Vitamin D compounds: clinical development as cancer therapy and prevention agents.
While 1,25 dihydroxycholecalciferol (calcitriol) is best recognized for its effects on bone and mineral metabolism, epidemiological data indicate that low vitamin D levels may play a role in the genesis and progression of breast, lung, colorectal and prostate cancer, as well as malignant lymphoma and melanoma. Calcitriol has strong antiproliferative effects in prostate, breast, colorectal, head/neck and lung cancer, as well as lymphoma, leukemia and myeloma model systems. Antiproliferative effects are seen in vitro and in vivo. The mechanisms of these effects are associated with G0/G1 arrest, induction of apoptosis, differentiation and modulation of growth factor-mediated signaling in tumor cells. In addition to the direct effects on tumor cells, recent data strongly support the hypothesis that the stromal effects of vitamin D analogs (e.g., direct effects on tumor vasculature) are also important in the antiproliferative effects. Antitumor effects are seen in a wide variety of tumor types and there are few data to suggest that vitamin D-based approaches are more effective in any one tumor type. Glucocorticoids potentiate the antitumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. In addition, calcitriol potentiates the antitumor effects of many cytotoxic agents. Preclinical data indicate that maximal antitumor effects are seen with pharmacological doses of calcitriol and that such exposure can be safely achieved in animals using a high dose, intermittent schedule of administration. AUC and C(max) calcitriol concentrations of 32 ng.h/ml and 9.2 ng/ml are associated with striking antitumor effects in a murine squamous cell carcinoma model and there is increasing evidence from clinical trials that such exposures can be safely attained in patients. Another approach to maximizing intra-tumoral exposure to vitamin D analogs is to inhibit their catabolism. The data clearly indicate that agents which inhibit the major vitamin D catabolizing enzyme, CYP24 (24 hydroxylase), potentiate calcitriol killing of prostate tumor cells in vitro and in vivo. Phase I and II trials of calcitriol, either alone or in combination with carboplatin, taxanes or dexamethasone, as well as the non-specific CYP24 inhibitor, ketoconazole, have been initiated in patients with androgen-dependent and -independent prostate cancer and other advanced cancers. The data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered, but the optimal dose and schedule remain to be delineated. Clinical responses have been seen with the combination of high-dose calcitriol + dexamethasone in androgen-independent prostate cancer (AIPC) and, in a large randomized trial in men with AIPC, potentiation of the antitumor effects of docetaxel were seen.


[Intraductal ultrasound of the bile ducts].
Intraluminal ultrasound with 12.5 and 20 MHz transducer allows precise analysis of the extrahepatic bile ducts and the adjacent structures. Inflammatory and malignant thickening of the bile duct wall can be assessed without difficulty. It is not possible, however, to differentiate between benign and malignant bile duct thickening, and for this purpose biopsy is required in addition. In tumor staging intraluminal ultrasound is superior to conventional ultrasound, because tumor infiltration into the adjacent tissues can be assessed and lymph nodes along the hepaticoduodenal ligament can be detected. Owing to the ultrasound frequencies available, local staging is limited to a circumference of 1.5/2 cm. Intraluminal ultrasound provides additional information that is useful in the diagnosis and therapy of bile duct stones and in different types of palliative tumor therapy. The procedure is simple and not too time consuming, and it involves no risks to the patient.


Linguistic acculturation and perceptions of quality, access, and discrimination in health care among Latinos in the United States.
This study examined the relationship between acculturation and Latinos' perceptions of health care treatment quality, discrimination, and access to health information. The results of this study indicated that participants who had lower levels of acculturation perceived: 1) greater discrimination in health care treatment; 2) a lower quality of health care treatment; 3) less confidence filling out health related forms; and 4) greater challenges understanding written information about their medical conditions. Participants who identified as immigrants also perceived that their poor quality of medical care was due to their inability to pay and to their race/ethnicity.


beta-Secretase, APP and Abeta in Alzheimer's disease.
Amyloid plaques, hallmark neuropathological lesions in Alzheimer's disease (AD) brain, are composed of the beta-amyloid peptide (Abeta). A large body of evidence suggests Abeta is central to the pathophysiology of AD and is likely to start this intractable neurodegenerative disorder. Mutations in three genes (amyloid precursor protein/APP, presenilin1, presenilin2) cause early on-set familial AD by increasing synthesis of the toxic 42 amino acid species of Abeta (Abeta42). Fibrillar Abeta in amyloid plaques appears to cause neurodegeneration, although recent studies suggest soluble Abeta oligomers may also be neurotoxic. Regardless, given the strong correlation between Abeta and AD, therapeutic strategies to lower cerebral Abeta levels should prove beneficial for the treatment of AD. Abeta is derived from APP via cleavage by two proteases, beta- and gamma-secretase. beta-secretase, recently identified as the novel aspartic protease BACEI, initiates the formation of Abeta. Consequently, BACE1 in principle is an excellent therapeutic target for strategies to reduce the production of Abeta in AD. However, the discovery of the homologue BACE2 raised the question of whether it too may be a beta-secretase. To settle this issue, our group and others have used gene targeting to generate BACE1 deficient (knockout) mice. These BACEI knockout mice have been instrumental in validating BACEI as the authentic beta-secretase in vivo. Here, I review the roles of BACE1, APP, and Abeta in AD and discuss the implications of therapeutic approaches that target BACE1 for the treatment of AD.


Fluorescence readout of near-field photochromic memory.
The fluorescence- and transmittance-detection readout methods of a near-field photochromic optical memory by a scanning-probe technique were studied theoretically. Shot noise, as the principal noise, was taken into account in an analysis of the signal-to-noise ratio (SNR). Under most conditions, fluorescence-detection readout yielded a better SNR than did transmittance-detection readout. For a transmittance change of 0.9-1.0 as a result of recording, a readout light power of approximately 100 nW, and a system bandwidth of 1 MHz, only the fluorescence-detection readout method, under the condition that the fluorescent layer of the medium have a fluorescence quantum yield greater than 0.4, can produce a sufficiently large SNR.


A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD).
Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.


Bacterial detection with amphiphilic carbon dots.
New bacterial detection and imaging methods are desirable for diagnostics and healthcare applications, as well as in basic scientific research. We present a simple analytical platform for bacterial detection and imaging based upon attachment of amphiphilic carbon dots (CDs) to bacterial cells. We show that CDs functionalized with hydrocarbon chains readily bind to bacterial cells following short incubation and enable detection of bacteria through both fluorescence spectroscopy and microscopy. Importantly, we demonstrate that the intensity and spectral position of the carbon dots' fluorescence depend upon bacterial species, providing a tool for distinguishing among bacteria even in cases of mixed bacterial populations. Moreover, bacterial labelling with the amphiphilic CDs enables visualization of physiological processes such as cell division.


Stability and stabilization studies of TAK-599 (Ceftaroline Fosamil), a novel N-phosphono type prodrug of anti-methicillin resistant Staphylococcus aureus cephalosporin T-91825.
TAK-599 (known as ceftaroline fosamil) is a novel N-phosphono type prodrug of a cephalosporin compound, T-91825, that exhibits strong activity against methicillin resistant Staphylococcus aureus (MRSA). The stability and stabilization of TAK-599 were investigated by kinetic analysis focused on crystallinity and moisture content. Initially it was planned to develop TAK-599 as an injectable formulation using the amorphous solid powder prepared by lyophilization. However, amorphous of TAK-599 free form was found to be chemically unstable even when stored at 8 degrees C, and thus development was focused on the crystalline material. After exhaustive screening of crystallization condition, the monoacetic acid solvate was found to yield TAK-599 in a crystalline form. Physicochemical properties were studied to identify the key factors affecting the stabilization of TAK-599 in order to improve long-term stability, and the results indicated that the crystallinity of TAK-599 correlated with stability. Furthermore, moisture content was also identified in our studies as an important factor in stabilizing TAK-599. TAK-599 containing about 3% moisture was found to be the most stable form. It was concluded that both sufficient crystallinity and strict moisture control of TAK-599 were essential to maintain long-term stability at 25 degrees C.


Membrane Applications in Autologous Cell Therapy.
Stem cell and cell therapies, particularly autologous cell therapies, are becoming a common practice. However, in order for these technologies to achieve wide-scale clinical application, the prohibitively high cost associated with these therapies must be addressed through creative engineering. Membranes can be a disruptive technology to reshape the bioprocessing and manufacture of cellular products and significantly reduce the cost of autologous cell therapies. Examples of successful membrane applications include expansions of CAR-T cells, various human stem cells, and production of extracellular vesicles (EVs) using hollow fibre membrane bioreactors. Novel membranes with tailored functions and surface properties and novel membrane modules that can accommodate the changing needs for surface area and transport properties are to be developed to fulfil this key role.


A cognitive model of hallucinations.
Hallucinations occur in a wide variety of altered states of consciousnes and are an important symptom in various psychiatric syndromes. Several psychological and biological theories of their origin have offered, ranging from the concept of wish fulfillment, to the hypothesis of an electorchemical release of the perceptual system, to denials that hallucinatory phenomena exist. No explanation has completely satisfied clinicans, probably because the word "hallucination" labels a complex set of phenomena. The author accepts this complexity and offers a conceptual analysis of four key dimensions of the halucinatory experience in an attempt to clarify the gamut of experiences that may be called hallucinations.


Phase 1 study of sorafenib in combination with bortezomib in patients with advanced malignancies.
Sorafenib (a VEGFR and multi-targeted kinase inhibitor) and Bortezomib (a proteasome inhibitor) have clinical antineoplastic activities as single agents, and combine synergistically in preclinical models. This Phase I study was undertaken to define the toxicity and the maximum tolerated doses (MTD) of the combination in patients with advanced solid tumors. Patients with cytologic or histologic proof of unresectable solid tumors were treated with escalating doses of sorafenib (twice daily) and bortezomib (days 1, 4, 8 and 11 intravenously) with 21-day cycles. Fourteen patients (7 males, median age 65, range 24-74), with renal (3), lung (3), pancreas (2), and breast, adrenal gland, melanoma, spindle cell tumor, chronic lymphocytic leukemia and multiple myeloma (1 each) were enrolled. All patients are off treatment, 10 due to disease progression. DLT was seen in two patients (one grade 3 abdominal pain and grade 4 lipase elevation; one with grade 3 vomiting) at sorafenib 200 mg twice daily and bortezomib 1.3 mg/m(2), establishing the MTD. No grade 4 hematologic or grade 5 toxicities were seen. One patient with renal cell cancer had a partial response and 5 patients attained stable disease. The combination of sorafenib and bortezomib was tolerated well. The recommended phase 2 doses are sorafenib 200 mg twice daily continuously with bortezomib 1 mg/m(2) on days 1, 4, 8, 11 (21 day cycles). The combination shows preliminary signs of efficacy, supporting phase 2 studies.


Procedural recommendations of cardiac PET/CT imaging: standardization in inflammatory-, infective-, infiltrative-, and innervation- (4Is) related cardiovascular diseases: a joint collaboration of the EACVI and the EANM: summary.
With this summarized document we share the standard for positron emission tomography (PET)/(diagnostic)computed tomography (CT) imaging procedures in cardiovascular diseases that are inflammatory, infective, infiltrative, or associated with dysfunctional innervation (4Is) as recently published in the European Journal of Nuclear Medicine and Molecular Imaging. This standard should be applied in clinical practice and integrated in clinical (multicentre) trials for optimal standardization of the procedurals and interpretations. A major focus is put on procedures using [18F]-2-fluoro-2-deoxyglucose ([18F]FDG), but 4Is PET radiopharmaceuticals beyond [18F]FDG are also described in this summarized document. Whilst these novel tracers are currently mainly applied in early clinical trials, some multicentre trials are underway and we foresee in the near future their use in clinical care and inclusion in the clinical guidelines. Diagnosis and management of 4Is related cardiovascular diseases are generally complex and often require a multidisciplinary approach by a team of experts. The new standards described herein should be applied when using PET/CT and PET/magnetic resonance, within a multimodality imaging framework both in clinical practice and in clinical trials for 4Is cardiovascular indications.


Staying connected: structural integration at the intervertebral disc-vertebra interface of human lumbar spines.
To investigate the microscopic fibrous integration between the intervertebral disc, cartilage endplates and vertebral endplates in human lumbar spines of varying degrees of degeneration using differential interference contrast (DIC) optics. Weakness at these junctions is considered to be an important factor in the aetiology of disc herniations. Magnetic resonance images (MRIs) of cadaveric lumbar spines were graded for degeneration and motion segments from a range of degenerative grades isolated and bisected sagittally. Following fixation and decalcification, these were cut into segments containing anterior or posterior annulus fibrosus or nucleus pulposus. The segments were cryo-sectioned and sections visualised using both standard light and DIC microscopy. Detachment at the interface between the disc and vertebrae increased with greater degenerative grade (from 1.9 % in Grade I to 28 % in Grade V), especially at the boundary between the cartilage and vertebral endplates. DIC microscopy revealed the fibrous organisation at the IVD-cartilage endplate interface with structural features, such as annular lamellae branching and nodal insertions in the nucleus pulposus region; these have been previously observed in ovine spines, but were less uniform in humans. Structural integrity of the IVD and cartilage endplate was also lost with increasing degeneration. This preliminary study shows that microscopic structural features may act to maintain attachment between the IVD and CEP in the human spine. Loss of structural integrity in this region may destabilise the spine, possibly altering the mechanical environment of the cells in the disc and so potentially contribute to the aetiopathogenesis of IVD degeneration.


Should Artificial Intelligence Augment Medical Decision Making? The Case for an Autonomy Algorithm.
A significant proportion of elderly and psychiatric patients do not have the capacity to make health care decisions. We suggest that machine learning technologies could be harnessed to integrate data mined from electronic health records (EHRs) and social media in order to estimate the confidence of the prediction that a patient would consent to a given treatment. We call this process, which takes data about patients as input and derives a confidence estimate for a particular patient's predicted health care-related decision as an output, the autonomy algorithm. We suggest that the proposed algorithm would result in more accurate predictions than existing methods, which are resource intensive and consider only small patient cohorts. This algorithm could become a valuable tool in medical decision-making processes, augmenting the capacity of all people to make health care decisions in difficult situations.


Interprofessional meetings in geriatric assessment units: a matter of care organization.
Inpatient geriatric assessment units (GAUs) exist in Quebec, Canada, to deliver comprehensive, integrated care to older vulnerable patients. Most cases should be discussed at interprofessional meetings (IMs), but research has shown this not to be so for 39% of GAU patients. Consequently, a study was undertaken to (1) describe GAU team composition and (2) identify GAU and patient characteristics associated with case discussion at IMs at least once during a patient's stay. To this end, 877 hospitalization records from 44 GAUs were reviewed. Results showed most teams were composed of attending physicians, nurses, physical and occupational therapists, dietitians and social workers; 66% included clinical pharmacists and 43% liaison nurses. Multilevel modeling showed longer length of stay to be the strongest predictor of case discussion at an IM. Case discussion was also more likely for patients admitted via in- or inter-hospital transfer rather than via the emergency department, if the GAU included a liaison nurse, and if the GAU was not located in an urban area. In summary, case discussion at an IM depended more on how and where a patient was admitted than on the patient characteristics per se, suggesting that this is a matter of care organization.


Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal.
Programmed cell death (PCD) has significant effects on the function of neural stem cells (NSCs) during brain development and degeneration. We have previously reported that adult rat hippocampal neural stem (HCN) cells underwent autophagic cell death (ACD) rather than apoptosis following insulin withdrawal despite their intact apoptotic capabilities. Here, we report a switch in the mode of cell death in HCN cells with calpain as a critical determinant. In HCN cells, calpain 1 expression was barely detectable while calpain 2 was predominant. Inhibition of calpain in insulin-deprived HCN cells further augmented ACD. In contrast, expression of calpain 1 switched ACD to apoptosis. The proteasome inhibitor lactacystin blocked calpain 2 degradation and elevated the intracellular Ca(2+) concentration. In combination, these effects potentiated calpain activity and converted the mode of cell death to apoptosis. Our results indicate that low calpain activity, due to absence of calpain 1 and degradation of calpain 2, results in a preference for ACD over apoptosis in insulin-deprived HCN cells. On the other hand, conditions leading to high calpain activity completely switch the mode of cell death to apoptosis. This is the first report on the PCD mode switching mechanism in NSCs. The dynamic change in calpain activity through the proteasome-mediated modulation of the calpain and intracellular Ca(2+) levels may be the critical contributor to the demise of NSCs. Our findings provide a novel insight into the complex mechanisms interconnecting autophagy and apoptosis and their roles in the regulation of NSC death.


Role of in vivo reflectance confocal microscopy in determining stability in vitiligo: a preliminary study.
Vitiligo is an acquired pigmentary disorder. In vivo reflectance confocal microscopy (RCM) reproducible imaging technique has already been reported to be useful in the diagnosis of other skin diseases. To define RCM features of vitiligo on different clinical stages. A total of 125 patients with a clinical diagnosis of vitiligo were included in this study. After informed consent, lesional skins of those vitiligo patients were characterized by using RCM. Five patients with inflammatory cell infiltration observed at the edge of skin lesions and another 5 patients without inflammatory cell infiltration were selected. Biopsies were performed at same sites of the RCM examination areas for histological and immune-histological analysis. In the active stage of vitiligo, the RCM examination revealed that the bright dermal papillary rings presented at the dermoepidermal junction level in normal skin lost their integrity or totally disappeared, border between vitiligo lesion and normal skin became unclear, and highly refractile cells that referred to infiltrated inflammatory cells could be seen within the papillary dermis at the edge of the lesions. In the stable stage of vitiligo, the RCM showed a complete loss of melanin in lesional skin and a clear border between lesional and normal skin. A simple clinical examination with RCM may reliably and efficiently allow evaluation of the stability status of vitiligo lesions.


Transplantation of human prostatic carcinoma into nude mice in Matrigel.
Previous successful transplantation of human primary prostatic carcinomas into nude mice has been described as "close to zero." When injected in Matrigel instead of culture medium, 25,000-fold fewer cells of the PC-3 human prostatic carcinoma cell line were required for the growth of tumors in nude mice during a 3-month period of observation; similar enhancement was observed with two other human prostatic carcinoma cell lines. Six of ten primary human prostatic carcinomas were transplanted successfully into nude mice when Matrigel was used as the vehicle.


Physical activity interventions promoted in the Arabic-speaking region: A review of the current literature.
The Arabic-speaking region suffers from insufficient levels of physical activity (PA). Assessing the effectiveness of PA interventions presents a scientifically evaluated method to reduce and prevent the current high burden of noncommunicable diseases affecting this region. This review examined implemented PA interventions and corresponding measured health outcomes in this region. The review was limited to studies prior to January 2020 using nine electronic academic databases. Only intervention-focused articles incorporating PA as the primary intervention or as a component of a multibehavioural intervention were included. Thirty-nine PA intervention studies were identified. Published PA interventions were implemented among 50% of the countries in the region. Seventy percent of the studies were conducted in the Gulf region and 25% in North Africa. A third of the studies was designed for children and adolescents. Accordingly, 40% of interventions were for patients living with comorbidities. Seventy percent of the studies included PA as part of a multidisciplinary intervention. Most studies included body mass index as an outcome parameter. Significant improvement (P < .05) in measured health outcomes was seen in 97% of studies. Thorough analysis includes social and culturally congruent aspects of the PA interventions and discussion of resultant health outcomes. This information furthers the understanding of effective PA interventions that can be adapted to target sedentary lifestyle behaviours in this region.


BPGA- an ultra-fast pan-genome analysis pipeline.
Recent advances in ultra-high-throughput sequencing technology and metagenomics have led to a paradigm shift in microbial genomics from few genome comparisons to large-scale pan-genome studies at different scales of phylogenetic resolution. Pan-genome studies provide a framework for estimating the genomic diversity of the dataset, determining core (conserved), accessory (dispensable) and unique (strain-specific) gene pool of a species, tracing horizontal gene-flux across strains and providing insight into species evolution. The existing pan genome software tools suffer from various limitations like limited datasets, difficult installation/requirements, inadequate functional features etc. Here we present an ultra-fast computational pipeline BPGA (Bacterial Pan Genome Analysis tool) with seven functional modules. In addition to the routine pan genome analyses, BPGA introduces a number of novel features for downstream analyses like core/pan/MLST (Multi Locus Sequence Typing) phylogeny, exclusive presence/absence of genes in specific strains, subset analysis, atypical G + C content analysis and KEGG &COG mapping of core, accessory and unique genes. Other notable features include minimum running prerequisites, freedom to select the gene clustering method, ultra-fast execution, user friendly command line interface and high-quality graphics outputs. The performance of BPGA has been evaluated using a dataset of complete genome sequences of 28 Streptococcus pyogenes strains.


Adaptationism--how to carry out an exaptationist program.
Adaptationism is a research strategy that seeks to identify adaptations and the specific selective forces that drove their evolution in past environments. Since the mid-1970s, paleontologist Stephen J. Gould and geneticist Richard Lewontin have been critical of adaptationism, especially as applied toward understanding human behavior and cognition. Perhaps the most prominent criticism they made was that adaptationist explanations were analogous to Rudyard Kipling's Just So Stories (outlandish explanations for questions such as how the elephant got its trunk). Since storytelling (through the generation of hypotheses and the making of inferences) is an inherent part of science, the criticism refers to the acceptance of stories without sufficient empirical evidence. In particular, Gould, Lewontin, and their colleagues argue that adaptationists often use inappropriate evidentiary standards for identifying adaptations and their functions, and that they often fail to consider alternative hypotheses to adaptation. Playing prominently in both of these criticisms are the concepts of constraint, spandrel, and exaptation. In this article we discuss the standards of evidence that could be used to identify adaptations and when and how they may be appropriately used. Moreover, building an empirical case that certain features of a trait are best explained by exaptation, spandrel, or constraint requires demonstrating that the trait's features cannot be better accounted for by adaptationist hypotheses. Thus, we argue that the testing of alternatives requires the consideration, testing, and systematic rejection of adaptationist hypotheses. Where possible, we illustrate our points with examples taken from human behavior and cognition.


The physics of unwound and wound strings on the electric guitar applied to the pitch intervals produced by tremolo/vibrato arm systems.
The physics of wound and unwound strings on the electric guitar are presented here, and the pitch intervals produced by the movements of a Fender Stratocaster tremolo unit are explained. Predicted changes in pitch sensitivity of different strings are given, and experimentally verified, for changes in saddle height, the distance of string free to move behind the nut and ratio of diameters/masses of the core and windings of wound strings. Also, it is shown that changes to the gauge of strings (assuming the string tension is sufficient for linear behaviour and in absence of changes to other construction details) don't alter the pitch intervals produced by a given angle of tremolo arm use assuming the instrument is set up with the same sounding pitches and starting bridge angle. It is demonstrated that it not possible to equalise the relative sensitivity of unwound steel stings on a Fender Stratocaster type tremolo unit through string construction techniques. The ratio of core to winding mass in the string, on the other hand, was found to be a very powerful design parameter for choosing the sensitivity of the string to tremolo arm use and standard pitch bends. For instance, the pitch intervals produced by operation of tremolo arm for wound strings may be made to approximately match that for one of the unwound strings if they share very similar core gauges (assuming the winding masses are chosen to give approximately the same tension at their sounding pitches). Such a design, only available currently by custom order, also delivers the optimum equalisation in sensitivity of strings for standard string bends (due to these also being produced by altering the length of the string to generate changes in tension and therefore pitch).


The route of enteric infection in normal mice.
This study followed the early pathogenesis of orally induced murine typhoid fever. Intragastrically administered Salmonella enteritidis moves quickly through the normal undisturbed gut so that only a small residuum remains in the cecum and large intestine after the first few hours. Dye injection of the gut wall was used to show that lymph from discrete portions of the gastrointestinal tract drains to separate lymph nodes, probably via the regional Peyer's patches. Plating techniques capable of detecting a single colony-forming unit of S. enteritidis within the different Peyer's patches and draining lymph nodes indicate that, although the cecum and large intestine are exposed to large numbers of Salmonella for longer time periods than the small intestine, the primary site of bacterial penetration involves the distal ileum. This area of the small intestine as well as the cecum are both drained by the distal mesenteric lymph nodes, and were the only nodes which contained detectable numbers of viable Salmonella over the first 24 h of infection. Neither the pyloric nor the proximal mesenteric lymph nodes (which drain the stomach and duodenum) nor the pancreatic and caudal lymph nodes (which drain the transverse and descending colon) contained viable Salmonella. Salmonella were observed to infect the ileal mucosa and its Peyer's patches. With time, this infection progresses to the draining lymph node and ultimately reaches the liver and spleen. Some of the implications of these findings relative to the development of acquired resistance to enteric disease are discussed.


Elucidating the Structures of the Low- and High-pH Mo(V) Species in Respiratory Nitrate Reductase: A Combined EPR, 14,15N HYSCORE, and DFT Study.
Respiratory nitrate reductases (Nars), members of the prokaryotic Mo/W-bis Pyranopterin Guanosine dinucleotide (Mo/W-bisPGD) enzyme superfamily, are key players in nitrate respiration, a major bioenergetic pathway widely used by microorganisms to cope with the absence of dioxygen. The two-electron reduction of nitrate to nitrite takes place at their active site, where the molybdenum ion cycles between Mo(VI) and Mo(IV) states via a Mo(V) intermediate. The active site shows two distinct pH-dependent Mo(V) electron paramagnetic resonance (EPR) signals whose structure and catalytic relevance have long been debated. In this study, we use EPR and HYSCORE techniques to probe their nuclear environment in Escherichia coli Nar (EcNar). By using samples prepared at different pH and through different enrichment strategies in 98Mo and 15N nuclei, we demonstrate that each of the two Mo(V) species is coupled to a single nitrogen nucleus with similar quadrupole characteristics. Structure-based density functional theory calculations allow us to propose a molecular model of the low-pH Mo(V) species consistent with EPR spectroscopic data. Our results show that the metal ion is coordinated by a monodentate aspartate ligand and permit the assignment of the coupled nitrogen nuclei to the Nδ of Asn52, a residue located ∼3.9 Å to the Mo atom in the crystal structures. This is confirmed by measurements on selectively 15N-Asn labeled EcNar. Further, we propose a Mo-O(H)···HN structure to account for the transfer of spin density onto the interacting nitrogen nucleus deduced from HYSCORE analysis. This work provides a foundation for monitoring the structure of the molybdenum active site in the presence of various substrates or inhibitors in Nars and other molybdenum enzymes.


Chronic Conditions and Utility-Based Health-Related Quality of Life in Adult Childhood Cancer Survivors.
Health utility, a summary measure of quality of life, has not been previously used to compare outcomes among childhood cancer survivors and individuals without a cancer history. We estimated health utility (0, death; 1, perfect health) using the Short Form-6D (SF-6D) in survivors (n = 7105) and siblings of survivors (n = 372) (using the Childhood Cancer Survivor Study cohort) and the general population (n = 12 803) (using the Medical Expenditures Panel Survey). Survivors had statistically significantly lower SF-6D scores than the general population (mean = 0.769, 95% confidence interval [CI] = 0.766 to 0.771, vs mean = 0.809, 95% CI = 0.806 to 0.813, respectively, ITALIC! P< .001, two-sided). Young adult survivors (age 18-29 years) reported scores comparable with general population estimates for people age 40 to 49 years. Among survivors, SF-6D scores were largely determined by number and severity of chronic conditions. No clinically meaningful differences were identified between siblings and the general population (mean = 0.793, 95% CI = 0.782 to 0.805, vs mean = 0.809, 95% CI = 0.806 to 0.813, respectively). This analysis illustrates the importance of chronic conditions on long-term survivor quality of life and provides encouraging results on sibling well-being. Preference-based utilities are informative tools for outcomes research in cancer survivors.


Atherogenic index of plasma and coronary artery disease: A systematic review.
Various studies suggest that the atherogenic index of plasma (AIP) is associated with the risk of coronary artery disease (CAD) in different clinical scenarios. This review aimed to synthesize evidence of the association between AIP values and CAD. A literature search was carried out on four databases, namely, PubMed, Scopus, Web of Science, and Ovid-Medline. A handsearch was performed on preprint repositories (MedRxiv and Research Square). The effect measurements were expressed as odds ratios (OR) with their corresponding 95% confidence intervals (CI). For the quantitative synthesis, we employed a random-effects model. We analyzed 14 articles (with 40,902 participants) from seven different countries. The quantitative analysis revealed that an increase in one unit of AIP was associated with higher odds of developing CAD (OR 2.11; 95% CI 1.65-2.69; P < 0.001; I 2 = 98%). We conducted subgroup analyses of Chinese (OR 1.89; 95% CI 1.40-2.56; P < 0.001) and non-Chinese studies (OR 2.51; 95% CI 1.42-4.42; P < 0.001). The sensitivity analysis by risk of bias continued to demonstrate an association, and the heterogeneity remained unchanged (OR 1.75; 95% CI 1.33-2.31; P < 0.001; I 2 = 98%). Higher AIP values were associated with higher odds of developing CAD.


Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation.
Endothelial dysfunction is an early manifestation of cigarette smoke (CS) toxicity. We have previously demonstrated that CS impairs nitric oxide (NO)-mediated endothelial function via increased generation of superoxide anion (O2*). In these studies, we investigated whether stable compounds present in CS activate specific pathways responsible for the increased endothelial O2* production. Short exposure of bovine pulmonary artery endothelial cells (BPAECs), human pulmonary artery endothelial cells, and rat pulmonary arteries to CS extracts (CSEs) resulted in a large increase in O2* production (20-fold, 3-fold, and 2-fold increase, respectively; P<0.05 versus control), which was inhibited by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodinium, apocynin, and gp91 docking sequence-tat peptide but not by oxypurinol, the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester, or the mitochondrial respiration inhibitor rotenone. Exposure of BPAECs to acrolein, a stable thiol-reactive agent found in CS, increased O2* production 5-fold, which was prevented by prior inhibition of NADPH oxidase. These studies demonstrate that thiol-reactive stable compounds in CS can activate NADPH oxidase and increase endothelial O2* production, thereby reducing NO bioactivity and resulting in endothelial dysfunction. Clinically, these studies may contribute to the development of agents able to mitigate CS-mediated vascular toxicity.


Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats.
Previous clinical and animal studies suggest that selective activators of M(1) and/or M(4) muscarinic acetylcholine receptors (mAChRs) have potential as novel therapeutic agents for treatment of schizophrenia and Alzheimer's disease. However, highly selective centrally penetrant activators of either M(1) or M(4) have not been available, making it impossible to determine the in vivo effects of selective activation of these receptors. We previously identified VU10010 [3-amino-N-(4-chlorobenzyl)-4, 6-dimethylthieno[2,3-b]pyridine-2-carboxamide] as a potent and selective allosteric potentiator of M(4) mAChRs. However, unfavorable physiochemical properties prevented use of this compound for in vivo studies. We now report that chemical optimization of VU10010 has afforded two centrally penetrant analogs, VU0152099 [3-amino-N-(benzo[d][1,3]dioxol-5-ylmethyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide] and VU0152100 [3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-b]pyridine carboxamide], that are potent and selective positive allosteric modulators of M(4). VU0152099 and VU0152100 had no agonist activity but potentiated responses of M(4) to acetylcholine. Both compounds were devoid of activity at other mAChR subtypes or at a panel of other GPCRs. The improved physiochemical properties of VU0152099 and VU0152100 allowed in vivo dosing and evaluation of behavioral effects in rats. Interestingly, these selective allosteric potentiators of M(4) reverse amphetamine-induced hyperlocomotion in rats, a model that is sensitive to known antipsychotic agents and to nonselective mAChR agonists. This is consistent with the hypothesis that M(4) plays an important role in regulating midbrain dopaminergic activity and raises the possibility that positive allosteric modulation of M(4) may mimic some of the antipsychotic-like effects of less selective mAChR agonists.


Resistin is closely related to systemic inflammation in obstructive sleep apnea.
Obstructive sleep apnea (OSA) is closely related to systemic inflammation. Resistin is an adipocyte-derived cytokine (adipokine) that may link obesity with inflammation. We aimed to investigate whether incremental changes in OSA severity, from normal to severe, primarily affect the levels of resistin and other adipokines. Serum levels of resistin, interleukin-6 (IL-6) and leptin were examined in 31 men with OSA and 10 men without OSA, matched for age, body mass index (BMI) and several metabolic profiles. In 11 of the 31 men with OSA, these mediators were reexamined after 3 months of nasal continuous airway pressure (nCPAP) therapy. Levels of resistin and IL-6 were simultaneously elevated in men with OSA compared with those in men without OSA (p < 0.05), while levels of leptin did not differ. The resistin and IL-6 levels tended to increase with increasing disease severity (p < 0.05), which was based on the apnea-hypopnea index (AHI). The average oxyhemoglobin saturation during sleep (p < 0.01) and IL-6 (p < 0.05) emerged as significant determinants of resistin, even after adjustments for age, BMI, leptin levels and metabolic risk factors. After nCPAP therapy, the elevated levels of resistin and IL-6 decreased, reaching almost baseline levels of controls. Before treatment, AHI correlated positively with the reduction rate in resistin (p < 0.05). In OSA patients, resistin production can be enhanced by hypoxic stress during sleep, possibly mediating systemic inflammatory processes. nCPAP therapy may play a beneficial role in the control of resistin production.


Effective containment explains subexponential growth in recent confirmed COVID-19 cases in China.
The recent outbreak of coronavirus disease 2019 (COVID-19) in mainland China was characterized by a distinctive subexponential increase of confirmed cases during the early phase of the epidemic, contrasting with an initial exponential growth expected for an unconstrained outbreak. We show that this effect can be explained as a direct consequence of containment policies that effectively deplete the susceptible population. To this end, we introduce a parsimonious model that captures both quarantine of symptomatic infected individuals, as well as population-wide isolation practices in response to containment policies or behavioral changes, and show that the model captures the observed growth behavior accurately. The insights provided here may aid the careful implementation of containment strategies for ongoing secondary outbreaks of COVID-19 or similar future outbreaks of other emergent infectious diseases.


Fusion of Video and Inertial Sensing for Deep Learning-Based Human Action Recognition.
This paper presents the simultaneous utilization of video images and inertial signals that are captured at the same time via a video camera and a wearable inertial sensor within a fusion framework in order to achieve a more robust human action recognition compared to the situations when each sensing modality is used individually. The data captured by these sensors are turned into 3D video images and 2D inertial images that are then fed as inputs into a 3D convolutional neural network and a 2D convolutional neural network, respectively, for recognizing actions. Two types of fusion are considered-Decision-level fusion and feature-level fusion. Experiments are conducted using the publicly available dataset UTD-MHAD in which simultaneous video images and inertial signals are captured for a total of 27 actions. The results obtained indicate that both the decision-level and feature-level fusion approaches generate higher recognition accuracies compared to the approaches when each sensing modality is used individually. The highest accuracy of 95.6% is obtained for the decision-level fusion approach.


Semaphorin 5A mediated cellular navigation: connecting nervous system and cancer.
The ultraprecise wiring of neurons banks on the instructions provided by guidance cue proteins that steer them to their appropriate target tissue during neuronal development. Semaphorins are one such family of proteins. Semaphorins are known to play major physiological roles during the development of various organs including the nervous, cardiovascular, and immune systems. Their role in different pathologies including cancer remains an intense area of investigation. This review focuses on a novel member of this family of proteins, semaphorin 5A, which is much less explored in comparison to its other affiliates. Recent reports suggest that semaphorins play important roles in the pathology of cancer by affecting angiogenesis, tumor growth and metastasis. We will firstly give a general overview of the semaphorin family and its receptors. Next, we discuss their roles in cellular movements and how that makes them a connecting link between the nervous system and cancer. Finally, we focus our discussion on semaphorin 5A to summarize the prevailing knowledge for this molecule in developmental biology and carcinogenesis.


Mutagenic metabolites in urine and feces of rats fed with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, a carcinogenic mutagen present in cooked meat.
To study the in vivo fate of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a carcinogenic mutagen present in cooked meat, rats were fed MeIQx in the diet and their urine and feces were analyzed for the metabolites. The isolation procedure included specific adsorption of MeIQx derivatives to blue cotton and subsequent fractionations by thin layer chromatography on silica gel and by high pressure liquid chromatography. Attention was focused on mutagenically active metabolites. Three metabolites were isolated from the urine, and their structures were elucidated on the basis of 1H nuclear magnetic resonance, ultraviolet, and mass spectra. The first metabolite characterized was 2-amino-8-hydroxymethyl-3-methylimidazo[4,5-f]quinoxaline (Compound I), the second was 2-acetylamino-3,8-dimethylimidazo[4,5-f]quinoxaline (Compound II), and the third was 2-amino-8-methylimidazo[4,5-f]quinoxaline (Compound III). Compound I was isolated also from the feces. Compounds I-III were mutagenic to Salmonella typhimurium TA98 with metabolic activation. The mutagenic potency of Compounds I and II was as high as that of MeIQx, and that of Compound III was much lower than that of MeIQx.


Differential changes in the gut microbiota between extrinsic and intrinsic atopic dermatitis.
Elevated serum level of total and (or) allergen-specific IgE is one of the key features of atopic dermatitis (AD). Previous studies have shown that the gut microbiome mediates interactions between external exposures and the immune system in AD; however, the relationship between the gut microbiota and IgE remains unclear. In the present study, analyses of environmental exposures for 250 AD patients and 138 healthy volunteers revealed an association between hygiene levels in the residential environment and the occurrence of AD and the IgE level. Metagenomic sequencing of the gut microbiota from 68 AD patients and 77 healthy controls showed that AD patients had a distinct gut microbiota composition; moreover, while L-histidine degradation was enriched in healthy controls, L-histidine biosynthesis was enriched in AD patients. Extrinsic and intrinsic AD showed different enrichment patterns of specific microbes and differential associations of functional pathways. Our study indicated that elevated levels of IgE in AD were related to specific microbes in the gut microbiota, which showed extensive interactions with environmental factors.


Cryosurgical ablation of the prostate: current technique and clinical outcomes.
In addition to established therapies such as radiotherapy and radical prostatectomy, a number of newer therapies have been suggested to be effective in treating patients with clinically localized prostate carcinoma (PCA). One of these is cryoablation, a procedure that infarcts the prostate by the in situ application of percutaneous cryoprobes. Although results with this approach were mixed when introduced initially in 1993, recent improvements in technique and understanding of the mechanisms of cryo-injury in the prostate have led to renewed interest in this treatment option for patients with PCA.


[Indications and results of combined urokinase-lys plasminogen in acute ischemic pathology of the legs].
Low dose urokinase-lys plasminogen was used to treat 10 patients with acute ischemia of lower limbs. Preliminary results are reported and indications defined, the combination producing effective relief and being very well tolerated biologically and clinically. All patients presented clear signs of ischemia provoking a short term risk for the limb. Direct femoral puncture arteriography of the ischemic limb was an essential pretreatment investigation. A thin catheter left in contact with the thrombus allowed localized fibrinolysis to be performed. Follow up arteriography examinations assessed clinicopathologic results, while biologic surveillance of principal coagulation parameters showed a lack of significant alterations during treatment. Ischemic signs were totally relieved in 7 cases, with arterial repermeabilization allowing recuperation of one (3 cases) or both (2 cases) distal pulses. Persistence of a popliteal thrombus in one case required a fogarty after a direct approach and the limb was saved. Two patients had to be amputated because of delayed treatment. These encouraging results suggest that this procedure of local thrombolysis be reserved for popliteal or infra-popliteal occlusions accompanied by sensory-motor signs and of recent (less than 72 hours) onset. Follow up for 8 months is insufficient but has shown the absence of deterioration, but this is obviously a function of the natural course of the underlying atheromatous disease.


A new chondrodystrophic mutant in mice. Electron microscopy of normal and abnormal chondrogenesis.
The occurrence of a new mutation affecting cartilage and bone in mice is reported. The gene is lethal, shows autosomal recessive inheritance, and has high penetrance. It is not allelic to shorthead and probably not to phocomelia or achondroplasia. It results in a foreshortened face, cleft palate, defective trachea, and shortened long bones with flared metaphyses. Chondrocytes of epiphyseal cartilage from the mutant are not aligned in columns, and there is a decrease in the usual staining of the cartilage matrix. Electron microscope observations show large, wide collagen fibrils with "native" banding in the matrix of mutant cartilage, which are not present in normal cartilage. Possible explanations for the expression of this genetic disorder of cartilage development are put forward.


Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome.
The aim of the present study was to examine to what extent maternal and offspring phenylalanine hydroxylase (PAH) genotypes in conjunction with maternal IQ and dietary control during pregnancy are related to cognitive development in offspring of women with phenylketonuria (PKU). PAH gene mutations were determined in 196 maternal PKU subjects and their offspring. The women were grouped according to PAH genotype, which predicts the metabolic phenotype (severe PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). IQ was determined in both the mothers (Wechsler Adult Intelligence Scale-Revised at >18 years) and their children (Wechsler Intelligence Scale for Children-Revised at > or = 6-7 years of age). According to PAH genotypes, 62% of the women exhibited severe PKU, 19% exhibited mild PKU, and 19% exhibited MHP. Maternal IQ increased, and the assigned phenylalanine (Phe) levels decreased with decreasing severity of PAH genotype. In offspring of mild maternal PKU, multiple regression analysis showed offspring IQ to be significantly related to maternal IQ but not to Phe exposure during pregnancy, which was <750 micromol/L in all cases of mild PKU. In offspring of mothers with severe PKU and average Phe exposure during pregnancy of 360 to 750 micromol/L, multiple regression analysis revealed both maternal IQ and Phe exposure to be significant predictors of offspring IQ. When average Phe exposure was <360 micromol/L, cognitive development was normal (mean IQ: 105), whereas an average Phe exposure of >750 micromol/L severely depressed offspring IQ (mean IQ: 56) in this group regardless of maternal IQ. It could not be documented that the offspring PAH genotype affects cognitive development. Female individuals with severe PKU should be offered a diet for a lifetime. If good metabolic control is established, then women with PKU will have children with IQ scores that are not influenced by their disease.


Sugar radicals in DNA: isolation of neutral radicals in gamma-irradiated DNA by hole and electron scavenging.
In this investigation of the radical formation and the reaction of radicals in gamma-irradiated DNA, we report the isolation of putative neutral radicals by the scavenging of holes by Fe(CN)6(4-) and of electrons by Fe(CN)6(3-). Experiments are performed under conditions that emphasize direct and quasi-direct effects (collectively called direct-type effects.) Samples containing Fe(CN)6(4-) show effective scavenging of holes and the ESR spectra obtained arise principally from DNA anion radicals and neutral radicals. On the other hand, for samples containing Fe(CN)6(3-), electron scavenging is highly efficient, and the resulting spectra arise principally from guanine cation radicals and neutral radicals. When both Fe(CN)6(4-) and Fe(CN)6(3-) are present, a near complete scavenging of cation radicals and anion radicals is observed at 77 K, and the ESR spectra that result originate predominantly with neutral radicals which are assigned predominantly to radicals on the sugar phosphate backbone. A notable finding is the presence of spectral components that indicate the formation, through the rupture of the C3'-O bond, of a neutral deoxyribose radical; a concurrent strand break must accompany formation of this radical. This radical was previously reported in argon-ion-irradiated DNA and now, for the first time, is reported in DNA irradiated with low-LET radiation.


Informed consent in uremia therapy.
Decision making in uremia therapy requires that patients be provided with a fair assessment of their course if untreated or if managed by any of several acceptable alternatives. Enthusiastic overselling of any treatment or intimidation of patients to accept a local regimen is unacceptable practice. Suiting patient to treatment requires time, patience, an acceptance of the patient as a partner in evaluating options.


Discoplana malagasensis sp. nov., a new turbellarian (Platyhelminthes: Polycladida: Leptoplanidae) symbiotic in an ophiuroid (Echinodermata), with a cladistic analysis of the Discoplana/Euplana species.
A new species of polyclad flatworm from Papua New Guinea is described. It is found symbiotic in the ophiuroid Ophiothrix purpurea von Martens, 1867 (Echinodermata: Ophiuroidea). Apparently it belongs to the taxon Discoplana Bock, 1913 and can be distinguished from the six previously described Discoplana species by its very short ejaculatory duct and a penial papilla covered with a penial sheath, but without any true sclerotised structures such as a stylet or spines. The cladistic analysis of the Discoplana/ Euplana species, based on morphological features and including two outgroups, reveals that all species of Discoplana, except D. pacificola, form a monophyletic taxon, that is not a synonym of Euplana Girard, 1893. Therefore the name Discoplana is conserved and the new species will be described as Discoplana malagasensis sp. nov. A key for the Discoplana/Euplana group is provided. In this key the biogeographical distribution and possible synonyms are given.


Mechanical properties of suture materials: an important characterization.
A comprehensive and systematic study of the stress-strain behavior of seven synthetic absorbable and nonabsorbable sutures was conducted. The purpose of the study was to provide detailed mechanical information on suture materials in order to assist surgeons in their selection of adequate sutures for specific surgical applications. The use of a yarn grip, newly designed specifically for fibrous materials, eliminated several difficulties imposed by conventional grips, and resulted in more dependable mechanical properties. A wide range of stress-strain characteristics was observed in the tested sutures. Suture materials of similar nominal properties may behave quite differently in their stress-strain relationship. This was true of sutures of the same chemical nature as well as of different geometric construction, such as Ethilon vs. Nurolon. Larger differences in stress-strain curves were observed after the yield point with yarn grips than with conventional grips. The unique shape of the stress-strain curves, and the associated data derived from them, provide better information in the discrimination between suture materials.


GlycoFly: a database of Drosophila N-linked glycoproteins identified using SPEG--MS techniques.
Protein glycosylation affects cellular functions of the central nervous system (CNS). Its deficiency leads to neurological disorders such as ataxia, paralysis, learning disability, mental retardation, and memory loss. However, the glycoproteins that are responsible for these diseases are not well characterized. In this study, Drosophila melanogaster was used as a model organism to identify the N-glycosylated proteins and N-glycosylation sites of its CNS by means of proteomics. Adult fly heads were digested with chymotrypsin or trypsin and the N-linked glycopeptides were captured using solid phase extraction of N-linked glycopeptides (SPEG) technique followed by mass spectrometry (MS) analysis using LTQ OrbiTrap Velos. Three hundred and thirty new and 147 previously known glycoproteins were identified from 721 uniquely detected peptides that have 740 NXS/T glycosylation sites. The N-glycosylation sites were highly abundant in cell adhesion, ion channel, and ion binding molecules, which are important for nerve maturation, organ development, axon guidance, learning, and memory. Identification of the N-glycosylated sites of these proteins will enhance our knowledge of these proteins and serve as a basis for future studies to address the roles of these proteins in neurological function and disorders. A database for Drosophila N-linked glycopeptides ( http://betenbaugh.jhu.edu/GlycoFly ) has been established in this study as a resource for study of neurological disorders.


Outcomes of infants born to women with influenza A(H1N1)pdm09.
Pregnant women with influenza are more likely to have complications, but information on infant outcomes is limited. Five state/local health departments collected data on outcomes of infants born to pregnant women with 2009 H1N1 influenza reported to the Centers for Disease Control and Prevention from April to December 2009. Collaborating sites linked information on pregnant women with confirmed 2009 H1N1 influenza, many who were severely ill, to their infants' birth certificates. Collaborators also collected birth certificate data from two comparison groups that were matched with H1N1-affected pregnancies on month of conception, sex, and county of residence. 490 pregnant women with influenza, 1,451 women without reported influenza with pregnancies in the same year, and 1,446 pregnant women without reported influenza with prior year pregnancies were included. Women with 2009 H1N1 influenza admitted to an intensive care unit (ICU; n = 64) were more likely to deliver preterm infants (<37 weeks), low birth weight infants, and infants with Apgar scores <=6 at 5 min than women in comparison groups (adjusted relative risk, aRR = 3.9 [2.7, 5.6], aRR = 4.6 [2.9, 7.5], and aRR = 8.7 [3.6, 21.2], for same year comparisons, respectively). Women with influenza who were not hospitalized and hospitalized women not admitted to the ICU did not have significantly elevated risks for adverse infant outcomes. Severely ill women with 2009 H1N1 influenza during pregnancy were more likely to have adverse birth outcomes than women without influenza, providing more support for influenza vaccination during pregnancy.


Pyrrolizidine alkaloids enhance alcohol-induced hepatocytotoxicity in vitro in normal human hepatocytes.
Herbal remedies containing pyrrilidozine alkaloids (PA)s can induce liver damage, including hepato-sinusoidal obstruction syndrome (HSOS) or veno-occlusive liver disease (VOD). Some individuals misusing alcohol consume also teas and/or herbal remedies containing PA. The interaction or additive toxicity of alcohol to PA toxicity needs to be addressed. The objectives of this study are 1) to review the scientific literature on the PA-induced liver toxicity; 2) identify possible mechanism(s) involved in PA-induced hepatocytotoxicity in the presence or absence of ethanol (EtOH) in vitro in normal human hepatocytes (NHH) in primary culture. To respond to the first objective, we systematically search all the literature engines (PubMed, Google Scholar) for liver induced damage due to PAs and summarize the results in an introductory systematic review. Cells were exposed to one dose of 100 mmol/L EtOH for 24 hrs and to 2 doses of 100 mmol/L EtOH for consecutive 24 hrs periods, in the presence or absence of PAs (10 mg/mL), or the caspase-3 inhibitor IDN-1965 (50 µmol/L). Cells were analyzed for apoptosis by light microscopy, immuno-histochemistry, measuring cytokeratin-18 fragmentation, and transmission electron microscopy (TEM) (6000 cells/treatment). Cytotoxicity was determined using succinate dehydrogenase (SDH) activity, an enzyme specific to the mitochondria. In NHH cells, a 100 mmol/L dose of Et-OH resulted in 22±2.5 apoptosis (p<0.001 vs. control). Two consecutive doses of 100 mmol/L Et-OH for 24 hrs each caused 36±3.0% apoptosis (p<0.001 vs. control and p<0.05 vs. one dose Et-OH). Pre-treatment with 50 µmol/L caspase inhibitor significantly reduced Et-OH-induced apoptosis [12±1.5% in 100 mmol/L (p<0.05) and 20±4.0% in 2×100 mmol/L (p<0.001)]. In addition, pre-treatment with 50 μmol caspase inhibitor in cells treated with PA + EtOH reduced apoptosis significantly (vs. non-exposed to caspase-inhibitor): Δ -22±3.0 % (p<0.05). HPC significantly decreased apoptosis compared to conditions lacking this supplementation in cells treated with EtOH-exposed cells present ballooning, Mallory bodies, changes in mitochondrial cristae and apoptosis by TEM. Pre-treatment with 50 μmol caspase inhibitor significantly reduced 100 mmol/L EtOH-induced (one dose) in NHH by 14±0.5% (p<0.05) compared to cells not exposed to the caspase-inhibitor. In cells treated concomitantly with PA and EtOH 100 mM Mallory-bodies and apo-necrotic cells have been observed. Pre-treatment with 50 μmol caspase inhibitor reduced the mitochondrial damage. A significant depletion in glutathione (GSH) was observed in Et-OH treated cells after 1 and 2 treatments (p<0.001 vs. control). Treatment with Et-OH enhanced PA-induced GSH-depletion and resulted in a significant increase in PA-induced cytotoxicity (p<0.001 vs. Et-untreated cells). Exposure to EtOH increased the cell culture media levels of the pro-inflammatory cytokine TNF. PA + EtOH-treated cells increased TNF-α levels in media compared to EtOH alone [86±8 vs. 53±5 pg/mL in cells exposed to 100 mmol/L EtOH (p<0.05) and 218±14 vs. 179±8 pg/mL in cells exposed to 2×100 mmol/L EtOH (p<0.05)]. PA up-regulates EtOH-induced hepatocytotoxicity by inducing the inflammatory cytokines and enhancing the apoptotic effects of ethanol. There is a need for monitoring herbal medicine in order to optimize traditional medicine use and maximize the clinical benefits. Additionally, there is necessary to communicate to physicians the possible negative results of herbal remedies use. Also, the interactions between herbal remedies and drugs of misuse should be communicated to consumers.


Evaluating the possibility of detecting evidence of positive selection across Asia with sparse genotype data from the HUGO Pan-Asian SNP Consortium.
The HUGO Pan-Asian SNP Consortium (PASNP) has generated a genetic resource of almost 55,000 autosomal single nucleotide polymorphisms (SNPs) across more than 1,800 individuals from 73 urban and indigenous populations in Asia. This has offered valuable insights into the correlation between the genetic ancestry of these populations with major linguistic systems and geography. Here, we attempt to understand whether adaptation to local climate, diet and environment partly explains the genetic variation present in these populations by investigating the genomic signatures of positive selection. To evaluate the impact to the selection analyses due to the considerably lower SNP density as compared to other population genetics resources such as the International HapMap Project (HapMap) or the Singapore Genome Variation Project, we evaluated the extent of haplotype phasing switch errors and the consistency of selection signals from three haplotype-based approaches (iHS, XP-EHH, haploPS) when the HapMap data is thinned to a similar density as PASNP. We subsequently applied haploPS to detect and characterize positive selection in the PASNP populations, identifying 59 genomics regions that were selected in at least one PASNP populations. A cluster analysis on the basis of these 59 signals showed that indigenous populations such as the Negrito from Malaysia and Philippines, the China Hmong, and the Taiwan Ami and Atayal shared more of these signals. We also reported evidence of a positive selection signal encompassing the beta globin gene in the Taiwan Ami and Atayal that was distinct from the signal in the HapMap Africans, suggesting the possibility of convergent evolution at this locus due to malarial selection. We established that the lower SNP content of the PASNP data conferred weaker ability to detect signatures of positive selection, but the availability of the new approach haploPS retained modest power. Out of all the populations in PASNP, we identified only 59 signals, suggesting a strong need for high-density population-level genotyping data or sequencing data in order to achieve a comprehensive survey of positive selection in Asian populations.


Recent contributions of elastin-like recombinamers to biomedicine and nanotechnology.
The emergence of the new scientific field known as nanomedicine is being catalyzed by multiple improvements in nanoscience techniques and significant progress in materials science, especially as regards the testing of novel and sophisticated biomaterials. This conjuncture has furthered the development of promising instruments in terms of detection, bioanalysis, therapy, diagnostics and imaging. Some of the most innovative new biomaterials are protein-inspired biomimetic materials in which modern biotechnology and genetic-engineering techniques complement the huge amount of information afforded by natural protein evolution to create advanced and tailor-made multifunctional molecules. Amongst these protein-based biomaterials, Elastin-like Recombinamers (ELRs) have demonstrated their enormous potential in the fields of biomedicine and nanoscience in the last few years. This broad applicability derives from their unmatched properties, particularly their recombinant and tailor-made nature, the intrinsic characteristics derived from their elastin-based origin (mainly their mechanical properties and ability to self-assemble as a result of their stimuli-responsive behavior), their proven biocompatibility and biodegradability, as well as their versatility as regards incorporating advanced chemical or recombinant modifications into the original structure that open up an almost unlimited number of multifunctional possibilities in this developing field. This article provides an updated review of the recent challenges overcome by using these recombinant biomaterials in the fields of nano- and biomedicine, ranging from nanoscale applications in surface modifications and self-assembled nanostructures to drug delivery and regenerative medicine.


[Secondary abscessing pneumonia in children].
Among 370 patients with staphylococcic abscessing pneumonia in 55 secondary pulmonary involvement (14.8%) was noted. Acute hematogenic osteomyelitis was the most frequent cause of sepsis. The treatment of patients with secondary staphylociccic abscessing pneumonia is described. The mortality was 40 per cent.


Multi-part modeling and segmentation of left atrium in C-arm CT for image-guided ablation of atrial fibrillation.
As a minimally invasive surgery to treat atrial fibrillation (AF), catheter based ablation uses high radio-frequency energy to eliminate potential sources of abnormal electrical events, especially around the ostia of pulmonary veins (PV). Fusing a patient-specific left atrium (LA) model (including LA chamber, appendage, and PVs) with electro-anatomical maps or overlaying the model onto 2-D real-time fluoroscopic images provides valuable visual guidance during the intervention. In this work, we present a fully automatic LA segmentation system on nongated C-arm computed tomography (C-arm CT) data, where thin boundaries between the LA and surrounding tissues are often blurred due to the cardiac motion artifacts. To avoid segmentation leakage, the shape prior should be exploited to guide the segmentation. A single holistic shape model is often not accurate enough to represent the whole LA shape population under anatomical variations, e.g., the left common PVs vs. separate left PVs. Instead, a part based LA model is proposed, which includes the chamber, appendage, four major PVs, and right middle PVs. Each part is a much simpler anatomical structure compared to the holistic one and can be segmented using a model-based approach (except the right middle PVs). After segmenting the LA parts, the gaps and overlaps among the parts are resolved and segmentation of the ostia region is further refined. As a common anatomical variation, some patients may contain extra right middle PVs, which are segmented using a graph cuts algorithm under the constraints from the already extracted major right PVs. Our approach is computationally efficient, taking about 2.6 s to process a volume with 256 × 256 × 245 voxels. Experiments on 687 C-arm CT datasets demonstrate its robustness and state-of-the-art segmentation accuracy.


A proof-of-concept study showing antibiotics to be more effective in irritable bowel syndrome with than without small-intestinal bacterial overgrowth: a randomized, double-blind, placebo-controlled trial.
Antibiotics relieve symptoms in half of the unselected patients with irritable bowel syndrome (IBS); however, their efficacy if selected according to small-intestinal bacterial overgrowth (SIBO) is unknown. The aim of this study was to evaluate (a) symptom resolution among IBS patients with or without SIBO on norfloxacin treatment, and (b) its efficacy in obtaining negative SIBO test results as compared with placebo. Eighty IBS patients (Rome III) were evaluated for SIBO by gut aspirate culture. Patients with (≥10 CFU/ml) and those without SIBO were separately randomized (computer-generated stratified) to 800 mg/day norfloxacin for 10 days or placebo. Global symptom score (blindly), Rome III criteria, aspirate culture, and glucose hydrogen breath test (GHBT) were assessed before and 1 month after treatment, and patients were followed up for 6 months. Although norfloxacin was more effective at reducing the symptom score at 1 month among patients with compared with those without SIBO [15/80, 19% on culture, four on GHBT too; 6.5 (2-13) vs. 2 (0-10), P=0.01; 8.5 (2-16) vs. 5 (0-12), P<0.001] but not placebo, the scores were comparable at 6 months [3 (1-10) vs. 9 (5-19), P=NS]. Symptoms more often resolved to turn Rome III negative in SIBO patients treated with norfloxacin compared with placebo at 1 month (7/8, 87.5 vs. 0/7, P=0.004); of the other 65 patients, 8/32 (25%) treated with norfloxacin but none of the 33 treated with placebo turned Rome III negative. Patients without SIBO and a colony count of 10-10 CFU/ml responded more than those with a colony count less than 10 CFU/ml. Overall, 15/40 (37.5%) patients responded to norfloxacin. At 6 months, 2/8 (25%) with and 5/32 (15.6%) without SIBO remained Rome III negative following norfloxacin. All 4/8 consenting patients treated with norfloxacin became SIBO negative (two each by culture+GHBT and GHBT alone), but 0/7 patients treated with placebo became SIBO negative. Norfloxacin is superior to placebo in relieving symptoms of SIBO-associated IBS.


Thermodynamic and Kinetic Aspects of Gold Adsorption in Micrometric Activated Carbon and the Impact of Their Loss in Adsorption, Desorption, and Reactivation Plants.
The production and loss of fine particles of activated carbon (AC) loaded with gold in the adsorption processes is a worldwide problem, mainly due to the behavior of increasing its adsorption capacity with respect to the decrease in particle size, which becomes relevant to determine the thermodynamic and kinetic activity of the gold adsorption and the economic impact of its loss, with the escape towards the later stages of the system of adsorption, desorption, and reactivation (ADR) plants of AC. Through the adsorption of gold in a synthetic medium with sodium cyanide concentration, using different particle sizes, AC weights, and adsorption times, data were generated for analysis by three different isotherm models, resulting in a better tendency for the Freundlich isotherm, from which thermodynamic parameters of ΔG equal to -2.022 kcal/mol, ΔH equal to -16.710 kcal/mol, and ΔS equal to -0.049 kcal/molK were obtained, which shows that it is a spontaneous, exothermic process with a lower degree of disorder. The kinetic analysis was performed with two different models, from which the pseudo-second-order model was used due to a better tendency and displayed a behavior that leaves open the interpretation of the increase in adsorption with respect to the decrease in the AC particle size but demonstrated the importance of recovering these particles in relation to their gold concentration and the economic impact from their poor recovery, which, for this case study, amounted to ~0.3 million dollars per year.


Evaluating the assessment of the ICD-11 personality disorder diagnostic system.
Proposed for the ICD-11 is a dimensional model of personality disorder that, if approved, would be a paradigm shift in the conceptualization of personality disorder. The proposal consists of a general severity rating, 5 maladaptive personality trait domains, and a borderline pattern qualifier. The general severity rating can be assessed by the Standardized Assessment of Severity of Personality Disorder (SASPD), the trait domains by the Personality Inventory for ICD-11 (PiCD), and the borderline pattern by the Borderline Pattern Scale (BPS), which is developed in the present study. To date, no study has examined the relations among all 3 components, due in part to the absence of direct measures for each component (until recently). The current study develops and provides initial validation evidence for the BPS, and examines the relations among the BPS, SASPD, and PiCD. Also considered is their relationship with the 5-factor model of general personality as well as with 2 other measures of personality disorder severity (including the DSM-5 Level of Personality Functioning Scale [LPFS]). Further, an alternative trait-based coding of the DSM-5 LPFS is examined (modeled after the ICD-11 SASPD), suggesting that its coverage of diverse maladaptivity may not be because it assesses the core of personality disorder, but rather because it has items specific to the different domains of personality. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Acceptability of a mobile health intervention to enhance HIV care coordination for patients with substance use disorders.
Persons living with HIV and substance use disorders face barriers to sustained engagement in medical care, leading to suboptimal antiretroviral treatment outcomes. Innovative mobile technology tools such as customizable smartphone applications have the potential to enhance existing care coordination programs, but have not been rigorously studied. We developed and implemented a two-component intervention consisting of peer health navigation supported by a smartphone application conducting ecologic momentary assessment (EMA) of barriers to care and medication adherence. Patients with a history of antiretroviral treatment failure and substance use were recruited to participate in the 9-month pilot intervention. Three peer health navigators were trained to provide social and logistical support while participants re-engaged in HIV care. We assessed the acceptability of the intervention components using qualitative analysis of in-depth interviews conducted with study participants and peer navigators. Of 19 patients enrolled in the study, 17 participated for at least 2 months and 15 completed the entire 9-month study protocol. The acceptability of the peer navigation intervention was rated favorably by all participants interviewed, who felt that peer support was instrumental in helping them re-engage in HIV care. Participants also responded favorably to the smartphone application, but described its usefulness mostly as providing reminders to take medications and attend appointments, rather than as a facilitator of patient navigation. Peer health navigation and smartphone-based EMA are acceptable approaches to facilitating engagement in HIV care for drug using populations. Future studies to evaluate the efficacy of this approach for improving long-term retention in care and antiretroviral treatment outcomes are warranted. ClinicalTrials.gov Identifier NCT01941108; registered on September 4, 2013.


Healthy but smaller herds: Predators reduce pathogen transmission in an amphibian assemblage.
Predators and pathogens are fundamental components of ecological communities that have the potential to influence each other via their interactions with victims and to initiate density- and trait-mediated effects, including trophic cascades. Despite this, experimental tests of the healthy herds hypothesis, wherein predators influence pathogen transmission, are rare. Moreover, no studies have separated effects mediated by density vs. traits. Using a semi-natural mesocosm experiment, we investigated the interactive effects of predatory dragonfly larvae (caged or lethal [free-ranging]) and a viral pathogen, ranavirus, on larval amphibians (grey treefrogs and northern leopard frogs). We determined the influence of predators on ranavirus transmission and the relative importance of density- and trait-mediated effects on observed patterns. Lethal predators reduced ranavirus infection prevalence by 57%-83% compared to no-predator and caged-predator treatments. The healthy herds effect was more strongly associated with reductions in tadpole density than behavioural responses to predators. We also assessed whether ranavirus altered the responses of tadpoles to predators. In the absence of virus, tadpoles reduced activity levels and developed deeper tails in the presence of predators. However, there was no evidence that virus presence or infection altered responses to predators. Finally, we compared the magnitude of trophic cascades initiated by individual and combined natural enemies. Lethal predators initiated a trophic cascade by reducing tadpole density, but caged predators and ranavirus did not. The absence of a virus-induced trophic cascade is ostensibly the consequence of limited virus-induced mortality and the ability of infected individuals to continue interacting within the community. Our results provide support for the healthy herds hypothesis in amphibian communities. We uniquely demonstrate that density-mediated effects of predators outweigh trait-mediated effects in driving this pattern. Moreover, this study was one of the first to directly compare trophic cascades caused by predators and pathogens. Our results underscore the importance of examining the interactions between predators and pathogens in ecology.


Detection of CEBPA double mutants in acute myeloid leukemia using a custom gene expression array.
Double (bi-allelic) mutations in the gene encoding the CCAAT/enhancer-binding protein-alpha (CEBPA) transcription factor have a favorable prognostic impact in acute myeloid leukemia (AML). Double mutations in CEBPA can be detected using various techniques, but it is a notoriously difficult gene to sequence due to its high GC-content. Here we developed a two-step gene expression classifier for accurate and standardized detection of CEBPA double mutations. The key feature of the two-step classifier is that it explicitly removes cases with low CEBPA expression, thereby excluding CEBPA hypermethylated cases that have similar gene expression profiles as a CEBPA double mutant, which would result in false-positive predictions. In the second step, we have developed a 55 gene signature to identity the true CEBPA double-mutation cases. This two-step classifier was tested on a cohort of 505 unselected AML cases, including 26 CEBPA double mutants, 12 CEBPA single mutants, and seven CEBPA promoter hypermethylated cases, on which its performance was estimated by a double-loop cross-validation protocol. The two-step classifier achieves a sensitivity of 96.2% (95% confidence interval [CI] 81.1 to 99.3) and specificity of 100.0% (95% CI 99.2 to 100.0). There are no false-positive detections. This two-step CEBPA double-mutation classifier has been incorporated on a microarray platform that can simultaneously detect other relevant molecular biomarkers, which allows for a standardized comprehensive diagnostic assay. In conclusion, gene expression profiling provides a reliable method for CEBPA double-mutation detection in patients with AML for clinical use.


Quantum frequency conversion of quantum memory compatible photons to telecommunication wavelengths.
We report an experiment demonstrating quantum frequency conversion of weak light pulses compatible with atomic quantum memories to telecommunication wavelengths. We use a PPLN nonlinear waveguide to convert weak coherent states at the single photon level with a duration of 30 ns from a wavelength of 780 nm to 1552 nm. We measure a maximal waveguide internal (external) conversion efficiency η(int) = 0.41 (η(ext) = 0.25), and we show that the signal to noise ratio (SNR) is good enough to reduce the input photon number below 1. In addition, we show that the noise generated by the pump beam in the crystal is proportional to the spectral bandwidth of the device, suggesting that narrower filtering could significantly increase the SNR. Finally, we demonstrate that the quantum frequency converter can operate in the quantum regime by converting a time-bin qubit and measuring the qubit fidelity after conversion.


Expression of an estrogen receptor alpha variant protein in cell lines and tumors.
Human estrogen receptor alpha (ER) mRNA is a mixture of wild type and alternatively spliced variants. Many studies have examined the potential of ER mRNA profiles to serve as diagnostic/prognostic cancer biomarkers, but only a few have attempted to correlate ER mRNA profiles with protein expression. Representative ER mRNA pools were reproduced from the cDNAs of MCF-7 cells, a human breast tumor and human uterus and translated in a protease-free environment by reticulocyte lysates to determine relative translation efficiencies between the various ER mRNA transcripts and to facilitate identification of translated proteins. Cell line and tumor extracts were then examined for expression of the ER variant proteins identified in reticulocyte lysate translations. Each of the ER mRNA pools were translated by reticulocyte lysates into two ER proteins with molecular weights of approximately 60 and 52 kD. Western immunoblotting with various C- and N-terminal-directed, anti-ER antibodies and comparison with expressed ER protein standards established that the 52 kD protein (ERDelta7P) was translated from the predominant splice variant mRNA in each pool, which is missing exon 7. The 60 kD protein contained wild type ER sequence minus 61 C-terminal amino acids lost due to an intentional run off truncation. ERDelta7P expression was subsequently demonstrated in MCF-7 cells by Western immunoblotting with the site-directed antibodies. A protein corresponding to ERDelta7P was also detected in other ER positive breast tumor cell lines, and extracts of ER positive breast and uterine tumors. This widespread expression of ERDelta7P in vivo suggests that it may have some biological function. ERDelta7P may also affect immunohistochemical evaluation of ER positivity in tumors depending upon the level of its expression and the antibody used.


Water and waste load allocation in rivers with emphasis on agricultural return flows: application of fractional factorial analysis.
In this paper, a new methodology is developed to handle parameter and input uncertainties in water and waste load allocation (WWLA) in rivers by using factorial interval optimization and the Soil, Water, Atmosphere, and Plant (SWAP) simulation model. A fractional factorial analysis is utilized to provide detailed effects of uncertain parameters and their interaction on the optimization model outputs. The number of required optimizations in a fractional factorial analysis can be much less than a complete sensitivity analysis. The most important uncertain inputs and parameters can be also selected using a fractional factorial analysis. The uncertainty of the selected inputs and parameters should be incorporated real time water and waste load allocation. The proposed methodology utilizes the SWAP simulation model to estimate the quantity and quality of each agricultural return flow based on the allocated water quantity and quality. In order to control the pollution loads of agricultural dischargers, it is assumed that a part of their return flows can be diverted to evaporation ponds. Results of applying the methodology to the Dez River system in the southwestern part of Iran show its effectiveness and applicability for simultaneous water and waste load allocation in rivers. It is shown that in our case study, the number of required optimizations in the fractional factorial analysis can be reduced from 64 to 16. Analysis of the interactive effects of uncertainties indicates that in a low flow condition, the upstream water quality would have a significant effect on the total benefit of the system.


Search for Mycobacterium avium Subspecies paratuberculosis Antigens for the Diagnosis of Paratuberculosis.
The aim of this study was to evaluate a wide panel of antigens of Mycobacterium avium subsp. paratuberculosis (MAP) to select candidates for the diagnosis of paratuberculosis (PTB). A total of 54 recombinant proteins were spotted onto nitrocellulose membranes and exposed to sera from animals with PTB (n = 25), healthy animals (n = 10), and animals experimentally infected with M. bovis (n = 8). This initial screening allowed us to select seven antigens: MAP 2513, MAP 1693, MAP 2020, MAP 0038, MAP 1272, MAP 0209c, and MAP 0210c, which reacted with sera from animals with PTB and showed little cross-reactivity with sera from healthy animals and animals experimentally infected with M. bovis. The second step was to evaluate the antigen cocktail of these seven antigens by ELISA. For this evaluation, we used sera from animals with PTB (n = 25), healthy animals (n = 26), and animals experimentally infected with M. bovis (n = 17). Using ELISA, the cocktail of the seven selected MAP antigens reacted with sera from 18 of the 25 animals with PTB and did not exhibit cross-reactivity with healthy animals and only low reactivity with animals with bovine tuberculosis. The combined application of these antigens could form part of a test which may help in the diagnosis of PTB.


Evaluation of the right and left ventricles: An integrated approach measuring the area, length, and width of the chambers in normal fetuses.
The purpose of this study was to simultaneously measure with speckle tracking software the end-diastolic ventricular area (A), basal transverse width (BW), mid-chamber transverse width (MW), and basal-apical length (BAL) in normal fetuses and those with pathology. The 4-chamber view of the fetal heart was obtained in 200 control fetuses between 20 and 40 weeks of gestation and in 9 third-trimester fetuses with heart malformations. The mean and standard deviation for the A, BW, MW, and BAL were computed from the control fetuses and Z scores computed from the 9 fetuses with cardiac malformations. The A, BAL, BW, and MW were correlated with 7 somatic and age-independent variables (R2 = .63-.85). The highest R2 values occurred for the head circumference, estimated fetal weight, and ultrasound mean gestational age (.82-.85). Z-score values and centiles from the 9 fetuses with cardiac malformations suggested that the A, BW, MW, and BAL were below or above the 5th and 95th centiles as expected for the corresponding ventricular pathology. This study reports an integrated approach to evaluate the end-diastolic size of the right and left ventricular chambers and demonstrated clinical utility in fetuses with cardiac malformations.


Potassium-Based Dual-Ion Batteries Operating at -60 °C Enabled By Co-Intercalation Anode Chemistry.
Battery performance at subzero is restricted by sluggish interfacial kinetics. To resolve this issue, potassium-based dual-ion batteries (K-DIBs) based on the polytriphenylamine (PTPAn) cathode with anion storage chemistry and the hydrogen titanate (HTO) anode with K+ /solvent co-intercalation mechanism are constructed. Both the PTPAn cathode and the HTO anode do not undergo the desolvation process, which can effectively accelerate the interfacial kinetics at subzero. As revealed by theoretical calculations and experimental analysis, the strong K+ /solvent binding energy in the dilute electrolyte, the charge shielding effect of the crystal water, and the uniform SEI layer with high content of the flexible organic species synergically promote HTO to undergo K+ /solvent co-intercalation behavior. The special co-intercalation mechanism and anion storage chemistry enable HTO||PTPAn K-DIBs with superior rate performance and cycle durability, maintaining a capacity retention of 94.1% after 6000 cycles at -40 °C and 91% after 1000 cycles at -60 °C. These results provide a step forward for achieving high-performance energy storage devices at low temperatures.


Serum sex hormone-binding globulin levels are independently associated with nonalcoholic fatty liver disease in people with type 2 diabetes.
To clarify the association between serum sex hormone-binding globulin (SHBG) levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes. Two hundred seventy nine patients with type 2 diabetes were consecutively enrolled and metabolic parameters were checked. High-grade NAFLD was defined as moderate or severe fatty liver disease, measured using liver ultrasound. SHBG, testosterone, and estradiol levels were measured. SHBG levels were lower in patients with high-grade NAFLD than in those with normal ultrasound and decreased significantly based on the severity of fatty liver disease. SHBG levels were negatively correlated with hypertension, body mass index (BMI), waist circumference, high-grade NAFLD, triglycerides, alanine aminotransferase (ALT), γ-glutamyltransferase (γGT), homeostasis model assessment-estimated insulin resistance (HOMA-IR), and C-reactive protein (CRP) and were positively correlated with testosterone and estradiol levels. The odds ratios (ORs) predicting the presence of high-grade NAFLD in men and women decreased significantly with increasing SHBG tertile. The ORs remained significant even after further adjusting for BMI, waist circumference, hypertension, triglycerides, γGT, ALT, CRP, HOMA-IR, testosterone, estradiol, and anti-diabetic medications. Serum SHBG levels were independently associated with the high-grade NAFLD in patients with type 2 diabetes.


Retinal non-visual photoreception in space.
Circadian rhythm disruption occurs during spaceflight, leading to crew health and performance decrements. Spaceflight-related retinal changes, including oxidative stress and neuronal loss, have been previously reported in mice. Animal tissue from experiments aboard shuttle missions STS-133 (BALB/cJ mice, albino strain) and STS-135 (C57BL mice, pigmented strain), along with ground controls, was examined to determine survival of intrinsically photosensitive retinal ganglion cells (ipRGC) and melanopsin expression in retinas of mice exposed to the spaceflight environment. Real-time qPCR (RTqPCT) and microarray approaches were used to analyze Opn4 (melanopsin) gene expression, while immunohistologic studies were conducted to detect melanopsin localization in the retina. Opn4 expression was decreased in albino BALB/cJ mice exposed to spaceflight, as measured by RTqPCR, but not in C57BL mice samples as analyzed by microarray. Opn4 expression returned to control levels at 7 d postreturn in the BALB/cJ samples. Melanopsin positive RGCs were found in the expected proportion in all samples, except for the BALB/cJ samples at 1 d after flight, where virtually no immunoreactive cells were found. Spaceflight environmental factors may affect the nonvisual function of the retina, mediated by a reduction in melanopsin expression and ipRGC survival, contributing to circadian disruption.


An HLA-DR-degenerate epitope pool detects insulin-like growth factor binding protein 2-specific immunity in patients with cancer.
Recent studies have shown the importance of helper CD4 T cells in initiating and sustaining tumor-specific CD8 T-cell immunity. This has paved the way for identifying MHC class II epitopes that could be incorporated into class I-based vaccines. In this study, the goal was to identify an HLA-DR-degenerate epitope pool derived from insulin-like growth factor binding protein 2 (IGFBP-2). IGFBP-2, a regulator of insulin-like growth factor action, is overexpressed in the majority of breast and ovarian cancers. Using algorithms, we predicted 29 HLA-DR1-binding epitopes. Binding assays targeting 15 different HLA-DRs revealed that 10 epitopes were degenerate, binding to at least four different HLA-DR variants. An IFN-gamma enzyme-linked immunosorbent spot assay was used to assess immunity to these 10 epitopes in 48 patients with either breast or ovarian cancer and 18 controls. Elevated T-cell immunity in patients was detected in 4 of the 10 epitopes (IGFBP2.17, IGFBP2.22, IGFBP2.249, and IGFBP2.293). The cumulative T-cell frequency of these four epitopes was elevated in patients relative to controls. All four peptides are naturally processed and presented to CD4 T-cells. The degenerate pool of peptides covers nearly 80% of patients and may be useful for augmenting CD4 T-cell immunity in patients undergoing immunization.


Redox responsive nanotubes from organometallic polymers by template assisted layer by layer fabrication.
Redox responsive nanotubes were fabricated by the template assisted layer-by-layer (LbL) assembly method and employed as platforms for molecular payload release. Positively and negatively charged organometallic poly(ferrocenylsilane)s (PFS) were used to construct the nanotubes, in combination with other polyions. During fabrication, multilayers of these polyions were deposited onto the inner pores of template porous membranes, followed by subsequent removal of the template. Anodized porous alumina and track-etched polycarbonate membranes were used as templates. The morphology, electrochemistry, composition and other properties of the obtained tubular structure were characterized by fluorescence microscopy, scanning (SEM) and transmission electron microscopy (TEM) and energy-dispersive X-ray (EDX) spectroscopy. Composite nanotubes, consisting of poly(acrylic acid) anions with PFS(+) and nanoparticles including fluorophore labelled dextran and decorated quantum dots, with PFS polyelectrolytes were also fabricated, broadening the scope of the structures. Cyclic voltammograms of PFS containing nanotubes showed similar redox responsive behaviour to thin LbL assembled films. Redox triggered release of labelled macromolecules from these tubular structures demonstrated application potential in controlled molecular delivery.


Early repair of mechanical complications after acute myocardial infarction.
Acute mitral regurgitation and ventricular septal defect after myocardial infarction are devastating complications with high mortality. Surgical intervention is warranted for these entities, but the timing of operation remains controversial. In a previous retrospective study of patients with acute mitral regurgitation, we concluded that early emergency operation be undertaken. We describe nine patients subsequently seen at the Mayo Clinic (seven with acute mitral regurgitation and two with acute ventricular septal defect) who underwent emergency operation within four days of evaluation. Four patients were operated on within four hours after the onset of their complications. All patients survived the perioperative period. Eight of nine are alive and well over a mean follow-up period of 9.7 months. We recommend early surgical repair of mechanical complications after acute myocardial infarction.