisms of interactions between different cell populations and main features of several diseases. In this frame, the tumor-immune microenvironment on a chip represents a powerful tool to profile key aspects of cancer progression, immune activation, and response to therapy in several immuno-oncology applications. In the present chapter, we provide a protocol to identify and characterize the time evolution of apoptosis by time-lapse fluorescence and confocal imaging in a 3D microfluidic coculture murine model including cancer and spleen cells.


A family with two female siblings with compound heterozygous FMR1 premutation alleles.
Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation (FMR1) gene have been linked to various types of clinical involvement ranging from mood and anxiety disorders to immunological disorders and executive function deficits. Carrier females typically have a premutation allele and a normal allele (<55 CGG repeats). Although rare, seven cases of females that carry two expanded alleles (compound heterozygous premutation) have been reported. Here, we report on four members of a family including two compound heterozygous premutation sisters with similar CGG allele sizes, affected with different levels of clinical severity.


Peritoneal keratin granulomas complicating endometrial carcinoma: a report of two cases and review of the literature.
Squamous differentiation in endometrial adenocarcinoma is common. Rarely, it may be complicated by peritoneal keratin granulomas. Keratin granulomas accompanied by viable adenocarcinoma cells are regarded as conventional metastatic foci. However, the significance of keratin granulomas without accompanying viable adenocarcinoma cells is difficult to ascertain. Only a small number of cases with significant follow up are documented in the literature. We present two cases of peritoneal keratin granulomas, review the literature and discuss the significance of these lesions.


Effect of overlapping projections on reconstruction image quality in multipinhole SPECT.
Multipinhole single photon emission computed tomography (SPECT) imaging has several advantages over single pinhole SPECT imaging, including an increased sensitivity and an improved sampling. However, the quest for a good design is challenging, due to the large number of design parameters. The effect of one of these, the amount of overlap in the projection images, on the reconstruction image quality, is examined in this paper. The evaluation of the quality is based on efficient approximations for the linearized local impulse response and the covariance in a voxel, and on the bias of the reconstruction of the noiseless projection data. Two methods are proposed that remove the overlap in the projection image by blocking certain projection rays with the use of extra shielding between the pinhole plate and the detector. Also two measures to quantify the amount of overlap are suggested. First, the approximate method, predicting the contrast-to-noise ratio (CNR), is validated using postsmoothed maximum likelihood expectation maximization (MLEM) reconstructions with an imposed target resolution. Second, designs with different amounts of overlap are evaluated to study the effect of multiplexing. In addition, the CNR of each pinhole design is also compared with that of the same design where overlap is removed. Third, the results are interpreted with the overlap quantification measures. Fourth, the two proposed overlap removal methods are compared. From the results we can conclude that, once the complete detector area has been used, the extra sensitivity due to multiplexing is only able to compensate for the loss of information, not to improve the CNR. Removing the overlap, however, improves the CNR. The gain is most prominent in the central field of view, though often at the cost of the CNR of some voxels at the edges, since after overlap removal very little information is left for their reconstruction. The reconstruction images provide insight in the multiplexing and truncation artifacts.


Associative learning increases trial-by-trial similarity of BOLD-MRI patterns.
Associative learning is a dynamic process that allows us to incorporate new knowledge within existing semantic networks. Even after years, a seemingly stable association can be altered by a single significant experience. Here, we investigate whether the acquisition of new associations affects the neural representation of stimuli and how the brain categorizes stimuli according to preexisting and emerging associations. Functional MRI data were collected during a differential fear conditioning procedure and at test (4-5 weeks later). Two pictures of faces and two pictures of houses served as stimuli. One of each pair coterminated with a shock in half of the trials (partial reinforcement). Applying Multivoxel Pattern Analysis (MVPA) in a trial-by-trial manner, we quantified changes in the similarity of neural representations of stimuli over the course of conditioning. Our findings show an increase in similarity of neural patterns throughout the cortex on consecutive trials of the reinforced stimuli. Furthermore, neural pattern similarity reveals a shift from original categories (faces/houses) toward new categories (reinforced/unreinforced) over the course of conditioning. This effect was differentially represented in the cortex, with visual areas primarily reflecting similarity of low-level stimulus properties (original categories) and frontal areas reflecting similarity of stimulus significance (new categories). Effects were not dependent on overall response amplitude and were still present during follow-up. We conclude that trial-by-trial MVPA is a useful tool for examining how the human brain encodes relevant associations and forms new associative networks.


Analysis of Lrrn1 expression and its relationship to neuromeric boundaries during chick neural development.
The Drosophila leucine-rich repeat proteins Tartan (TRN) and Capricious (CAPS) mediate cell affinity differences during compartition of the wing imaginal disc. This study aims to identify and characterize the expression of a chick orthologue of TRN/CAPS and examine its potential function in relation to compartment boundaries in the vertebrate central nervous system. We identified a complementary DNA clone encoding Leucine-rich repeat neuronal 1 (Lrrn1), a single-pass transmembrane protein with 12 extracellular leucine-rich repeats most closely related to TRN/CAPS. Lrrn1 is dynamically expressed during chick development, being initially localized to the neural plate and tube, where it is restricted to the ventricular layer. It becomes downregulated in boundaries following their formation. In the mid-diencephalon, Lrrn1 expression prefigures the position of the anterior boundary of the zona limitans intrathalamica (ZLI). It becomes progressively downregulated from the presumptive ZLI just before the onset of expression of the signalling molecule Sonic hedgehog (Shh) within the ZLI. In the hindbrain, downregulation at rhombomere boundaries correlates with the emergence of specialized boundary cell populations, in which it is subsequently reactivated. Immunocolocalization studies confirm that Lrrn1 protein is endocytosed from the plasma membrane and is a component of the endosomal system, being concentrated within the early endosomal compartment. Chick Lrrn1 is expressed in ventricular layer neuroepithelial cells and is downregulated at boundary regions, where neurogenesis is known to be delayed, or inhibited. The timing of Lrrn1 downregulation correlates closely with the activation of signaling molecule expression at these boundaries. This expression is consistent with the emergence of secondary organizer properties at boundaries and its endosomal localisation suggests that Lrrn1 may regulate the subcellular localisation of specific components of signalling or cell-cell recognition pathways in neuroepithelial cells.


Adhesive intestinal obstruction in infants and children: the place of conservative treatment.
Objectives. Adhesive intestinal obstruction (AIO) is rare in the pediatric age group and its treatment is still controversial. This is a retrospective review of our experience in infants and children with AIO. Patients and Methods. The records of infants and children with AIO between January 2001 and December 2010 were retrospectively reviewed for age at diagnosis, sex, initial operation, interval between initial operation and presentation, diagnosis, treatment and outcome. Results. 44 infants and children were admitted with AIO. There were 28 males and 16 females who had 46 episodes. Their ages at presentation ranged from 1 month to 12 years (mean 5.4 years), while their ages at initial operation ranged from 2 days to 12 years (mean 4.15 years). Time elapsed from initial operation to presentation ranged from 7 days to 8 years (mean 1.5 years), and 66% developed AIO within 1 year from initial operation. Appenedecectomy was the commonest operation (29.5%). Four (9%) responded to conservative treatment. The other 40 (91%) required surgical intervention. Twenty-nine had release of adhesions only, while 10 (25%) had resection of small intestines and one underwent stricturoplasty. Two developed recurrence and one died. Conclusions. AIO is rare in the pediatric age group and the majority becomes symptomatic within 1 year of operation. Appendecectomy is the commonest operation leading to AIO. The place of conservative treatment is limited and to obviate delay and decrease the chance of intestinal ischemia, they should be treated early with surgical adhesiolysis.


A population-based experimental model for protein evolution: effects of mutation rate and selection stringency on evolutionary outcomes.
Protein evolution is a critical component of organismal evolution and a valuable method for the generation of useful molecules in the laboratory. Few studies, however, have experimentally characterized how fundamental parameters influence protein evolution outcomes over long evolutionary trajectories or multiple replicates. In this work, we applied phage-assisted continuous evolution (PACE) as an experimental platform to study evolving protein populations over hundreds of rounds of evolution. We varied evolutionary conditions as T7 RNA polymerase evolved to recognize the T3 promoter DNA sequence and characterized how specific combinations of both mutation rate and selection stringency reproducibly result in different evolutionary outcomes. We observed significant and dramatic increases in the activity of the evolved RNA polymerase variants on the desired target promoter after selection for 96 h, confirming positive selection occurred under all conditions. We used high-throughput sequencing to quantitatively define convergent genetic solutions, including mutational "signatures" and nonsignature mutations that map to specific regions of protein sequence. These findings illuminate key determinants of evolutionary outcomes, inform the design of future protein evolution experiments, and demonstrate the value of PACE as a method for studying protein evolution.


Phleboviruses detection in Phlebotomus perniciosus from a human leishmaniasis focus in South-West Madrid region, Spain.
Phlebotomus-borne (PhB-) viruses are distributed in large areas of the Old World and are widespread throughout the Mediterranean basin, where recent investigations have indicated that virus diversity is higher than initially suspected. Some of these viruses are causes of meningitis, encephalitis and febrile illnesses. In order to monitor the viral presence and the infection rate of PhB-viruses in a recently identified and well characterized human zoonotic leishmaniasis focus in southwestern Madrid, Spain, a sand fly collection was carried out. Sand fly insects were collected in four stations using CDC light traps during 2012-2013 summer seasons. Screening for Phlebovirus presence both via isolation on Vero cells and via polymerase chain reaction (PCR), using degenerated primers targeting a portion of the L segment, was performed. The serological identity and phylogenetic relationships on the three genomic segments of the viral isolates were carried out. Six viral isolates belonging to different serological complexes of the genus Phlebovirus were obtained from fifty pools on a total of 963 P. perniciosus (202 females). Phylogenetic analysis and serological assays allowed the identification of two isolates of Toscana virus (TOSV) B genotype, three isolates strongly related to Italian Arbia virus (ARBV), and one isolate of a novel putative Phlebovirus related to the recently characterized Arrabida virus in South Portugal, tentatively named Arrabida-like virus. Positive male sand fly pools suggested that transovarial or venereal transmission could occur under natural conditions. Our findings highlighted the presence of different Phlebovirus species in the South-West area of the Madrid Autonomous Community where an outbreak of cutaneous and visceral human leishmaniasis has been recently described. The evidence of viral species never identified before in Spain, as ARBV and Arrabida-like virus, and TOSV B genotype focus stability was demonstrated. Environmental aspects such as climate change, growing urbanization, socio-economic development could have contributed to the genesis of this wide ecological niche of PhB-viruses and Leishmania spp. The potential role of vertebrates as reservoir for the phleboviruses identified and the possibility of Phleboviruses-Leishmania co-infection in the same sand fly should be assessed. Furthermore the PhB-viruses impact on human health should be implemented.


Influence of the Comprehensive Unit-based Safety Program in ICUs: Evidence From the Keystone ICU Project.
Using data from the Keystone ICU project, this study examined whether the intensive care units (ICUs) that implemented the Comprehensive Unit-based Safety Program (CUSP) would have greater improvement in safety climate, team progress barriers, and central line-associated bloodstream infections (CLABSIs) than ICUs not implementing CUSP. The study population consisted of 103 ICUs; 60 ICUs (58%) used CUSP, with 6 of them later discontinuing CUSP, and 17 ICUs (16.5%) never used CUSP. The researchers could not determine CUSP use status for the remaining 26 ICUs because of missing data. The use of CUSP was associated with improved safety climate, job satisfaction, and working conditions after a 2-year period, as measured by the Safety Attitudes Questionnaire. Study results on barriers and CLABSIs are inconclusive. This study demonstrated that unit-based, formalized processes targeting cultural improvements in teamwork, communication, self-identification of hazards, and hazard mitigation can improve several aspects of patient safety climate in ICUs.


[The iodine supply of newborns. Comparison of iodine absorption and iodine excretion of mother and child].
Since 1989 the use of iodized salt has been allowed in Germany, additional supplementation with iodide tablets has been recommended during pregnancy and lactation. This study was undertaken to clarify whether the iodine intake of neonates and young infants improved since then. In the first part of the study the urinary iodine excretion of 52 newborns and their mothers in 1998 was compared to data of similar studies 1983 in the area of Göttingen and 1982 in the areas of Heidelberg and Rothenburg, Germany. All these are geographically low-iodine areas. In the second part the iodine supply of infants in 1998-1999 under feeding with mother's milk or formulas in 1998 and 1999 was obtained by measuring iodide concentrations in urine and milk using a high pressure liquid chromatography (HPLC) method. 45% of pregnant women were without iodide supplementation in 1998. In 1998 the median urinary iodide concentration during the first week of life was 4.3 micrograms/dl, which was more than twice that found in 1983 (1.75 micrograms/dl). Infants feeding by mother's milk without maternal iodine supplementation or by semi-elementary diet had the lowest urinary iodine excretion, whereas significantly higher values were measured when feeding formulas for term or preterm infants. The iodine intake of newborns has markedly improved during 15 years. The WHO criterias for adequate iodine supply (TSH < 5 microU/ml and urinary iodine >/ = 10 micrograms/dl) were only partly fulfilled in Göttingen indicating that a mild iodine deficiency still exists with the risk of iodine deficiency disorders.


The performance of administrative and self-reported measures for risk adjustment of Veterans Affairs expenditures.
To evaluate the performance of different prospective risk adjustment models of outpatient, inpatient, and total expenditures of veterans who regularly use Veterans Affairs (VA) primary care. We utilized administrative, survey and expenditure data on 14,449 VA patients enrolled in a randomized trial that gave providers regular patient health assessments. This cohort study compared five administrative data-based, two self-report risk adjusters, and base year expenditures in prospective models. VA outpatient care and nonacute inpatient care expenditures were based on unit expenditures and utilization, while VA expenditures for acute inpatient care were calculated from a Medicare-based inpatient cost function. Risk adjusters for this sample were constructed from diagnosis, medication and self-report data collected during a clinical trial. Model performance was compared using adjusted R2 and predictive ratios. In all expenditure models, administrative-based measures performed better than self-reported measures, which performed better than age and gender. The Diagnosis Cost Groups (DCG) model explained total expenditure variation (R2=7.2 percent) better than other models. Prior outpatient expenditures predicted outpatient expenditures best by far (R2=42 percent). Models with multiple measures improved overall prediction, reduced over-prediction of low expenditure quintiles, and reduced under-prediction in the highest quintile of expenditures. Prediction of VA total expenditures was poor because expenditure variation reflected utilization variation, but not patient severity. Base year expenditures were the best predictor of outpatient expenditures and nearly the best for total expenditures. Models that combined two or more risk adjusters predicted expenditures better than single-measure models, but are more difficult and expensive to apply.


Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin-dependent diabetes mellitus patients.
The effectiveness of GS4, an extract from the leaves of Gymnema sylvestre, in controlling hyperglycaemia was investigated in 22 Type 2 diabetic patients on conventional oral anti-hyperglycaemic agents. GS4 (400 mg/day) was administered for 18-20 months as a supplement to the conventional oral drugs. During GS4 supplementation, the patients showed a significant reduction in blood glucose, glycosylated haemoglobin and glycosylated plasma proteins, and conventional drug dosage could be decreased. Five of the 22 diabetic patients were able to discontinue their conventional drug and maintain their blood glucose homeostasis with GS4 alone. These data suggest that the beta cells may be regenerated/repaired in Type 2 diabetic patients on GS4 supplementation. This is supported by the appearance of raised insulin levels in the serum of patients after GS4 supplementation.


A new CD44V3-containing isoform is involved in tumor cell growth and migration during human breast carcinoma progression.
CD44 isoforms belong to a family of cell adhesion molecules expressed on the cell surface of many tumor cells during human breast cancer progression. In this study we have analyzed the expression of CD44v3-containing isoforms [containing heparan sulfate addition sites for growth factor binding] in primary breast tumors, axillary nodal metastases and normal breast tissue. Using reverse transcriptase-polymerase chain reaction (RT-PCR) followed by Southern blot, cloning, nucleotide sequencing and RT-in situ-PCR analyses, we have found that at least two CD44v3-containing isoforms, including one new species of CD44v2,deltav3-10 (deltav3 defined as a v3 exon lacking the first 24 base pairs) and another previously reported CD44v3,8-10 are preferentially expressed in human primary breast tumor and axillary nodal metastases but not in normal breast tissues. These finding suggest that these CD44v3-containing isoforms are closely associated with breast cancer metastasis.


Effect of diameter on membrane capacity and conductance of sheep cardiac Purkinje fibers.
Membrane electrical properties were measured in sheep cardiac Purkinje fibers, having diameters ranging from 50 to 300 mum. Both membrane capacitance and conductance per unit area of apparent fiber surface varied fourfold over this range. Membrane time constant, and capacitance per unit apparent surface area calculated from the foot of the action potential were independent of fiber diameter, having average values of 18.8 +/- 0.7 ms, and 3.4 +/- 0.25 muF/cm2, respectively (mean +/- SEM). The conduction velocity and time constant of the foot of the action potential also appeared independent of diameter, having values of 3.0 +/- 0.1 m/s and 0.10 +/- 0.007 ms. These findings are consistent with earlier suggestions that in addition to membrane on the surface of the fiber, there exists a large fraction of membrane in continuity with the extracellular space but not directly on the surface of the fiber. Combining the electrical and morphological information, it was possible to predict a passive length constant for the internal membranes of about 100 mum and a time constant for chaning these membranes in a passive 100-mum fiber of 1.7 ms.


[Subfrontal schwannoma: case report].
Schwannoma are benign, slowly growing nerve sheath tumors. They can arise from any peripheral nerve containing Schwann cells including distal portions of cranial nerves. Intracranial schwannomas arising from a subfrontal lesion are very rare. We report a case of subfrontal schwannoma in a 38-year-old woman who presented with seizures in February 2003. MRI features resembled an olfactory groove meningioma. The left carotid angiography revealed that the tumor was supplied from the anterior ethomoidal artery, but no remarkable tumor stain was detected. Bifrontal craniotomy with total excision of the tumor revealed a tumor in the left subfrontal lesion. The tumor was attached to the falx, the left frontal lobe, and the skull base, but those structures were not invaded. Unfortunately, we could not detect the left olfactory nerve. Subsequent histological examination proved that this tumor was schwannoma. A review of the literature found 27 cases including this case previously described. Arguments are raised that schwannomas in a subfrontal lesion are comparable to or even occur as intracranial schwannomas with frontal localization. Subfrontal schwannomas are very rare. For this reason they have not been diagnosed preoperatively. Further cases of subfrontal schwannoma are necessary to solve the enigma of the origin of this tumor.


Intermittent Massage as a Therapeutic Option for Compartment Syndrome after Embolectomy of the Lower Limbs.
The case of a 54-year-old cardiac patient is reported, who was admitted to hospital with a complaint of sudden pain in the legs associated with edema, paresthesia, and coldness. Arterial embolism of the lower limbs was diagnosed and the patient was submitted to bilateral embolectomy. The patient evolved with a burning sensation, hypersensitivity in the right leg, swelling, and difficulty bending and stretching the sole of the foot and the knee. A physical examination detected edema and increased tension in the anterior, lateral, and posterior compartments. Treatment using intermittent massage of the leg during the evaluation of the patient was chosen in an attempt to stimulate lymphatic and venous drainage. After a few minutes of stimulation, there was significant improvement in the pain and edema. In 40 minutes, there was total reduction of the pain in the posterior and lateral compartments and improvement of over 50% in the anterior compartment. After this, the patient started to bend the knee without pain and bend the sole of the foot with slight pain. On the following day, the patient was walking around the hospital ward without difficulty. It seems that intermittent massage is a therapeutic option in selected cases of compartment syndrome.


Comparison of Physical Activity by Lifestyle Between Two Rural Pediatric Population Groups.
Obesity prevalence is higher among rural populations than urban, including youth. Reduced physical activity levels are associated with childhood obesity. It could be assumed that the obesity disparity between rural and urban children is attributable, in part, to differences in physical activity levels; however, previous research quantifying and comparing physical activity levels between rural and urban youth are mixed. Lifestyle may be more important than geographic location in determining physical activity levels. Therefore, the objective of this study was to compare sex and lifestyle group (Hutterite vs. non-Hutterite) differences in physical activity in a free-living, rural pediatric population. Youth (n=58) were instructed to wear accelerometers for seven days. Mean percent time in light, moderate or vigorous activity during waking hours was calculated. Two-way ANOVAs and multiple regression models were used for analyses. Percent time in vigorous activity was significantly greater for Hutterite males than Hutterite females, and Hutterite males had greater percent time in vigorous activity and moderate plus vigorous activity than non-Hutterite males. There is evidence to support differences in rural lifestyles to be associated with differences in physical activity levels between children living in the same geographic location, particularly among males. Active transportation and having a safe environment for unstructured outdoor play may account for activity and lifestyle differences between the two rural groups.


The first urinary tract infection in male children.
In a prospective study of urinary tract infection in 57 boys, diagnosis in 50 patients was based on the presence of more than 10(5) organisms per milliliter of urine. Gram-positive cocci were more prevalent, and Escherichia coli was less prevalent than previously reported in girls. Fever and urinary tract abnormalities were frequent in boys younger than 10 years of age; less common in boys 10 to 14 years old. Excretory urography and voiding cystourethrography were performed in 30 boys. In 15, one or both showed abnormalities, usually vesicoureteral reflux. Most of the abnormalities, and all of those that necessitated surgical correction, were in boys under 10 years old. In the remaining seven patients, less than 10(3) organisms per milliliter grew on urine culture. All of the seven were younger than 10 years of age, and all had serious renal abnormalities, three requiring surgical correction.


Effectiveness of Hospital Functions for Acute Ischemic Stroke Treatment on In-Hospital Mortality: Results From a Nationwide Survey in Japan.
Though evidence is limited in Japan, clinical controlled studies overseas have revealed that specialized care units are associated with better outcomes for acute stoke patients. This study aimed to examine the effectiveness of hospital functions for acute care of ischemic stroke on in-hospital mortality, with statistical accounting for referral bias. We derived data from a large Japanese claim-based inpatient database linked to the Survey of Medical Care Institutions and Hospital Report data. We compared the mortality of acute ischemic stroke patients (n = 41 476) in hospitals certified for acute stroke treatment with that in non-certified institutions. To adjust for potential referral bias, we used differential distance to hospitals from the patient's residence as an instrumental variable and constructed bivariate probit models. With the ordinary probit regression model, in-hospital mortality in certified hospitals was not significantly different from that in non-certified institutions. Conversely, the model with the instrumental variable method showed that admission to certified hospitals reduced in-hospital mortality by 30.7% (P < 0.001). This difference remained after adjusting for hospital size, volume, staffing, and intravenous use of tissue plasminogen activator. Comparison accounting for referral selection found that certified hospital function for acute ischemic stroke care was associated with significantly lower in-hospital mortality. Our results indicate that organized stroke care--with certified subspecialty physicians and around-the-clock availability of personnel, imaging equipment, and emergency neurosurgical procedures in an intensive stroke care unit-is effective in improving outcomes in acute ischemic stroke care.


The effect of circumcision status on periurethral and glanular bacterial flora.
Circumcision is a historical operation which is still performed for different purposes. The aim of this study is to investigate the changes in periurethral and glanular sulcus flora due to circumcision to determine the role of circumcision on urinary tract infections (UTIs). Fifty patients who were circumcised for social-religious reasons between January 2000 and January 2001 were evaluated in this prospective study. Two swabs were taken from the periurethral and glanular sulcus regions both just before circumcision and 4 weeks after, and the bacteria cultured were recorded. We isolated pathogenic bacteria in the periurethral region of 32 (64%) patients (enterococci in 14 cases; Escherichia coli in 12 cases) before circumcision, and this number decreased to 5 (10%) after circumcision. Similarly, pathogenic bacteria were cultured from the glanular sulcus swabs of 33 (68%) patients (enterococci in 14 cases; E. coli in 10 cases), as well as coagulase-negative staphylococci in another 15 patients before circumcision. Following circumcision, we detected pathogenic bacteria in the glanular cultures of only 4 cases, whereas 40 children had non-pathogenic skin flora. Only 1 of 5 children with history of UTIs (n = 1) and retractable phimosis (n = 4) had periurethral pathogenic bacteria (Proteus spp.) in the post-circumcision period. The differences between pre- and post-circumcision values of the pathogenic bacterial colonizations were statistically significant in both groups sampled (p < 0.05). Non-circumcised patients have similar pathogenic bacterial colonizations in the periurethral and the inner preputial regions, although they have no phimosis. The origin of periurethral flora should be the deeper preputial regions. The flora greatly changed with skin commensals after circumcision. Circumcision might be beneficial from this point of view.


Promoter-proximal Pol II: when stalling speeds things up.
Expression of genes was long thought to be regulated primarily at the level of RNA polymerase II (Pol II) recruitment to a gene promoter, and the dozen genes that did not fit this paradigm were regarded as exceptions. However, recent analyses of genome-wide Pol II distribution in Drosophila and mammalian systems have indicated that a large number of genes might be regulated at a step subsequent to Pol II recruitment, during early transcription elongation. At these genes, Pol II begins transcription but stalls after synthesizing a short RNA, and it is the release of this engaged Pol II from the promoter-proximal region that is rate limiting for transcription. Notably, promoter-proximal Pol II stalling is prevalent at genes involved in development and response to stimuli, suggesting that Pol II stalling during early elongation plays important roles in rapid and precise control of gene expression. Here we briefly summarize the current data on promoter-proximal Pol II stalling and discuss implications of this newly appreciated regulatory strategy.


Authors of clinical trials reported individual and financial conflicts of interest more frequently than institutional and nonfinancial ones: a methodological survey.
Conflicts of interest (COIs) are increasingly recognized as important to disclose and manage in health research. The objective of this study was to assess the reporting of both financial and nonfinancial COI by authors of randomized controlled trials published in a representative sample of clinical journals. We searched Ovid Medline and included a random sample of 200 randomized controlled trials published in 2015 in one of the 119 Core Clinical Journals. We classified COI using a comprehensive framework that includes the following: individual COIs (financial, professional, scholarly, advocatory, personal) and institutional COIs (financial, professional, scholarly, and advocatory). We conducted descriptive and regression analyses. Of the 200 randomized controlled trials, 188 (94%) reported authors' COI disclosures that were available in the main document (92%) and as International Committee of Medical Journal Editors forms accessible online (12%). Of the 188 trials, 57% had at least one author reporting at least one COI; in all these trials, at least one author reported financial COI. Institutional COIs (11%) and nonfinancial COIs (4%) were less commonly reported. References to COI disclosure statements for editors (1%) and medical writers (0%) were seldom present. Regression analyses showed positive associations between reporting individual financial COI and higher journal impact factor (odds ratio [OR] = 1.06, 95% confidence interval [CI] = 1.02-1.10), larger number of authors (OR = 1.10, 95% CI 1.02-1.20), affiliation with an institution from a high-income country (OR = 16.75, 95% CI 3.38-82.87), and trials reporting on pharmacological interventions (OR = 2.28, 95% CI 1.13-4.62). More than half of published randomized controlled trials report that at least one author has a COI. Trial authors report financial COIs more often than nonfinancial COIs and individual COIs more frequently than institutional COIs.


MSAProbs-MPI: parallel multiple sequence aligner for distributed-memory systems.
MSAProbs is a state-of-the-art protein multiple sequence alignment tool based on hidden Markov models. It can achieve high alignment accuracy at the expense of relatively long runtimes for large-scale input datasets. In this work we present MSAProbs-MPI, a distributed-memory parallel version of the multithreaded MSAProbs tool that is able to reduce runtimes by exploiting the compute capabilities of common multicore CPU clusters. Our performance evaluation on a cluster with 32 nodes (each containing two Intel Haswell processors) shows reductions in execution time of over one order of magnitude for typical input datasets. Furthermore, MSAProbs-MPI using eight nodes is faster than the GPU-accelerated QuickProbs running on a Tesla K20. Another strong point is that MSAProbs-MPI can deal with large datasets for which MSAProbs and QuickProbs might fail due to time and memory constraints, respectively. Source code in C ++ and MPI running on Linux systems as well as a reference manual are available at http://msaprobs.sourceforge.net CONTACT: email@example.com information: Supplementary data are available at Bioinformatics online.


Histone deacetylase inhibitors enhance the anticancer activity of nutlin-3 and induce p53 hyperacetylation and downregulation of MDM2 and MDM4 gene expression.
Nutlin-3, a small-molecule MDM2 inhibitor, restores p53 function and is, thus, an appealing candidate for the treatment of cancers retaining wild-type p53. However, nutlin-3 applied as single agent may be insufficient for cancer therapy. Therefore, we explored whether the anticancer activity of nutlin-3 could be enhanced by combination with histone deacetylase inhibitors (HDACi), i.e. vorinostat, sodium butyrate, MS-275 and apicidin. We found that nutlin-3 and HDACi cooperated to induce cell death in the p53 wild-type cell lines A549 and A2780, but not in the p53 null cell line PC-3, as assessed by Alamar Blue assay and flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization. Combination index analysis showed that the effect was synergistic. For comparison, we tested nutlin-3 in combination with paclitaxel, revealing that nutlin-3 antagonized the cytotoxic activity of paclitaxel. To shed light on the underlying mechanism of the synergistic action of nutlin-3 and HDACi, we determined the acetylation status of p53 by immunoblotting and the mRNA levels of MDM2 and MDM4 by real-time RT-PCR. We observed vorinostat to induce p53 hyperacetylation, to reduce the constitutive gene expression of MDM2 and MDM4, and to counteract the nutlin-3-induced upregulation of MDM2 gene expression. In conclusion, our study shows that HDACi amplify the antitumor activity of nutlin-3-possibly by inducing p53 hyperacetylation and/or MDM2 and/or MDM4 downregulation-suggesting that treatment with a combination of nutlin-3 and HDACi may be an effective strategy for treating tumors with wild-type p53.


Linking fate model in freshwater and PBPK model to assess human internal dosimetry of B(a)P associated with drinking water.
In the present study, we demonstrate an integrated modeling approach for predicting internal tissue concentrations of chemicals by coupling a multimedia environmental model and a generic physiologically based pharmacokinetic (PBPK) model. A case study was designed for a region situated on the Seine river watershed, downstream of the Paris megacity, and for benzo(a)pyrene emitted from industrial zones in the region. In this case study, these two models are linked only by water intake from riverine system for the multimedia model into human body for the PBPK model. The limited monitoring data sets of B(a)P concentrations in bottom sediment and in raw river water, obtained at the downstream of Paris, were used to re-construct long-term daily concentrations of B(a)P in river water. The re-construction of long-term series of B(a)P level played a key role for the intermediate model calibration (conducted in multimedia model) and thus for improving model input to PBPK model. In order to take into account the parametric uncertainty in the model inputs, some input parameters relevant for the multimedia model were given by probability density functions (PDFs); some generic PDFs were updated with site-specific measurements by a Bayesian approach. The results of this study showed that the multimedia model fits well with actual annual measurements in sediments over one decade. No accumulation of B(a)P in the organs was observed. In conclusion, this case study demonstrated the feasibility of a full-chain assessment combining multimedia environmental predictions and PBPK modeling, including uncertainty and sensitivity analyses.


Retirement: getting it right the first time.
After a lifetime of being on call, retirement should be a snap. But getting to that state called "retirement" can be as hazardous as wading through an alligator infested swamp. Like anything else in life, retirement requires more preparation than meets the eye.


Crystallization and initial crystallographic analysis of the Kelch domain from human Keap1.
The human Keap1 protein is a substrate adaptor for an E3 ubiquitin ligase complex that specifically targets the transcription factor Nrf2 for degradation. Keap1 functions as a sensor of oxidative stress, such that the inhibition of Keap1-dependent degradation of Nrf2 activates a genetic program that protects cells from reactive chemicals and maintains cellular redox homeostasis. Keap1 interacts with Nrf2 through its C-terminal Kelch-repeat domain. Kelch-repeat domains are found in a large number of proteins and are predicted to assemble into a beta-propeller structure. Only a single Kelch-repeat domain, that from the fungal enzyme galactose oxidase, has had its structure determined. Here, the crystallization of the Kelch domain of human Keap1 protein by hanging-drop vapor diffusion is reported in space group P6(5)22. Crystals diffract to 1.85 A resolution under cryocooling conditions. A selenomethionine-substituted version of the Kelch domain has also been purified and crystallizes isomorphously with the native protein. Structure determination by MAD phasing is under way. The role of Keap1 in oxidative stress and cytoprevention suggests that the Kelch domain will be an attractive target for therapeutic drug design.


Current trials of interventions to prevent radiocontrast-induced nephropathy.
Radiocontrast administration is a common cause of hospital-acquired acute renal failure. It is associated with significant in-hospital and long-term morbidity and mortality and increases the costs of medical care by at least extending the hospital stay. A variety of therapeutic interventions, including saline hydration, diuretics, mannitol, calcium channel antagonists, theophylline, endothelin receptor antagonists, and dopamine, have been employed to prevent radiocontrast-induced acute renal failure. Recent advances have examined the impact of fenoldopam (dopamine-1 receptor agonist), N-acetylcysteine (antioxidant), iso-osmolar contrast agents, hemodialysis, and hemofiltration on ameliorating radiocontrast-induced acute renal failure. Although hydration with half-normal saline had remained the gold standard for the prevention of radiocontrast-induced nephropathy, recent data have revealed the superiority of hydration with normal saline over half-normal saline. This review focuses on the most recent studies of interventions to ameliorate radiocontrast-induced acute renal failure and provides a critical analysis of some of the recent studies conducted to prevent radiocontrast-induced nephropathy.


Immune Mechanisms and Related Targets for the Treatment of Fibrosis in Various Organs.
Inflammation and fibrosis are two interrelated disease pathologies with several overlapping components. Three specific cell types, namely macrophages, T helper cells, and myofibroblasts, play important roles in regulating both processes. Following tissue injury, an inflammatory stimulus is often necessary to initiate tissue repair, where cytokines released from infiltrating and resident immune and inflammatory cells stimulate the proliferation and activation of extracellular matrix-producing myofibroblasts. However, persistent tissue injury drives an inappropriate pro-fibrotic response. Additionally, activated myofibroblasts can take on the role of traditional antigen-presenting cells, secrete pro-inflammatory cytokines, and recruit inflammatory cells to fibrotic foci, amplifying the fibrotic response in a vicious cycle. Moreover, inflammatory cells have been shown to play contradictory roles in the initiation, amplification, and resolution of fibrotic disease processes. The central role of the inflammasome molecular platform in contributing to fibrosis is only beginning to be fully appreciated. In this review, we discuss the immune mechanisms that can lead to fibrosis, the inflammasomes that have been implicated in the fibrotic process in the context of the immune response to injury, and also discuss current and emerging therapies that target inflammasome-induced collagen deposition to treat organ fibrosis.


Cannabis and tobacco use prior to pregnancy and subsequent offspring birth outcomes: a 20-year intergenerational prospective cohort study.
There is increasing evidence that the life-course origins of health and development begin before conception. We examined associations between timing and frequency of preconception cannabis and tobacco use and next generation preterm birth (PTB), low birth weight (LBW) and small for gestational age. 665 participants in a general population cohort were repeatedly assessed on tobacco and cannabis use between ages 14-29 years, before pregnancy. Associations were estimated using logistic regression. Preconception parent (either maternal or paternal) daily cannabis use age 15-17 was associated with sixfold increases in the odds of offspring PTB (aOR 6.65, 95% CI 1.92, 23.09), and offspring LBW (aOR 5.84, 95% CI 1.70-20.08), after adjusting for baseline sociodemographic factors, parent sex, offspring sex, family socioeconomic status, parent mental health at baseline, and concurrent tobacco use. There was little evidence of associations with preconception parental cannabis use at other ages or preconception parental tobacco use. Findings support the hypothesis that the early life origins of growth begin before conception and provide a compelling rationale for prevention of frequent use during adolescence. This is pertinent given liberalisation of cannabis policy.


Evaluation of physical properties of human hair by diffuse reflectance near-infrared spectroscopy.
The objective of the present study is to develop a novel nondestructive, simple, and quick method to evaluate the friction, twist, and gloss of human hair based on near-infrared diffuse reflectance (NIR-DR) spectroscopy and chemometrics. NIR-DR spectra were measured for human hair, which was collected from eleven Japanese women (age 5-44 years), by use of an optical fiber probe. Partial least squares (PLS) regression has been applied to the NIR-DR spectra of human hair after mean centering (MC), standard normal variate (SNV), and first derivative (1d) or second derivative (2d) analysis to develop calibration models that predict the friction, twist, and gloss of human hair. We identified the most suitable wavenumber region for the evaluation of each physical property. Correlation coefficients and standard errors of calibration of the PLS calibration models for the friction, twist, and gloss of hair were calculated to be 0.96 and 0.023, 0.81 and 3.27, and 0.90 and 0.36, respectively. Thus, the calibration models have high accuracy.


Attempts to control haemonchosis in grazing ewes by vaccination with gut membrane proteins of the parasite.
A vaccination trial was conducted to evaluate the potential benefit of Haemonchus contortus gut membrane proteins as vaccine antigens under field conditions in Louisiana. The trial was conducted in the summer of 1996 in a flock of ewes grazing pasture naturally infected with H. contortus. Ewes were randomly assigned to three treatment groups (vaccine, adjuvant only, and saline) and fecal egg counts (FEC, measured as eggs per gram of feces), packed cell volumes (PCV), and antibody levels were monitored fortnightly for 12 weeks. It was shown by FEC that there were large individual variations in susceptibility to H. contortus in both vaccinated and non-vaccinated sheep, a finding which could have masked differences between treatments when analyzed by conventional statistical methods. Based on their egg counts before the period when the vaccination could have had an effect, all ewes were categorized as 'susceptible' or 'relatively resistant'. The significance of differences between FEC, PCV and antibody responses of vaccinated and control sheep were tested separately for the 'susceptible' and 'relatively resistant' category. The 'susceptible' vaccinates shed 65% fewer worm eggs during the period when the vaccine could have had an effect, but the difference was only significant on Week 6 post-vaccination. In these experiments, it was difficult to completely exclude the confounding effect of having 'relatively resistant' sheep in the control group. More studies are needed to further evaluate H11 and H-gal-GP antigens under field conditions.


[Potential adaptation of the gastrointestinal system. Existence of an enteropancreatic trophic axis, the role of hormones and polyamines].
The evidence for an enteropancreatic trophic axis is reviewed. Luminal nutrition is essential for the maintenance of normal intestinal mucosal, as well as exocrine pancreatic structure and function. Exclusion of luminal nutrition leads to mucosal hypoplasia and hypofunction with similar changes in the pancreas. The trophic effect of luminal nutrition may be mediated through the release of regulatory peptides with endocrine or paracrine effects. Enteroglucagon is the strongest candidate for the role of "enterotrophin" while cholecystokinin (CCK) markedly influences pancreatic growth. Thus, CCK not only stimulates exocrine pancreatic secretion but makes acinar cells divide and the pancreas grow. The cellular mechanisms whereby trophic peptides influence normal and adaptive growth are also discussed with emphasis on polyamines (putrescine, spermidine and spermine) and the key enzymes controlling their synthesis (ornithine decarboxylase [ODC]) and degradation (diamine oxidase [DAO]). When polyamine synthesis is blocked with the ODC inhibitor difluoromethyl ornithine (DFMO), the adaptive intestinal hyperplasia of pancreaticobiliary diversion is either inhibited or completely prevented. A proposed sequence of events might be: luminal nutrients, particularly long chain fat, reach the ileum and colon and stimulate increased enteroglucagon release. Enteroglucagon binds to cell receptors and triggers an intracellular cascade involving ODC and the polyamines which, in turn, stimulate RNA polymerase, DNA, RNA and protein synthesis, cell division and adaptive tissue growth.


Bose-Einstein condensation of magnons in atomic hydrogen gas.
We report on experimental observation of Bose-Einstein condensation (BEC)-like behavior of quantized electron spin waves (magnons) in a dense gas of spin-polarized atomic hydrogen. The magnons are trapped and controlled with inhomogeneous magnetic fields and described by a Schrödinger-like wave equation, in analogy to the BEC experiments with neutral atoms. We have observed the appearance of a sharp feature in the ESR spectrum displaced from the normal spin wave spectrum. We believe that this observation corresponds to a sudden growth of the ground-state population of the magnons and emergence of their spontaneous coherence for hydrogen gas densities exceeding a critical value, dependent on the trapping potential. We interpret the results as a BEC of nonequilibrium magnons which were formed by applying the rf power.


Olfactory perception of 6 amino acids by human subjects.
The olfactory properties of 6 amino acids were assessed in 20 human subjects using psychophysical tests of detectability, discriminability, and chemesthesis. Mean olfactory detection thresholds were found to be 10 microM for D-methionine, 80 microM for L-methionine, 200 microM for L-cysteine, 220 microM for D-cysteine, 75 mM for D-proline, and 100 mM for L-proline. When presented at clearly detectable and intensity-matched concentrations, the subjects readily discriminated between the odors of the L-forms of cysteine, methionine, and proline, whereas they failed to distinguish between the L- and D-forms of a given amino acid. The subjects also failed in localizing the side of monorhinal stimulation with all 6 amino acids when presented at the same concentrations as in the discrimination tasks. These results suggest that amino acids may contribute to the flavor of food not only as taste stimuli but also as olfactory stimuli perceived via ortho- or retronasal smelling. In contrast, it is unlikely that amino acids contribute to flavor perception via chemesthesis. Given that the odors of 4 of the 6 amino acids tested here were detected at concentrations lower than their corresponding taste detection thresholds, this may have important implications for the widespread use of amino acids as food additives as well as for the evaluation of off-flavors caused by amino acids.


[Effect of hyperbaric air on biorhythms of the pain sensitivity and analgesic effect of morphine].
The circadian and high-frequency (2-2.5 h) pain sensitivity rhythms were observed in male mongrel rats under natural illumination conditions (LD 24, January-February). A minimum pain sensitivity threshold with respect to subcutaneous electrode stimulation was observed in the dark phase of the LD 24 cycle. Morphine injections (5 mg/kg, i.p.) led to inversion of the circadian rhythm and expansion of the high-frequency spectrum. The rhythm synchronism was broken under the hyperbaria conditions, whereby the circadian acrophase shifted to exhibit a maximum within the day light phase. The concurrent morphine administration on the hyperbaria background induced the back inversion of the circadian pain sensitivity rhythm. The high-frequency rhythm was not significantly affected by increased pressure--neither alone nor in combination with morphine injections.


Local Pressure Application Effects on Discomfort, Temperature, and Limb Oxygenation.
Despite significant investment into the development and improvement of military helicopter seat systems, military aviators continue to report seat system related pain and discomfort during prolonged missions. Using a factorial repeated measures design, 15 healthy subjects completed the study, in which focal pressure was applied to two locations on the sitting surfaces of the body (ischial tuberosity and middle of the posterior thigh). Pressure was applied using a purpose-built pressure application system allowing subjects to sit in a position mimicking the sitting position in the UH-60 Black Hawk helicopter. The researchers measured pain using the Category Partitioning Scale and McGill Pain Questionnaire and vascular function using dynamic infrared thermography in the lower leg and pulse oximetry at the great toe. Data were collected before and during a 10-min application of focal pressure applied to either the ischial tuberosity or middle of the posterior thigh and at two different pressure magnitudes (36 or 44 kPa). We found that during a 10-min pressure application, superficial skin temperature increased by 0.61°C, suggesting a decreased venous return during pressure application. We found that lower extremity blood oxygenation remained unchanged during pressure application. Subjects' reported pain increased during pressure application and was greater with 44 kPa of application compared to 36 kPa. These results support the hypothesis that locally high pressure creates symptoms of discomfort and paresthesia. Research examining the effects of local pressure application on physiological and neurological function is needed. Games KE, Lakin JM, Quindry JC, Weimar WH, Sefton JM. Local pressure application effects on discomfort, temperature, and limb oxygenation. Aerosp Med Hum Perform. 2016; 87(8):697-703.


Information-processing, storage characteristics and worry.
Eysenck (1984, Bulletin of the Psychonomic Society, 22, 545-548) suggested that storage characteristics may be an important determinant of worry, and postulated that prolonged worry occurs in individuals who have tightly organised clusters of worry-related information stored in long-term memory. These clusters reflect areas or domains of worry. Because the information is stored in tight clusters, it becomes more accessible, more rapidly activated and therefore retrieved more quickly. The Worry Domains Questionnaire (WDQ) (Tallis, 1991c) is used to determine which domain worried subjects most (Primary) and least (Secondary). Two experiments are reported using a word allocation task, which requires subjects to make categorical decisions, based on these worry domains. It is reported that priming facilitates the emergence of domain effects, thus providing support for a structural hypothesis. High worries take longer to reject negative words if they are from the Primary domain and have difficulty rejecting Primary domain words when they are under a congruent heading. In addition, high worriers are reported to show retarded latencies when attempting to process ambiguous information, consistent with Metzger et al.'s studies (1990, Journal of Clinical Psychology, 48, 76-88). It is suggested that the initiation and maintenance of worry is largely attributable to an elevated evidence requirement and this may link to the personality trait of perfectionism.


Needs, difficulties, and possible approaches to providing quality clinical veterinary education with the aim of improving standards of companion animal medicine in sri lanka.
Companion animal medicine has now gained prominence in Sri Lanka as a result of an increased public interest in pets; however, veterinary education has not kept pace with current developments. The main constraints faced by the veterinary education system are those common to all university education in Sri Lanka. Changes in the current system, though important, depend heavily on political will and vision, which are not forthcoming in the near future. It is therefore both necessary and important that the private sector provide the impetus to improve standards of veterinary medicine in Sri Lanka. The immediate focus should be on improving the skills of practitioners through clinically based continuing education programs. Later, more specialized and intensive programs may be initiated. Interaction and sharing of knowledge with more developed countries are critical in leading the way to improved standards of companion animal medicine in Sri Lanka.


Activated alkene dependent one-pot, three-component aza-Morita-Baylis-Hillman reaction of ferrocenealdehyde: synthesis of highly functionalized diverse ferrocene derivatives.
Activated alkene dependent one-pot, three-component aza-Morita-Baylis-Hillman (aza-MBH) reaction of ferrocenealdehyde afforded simple aza-MBH adduct of ferrocenealdehyde, unusual piperidine, β-amino acid residue, and γ-ketoester derivatives of ferrocene in good yield. The synthetic protocol with MVK has led to an unexpected ferrocenyl piperidine derivative in an excellent yield via diastereoselective domino aza-Michael/double Aldol pathway. Plausible mechanisms for the formation of unusual products and diastereoselectivity have also been described. The products can be used for the concise synthesis of ferrocenyl nitrogen heterocycles and bioconjugates.


Validation of the Rainbow Model of Integrated Care Measurement Tools (RMIC-MTs) in renal care for patient and care providers.
Integrated service delivery is considered to be an essential condition for improving the management and health outcomes of people with chronic kidney disease (CKD). However, research on the assessment of integrated care by patients and care providers is hindered by the absence of brief, reliable, and valid measurement tools. The aim of this study was to develop survey instruments for healthcare professionals and patients based on the Rainbow Model of Integrated Care (RMIC), and to evaluate their psychometric properties. The development process was based on the US Food and Drug Administration guidelines. This included item generation from systematic reviews of existing tools and expert opinion on clarity and content validity, involving renal care providers and chronic kidney patients. A cross-sectional, multi-centre design was used to test for internal consistency and construct validity. Outpatient clinics in a large renal network. A sample of 30.788 CKD patients, and 8.914 renal care providers. Both survey instruments were developed using previous qualitative work and published literature. A multidisciplinary expert panel assessed the face and content validity of both instruments and following a pilot study, the psychometric properties of both instruments were explored. Exploratory factor analysis with principal axis factoring and with promax rotation was used to assess the underlying dimensions of both instruments; Cronbach's alpha was used to determine the internal constancy reliability. 17.512 patients (response rate: 56.9%) and 8.849 care providers (response rate: 69.5%) responded to the questionnaires. Factor analysis of the patient questionnaire yielded three internally consistent (Cronbach's alpha > 0.7) factors: person-centeredness, clinical coordination, and professional coordination. Factor analysis of the provider questionnaire produced eight internally consistent (Cronbach's alpha > 0.7) factors: person-centeredness, community centeredness, clinical coordination, professional coordination, organisational coordination, system coordination, technical and cultural competence. As hypothesised, care coordination patient and providers scores significantly correlated with questions about quality of care, treatment involvement, reported health, clinics' organisational readiness, and external care coordination capacity. This study provides evidence for the reliability and validity of the RMIC patient and provider questionnaires as generic tools to assess the experience with or perception of integrated renal care delivery. The instruments are recommended in future applications testing test-retest reliability, convergent and predictive validity, and responsiveness.


Probing the organic-mineral interface at the molecular level in model biominerals.
It is widely known that macromolecules, such as proteins, can control the nucleation and growth of inorganic solids in biomineralizing organisms. However, what is not known are the complementary molecular interactions, organization, and rearrangements that occur when proteins interact with inorganic solids during the formation of biominerals. The organic-mineral interface (OMI) is expected to be the site for these phenomena, and is therefore extraordinarily interesting to investigate. In this report, we employ X-ray absorption near edge (XANES) spectromicroscopy to investigate the electronic structure of both calcium carbonate mineral crystals and polypeptides, and detect changing bonds at the OMI during crystal growth in the presence of polypeptides. We acquired XANES spectra from calcium carbonate crystals grown in the presence of three mollusk nacre-associated polypeptides (AP7N, AP24N, n16N) and in the presence of a sea urchin spicule matrix protein, LSM34. All these model biominerals gave similar results, including the disruption of CO bonds in calcite and enhancement of the peaks associated with C-H bonds and C-O bonds in peptides, indicating ordering of the amino acid side chains in the mineral-associated polypeptides and carboxylate binding. This is the first evidence of the mutual effect of calcite on peptide chain and peptide chain on calcite during biomineralization. We also show that these changes do not occur when Asp and Glu are replaced in the n16N sequence with Asn and Gln, respectively, demonstrating that carboxyl groups in Asp and Glu do participate in polypeptide-mineral molecular associations.


Designer protein-based scaffolds for neural tissue engineering.
A key attribute missing from many current biomaterials is the ability to independently tune multiple biomaterial properties without simultaneously affecting other material parameters. Because cells are well known to respond to changes in the initial elastic modulus, degradation rate, and cell adhesivity of a biomaterial, it is critical to develop synthetic design strategies that allow decoupled tailoring of each individual parameter in order to systematically optimize cell-scaffold interactions. We present the development of a family of biomimetic scaffolds composed of chemically crosslinked, elastin-like proteins designed to support neural regeneration through a combination of cell adhesion and cell-induced degradation and remodeling. Through use of a modular protein-design strategy, a range of biomaterials is created that allows independent tuning over the initial elastic modulus, degradation rate, cell adhesivity, and neurite outgrowth. By combining these engineered proteins into composite structures, biomaterials are created with 3D patterns that emerge over time in response to cell-secreted enzymes. These dynamic 3D structures enable the delivery of multiple drugs with precise spatial and temporal resolution and also enable the design of biomaterials that adapt to changing scaffold needs.