PdPtB Electrochemiluminescence Nanoenhancer and SiC@Au-PEDOT Nanowires-Based Detection of β-Amyloid Oligomers in Alzheimer's Disease.
β-Amyloid oligomers (AβOs) are promising biomarkers for the diagnosis of Alzheimer's disease (AD). The present research introduces a novel electrochemiluminescence (ECL) immunosensor based on PdPtB nanoenhancer and SiC@Au-PEDOT nanowires (NWs) for the specific and ultrasensitive detection of AβOs. The PdPtB nanoenhancer exhibited excellent oxidase-like catalytic activity with in situ generation of reactive oxygen species (ROS) to enhance luminol ECL in neutral media. In addition, SiC@Au-PEDOT NWs were utilized as a biocompatible and conductive substrate for the modification of the glassy carbon electrode (GCE). With this design, the ECL immunosensor showed outstanding AβOs analytical performance without exogenous coreactant. The ECL immunosensor demonstrated a favorable linear range of 20 pM to 20 nM and a detection limit of 10 pM under optimized conditions with potential straightforward clinical application. In general, the developed ECL immunosensor provides a promising strategy for the early diagnosis of AD.


The role of her4 in inner ear development and its relationship with proneural genes and Notch signalling.
The generation of sensory neurons and hair cells of the inner ear is under tight control. Different members of the Hairy and Enhancer of Split genes (HES) are expressed in the inner ear, their full array of functions still not being disclosed. We have previously shown that zebrafish her9 acts as a patterning gene to restrict otic neurogenesis to an anterior domain. Here, we disclose the role of another her gene, her4, a zebrafish ortholog of Hes5 that is expressed in the neurogenic and sensory domains of the inner ear. The expression of her4 is highly dynamic and spatiotemporally regulated. We demonstrate by loss of function experiments that in the neurogenic domain her4 expression is under the regulation of neurogenin1 (neurog1) and the Notch pathway. Moreover, her4 participates in lateral inhibition during otic neurogenesis since her4 knockdown results in overproduction of the number of neurog1 and deltaB-positive otic neurons. In contrast, during sensorigenesis her4 is initially Notch-independent and induced by atoh1b in a broad prosensory domain. At later stages her4 expression becomes Notch-dependent in the future sensory domains but loss of her4 does not result in hair cell overproduction, suggesting that there other her genes can compensate its function.


Declining survival probability threatens the North Atlantic right whale.
The North Atlantic northern right whale (Eubalaena glacialis) is considered the most endangered large whale species. Its population has recovered only slowly since the cessation of commercial whaling and numbers about 300 individuals. We applied mark-recapture statistics to a catalog of photographically identified individuals to obtain the first statistically rigorous estimates of survival probability for this population. Crude survival decreased from about 0.99 per year in 1980 to about 0.94 in 1994. We combined this survival trend with a reported decrease in reproductive rate into a branching process model to compute population growth rate and extinction probability. Population growth rate declined from about 1. 053 in 1980 to about 0.976 in 1994. Under current conditions the population is doomed to extinction; an upper bound on the expected time to extinction is 191 years. The most effective way to improve the prospects of the population is to reduce mortality. The right whale is at risk from entanglement in fishing gear and from collisions with ships. Reducing this human-caused mortality is essential to the viability of this population.


Inducibility of RANTES mRNA by IL-1beta in human bronchial epithelial cells is associated with increased NF-kappaB DNA binding activity.
RANTES is a member of a large supergene family of proinflammatory chemokines that seems to play an important role in inflammatory processes. It is produced by many cell types in response to specific stimuli and during inflammatory reactions, but the marked differences in the pattern of induced expression suggest that different control mechanisms regulate transcription of RANTES in various tissue types. This is supported by the presence of a large number of potential binding sites for transcriptional factors in the promoter region of the RANTES gene. Our data indicate that expression of RANTES mRNA induced by IL-1beta in human lung epithelial cells is associated with the activation of the transcriptional factor NF-kappaB.


Get the fat out!
Obesity is associated with increased risk of a number of cancers in humans, but the mechanism(s) responsible for these associations have not been established. It is estimated that 68% of adults are overweight or obese and that obesity may be causative in 4% to 7% of cancers in the United States. Several hypotheses have been put forward to explain the association between obesity and cancer including adipose-directed signaling (e.g., mTOR, AMPK), production of factors (e.g., insulin growth factor 1, fibroblast growth factor 1, and/or chronic inflammation associated with obesity. Huffman and colleagues used surgical methods to determine if visceral fat was causally related to intestinal tumorigenesis in the Apc(1638/N+) mouse in a manner independent of confounding factors such as caloric restriction. They found that caloric restriction could extend survival in both male and female Apc(1638/N+) mice but found that surgical removal of visceral fat was only effective in reducing macroadenomas in females. The results of this study do not identify the specific mechanism of association between visceral fat and intestinal carcinogenesis in female mice but do support the rationale for future cancer prevention trials that evaluate pharmacologic and behavioral strategies to reduce abdominal obesity in humans. Cancer Prev Res; 6(3); 161-4. ©2013 AACR.


[Bigdata, artificial intelligence and blockchain for dummies].
Digitalization is transforming every aspect of life, it is also transforming deeply medicine. The digitalization era is characterized by a large production of new data streams while existing processes are progressively migrated, such as writing or imaging. The very large and fast-growing amount of data available requires new storage, transport and analytical tools. This paper presents some of them, such as natural language processing, artificial intelligence, and graph databases. A short introduction to the technology of blockchain is also provided, as it is increasingly used in some non-monetary transaction in medicine, such as data exchanges and consent management.


A novel model for predicting hospitalization risk among hemodialysis patients based on blood test variables.
Hemodialysis patients are at high risk of hospitalization. Predicting such risk in dialysis patients may be critical to maintaining quality of life and reducing costs to the healthcare system. In this paper, we present and fractional polynomial stepwise logistic regression model to specify how routinely collected blood test variables could be linked to a significant increase in hospitalization risk. We found that eight of nineteen variables were significantly able to predict hospitalization risk; albumin (p<0.05), creatinine (p<0.05), calcium (p<0.01), bicarbonate (p<0.01), hemoglobin (p<0.05), mean cell hemoglobin concentration (MCHC) (p<0.0001), mean corpuscular volume (MCV) (p<0.0001), and potassium (p<0.01). The model achieved accuracy, sensitivity, and specificity of 77.31%, 83.03%, and 69.05%, respectively.


Evolutionary design of regulatory control. I. A robust control theory analysis of tradeoffs.
The evolutionary design of regulatory control balances various tradeoffs in performance. Fast reaction to environmental change tends to favor plastic responsiveness at the expense of greater sensitivity to perturbations that degrade homeostatic control. Greater homeostatic stability against unpredictable disturbances tends to reduce performance in tracking environmental change. This article applies the classic principles of engineering control theory to the evolutionary design of regulatory systems. The engineering theory clarifies the conceptual aspects of evolutionary tradeoffs and provides analytic methods for developing specific predictions. On the conceptual side, this article clarifies the meanings of integral control, feedback, and design, concepts that have been discussed in a confusing way within the biological literature. On the analytic side, this article presents extensive methods and examples to study error-correcting feedback, which is perhaps the single greatest principle of design in both human-engineered and naturally designed systems. The broad framework and associated software code provide a comprehensive how-to guide for making models that focus on functional aspects of regulatory control and for making comparative predictions about regulatory design in response to various kinds of environmental challenge. The second article in this series analyzes how alternative regulatory designs influence the relative levels of genetic variability, stochasticity of trait expression, and heritability of disease.


Opposing role of NMDA receptor GluN2B and GluN2D in somatosensory development and maturation.
Development of correct topographical connections between peripheral receptors and central somatosensory stations requires activity-dependent synapse refinement, in which the NMDA type of glutamate receptors plays a key role. Here we compared functional roles of GluN2B (GluRε2 or NR2B) and GluN2D (GluRε4 or NR2D), two major regulatory subunits of neonatal NMDA receptors, in development of whisker-related patterning at trigeminal relay stations. Compared with control littermates, both the appearance of whisker-related patterning and the termination of the critical period, as assessed by unilateral infraorbital nerve transection, were delayed by nearly a day in the somatosensory cortex of GluN2B(+/-) mice but advanced by nearly a day in GluN2D(-/-) mice. Similar temporal shifts were found at subcortical relay stations in the thalamus and brainstem of GluN2B(+/-) and GluN2D(-/-) mice. In comparison, the magnitude of lesion-induced critical period plasticity in the somatosensory cortex, as assessed following row-C whisker removal, was normal in both mutants. Thus, GluN2B and GluN2D play counteractive roles in temporal development and maturation of somatosensory maps without affecting the magnitude of critical period plasticity. To understand the opposing action, we then examined neuronal and synaptic expressions of the two subunits along the trigeminal pathway. At each trigeminal station, GluN2B was predominant at asymmetrical synapses of non-GABAergic neurons, whereas GluN2D was selective to asymmetrical synapses of GABAergic neurons. Together, our findings suggest that GluN2B expressed at glutamatergic synapses on glutamatergic projection neurons facilitates refinement of ascending pathway synapses directly, whereas GluN2D expressed at glutamatergic synapses on GABAergic interneurons delays it indirectly.


Paediatric non-alcoholic fatty liver disease: an approach to pathological evaluation.
Non-alcoholic fatty liver disease (NAFLD) is becoming an increasingly important healthcare issue along with the rising rates of obesity worldwide. It is the most common chronic liver disease in the paediatric population and the fastest growing indication for liver transplant in young adults. The pathogenesis is complex with contributions from multiple factors and genetic predisposition. While non-invasive laboratory tests and imaging modalities are being increasingly used, the liver biopsy continues to play a crucial role in the diagnosis and prognosis of NAFLD. Histologically, the assessment of paediatric fatty liver disease requires special considerations with respect to a periportal predominant pattern seen in prepubertal patients, as well as a different set of disease processes in the differential diagnosis. In this review, we provide a summary of current knowledge on the epidemiology, pathogenesis and clinical course of paediatric NAFLD as well as the clinical guidelines on diagnosis and management. We discuss the indications and limitations of liver biopsy, histological patterns seen in paediatric NAFLD, other entities to be considered in the differential diagnosis, and conclude with appropriate triaging of liver biopsies and essential elements of pathology reporting.


Effectiveness of Workplace Lactation Interventions on Breastfeeding Outcomes in the United States: An Updated Systematic Review.
Returning to work is one of the main barriers to breastfeeding duration among working mothers in the United States. However, the impact of workplace lactation programs is unclear. The aim of this study was to evaluate the effectiveness of workplace lactation programs in the United States on breastfeeding practices. A systematic search was conducted of seven databases through September 2017. Articles ( N = 10) meeting the inclusion criteria of describing a workplace lactation intervention and evaluation in the United States and measuring initiation, exclusivity, or duration using an experimental or observational study design were critically evaluated. Two reviewers conducted quality assessments and reviewed the full-text articles during the analysis. Common services provided were breast pumps, social support, lactation rooms, and breastfeeding classes. Breastfeeding initiation was very high, ranging from 87% to 98%. Several factors were significantly associated with duration of exclusive breastfeeding: (a) receiving a breast pump for one year (8.3 versus 4.7 months), (b) return-to-work consultations (40% versus 17% at 6 months), and (c) telephone support (42% versus 15% at 6 months). Each additional service (except prenatal education) dose-dependently increased exclusively breastfeeding at 6 months. Sociodemographic information including older maternal age, working part-time, longer maternity leave, and white ethnicity were associated with longer breastfeeding duration. Workplace lactation interventions increased breastfeeding initiation, duration, and exclusive breastfeeding, with greater changes observed with more available services. More evidence is needed on the impact of workplace support in low-income populations, and the cost-effectiveness of these programs in reducing health care costs.


Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro.
Human peripheral neuropathies are poorly understood, and the availability of experimental models limits further research. The PeriTox test uses immature dorsal root ganglia (DRG)-like neurons, derived from induced pluripotent stem cells (iPSC), to assess cell death and neurite damage. Here, we explored the suitability of matured peripheral neuron cultures for the detection of sub-cytotoxic endpoints, such as altered responses of pain-related P2X receptors. A two-step differentiation protocol, involving the transient expression of ectopic neurogenin-1 (NGN1) allowed for the generation of homogeneous cultures of sensory neurons. After >38 days of differentiation, they showed a robust response (Ca2+-signaling) to the P2X3 ligand α,β-methylene ATP. The clinical proteasome inhibitor bortezomib abolished the P2X3 signal at ≥5 nM, while 50−200 nM was required in the PeriTox test to identify neurite damage and cell death. A 24 h treatment with low nM concentrations of bortezomib led to moderate increases in resting cell intracellular Ca2+ concentration but signaling through transient receptor potential V1 (TRPV1) receptors or depolarization-triggered Ca2+ influx remained unaffected. We interpreted the specific attenuation of purinergic signaling as a functional cell stress response. A reorganization of tubulin to form dense structures around the cell somata confirmed a mild, non-cytotoxic stress triggered by low concentrations of bortezomib. The proteasome inhibitors carfilzomib, delanzomib, epoxomicin, and MG-132 showed similar stress responses. Thus, the model presented here may be used for the profiling of new proteasome inhibitors in regard to their side effect (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity. P2X3 signaling proved useful as endpoint to assess potential neurotoxicants in peripheral neurons.


A multistakeholder evaluation of Lazos Hispanos: An application of a community-based participatory research conceptual model.
The goal of Lazos Hispanos is to enhance the health and well-being of the Latinx community through promotoras, who connect community members with service providers for multiple health and social needs. A community-based participatory research conceptual model framed the multimethod evaluation of promotoras, service providers, and community participants at baseline and at the 1-year follow up. The promotoras increased their self-efficacy and knowledge, felt a strong sense of commitment to the community, viewed themselves as a bridge between participants and providers, and felt empowered by their new role. Service providers valued the promotoras as their ambassadors in the community and Lazos Hispanos as central to connecting service providers, promotoras, and community members; they noted that this collaboration increased their accountability with the Latinx community. This multistakeholder evaluation highlights the depth of positive changes achieved during the first year and the challenges of a community-embedded project and the benefits and possibilities of calling upon theoretically informed evaluation models.


Frontiers in Understanding the Pathological Mechanism of Diabetic Retinopathy.
The retina is a light-sensitive membrane responsible for optical signal reception and concatenation with the optic nerve. Retinal damage causes blurred vision or visual dysfunction. Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus (DM) that is induced by the interaction of multiple factors and mechanisms. Hyperglycemia and hypertension are potential risk factors for DR. With the growing number of DM patients, the incidence of DR increases if DM is untreated. Epidemiological data show that DR is a leading cause of blindness in working-aged adults. Regular ophthalmological check-ups, laser treatment, and interdisciplinary consultation for reducing visual atrophy can help prevent and treat DR. Although the pathogenesis of DR is complex, and the exact pathological mechanism of DR needs to be further elucidated to promote new drug research and development against DR. The entire pathological process of DR involves increased oxidative stress (microvascular dysfunction, mitochondrial dysfunction) and chronic inflammation (inflammatory infiltration, cell necrosis) and impairment of the renin-angiotensin system (microcirculation dysregulation). This review aims to summarize the pathological mechanisms underlying the development of DR to improve clinical diagnosis and effective treatment of DR.


Spontaneous and mutagen induced sister chromatid exchange in multiple sclerosis.
Spontaneous and mutagen induced sister chromatid exchange (SCE) frequencies have been studied in nine patients with multiple sclerosis and in nine age and sex matched healthy controls. The incidence of spontaneous SCE in lymphocytes of the MS patients was significantly greater, by about 50%, than in those of the control subjects. When exposed to mitomycin C (MMC) or ethyl methane sulfonate (EMS) in vitro, cells from both groups showed typical dose dependent increases in SCE frequency, with yields from MS patients slightly higher than from controls. The higher SCE yields in mutagen treated MS cells relative to controls is considered to reflect initial basal differences between the cell types, so that MS cells are not intrinsically hypersensitive to mutagen treatment.


Polarimetric imaging of crystals.
Classical crystal optics has recently undergone a renaissance as developments in optical microscopy and polarimetry, enabled in part by sensitive imaging CCD cameras and personal computers, now permit the analytical separation of various optical effects that are otherwise convolved in polarized light micrographs. In this tutorial review, we review recent developments in the measurement of the principal crystallo-optical quantities including linear birefringence, linear dichroism, circular birefringence, and circular dichroism, as well as new effects in crystal optics encountered in unusual mixed crystals. The new microscopies and polarimetries are applied to problems of crystallographic twinning, phase transformations, stress birefringence, symmetry reduction, and the design of new crystalline materials.


Galvanic replacement synthesis of multi-branched gold nanocrystals for photothermal cancer therapy.
We present a facile organic phase synthesis method for producing multi-branched gold nanocrystals (nanostars) with a broad localized surface plasmon resonance (LSPR) across near-infrared (NIR) to short-wave infrared (SWIR) wavelengths. In this approach, galvanic replacement of copper by gold, in seed particles produced in situ, initiates growth of multi-branched structures. The method enables broad tuning of the LSPR energy by manipulating the branch length, with peak LSPR absorbance tuned from 850 to 1880 nm, reaching SWIR wavelengths covering the second and third optical transparency windows in biological media, rarely achieved with noble metal plasmonic nanostructures. After a ligand-exchange process, the gold nanostars readily disperse in water while retaining their LSPR absorbance. The multi-branched Au nanocrystals (NCs) exhibit exceptionally high photothermal transduction efficiency, exceeding that of Au nanorods and nanoparticles, to which we make direct comparisons here. At the same time, their synthesis is much more straightforward than hollow structures like nanocages, nanoshells, and nanomatryoshkas that can also exhibit high photothermal efficiency at NIR wavelengths. In vitro photothermal heating of multi-branched Au NCs in the presence of human cervical cancer cells causes effective cell ablation after 10 min laser irradiation. Cell viability assays demonstrate that the NCs are biocompatible at doses required for photothermal therapy. These results suggest that the multi-branched Au NCs can serve as a new type of photothermal therapy agent and in other applications in which strong NIR to SWIR absorbers are needed.


Medical evacuations in Greenland in 2018: a descriptive study.
Information regarding medical evacuations in Greenland is sparse. This study provides an overview of incidence, costs, and diagnoses leading to medical evacuations in Greenland in 2018. This is a retrospective, observational study. Patients with a valid Danish civil personal registration number were included. Data were obtained by scrutinising the itinerary of the Greenland travel coordination office and the medical records. 481 patients were identified. Forty-nine patients were excluded. 432 patients were analysed. Two-thirds of the evacuations were carried out within Greenland. The overall incidence of evacuations was 7.7 evacuations per 1,000 inhabitants per year. This differed, however, between the five different health regions. The cost of a medical evacuation ranged from less than 4,800 US dollars to more than 50,000 US dollars per case. Pregnancy and childbirth accounted for the majority of evacuations in women (31.2%) while diseases within the circulatory system and digestive tract accounted for the majority of evacuations in men (39.8%). The costs of medical evacuations may be reduced when combining evacuations of more than one patient. This indicates that combining evacuations of multiple patients from one health region by applying mandatory use of a central coordinating service may be beneficial.


Firm responses to targeted consumer incentives: Evidence from reference pricing for surgical services.
This paper examines how health care providers respond to a reference pricing insurance program that increases consumer cost sharing when consumers choose high-priced surgical providers. We use geographic variation in the population covered by the program to estimate supply-side responses. We find limited evidence of market segmentation and price reductions for providers with baseline prices above the reference price. Finally, approximately 75% of the reduction in provider prices is in the form of a positive externality that benefits a population not subject to the program.


Oral microbiota maturation during the first 7 years of life in relation to allergy development.
Allergic diseases have become a major public health problem in affluent societies. Microbial colonization early in life seems to be critical for instructing regulation on immune system maturation and allergy development in children. Even though the oral cavity is the first site of encounter between a majority of foreign antigens and the immune system, the influence of oral bacteria on allergy development has not yet been reported. We sought to determine the bacterial composition in longitudinally collected saliva samples during childhood in relation to allergy development. Illumina sequencing of the 16S rDNA gene was used to characterize the oral bacterial composition in saliva samples collected at 3, 6, 12, 24 months, and 7 years of age from children developing allergic symptoms and sensitization (n = 47) and children staying healthy (n = 33) up to 7 years of age. Children developing allergic disease, particularly asthma, had lower diversity of salivary bacteria together with highly divergent bacterial composition at 7 years of age, showing a clearly altered oral microbiota in these individuals, likely as a consequence of an impaired immune system during infancy. Moreover, the relative amounts of several bacterial species, including increased abundance of Gemella haemolysans in children developing allergies and Lactobacillus gasseri and L. crispatus in healthy children, were distinctive during early infancy, likely influencing early immune maturation. Early changes in oral microbial composition seem to influence immune maturation and allergy development. Future experiments should test the probiotic potential of L. gasseri and L. crispatus isolates.


Preparation and in-vitro transfection efficiency evaluation of modified cationic liposome-polyethyleneimine-plasmid nanocomplexes as a novel gene carrier.
Liposome-linear polyethyleneimine (PEI)-DNA nanocomplexes have shown to be effective non-viral gene delivery vectors. In the present study, we tried to improve the transfection efficiency of these nanocomplexes by liposome modification. For this purpose, the lipopolymer was prepared by the conjugation of hexylacrylate to the PEI. Liposomes comprising lipopolymer and DOTAP (1.2-DiOleoyl-3-Trimethyl Ammonium-Propane) were prepared and extruded through polycarbonate filters to obtain the desired size. The 2.5, 25 and 250 KDa molecular weights of linear PEI have been used in order to prepare modified liposome-PEI-DNA nanocomplexes. Three C/P ratios of each nancomplex were premixed. Size, zeta potential and the DNA condensation ability of these complexes were determined separately, and in the end, the transfection efficiency and cell cytotoxicity of prepared vectors were evaluated on Neuro2A cell line. Mean particle size of all of these nanocomplexes was lower than 220 nm with surface charge of 17.5 to 25.9 mV. The lipopolyplexes (comprising modified liposome:PEI:DNA), modified liposome (as lipoplex) and PEI 250KDa (as polyplex) showed the highest transfection efficacy. This activity was amplified by increase carrier to plasmid (C/P) ratio. In addition, the metabolic activity of prepared vectors was 80-100% for control group. In conclusion, the prepared lipopolyplexes showed high ability to enhance gene transfer.


Adaptive Evolution: How Bacteria and Cancer Cells Survive Stressful Conditions and Drug Treatment.
Cancer is characterized by loss of the regulatory mechanisms that preserve homeostasis in multicellular organisms, such as controlled proliferation, cell-cell adhesion, and tissue differentiation. The breakdown of multicellularity rules is accompanied by activation of "selfish," unicellular-like life features, which are linked to the increased adaptability to environmental changes displayed by cancer cells. Mechanisms of stress response, resembling those observed in unicellular organisms, are actively exploited by mammalian cancer cells to boost genetic diversity and increase chances of survival under unfavorable conditions, such as lack of oxygen/nutrients or exposure to drugs. Unicellular organisms under stressful conditions (e.g., antibiotic treatment) stop replicating or slowly divide and transiently increase their mutation rates to foster diversity, a process known as adaptive mutability. Analogously, tumor cells exposed to drugs enter a persister phenotype and can reduce DNA replication fidelity, which in turn fosters genetic diversity. The implications of adaptive evolution are of relevance to understand resistance to anticancer therapies.


DiPOA ([8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic acid), a novel, systemically available, and peripherally restricted Mu opioid agonist with antihyperalgesic activity: II. In vivo pharmacological characterization in the rat.
Mu opioid receptors are expressed throughout the central and peripheral nervous systems. Peripheral inflammation leads to an increase in mu receptor present on the peripheral terminals of primary sensory neurons. Activation of peripheral mu receptors produces potent antihyperalgesic effects in both humans and animals. Here, we describe the in vivo pharmacological properties of the structurally novel, highly potent, systemically available yet peripherally restricted mu opioid agonist, [8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]dec-3-yl]-acetic acid (DiPOA). DiPOA administered i.p. produced naltrexone-sensitive, dose-dependent reversal of Freund's complete adjuvant-induced inflammatory mechanical hyperalgesia (1-10 mg/kg). Maximum percent reversal (67%) was seen 1 h postadministration at 10 mg/kg (the highest dose studied). DiPOA also proved antihyperalgesic in a model of postsurgical pain with a maximum percent reversal of 85% 1 h postadministration at 30 mg/kg i.p. (the highest dose studied). DiPOA administered i.p. had no effect in the tail flick assay of acute pain (0.1-10 mg/kg), produced no ataxia as measured by latency to fall from an accelerating rotarod (3-30 mg/kg), and was not antihyperalgesic in the Seltzer model of neuropathic pain (1-10 mg/kg). This is the first report of a peripherally restricted, small-molecule mu opioid agonist that is nonsedating, antihyperalgesic, and effective against inflammatory and postsurgical pain when administered systemically.


Understanding clinical and biological heterogeneity to advance precision medicine in paediatric acute respiratory distress syndrome.
Paediatric acute respiratory distress syndrome (PARDS) is a heterogeneous clinical syndrome that is associated with high rates of mortality and long-term morbidity. Factors that distinguish PARDS from adult acute respiratory distress syndrome (ARDS) include changes in developmental stage and lung maturation with age, precipitating factors, and comorbidities. No specific treatment is available for PARDS and management is largely supportive, but methods to identify patients who would benefit from specific ventilation strategies or ancillary treatments, such as prone positioning, are needed. Understanding of the clinical and biological heterogeneity of PARDS, and of differences in clinical features and clinical course, pathobiology, response to treatment, and outcomes between PARDS and adult ARDS, will be key to the development of novel preventive and therapeutic strategies and a precision medicine approach to care. Studies in which clinical, biomarker, and transcriptomic data, as well as informatics, are used to unpack the biological and phenotypic heterogeneity of PARDS, and implementation of methods to better identify patients with PARDS, including methods to rapidly identify subphenotypes and endotypes at the point of care, will drive progress on the path to precision medicine.


Treatment and outcomes in breast cancer patients: A cross section study from the EUSOMA breast centre network.
The present study was designed to describe tumour features and treatments for patients with breast cancer. It also aimed at assessing the risk of distant metastases in relation to biological profiles, disease stages and treatment. Data were analysed from 81,882 patients in the EUSOMA database (disease stages at diagnosis 0-IV; median age 61 years; range 20-100 years). All patients were treated between January 2016 and December 2021 in 53 Breast Centres within the EUSOMA certification process in 13 European countries. Cases were classified as HR+ /HER2-, HR+ /HER2 + , HR-/HER2 + or HR-/HER2- and data were analysed accordingly. Univariable and multivariable analyses for distant metastases were conducted on a subset of 38,119 cases with information on whether or not they had developed them. Potential determinants included sub-group type, Ki67 value, disease stage, adjuvant systemic therapies and post-operative radiation therapy. In multivariable analysis, the HR-/HER2 + and HR-/HER2- sub-groups were associated with a higher risk of distant metastases than HR+ /HER2-. Ki67 > 20 % and advanced stage disease also carried a high risk. Radiation therapy emerged as a protective factor against distant metastases. Present results show a large patient database offers an information stream that can be applied to reduce uncertainties in clinical practice. Database parameters need to be updated dynamically for outcome monitoring. Molecular prognostic factors, gene-expression signatures, tumour-infiltrating lymphocytes and circulating tumoral DNA should be added.


Focus on ivabradine: a new heart rate-controlling drug.
Angina pectoris is a cardiac condition characterized by an insufficient perfusion to meet myocardial metabolic demand. A high heart rate represents an important factor in the induction of myocardial ischemia and subsequent angina. beta-blocker drugs are effective at reducing angina pectoris by decreasing the heart rate and are usually preferred as initial therapy in the absence of contraindication or intolerance. Ivabradine, a new oral drug for the symptomatic treatment of chronic stable angina pectoris, decreases the resting heart rate of patients with normal sinus rhythm. In many clinical trials, ivabradine has been directly compared with placebo, beta-blocker drugs (e.g., atenolol and propranolol) and calcium channel blockers (e.g., amlodipine). These studies have demonstrated ivabradine, given in doses of 5-10 mg twice daily, to be more effective than placebo for increasing time to angina onset and noninferior to atenolol 50-100 mg daily and amlodipine 10 mg daily for increasing total exercise duration in patients with chronic stable angina. Visual symptoms, a transient, enhanced brightness in a limited area of the visual field known as luminous phenomena or phosphenes, were the most common adverse effects in clinical trials. This article aims to provide a research update regarding this new drug, based on a literature search.


[In vitro cytotoxicity of Ganoderma lucidum on oral cancer cells].
The extract from the mycelium of Ganoderma lucidum was diluted into serial concentrations and added into in vitro cultured oral cancer and normal cell lines. After incubation for 24 hours, the survival fraction was determined by MTT colorimetric assay. The result revealed that the ID50 was about 3mg/ml and the total lethal dosage was beyond 4 mg/ml. This toxic effect was the same in both cancer and normal cells. Not only was there no difference between cancer and normal cells, but also the high dosage required in toxicity leads to the conclusion that the GL has no direct cytotoxic effect in cancer treatment.


Identifying Potential Ageing-Modulating Drugs In Silico.
Increasing human life expectancy has posed increasing challenges for healthcare systems. As people age, they become more susceptible to chronic diseases, with an increasing burden of multimorbidity, and the associated polypharmacy. Accumulating evidence from work with laboratory animals has shown that ageing is a malleable process that can be ameliorated by genetic and environmental interventions. Drugs that modulate the ageing process may delay or even prevent the incidence of multiple diseases of ageing. To identify novel, anti-ageing drugs, several studies have developed computational drug-repurposing strategies. We review published studies showing the potential of current drugs to modulate ageing. Future studies should integrate current knowledge with multi-omics, health records, and drug safety data to predict drugs that can improve health in late life.


A novel robust and high-throughput method to measure cell death in Nicotiana benthamiana leaves by fluorescence imaging.
Assessing immune responses and cell death in Nicotiana benthamiana leaf agro-infiltration assays is a powerful and widely used experimental approach in molecular plant pathology. Here, we describe a reliable high-throughput protocol to quantify strong, macroscopically visible cell death responses in N. benthamiana agro-infiltration assays. The method relies on measuring the reduction of leaf autofluorescence in the red spectrum upon cell death induction and provides quantitative data suitable for straightforward statistical analysis. Two different well-established model nucleotide-binding and leucine-rich repeat domain proteins (NLRs) were used to ensure the genericity of the approach. Its accuracy and versatility were compared to visual scoring of the cell death response and standard methods commonly used to characterize NLR activities in N. benthamiana. A discussion of the advantages and limitations of our method compared to other protocols demonstrates its robustness and versatility and provides an effective means to select the best-suited protocol for a defined experiment.


Evidence for a link between certain psychological factors and the risk of breast cancer in a case-control study. Psycho-Oncologic Group (P.O.G.).
The relationship between psychosomatic characteristics and the risk of breast cancer was studied in women aged from 35 to 65 years, presenting with a clinically palpable breast tumor. To permit a double-blind design, the psychosomatic evaluation obtained by a long open-ended interview was completed before any diagnostic procedure. On the basis of this evaluation, the psychosomatician concluded that the patient was at high or low risk of serious disease. Several other psychological parameters were also recorded, and the diagnosis was then established by cytology or histology. Nineteen of the 77 patients finally included in the study had histologically verified breast cancer. The relative risk (RR) of breast cancer associated with psychosomatic factors was estimated by multivariate unconditional logistic regression, taking into account age at interview, family history of breast cancer, parity and age at first delivery. A significant relationship (p = 0.02) was found between psychosomatic prognosis and the relative risk of breast cancer. Both the low and high risk groups identified by the psychosomaticians had a similar mean age (46.1 versus 47.6 years). Fundamental mental structure played a predominant role in the risk of breast cancer, since no case was observed among the 18 patients with well organized neurosis, and all the 19 malignant tumors were observed among patients with poorly organized neurosis or psychosis (RR = 7.8, p = 0.009). In addition, excessive self-esteem (RR = 10.0, p = 0.02), hysterical disposition (RR = 7.5, p = 0.02), and unresolved recent grief (RR = 8.2, p = 0.05), were found to be significantly related to the risk of breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)


[Arkhangelsk Military Hospital celebrates 200th anniversary].
Military hospital in Arkhangelsk is the branch No 1 of 1469 naval clinical hospital of Northern Fleet. This hospital is the basic medical and preventive treatment facility and also clinical, training centre for students of Northern state medical university. Annually 3, 5 thousand people receive treatment in the hospital. The hospital has governmental licenses for 56 types of medical activities. There are 2 department of surgery, 1 surgery block. Patients can receive the therapeutic treatment in 4 medical departments.


Omethoate induces pharyngeal cancer cell proliferation and G1/S cell cycle progression by activation of Akt/GSK-3β/cyclin D1 signaling pathway.
Omethoate is a broad category of organophosphorous pesticides (OPs) and has toxic effects on human health under long-term, low-dose exposure. However, the role of omethoate in cancer development remains elusive. The incidence of global head and neck squamous cell carcinomas (HNSCC) has markedly increased in recent years. Thus, we examined whether omethoate induced the proliferation of FaDu cells (a cell line of HNSCC) and if so, what the underlying mechanism was. The study revealed that omethoate induced FaDu cell growth in a dose- and time-dependent manner. Omethoate stimulated FaDu cell proliferation was mainly due to enhancing the G1 to S phase transition by flow cytometry analysis. We also found that omethoate up-regulated cyclin D1, a key gene controlling the G1-S transition. Furthermore, we showed that omethoate was capable of activating the Akt/GSK-3β signaling pathway. Blockage of Akt by siRNA or small molecule inhibitor significantly suppressed omethoate-induced cyclin D1 expression and cell proliferation. Collectively, these findings demonstrated for the first time that omethoate could induce the pharyngeal cancer cell proliferation by activation of the Akt/GSK-3β/cyclin D1 signaling pathway.


Fregene: simulation of realistic sequence-level data in populations and ascertained samples.
FREGENE simulates sequence-level data over large genomic regions in large populations. Because, unlike coalescent simulators, it works forwards through time, it allows complex scenarios of selection, demography, and recombination to be modelled simultaneously. Detailed tracking of sites under selection is implemented in FREGENE and provides the opportunity to test theoretical predictions and gain new insights into mechanisms of selection. We describe here main functionalities of both FREGENE and SAMPLE, a companion program that can replicate association study datasets. We report detailed analyses of six large simulated datasets that we have made publicly available. Three demographic scenarios are modelled: one panmictic, one substructured with migration, and one complex scenario that mimics the principle features of genetic variation in major worldwide human populations. For each scenario there is one neutral simulation, and one with a complex pattern of selection. FREGENE and the simulated datasets will be valuable for assessing the validity of models for selection, demography and population genetic parameters, as well as the efficacy of association studies. Its principle advantages are modelling flexibility and computational efficiency. It is open source and object-oriented. As such, it can be customised and the range of models extended.


Adaptive melanin response of the soil fungus Aspergillus niger to UV radiation stress at "Evolution Canyon", Mount Carmel, Israel.
Adaptation is an evolutionary process in which traits in a population are tailored by natural selection to better meet the challenges presented by the local environment. The major discussion relating to natural selection concerns the portraying of the cause and effect relationship between a presumably adaptive trait and selection agents generating it. Therefore, it is necessary to identify trait(s) that evolve in direct response to selection, enhancing the organism's fitness. "Evolution Canyon" (EC) in Israel mirrors a microcosmic evolutionary system across life and is ideal to study natural selection and local adaptation under sharply, microclimatically divergent environments. The south-facing, tropical, sunny and xeric "African" slope (AS) receives 200%-800% higher solar radiation than the north-facing, temperate, shady and mesic "European" slope (ES), 200 meters apart. Thus, solar ultraviolet radiation (UVR) is a major selection agent in EC influencing the organism-environment interaction. Melanin is a trait postulated to have evolved for UV-screening in microorganisms. Here we investigate the cause and effect relationship between differential UVR on the opposing slopes of EC and the conidial melanin concentration of the filamentous soil fungus Aspergillus niger. We test the working hypothesis that the AS strains exhibit higher melanin content than strains from the ES resulting in higher UV resistance. We measured conidial melanin concentration of 80 strains from the EC using a spectrophotometer. The results indicated that mean conidial melanin concentration of AS strains were threefold higher than ES strains and the former resisted UVA irradiation better than the latter. Comparisons of melanin in the conidia of A. niger strains from sunny and shady microniches on the predominantly sunny AS and predominantly shady ES indicated that shady conditions on the AS have no influence on the selection on melanin; in contrast, the sunny strains from the ES displayed higher melanin concentrations. We conclude that melanin in A. niger is an adaptive trait against UVR generated by natural selection.


Overview of food allergy diagnosis.
Food allergy is a condition with significant social and economic impact and a topic of intense concern for scientists and clinicians alike. Worldwide, over 220 million people suffer from some form of food allergy, but the number reported is just the tip of the iceberg. Recent years have brought new perspectives in diagnosing food allergy. Elucidating incriminated immunological mechanisms, along with drawing the clinical phenotype of food hypersensitivity reactions ensures an accurate diagnosis of food allergy. Moreover, molecular based allergy diagnosis, which is increasingly used in routine care, is a stepping-stone to improved management of food allergy patients. The aim of this review is to summarize the topic of IgE-mediated food allergy from the perspective of current diagnostic methods.


Psychosis and the disintegration of dialogical self-structure: problems posed by schizophrenia for the maintenance of dialogue.
Researchers and theoreticians across widely varying disciplines have increasingly stressed how sense of self is inherently 'dialogical', or the product of ongoing dialogue both within the individual and between the individual and others. This perspective emphasizes that self-awareness is not an awareness of an isolated or seamless viewpoint, but a collective of numerous complementary, competing, and sometimes contradictory, voices. In this paper we suggest that changes in subjective sense of self in schizophrenia spectrum disorders may represent the collapse of this essential dialogue. We suggest that this collapse can have the end-result of mentally ill persons either coming to embrace a singular, all-incorporating self-position or standing precariously on the brink of cacophony which is experienced as self-dissolution. We point to two phenomena associated with schizophrenia that could contribute to the derailment of internal and external dialogue: impairments in associative processes and affect dysregulation. Illustrated with a case example, we finally suggest how psychotherapy has the potential to revive internal dialogue through its explicit use of external dialogue helping to restore previous levels of social function.


In-hospital stroke: characteristics and outcomes.
In-hospital stroke (IS) made up 6.5% of strokes recorded in the Irish National Stroke Register in 2012. International research has demonstrated poorer outcomes post IS compared to out of hospital stroke (OS). We aimed to profile all IS and OS over a 22 month period and compare the two groups by gathering data from the HIPE portal stroke register. The study site is a primary stroke centre. IS represented 11% (50/458) of total strokes with over half (27/50, 54%) admitted initially with medical complaints. IS patients had a significantly longer length of stay (79.2 +/- 87.4 days vs. 21.9 +/- 45.9 days, p < 0.01) and higher mortality (13/50 vs. 39/408, p < 0.01). Patients in the IS group were also less likely to receive stroke unit care (1/50 vs. 136/408, p < 0.01). This study demonstrates the significant morbidity and mortality associated with IS and highlights the need for efforts to be made to optimize identification and management of acute stroke in this cohort.


Naked but not Hairless: the pitfalls of analyses of molecular adaptation based on few genome sequence comparisons.
The naked mole-rat (Heterocephalus glaber) is the only rodent species that naturally lacks fur. Genome sequencing of this atypical rodent species recently shed light on a number of its morphological and physiological adaptations. More specifically, its hairless phenotype has been traced back to a single amino acid change (C397W) in the hair growth associated (HR) protein (or Hairless). By considering the available species diversity, we show that this specific position is in fact variable across mammals, including in the horse that was misleadingly reported to have the ancestral Cysteine. Moreover, by sequencing the corresponding HR exon in additional rodent species, we demonstrate that the C397W substitution is actually not a peculiarity of the naked mole-rat. Instead, this specific amino acid substitution is present in all hystricognath rodents investigated, which are all fully furred, including the naked mole-rat closest relative, the Damaraland mole-rat (Fukomys damarensis). Overall, we found no statistical correlation between amino acid changes at position 397 of the HR protein and reduced pilosity across the mammalian phylogeny. This demonstrates that this single amino acid change does not explain the naked mole-rat hairless phenotype. Our case study calls for caution before making strong claims regarding the molecular basis of phenotypic adaptation based on the screening of specific amino acid substitutions using only few model species in genome sequence comparisons. It also exposes the more general problem of the dilution of essential information in the supplementary material of genome papers thereby increasing the probability that misleading results will escape the scrutiny of editors, reviewers, and ultimately readers.


Properties of a novel DNA virus from the tsetse fly, Glossina pallidipes.
Virus particles were isolated from hypertrophied salivary glands of the tsetse fly, Glossina pallidipes collected near Mombasa, Kenya. Purified virus particles were rod-shaped, 57 nm wide by 700 to 1300 nm long. Particle lengths fell into two size classes, with 'short' particles averaging 869 nm and 'long' particles 1175 nm. The virus particles morphologically resembled elongated baculovirus nucleocapsids although, unlike baculoviruses, no fully enveloped virions were found in purified preparations. The particles contained double-stranded DNA which appeared to be linear when analysed by electrophoresis in agarose gels, ethidium bromide-caesium chloride gradient centrifugation or electron microscopy (EM). There was some evidence for the DNA being heterogeneous in size from EM studies and from the observation that restriction enzyme analysis failed to provide a clear profile of DNA fragments. Protein from purified virions contained at least 12 polypeptides with a major component of 39 000 mol. wt. These results suggest that the virus cannot be placed in any of the existing taxonomic groupings of DNA viruses.


Bone metastasis in gastric cancer patients.
Bone metastasis from stomach cancer occurs only rarely and it is known to have a very poor prognosis. This study examined the clinical characteristics and prognosis of patients who were diagnosed with stomach cancer and bone metastasis. The subjects were 19 patients who were diagnosed with stomach cancer at Hanyang University Medical Center from June 1992 to August 2010 and they also had bone metastasis. The survival rate according to many clinicopathologic factors was retrospectively analyzed. 11 patients out of 18 patients (61%) who received an operation were in stage IV and the most common bone metastasis location was the spine. Bone scintigraphy was mostly used for diagnosing bone metastasis and PET-CT and magnetic resonance imaging were used singly or together. The serum alkaline phosphatase at the time of diagnosis had increased in 12 cases and there were clinical symptoms (bone pain) in 16 cases. Treatment was given to 14 cases and it was mostly radiotherapy. There were 2 cases of discovering bone metastasis at the time of diagnosing stomach cancer. The interval after operation to the time of diagnosing bone metastasis for the 18 cases that received a stomach cancer operation was on average 14.9±17.3 months and the period until death after the diagnosis of bone metastasis was on average 3.8±2.6 months. As a result of univariate survival rate analysis, the group that was treated for bone metastasis had a significantly better survival period when the bone metastasis was singular rather than multiple, as compared to the non-treatment group, yet both factors were not independent prognosis factors on multivariate survival analysis. An examination to confirm the status of bone metastasis when conducting a radio-tracer test after the initial diagnosis and also after an operation is needed for stomach cancer patients, and bone scintigraphy is the most helpfully modality. Making the diagnosis at the early stage and suitable treatments are expected to enhance the survival rate and improve the quality of life even for the patients with bone metastasis.


Different Protein Groups Involved in Transcription Regulation in Development and Housekeeping Genes in Drosophila.
Antibodies to histone modifications and an insulator protein involved in the processes of transcription initiation and elongation are mapped in Drosophila polytene chromosomes. The CHRIZ protein (chromatin insulator) and H3K36me3 histone modification (RNA elongation) are detected only in the localization of housekeeping genes (interbands and gray bands of polytene chromosomes) and never in the regions of developmental genes (black bands and large puffs arising from them). Antibodies to H3S10P histone modification, which is associated with the initial elongation of the RNA strand during transcription, are found exclusively in small puffs, but not in housekeeping gene localization sites or large ecdysone-induced puffs, where housekeeping genes are localized. Antibodies to H4R3me2 histone modification (a co-repressor of the ecdysone receptor) are detected only in large ecdysone-induced puffs.


Terminal structure and heterogeneity in human cytomegalovirus strain AD169.
We have characterized the heterogeneity occurring at the junction of the long (L) and short (S) segments and at the termini of the strain AD169 human cytomegalovirus (HCMV) genome by restriction endonuclease mapping and nucleotide sequence analyses. The HCMV a sequence was identified by its position at both termini and inverted orientation at the L-S junction. Heterogeneity at both termini and the L-S junction was generated by the presence of fused and tandem a sequences. Some S termini lacked an a sequence. In addition, near the L terminus and at the L-S junction there were a variable number of 217-base-pair (bp) XhoI fragments arranged in tandem. The 217-bp fragments consisted of a portion of the a and adjacent b sequences (in the L-segment repeat) bounded by the same direct repeats (DR1) found at the boundaries of the a sequence. A model for the generation of these heterogeneous fragments is presented. We also determined the sequence of seven cloned terminal fragments, five from the L terminus and two from the S terminus. All L termini contained identical terminal sequences ending with base 32 of a 33-bp DR1. The S termini differed from each other and from the L-segment termini. One S terminus lacked an a sequence and terminated within S-segment repeat (c) sequences. The second S terminus contained an a sequence and terminated with bases 20 to 33 of a 33-bp DR1. A comparison of the cloned L and S terminal sequences with cloned L-S junction sequences suggested that the termini contained 3' single base extensions which were removed during the cloning. We also show that the herpesvirus conserved sequence is in a similar position relative to the termini of HCMV and several other herpesviruses, thus adding further support for the role of the sequence in the maturation of viral DNA.


Feedback regulation of pancreatic enzyme secretion. Suppression of cholecystokinin release by trypsin.
Feedback regulation of pancreatic enzyme secretion occurs in rats. Whether such a system exists in man remains unsettled and the responsible mechanism is unknown. To investigate this question gastrointestinal intubation and perfusion were performed in 12 healthy subjects. Intraduodenal perfusion of trypsin-inhibited phenylalanine-, oleic acid-, and meal-stimulated chymotrypsin and lipase outputs in a dose-related manner. The minimal concentration of bovine trypsin needed to inhibit pancreatic enzyme secretion was 0.5 g/liter. 1 g/liter caused a maximal suppression of 35 +/- 4% of the phenylalanine-stimulated chymotrypsin release. This inhibitory effect was protease-specific. Intraduodenal perfusion of phenylalanine and oleic acid increased plasma cholecystokinin (CCK) from a basal level of 0.9 +/- 0.06 to 5.3 +/- 0.9 pM and 7.2 +/- 1.3 pM, respectively. Addition of bovine trypsin to the perfusates significantly reduced the plasma CCK level to basal values. This inhibitory effect of trypsin on CCK release was dose dependent and specific to proteases. Therefore, the present studies indicate that feedback regulation of pancreatic enzyme secretion is operative in man and it is mediated by release of CCK.


Simultaneous measurement of 10,000 protein-ligand affinity constants using microarray-based kinetic constant assays.
Fluorescence-based endpoint detection of microarrays with 10,000 or more molecular targets is a most useful tool for high-throughput profiling of biomolecular interactions, including screening large molecular libraries for novel protein ligands. However, endpoint fluorescence data such as images of reacted microarrays contain little information on kinetic rate constants, and the reliability of endpoint data as measures of binding affinity depends on reaction conditions and postreaction processing. We here report a simultaneous measurement of binding curves of a protein probe with 10,000 molecular targets in a microarray with an ellipsometry-based (label-free) optical scanner. The reaction rate constants extracted from these curves (k(on), k(off), and k(a)=k(on)/k(off)) are used to characterize the probe-target interactions instead of the endpoints. This work advances the microarray technology to a new milestone, namely, from an endpoint assay to a kinetic constant assay platform. The throughput of this binding curve assay platform is comparable to those at the National Institutes of Health Molecular Library Screening Centers, making it a practical method in screening compound libraries for novel ligands and for system-wide affinity profiling of proteins, viruses, or whole cells against diverse molecular targets.


Effects of Buprenorphine, Methadone and Substance-Use on COVID-19 Morbidity and Mortality.
Substance use disorder has been associated with increased morbidity in COVID-19 infection. However, less is known about the impact of active substance use and medications for opioid use disorder (MOUD) on COVID-19 outcomes. We conducted a retrospective cohort study to evaluate the impact of substance use, namely cannabis, cocaine, alcohol, sedative and opioid use as well as buprenorphine or methadone = on COVID-19 morbidity and mortality. Using electronic-health record data at a large urban hospital system, patients who tested positive for COVID-19 between January 1, 2020 to December 31, 2021 were included. Substance use was identified from urine toxicology and MOUD prescriptions within 90 days prior to admission. COVID-19 outcomes included mortality, ICU admission, need for ventilatory support, number and duration of hospitalizations. Multivariable logistic regression was performed controlling for variables such as age, sex, medical comorbidity, tobacco use, and social disadvantage. Among COVID-19 positive patients (n=17,423), sedative, cannabis, cocaine, and opioid use was associated with statistically significant increases in need for ICU care, need for ventilatory support, number of hospitalizations and duration of hospitalization. Substance use was not associated with an increase in all-cause mortality. There were no statistically significant differences between methadone, buprenorphine and other opioids on COVID-19 outcomes. Active substance use were associated with increased morbidity in COVID-19 infection. MOUD was not associated with worse COVID-19 outcomes compared to OUD. Future studies focused on MOUD treatments that reduce morbidity may help improve clinical outcomes in COVID-19.


Revisiting Drug Development Against the Neglected Tropical Disease, Amebiasis.
Amebiasis is a neglected tropical disease which is caused by the protozoan parasite Entamoeba histolytica. This disease is one of the leading causes of diarrhea globally, affecting largely impoverished residents in developing countries. Amebiasis also remains one of the top causes of gastrointestinal diseases in returning international travellers. Despite having many side effects, metronidazole remains the drug of choice as an amebicidal tissue-active agent. However, emergence of metronidazole resistance in pathogens having similar anaerobic metabolism and also in laboratory strains of E. histolytica has necessitated the identification and development of new drug targets and therapeutic strategies against the parasite. Recent research in the field of amebiasis has led to a better understanding of the parasite's metabolic and cellular pathways and hence has been useful in identifying new drug targets. On the other hand, new molecules effective against amebiasis have been mined by modifying available compounds, thereby increasing their potency and efficacy and also by repurposing existing approved drugs. This review aims at compiling and examining up to date information on promising drug targets and drug molecules for the treatment of amebiasis.


Ranking occupations based upon the costs of job-related injuries and diseases.
In this article, we construct a ranking of occupations based upon the costs of job-related injuries and illnesses. Data are drawn from large nationally representative Bureau of Labor (BLS) data sets. Information is obtained on occupation and workers' compensation (WC) category of the injury or illness, which are then matched to information on costs. Six broad occupations and 413 specific (3-digit) occupations are ranked by total costs. Six broad and 223 specific occupations are ranked by costs per worker (average cost). Operators and laborers is the broad occupation category that contributes both the highest total and average cost. Specific occupations that contributed the most to total costs include heavy truck drivers, non-construction laborers, machine operators (not specified), occupations not classified, janitors, nursing orderlies, construction laborers, assemblers, retail sales workers (not elsewhere specified), miscellaneous machine operators, and carpenters. Occupations high on the average cost list include not-specified mechanics, general and construction laborers, press apprentices, welders, stone cutters, and warehouse workers. Although the BLS data are limited, they can be used to provide a preliminary look at which occupations are contributing the most and the least to the overall economic costs of occupational injuries and illnesses.


Study protocol: A randomised trial of the effectiveness of the Common Elements Treatment Approach (CETA) for improving HIV treatment outcomes among women experiencing intimate partner violence in South Africa.
Intimate partner violence (IPV) is a barrier to consistent HIV treatment in South Africa. Previous trials have established that the Common Elements Treatment Approach (CETA), a cognitive-behavioural-based intervention, is effective in reducing mental and behavioural health problems but has not been trialled for effectiveness in improving HIV outcomes. This paper describes the protocol for a randomised trial that is testing the effectiveness of CETA in improving HIV treatment outcomes among women experiencing IPV in South Africa. We are conducting a randomised trial among HIV-infected women on antiretroviral therapy, who have experienced sexual and/or physical IPV, to test the effect of CETA on increasing retention and viral suppression and reducing IPV. Women living with HIV who have an unsuppressed viral load or are at high risk for poor adherence and report experiencing recent IPV, defined as at least once within in the last 12 months, will be recruited from HIV clinics and randomised 1:1 to receive CETA or an active attention control (text message reminders). All participants will be followed for 24 months. Follow-up HIV data will be collected passively using routinely collected medical records. HIV outcomes will be assessed at 12 and 24 months post-baseline. Questionnaires on violence, substance use and mental health will be administered at baseline, post-CETA completion and at 12 months post-baseline. Our primary outcome is retention and viral suppression (<50 copies/mL) by 12 months post-baseline. We will include 400 women which will give us 80% power to detect an absolute 21% difference between arms. Our primary analysis will be an intention-to-treat comparison of intervention and control by risk differences with 95% CIs. Ethics approval provided by University of the Witwatersrand Human Research Ethics Committee (Medical), Boston University Institutional Review Board and Johns Hopkins School Institutional Review Board. Results will be published in peer-reviewed journals. NCT04242992.


[A food and the food status of workers brainwork with low physical activity].
The data of the investigation of 340 average income men and women ages 18-60 whose labour is characterized by low power expenditure, are represented in this article. Their food ration contains about 13% of protein and more than 40% of fat, the most part of it contains the saturated fatty acids. 55% of men and 50% of women have got body mass index (BMI) more than 25; obesity is revealed with 7% of men and 18% of women. Glucose blood level is raised at 30% of the surveyed and is correlated with the consumption of the added sugar (r = 0.44; p < 0.05). The cholesterol maintenance in blood is above normal with 60% of the surveyed, cholesterol connection with the cholesterol food maintenance is not revealed.


Strongly coupled plasmonic metal nanoparticles with reversible pH-responsiveness and highly reproducible SERS in solution.
We report a facile method to prepare polymer-grafted plasmonic metal nanoparticles (NPs) that exhibit pH-responsive surface-enhanced Raman scattering (SERS). The concept is based on the use of pH-responsive polymers, such as poly(acrylic acid) (PAA) and poly(allylamine hydrochloride) (PAH), as multidentate ligands to wrap around the surface of NPs instead of forming polymer brushes. Upon changing the solvent quality, the grafted pH-responsive polymers would drive reversible aggregation of NPs, leading to a decreased interparticle distance. This creates numerous hot spots, resulting in a secondary enhancement of SERS as compared to the SERS from discrete NPs. For negatively charged PAA-grafted NPs, the SERS response at pH 2.5 showed a secondary enhancement of up to 104-fold as compared to the response for discrete NPs at pH 12. Similarly, positively charged PAH-grafted AuNPs showed an opposite response to pH. We demonstrated that enhanced SERS with thiol-containing and charged molecular probes was indeed from the pH-driven solubility change of polymer ligands. Our method is different from the conventional SERS sensors in the solid state. With pH-responsive polymer-grafted NPs, SERS can be performed in solution with high reproducibility and sensitivity but without the need for sample pre-concentration. These findings could pave the way for innovative designs of polymer ligands for metal NPs where polymer ligands do not compromise interparticle plasmon coupling.


Insights from von Willebrand disease animal models.
von Willebrand disease is a genetic bleeding disorder that arises from abnormalities in von Willebrand factor, an adhesive glycoprotein involved in both primary hemostasis and coagulation. It is the most common inherited bleeding disorder in humans, and over the years several animal species have also been described as suffering from this disease whether through a spontaneous mutation (pigs, dogs) or a genetically engineered one (mouse). These different animal models are extremely useful in exploring the characteristics of von Willebrand disease and in testing new treatments. This review provides an update of the various von Willebrand disease models and the contribution that these models can make to a better understanding of human von Willebrand disease.


London-van der Waals Force Field of a Chemically Patterned Surface To Enable Selective Adhesion.
The London-van der Waals (L-vdW) force between a particle and a surface strongly depends on the topography and the chemical properties of the interacting surfaces. Although a great deal of work has been done to understand the effect of topographical heterogeneity on the L-vdW adhesion, the role of chemical heterogeneity has been discussed only rarely. This study makes an attempt to quantify the magnitude and range of the L-vdW force acting on a spherical particle in the vicinity of a chemically patterned surface. Specifically, an ideal system of a smooth spherical particle approaching a surface composed of parallel stripes of chemically distinct materials with different Hamaker constants is considered. The L-vdW forces for such systems are determined by solving the London dispersion potential for the entire volumes of the adhering bodies from first principles, using Hamaker's microscopic approach. The computational results elucidate that a chemical interface can apply a tangential L-vdW force, in addition to the normal L-vdW force, on nearby particles. This can cause lateral motion of particles neighboring a chemically inhomogeneous surface. The magnitude of the tangential L-vdW force is found to be maximum when the particle is centered at the interface and shows a gradual drop as it moves away from this location. The magnitude and range of the tangential L-vdW force can be large for large colloidal particles in close contact with a chemically patterned surface whose materials have distinct Hamaker constants. This study suggests that the tangential L-vdW force field generated by a chemical interface can be utilized as a tool to manipulate the path of an approaching particle to facilitate selective adhesion.


Serum Uric Acid, Alanine Aminotransferase, Hemoglobin and Red Blood Cell Count Levels in Pseudoexfoliation Syndrome.
Purpose. The pathogenesis of pseudoexfoliation (PEX), the most common cause of secondary glaucoma, has not been clearly identified, but there is increasing evidence that points out the role of oxidative stress. The aim of this study is to evaluate some of the most commonly used blood parameters, hemoglobin (Hb), red blood cell count (RBC), alanine aminotransferase (ALT), and uric acid (UA) levels, in subjects with PEX. Materials and Methods. This study is performed in a state hospital between November 2011 and December 2012. Retrospective chart review of subjects who underwent cataract surgery was performed. Thirty-one healthy subjects with PEX and 34 healthy subjects without PEX were evaluated. Hb, RBC, ALT, and UA levels were recorded. Student's t-test was used to compare the two groups. Results. The mean age was 73.6 ± 14.1 years in PEX group and 70.1 ± 12.7 in control group (p = 0.293). Hb, RBC, ALT, and UA levels did not show a statistically significant difference among PEX and control groups (p > 0.05 for all). Conclusion. Serum levels of Hb, RBC, ALT, and UA levels were similar in subjects with and without PEX. Further studies are needed to clarify the precise role of Hb, RBC, ALT, and UA in the pathogenesis of PEX.


Doppler angle estimation using correlation.
Conventional Doppler techniques can only detect the axial component of blood flow. To obtain the transverse flow component, an approach based on the dependence of Doppler bandwidth on Doppler angle has been widely investigated. To compute the bandwidth, a full Doppler spectrum is often required. Therefore, this approach has not been applied to real-time, two-dimensional Doppler imaging because of the long data acquisition time. To overcome this problem, a correlation-based method is proposed. Specifically, variance of the Doppler spectrum is used to approximate the square of the Doppler bandwidth. Because variance is computed efficiently and routinely in correlation-based color Doppler imaging systems, implementation of this method is straightforward. In addition, the two-dimensional velocity vector can be calculated and mapped to different colors using the color mapping function of current systems. Simulations were performed, and experimental data were also collected using a string phantom with the Doppler angle varying from 23 degrees to 82 degrees . Results indicate that the correlation-based method may produce significant errors if only a limited number of flow samples are available. With averaging, however, the Doppler angles estimated by the correlation-based method can achieve good agreement with the true angles by using only four flow samples with proper variance averaging.


A bimodal MRI and NIR liposome nanoprobe for tumor targeted molecular imaging.
The combination of complementary MRI and NIR imaging methods evolved to provide an even more powerful bioimaging tool. Herein, a novel bimodal MRI/NIR nanoprobe GCF-HDA was prepared via a facile self-assembly approach of three types of amphiphilic structures in aqueous solution. The Stokes shift of the NIR moiety increased from 30 to 150 nm and fluorescence quantum yield increased from 1.5 to 8% after conjugation with electron-rich hexadecylamine (HDA) to organic dye Cy7. The photostability of the nanoprobe GCF-HDA was dramatically improved after involving the newly synthesized dye. Molecular dynamics simulation demonstrated that the GCF-HDA is composed of 2.0-3.5 nm clusters and in each cluster the head groups of the amphiphilic molecules assemble together and the tail groups point outwards. The r1 and r2 relaxivities of GCF-HDA were found to be 11.87 and 19.91 mM-1 s-1 per Gd(iii) chelate at 0.5 T, respectively. In vitro cellular imaging with human glioma U-87 MG cells showed that the GCF-HDA was able to enter the cells and accumulate in the cytoplasm. The targeted GCF-HDA resulted in higher MR contrast enhancement and stronger fluorescence intensity than the corresponding non-targeted probe GC-HDA in the tumor tissue 96 hours post injection. Ex vivo fluorescence imaging and histological analysis of the tumor tissue further confirmed the specific binding ability of the GCF-HDA.


Dual-Catalysed Intermolecular Reductive Coupling of Dienes and Ketones.
We report a mild, catalytic method for the intermolecular reductive coupling of feedstock dienes and styrenes with ketones. Our conditions allow concomitant formation of a cobalt hydride species and single-electron reduction of ketones. Subsequent selective hydrogen-atom transfer from the cobalt hydride generates an allylic radical which can selectively couple with the persistent radical-anion of the ketone. This radical-radical coupling negates unfavourable steric interactions of ionic pathways and avoids the unstable alkoxy radical of previous radical olefin-carbonyl couplings, which were limited, as a result, to aldehydes. Applications of this novel and straightforward approach include the efficient synthesis of drug molecules, key intermediates in drug synthesis and site-selective late-stage functionalisation.


Mechanism of C-terminal intein cleavage in protein splicing from QM/MM molecular dynamics simulations.
Protein splicing is a post-translational process in which a biologically inactive protein is activated by the release of a segment denoted as an intein. The process involves four steps. In the third, the scission of the intein takes place after the cyclization of the last amino acid of the segment, an asparagine. Little is known about the chemical reaction necessary for this cyclization. Experiments demonstrate that two histidines (the penultimate amino acid of the intein, and a histidine located 10 amino acids upstream) are relevant in the cyclization of the asparagine. We have investigated the mechanism and determinants of reaction in the GyrA intein focusing on the requirements for asparagine activation for its cyclization. First, the influence that the protonation states of these two histidines have on the orientation of the asparagine side chain is investigated by means of molecular dynamics simulation. Molecular dynamics simulations using the CHARMM27 force field were carried out on the three possible protonation states for each of these two histidines. The results indicate that the only protonation state in which the conformation of the system is suitable for cyclization is when the penultimate histidine is fully protonated (positively charged), and the upstream histidine is in the His(ε) neutral tautomeric form. The free energy profile for the reaction in which the asparagine is activated by a proton transfer to the upstream histidine is presented, computed by hybrid quantum mechanics/molecular mechanics (QM/MM) umbrella sampling molecular dynamics at the SCCDFTB/CHARMM27 level of theory. The calculated free energy barrier for the reaction is 19.0 kcal mol(-1). B3LYP/6-31+G(d) QM/MM single-point calculations give a qualitatively a similar energy profile, although with somewhat higher energy barriers, in good agreement with the value derived from experiment of 25 kcal mol(-1) at 60 °C. QM/MM molecular dynamics simulations of the reactant, activated reactant and intermediate states highlight the importance of the Arg181-Val182-Asp183 segment in catalysing the reaction. Overall, the results indicate that nucleophilic activation of the asparagine for its cyclization by the upstream histidine acting as the base is a plausible mechanism for the C-terminal cleavage in protein splicing.


Panic attacks in chronic schizophrenia.
Of 20 patients attending a clinic for maintenance therapy of schizophrenia, seven had regular panic attacks, and these were often associated with agoraphobia and social phobia. Similar fears and avoidance in other cases were associated with paranoid ideas and negative symptoms. The relationship of panic to psychotic symptoms varied greatly. In two patients neuroleptics were associated with an increase in panic attacks.


Myelin basic protein-related proteins in mouse brain and immune tissues.
Brain and immune system tissues express myelin basic protein (MBP) mRNAs that contain novel exons upstream of those of the classic MBPs. We have generated antisera against a recombinant protein that includes the deduced sequence for one of the predicted species of the new MBP-related protein, hemopoietic HMBPR1. We report here the presence of multiple proteins reactive to the antisera in a range of tissues. The principal finding is that the antisera recognize a family of proteins of approximately 25 kDa that are restricted to brain, thymus, and spleen, the only tissues in which the new MBP-related transcripts are present. These antisera also detect other proteins of apparent molecular mass consistent with other isoforms of predicted MBP-related proteins. The expression of MBP-related proteins in immune system tissues may be important for self-tolerance to CNS MBPs and the initiation of immune-associated demyelinating diseases.


Genetics of resistance to colicins in Escherichia coli K-12: cross-resistance among colicins of group A.
By using each of the available colicins, we have isolated a large number of colicin-resistant mutants. They included both receptor and tolerant mutants and each was screened for cross-resistance to all other colicins. On the basis of the cross-resistance of these mutants it was possible to place known colicins into two mutually exclusive groups, group A and group B. Mutants selected as resistant to colicins of group A may or may not be cross-resistant to other colicins of group A, BUT Are never resistant to colicins of group B. The reverse also applies. The mutants isolated as resistant to colicins of group A (A, E1, E2, E3, K, L, N, S4, and X) have been divided into 21 phenotypic classes on the basis of their colicin resistance patterns. These include most of the tolerant and receptor mutants previously isolated, some of which were previously shown to also have an increased sensitivity to certain antibiotics and detergents. Type strains from each of the phenotypic classes were therefore tested for sensitivity to a range of antibiotics, detergents, and surfactants that included all those previously used. With these new data, it has been possible to speculate informatively on the mode of action of the different colicins. We have confirmed the position of previously isolated mutations on the Escherichia coli K-12 genetic map, and located approximately the loci conferring colicin resistance in some of the newly isolated mutants.


Mechanisms of Helicobacter pylori antibiotic resistance: An updated appraisal.
Helicobacter pylori (H. pylori) antibiotic resistance is the main factor affecting the efficacy of the current eradicating therapies. The aim of this editorial is to report on the recent information about the mechanisms accounting for the resistance to the different antibiotics currently utilized in H. pylori eradicating treatments. Different mechanisms of resistance to clarithromycin, metronidazole, quinolones, amoxicillin and tetracycline are accurately detailed (point mutations, redox intracellular potential, pump efflux systems, membrane permeability) on the basis of the most recent data available from the literature. The next hope for the future is that by improving the knowledge of resistance mechanisms, the elaboration of rational and efficacious associations for the treatment of the infection will be possible. Another auspicious progress might be the possibility of a cheap, feasible and reliable laboratory test to predict the outcome of a therapeutic scheme.


Are Barbie and Ken too cool for school? A case-control study on the relation between gender and dropout.
As school dropout is an important public health problem that needs to be addressed, we set out to examine whether and how, beyond the well-known effects of sex, gender beliefs and self-reported masculinity and femininity are related to school dropout. The study used a case-control design, consisting of 330 dropout cases and 330 controls still attending school. The respondents, aged between 18 and 23 years, living in the south-east of the Netherlands, were sent a self-administered questionnaire. Separate logistic regression analyses for the male and female participants were used to explore the relation between dropout and gender, controlling for sociodemographic determinants. As indicated by significant curvilinearity, young women were less likely to drop out when they occupied an intermediate positions on the gender variables. Odds of dropout were elevated among highly masculine women (odds ratio = 2.1, 95% confidence interval: 1.1-4.1), and, as indicated by significant interactions, also among highly masculine men with strong normative masculine beliefs and in feminine men who simultaneously considered themselves low on masculinity. Beyond sex, gender is important in the explanation of school dropout. To prevent dropout, public health professionals should assess, monitor and intervene on the basis of gender characteristics.


Site-directed mutagenesis of cytochrome c(6) from Anabaena species PCC 7119. Identification of surface residues of the hemeprotein involved in photosystem I reduction.
A number of surface residues of cytochrome c(6) from the cyanobacterium Anabaena sp. PCC 7119 have been modified by site-directed mutagenesis. Changes were made in six amino acids, two near the heme group (Val-25 and Lys-29) and four in the positively charged patch (Lys-62, Arg-64, Lys-66, and Asp-72). The reactivity of mutants toward the membrane-anchored complex photosystem I was analyzed by laser flash absorption spectroscopy. The experimental results indicate that cytochrome c(6) possesses two areas involved in the redox interaction with photosystem I: 1) a positively charged patch that may drive its electrostatic attractive movement toward photosystem I to form a transient complex and 2) a hydrophobic region at the edge of the heme pocket that may provide the contact surface for the transfer of electrons to P(700). The isofunctionality of these two areas with those found in plastocyanin (which acts as an alternative electron carrier playing the same role as cytochrome c(6)) are evident.


From Syringe to Spoon Feeding: A Case Report of How Occupational Therapy Treatment Successfully Guided the Parents of a Child with Autism Spectrum Disorder and Prematurity in an Outpatient Clinic.
This case report details how occupational therapy treatment in an outpatient setting successfully guided the parents of a child with autism spectrum disorder and a history of prematurity from restrained syringe feedings to the acceptance of spoon feedings. Occupational therapy practitioners are qualified, needed and available to assess and treat feeding disorders in children with autism spectrum disorder and a history of prematurity. Family-centered practice must be utilized for successful outcomes in an outpatient service delivery model.


Prognostic value of the lymph node ratio in stage III colorectal cancer: a systematic review.
Although nodal invasion represents one of the most powerful prognostic indicators in colorectal cancer, marked heterogeneity exists within stage III patients. Recently, the lymph node ratio (LNR), defined as the ratio of the number of positive nodes over the total number of examined nodes, was proposed to stratify outcome in stage III patients. A systematic search was performed for studies examining the prognostic significance of the LNR in colon or rectal cancer. Individual studies were assessed for methodological quality and summary data extracted. Hazard ratios from multivariate analyses were entered in a fixed-effects meta-analysis model. In total, 16 studies were identified including 33,984 patients with stage III colon or rectal cancer. In all identified studies, the LNR was identified as an independent prognostic factor in patients with stage III cancer of the colon or rectum. The prognostic separation obtained by the LNR was superior to that of the number of positive nodes (N stage). The pooled hazard ratios for overall and disease-free survival were 2.36 (95% confidence interval, 2.14-2.61) and 3.71 (95% confidence interval, 2.56-5.38), respectively. The LNR allows superior prognostic stratification in stage III colorectal cancer and should be validated in prospective studies.


Relationship Between Age and Rotator Cuff Retear: A Study of 1,600 Consecutive Rotator Cuff Repairs.
The prevalence of rotator cuff tears increases with age, and many patients undergo surgical repair. Retears are not uncommon, with rates ranging between 9% and 36% in recent studies, and are a major concern. The aim of this study was to investigate the relationship between patient age and the chance of healing following rotator cuff repair. This was a retrospective cohort study of patients who had undergone arthroscopic rotator cuff repair performed by a single surgeon. All patients had an ultrasound performed by a musculoskeletal sonographer 6 months after rotator cuff repair to assess the repair integrity. The cohort of 1,600 patients was normally distributed in terms of age, with a mean age (and standard error of the mean) of 59 ± 0.3 years and a range of 15 to 91 years. The 212 patients (13%) who had a retear at 6 months were also normally distributed in terms of age, with a mean age of 65 ± 0.8 years and a range of 15 to 88 years. The retear rate in patients <50 years old was 5%. This increased to 10% in patients aged 50 to 59 years, 15% in those aged 60 to 69 years, 25% in those aged 70 to 79 years, and 34% in those aged ≥80 years. Multiple logistic regression analysis showed that patient age was an independent factor strongly associated with retears. The rate of rotator cuff retears is low in patients <50 years of age. The relationship between age and rotator cuff retears is linear in patients 50 to 69 years of age, with an increase of 5% between decades, and increases substantially in patients ≥70 years old. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Total Medicare Costs Associated With Diagnosis and Treatment of Prostate Cancer in Elderly Men.
Localized prostate cancer diagnosis and treatment among elderly men who are not likely to benefit represents a potential source of low-value health care services. To quantify the costs to the Medicare program associated with detection and treatment of prostate cancer among elderly men in the United States. This nationwide, population-based, retrospective cohort study uses the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to identify men 70 years or older diagnosed with localized prostate cancer between 2004 and 2007 and to ascertain Medicare costs associated with diagnosis and workup, treatment, follow-up, and morbidity management of the disease. National Medicare costs were estimated using per-person costs, stage-adjusted prostate cancer incidence rates by age from SEER 2007 through 2011, and 2010 Census population estimates by age. Estimated costs to the Medicare program overall, and in each (mutually exclusive) category related to diagnosis and workup, treatment, follow-up, and morbidity management. This nationwide, population-based, retrospective cohort study included 49 692 men with nonmetastatic prostate cancer from the SEER-Medicare database (all participants were 70 years or older; 25 981 [52.3%] were 76 years or older). The median per-patient cost within 3 years after prostate cancer diagnosis was $14 453 (interquartile range [IQR], $4887-$27 899). The majority of this cost was attributable to treatment costs (median, $10 558; IQR, $1990-$23 718). Patients with a Gleason score of 6 or lower who pursued initial conservative management (no treatment within 12 months of diagnosis) had a 3-year median total cost of $1914 per patient. The estimated total 3-year cost to the Medicare program associated with the annual detection of prostate cancer in men 70 years or older is approximately $1.2 billion. Increasing active surveillance use in those with Gleason score of 6 or lower could reduce this cost by $320 million. There is substantial cost to the Medicare program associated with the diagnosis and treatment of localized prostate cancer among elderly men in the United States, despite the fact that these men are unlikely to die of prostate cancer. The majority of costs are related to treatment. Reducing provision of low-value health care services among this patient population could result in significant health care savings.


Distribution of BODIPY-labelled phosphatidylethanolamines in lipid bilayers exhibiting different curvatures.
In this paper we have investigated the behaviour of newly synthesised mono-palmitoyl- and dipalmitoyl-phosphatidylethanolamine probes (abbreviated as mPE and dPE, respectively) labelled in the polar headgroup region by either the FL-BODIPY or the 564/570-BODIPY fluorophore and solubilised in lipid systems that exhibit different curvatures. Because of the bulky BODIPY-groups, the monoacyl-form derivatives have a conic-like shape, whereas that for the diacyl derivatives is rather cylindrical. A careful analysis of time-resolved resonance energy transfer experiments by means of analytical models as well as Monte Carlo simulations shows that the mPE derivatives have a comparable affinity to highly curved bilayer regions (torroidal pores formed by magainin-2 in lipid bilayers, or the rims of discoid bicelles) and to planar bilayer regions (i.e. the flat region of lipid bilayers and bicelles). Furthermore, the monoacyl-probes are as compared to the diacyl-probes effectively closer to each other in a lipid bilayer, while none of these probes seems to be randomly distributed. Self-aggregation is most efficiently induced by the larger aromatic 564/570-BODIPY chromophore, but it is suppressed when using the diacyl instead of the monoacyl-form, and/or by attaching BODIPY-groups to the acyl-chain.


Expression capable library for studies of Neisseria gonorrhoeae, version 1.0.
The sexually transmitted disease, gonorrhea, is a serious health problem in developed as well as in developing countries, for which treatment continues to be a challenge. The recent completion of the genome sequence of the causative agent, Neisseria gonorrhoeae, opens up an entirely new set of approaches for studying this organism and the diseases it causes. Here, we describe the initial phases of the construction of an expression-capable clone set representing the protein-coding ORFs of the gonococcal genome using a recombination-based cloning system. The clone set thus far includes 1672 of the 2250 predicted ORFs of the N. gonorrhoeae genome, of which 1393 (83%) are sequence-validated. Included in this set are 48 of the 61 ORFs of the gonococcal genetic island of strain MS11, not present in the sequenced genome of strain FA1090. L-arabinose-inducible glutathione-S-transferase (GST)-fusions were constructed from random clones and each was shown to express a fusion protein of the predicted size following induction, demonstrating the use of the recombination cloning system. PCR amplicons of each ORF used in the cloning reactions were spotted onto glass slides to produce DNA microarrays representing 2035 genes of the gonococcal genome. Pilot experiments indicate that these arrays are suitable for the analysis of global gene expression in gonococci. This archived set of Gateway entry clones will facilitate high-throughput genomic and proteomic studies of gonococcal genes using a variety of expression and analysis systems. In addition, the DNA arrays produced will allow us to generate gene expression profiles of gonococci grown in a wide variety of conditions. Together, the resources produced in this work will facilitate experiments to dissect the molecular mechanisms of gonococcal pathogenesis on a global scale, and ultimately lead to the determination of the functions of unknown genes in the genome.


[Clostridium difficile infections, specific issues in the elderly].
Clostridium difficile is a well-established cause of infectious nosocomial diarrhea in adults. Each time diarrhea is observed in a patient receiving antibiotic treatment, Clostridium colitis should be suspected; diagnosis should be confirmed by the identification of toxin in the patient's stools. Its incidence is increasing due to growing use of several classes of antibiotics, and is associated with a high relapse rate and a significant case-fatality rate. The elderly are particularly at risk for this type of infection. Recent developments include the occurrence of epidemics in restricted communities and settings and the appearence of new virulent strains of this pathogen (especially PCR Ribotype 027). Vancomycin should be preferred over metronidazole in severe cases of diarrhea. New treatments are currently being tested and evaluated. Prevention remains a priority; high standards of hygiene and careful attention to the judicious prescription of antibiotics are crucial in this regard.


Magnetic resonance diffusion characteristics of histologically defined prostate cancer in humans.
The contrast provided by diffusion-sensitive magnetic resonance offers the promise of improved tumor localization in organ-confined human prostate cancer (PCa). Diffusion tensor imaging (DTI) measurements of PCa were performed in vivo, in patients undergoing radical prostatectomy, and later, ex vivo, in the same patients' prostatectomy specimens. The imaging data were coregistered to histological sections of the prostatectomy specimens, thereby enabling unambiguous characterization of diffusion parameters in cancerous and benign tissues. Increased cellularity, and hence decreased luminal spaces, in peripheral zone PCa led to approximately 40% and 50% apparent diffusion policy (ADC) decrease compared with benign peripheral zone tissues in vivo and ex vivo, respectively. In contrast, no significant diffusion anisotropy differences were observed between the cancerous and noncancerous peripheral zone tissues. However, the dense fibromuscular tissues in prostate, such as stromal tissues in benign prostatic hyperplasia in central gland, exhibited high diffusion anisotropy. A tissue classification method is proposed to combine DTI and T2-weighted image contrasts that may provide improved specificity of PCa detection over T2-weighted imaging alone. PCa identified in volume rendered MR images qualitatively correlates well with histologically determined PCa foci.