Calcium phosphates in Ca(2+)-fortified milk: phase identification and quantification by Raman spectroscopy.
Calcium phosphate nanoclusters (CPNs) are important for the structure, function, and nutrient density of many dairy products. Phosphorylated amino acids in caseins stabilize calcium phosphate as nanoclusters which are amorphous to X-ray diffraction and exist within casein micelles, and these CPNs play a key role in micelle stability. Addition of calcium to milk results in further calcium phosphate removal from the serum, and there is uncertainty about the nature of the material formed and its stability. In this work we investigate both the solution and colloidal phases in CaCl2 enriched bovine milk to identify, quantify, and determine the solubility of the calcium phosphate material formed in response to calcium addition to milk. The P-O stretching bands are quite distinct in the Raman spectra of the main synthetic calcium phosphate mineral phases, including the amorphous calcium phosphate phase. In response to adding between 5 and 40 mM CaCl2 to milk, the serum phosphate concentration decreased asymptotically from 7.5 ± 0.2 to 0.54 ± 0.05 mM. Using Raman spectroscopy with a combination of internal and external standards, it was possible to show that the calcium phosphate material formed after Ca(2+) addition to milk was the same as amorphous calcium phosphate nanoclusters present in the absence of added calcium. The use of an internal standard allowed a quantitative analysis of the spectra which demonstrated that the amorphous calcium phosphate formed accounted for all of the calcium and phosphate that was removed from solution in response to calcium addition.


Growth hormone and prostate cancer: guilty by association?
Recent case-control studies have found a 7-8% increase in the serum levels of insulin-like growth factor (IGF)-I in patients with prostate cancer (CaP), the most frequently diagnosed cancer in men. We hereby review what is currently known about growth hormone (GH) and the IGF axis in CaP, take a closer inspection of the studies published to date reporting IGF-I levels in CaP patients, and derive implications for the future medical management of patients receiving trophic hormone therapies as well as those at risk for developing CaP. The role of GH in controlling prostate growth and carcinogenesis is still unclear from animal studies and human disease patterns. However, multilayered perturbations of the IGF axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases, such as prostate-specific antigen, have been identified in CaP cells and tissues. Interestingly, IGFBP-3 is a potent inhibitor of prostatic IGF action and also mediates prostate apoptosis via an IGF-independent mechanism. Serum IGFBP-3 levels have been identified to be negatively correlated to the risk of CaP. Notably, GH therapy raises both IGF-I and IGFBP-3 levels in serum. Conclusions based on the studies of IGF-I levels in CaP patients are affected by both the populations studied and the types of IGF-I assay employed. While the studies do indicate an association between serum IGF-I levels and CaP risk, causality has not been established. Thus, serum IGF-I level may actually be a confounding variable, serving as a marker for local prostatic IGF-I production. Increased GH levels as seen in acromegaly have been associated with benign prostatic hyperplasia but not with CaP. Thus, serum IGF-I may lead to an ascertainment bias among younger men with benign prostatic hyperplasia who are more likely to present with prostatic symptoms and have subclinical CaP diagnosed. Should serum IGF-I levels be proven to play a causal role in the pathogenesis of CaP, interpreting the risk associated with therapies such as GH must take into account both the duration of exposure and the risk magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient patients often have a subnormal IGF-I serum level, which normalizes on therapy, their CaP risk on GH therapy probably does not increase substantially above that of the normal population. Until further research in the area dictates otherwise, ongoing surveillance and routine monitoring of IGF-I and IGFBP-3 levels in GH recipients must become standard of care.


Deletion of astrocyte connexins 43 and 30 leads to a dysmyelinating phenotype and hippocampal CA1 vacuolation.
Astrocytes are coupled via gap junctions (GJs) comprising connexin 43 (Cx43) (Gja1) and Cx30 (Gjb6), which facilitate intercellular exchange of ions. Astrocyte connexins also form heterotypic GJs with oligodendrocytic somata and lamellae. Loss of oligodendrocyte gap junctions results in oligodendrocyte and myelin pathology. However, whether loss of astrocyte GJs affects oligodendrocytes and myelin is not known. To address this question, mice with astrocyte-targeted deletion of Cx43 and global loss of Cx30 [double knock-out (dKO)] were studied using Western blotting, immunohistochemistry, electron microscopy, and functional assays. Commencing around postnatal day 23 and persisting into old age, we found widespread pathology of white matter tracts comprising vacuolated oligodendrocytes and intramyelinic edema. In contrast, gray matter pathology was restricted to the CA1 region of the hippocampus, and consisted of edematous astrocytes. No differences were observed in synaptic density or total NeuN(+) cells in the hippocampus, or olig2(+) cells in the corpus callosum. However, in dKO mice, fewer CC1-positive mature oligodendrocytes were detected, and Western blotting indicated reduced myelin basic protein. Pathology was not noted in mice expressing a single allele of either Cx43 or Cx30. When compared with single connexin knock-outs, dKO mice were impaired in sensorimotor (rotarod, balance beam assays) and spatial memory tasks (object recognition assays). We conclude that loss of astrocytic GJs can result in white matter pathology that has functional consequences.


AKI and Long-Term Risk for Cardiovascular Events and Mortality.
AKI associates with increased long-term risk of mortality, but the prognostic significance of AKI in terms of long-term cardiovascular disease remains unconfirmed. We conducted a systematic review and meta-analysis to assess whether AKI associates with long-term cardiovascular disease. We included cohort studies that examined adults with and without AKI and reported a multivariable-adjusted relative risk (RR) for the association between AKI and cardiovascular mortality, major cardiovascular events, and disease-specific events: congestive heart failure, acute myocardial infarction, and stroke. Twenty-five studies involving 254,408 adults (55,150 with AKI) were included. AKI associated with an 86% and a 38% increased risk of cardiovascular mortality and major cardiovascular events, respectively ([RR 1.86; 95% confidence interval (95% CI), 1.72 to 2.01] and [RR 1.38; 95% CI, 1.23 to 1.55], respectively). For disease-specific events, AKI associated with a 58% increased risk of heart failure (RR 1.58; 95% CI, 1.46 to 1.72) and a 40% increased risk of acute myocardial infarction (RR 1.40; 95% CI, 1.23 to 1.59). The elevated risk of heart failure and acute myocardial infarction persisted in subgroup analyses on the basis of AKI severity and the proportion of adults with baseline ischemic heart disease. Finally, AKI was associated with a 15% increased risk of stroke (RR 1.15; 95% CI, 1.03 to 1.28). In conclusion, AKI associates with an elevated risk of cardiovascular mortality and major cardiovascular events, particularly heart failure and acute myocardial infarction.


Cross-adaptive effects of cold, hypoxia, or physical training on decompression sickness in mice.
The effects of adaptation to cold, hypoxia, or exercise on hyperbaric decompression tolerance were investigated in two factorial experiments. For either 14 or 28 days, groups of mice were handled (control); exposed discontinuously for 4 h to cold (4 degrees C) or hypoxia (P approximately 379 or 320 Torr); or exercised by swimming (15 min at 31 degrees C) or treadmill excursion (8.1 m/min for 1 or 1.5 h). The animals were divided into subgroups, exposed to one of three hydrostatic pressures (7.6--11.1 ATA) for 30 min, decompressed, and observed to determine survival rate or bends incidence (type II decompression sickness). Decompression sickness was significantly reduced (P less than 0.05) in the treadmill-trained animals, was unchanged in cold-exposed and swim-exercised mice, and tended to increase in animals adapted to hypoxia. Enhanced tolerance by treadmill training is presumably due to lean body conformation, which could reduce nitrogen saturation of tissues, and greater muscle capillarization and cardiovascular fitness, which may improve nitrogen elimination. Reduced tolerance with adaptation to hypoxia may be attributed to rheological changes associated with polycythemia, which facilitate bubble production.


Nothing About Us Without Us? A Comparison of Adolescent and Adult Health-State Values for the Child Health Utility-9D Using Profile Case Best-Worst Scaling.
The main objective of this study was to compare and contrast adolescent and adult values for the Child Health Utility-9D (CHU9D), a new generic preference-based measure of health-related quality of life designed for application in the economic evaluation of treatment and preventive programmes for children and adolescents. Previous studies have indicated that there may be systematic differences in adolescent and adult values for identical health states. An online survey including a series of best-worst scaling discrete choice experiment questions for health states defined by the CHU9D was administered to two general population samples comprising adults and adolescents, respectively. The results highlight potentially important age-related differences in the values attached to CHU9D dimensions. Adults, in general, placed less weight upon impairments in mental health (worried, sad, annoyed) and more weight upon moderate to severe levels of pain relative to adolescents. The source of values (adults or adolescents) has important implications for economic evaluation and may impact significantly upon healthcare policy.


Quantitative photoacoustic image reconstruction improves accuracy in deep tissue structures.
Photoacoustic imaging (PAI) is emerging as a potentially powerful imaging tool with multiple applications. Image reconstruction for PAI has been relatively limited because of limited or no modeling of light delivery to deep tissues. This work demonstrates a numerical approach to quantitative photoacoustic image reconstruction that minimizes depth and spectrally derived artifacts. We present the first time-domain quantitative photoacoustic image reconstruction algorithm that models optical sources through acoustic data to create quantitative images of absorption coefficients. We demonstrate quantitative accuracy of less than 5% error in large 3 cm diameter 2D geometries with multiple targets and within 22% error in the largest size quantitative photoacoustic studies to date (6cm diameter). We extend the algorithm to spectral data, reconstructing 6 varying chromophores to within 17% of the true values. This quantitiative PA tomography method was able to improve considerably on filtered-back projection from the standpoint of image quality, absolute, and relative quantification in all our simulation geometries. We characterize the effects of time step size, initial guess, and source configuration on final accuracy. This work could help to generate accurate quantitative images from both endogenous absorbers and exogenous photoacoustic dyes in both preclinical and clinical work, thereby increasing the information content obtained especially from deep-tissue photoacoustic imaging studies.


Synthetic Control of Two-Dimensional NiTe2 Single Crystals with Highly Uniform Thickness Distributions.
Two-dimensional (2D) layered materials have stimulated extensive research interest for their unique thickness-dependent electronic and optical properties. However, the layer-number-dependent studies on 2D materials to date are largely limited to exfoliated flakes with relatively small lateral size and poor yield. The direct synthesis of 2D materials with a precise control of the number of atomic layers remains a substantial synthetic challenge. Here we report a systematic study of chemical vapor deposition synthesis of large-area atomically thin 2D nickel telluride (NiTe2) single crystals and investigate the thickness dependent electronic properties. By controlling the growth temperature, we show that the highly uniform NiTe2 single crystals can be synthesized with precisely tunable thickness varying from 1, 2, 3, . . . to multilayers with a standard deviation (∼0.3 nm) of less than the thickness of a monolayer layer NiTe2. Our studies further reveal a systematic evolution of single crystal domain size and nucleation density with the largest lateral domain size up to ∼440 μm. X-ray diffraction, transmission electron microscopy, and high resolution scanning transmission electron microscope studies demonstrate that the resulting 2D crystals are high quality single crystals and adopt hexagonal 1T phase. Electrical transport studies reveal that the 2D NiTe2 single crystals show a strong thickness-tunable electrical properties, with an excellent conductivity up to 7.8 × 105 S m-1 and extraordinary breakdown current density up to 4.7 × 107 A/cm2. The systematic study and robust synthesis of NiTe2 nanosheets defines a reliable chemical route to 2D single crystals with precisely tailored thickness and could enable the design of new device architectures based on thickness-tunable electrical properties.


Restriction by APOBEC3 proteins of endogenous retroviruses with an extracellular life cycle: ex vivo effects and in vivo "traces" on the murine IAPE and human HERV-K elements.
APOBEC3 cytosine deaminases have been demonstrated to restrict infectivity of a series of retroviruses, with different efficiencies depending on the retrovirus. In addition, APOBEC3 proteins can severely restrict the intracellular transposition of a series of retroelements with a strictly intracellular life cycle, including the murine IAP and MusD LTR-retrotransposons. Here we show that the IAPE element, which is the infectious progenitor of the strictly intracellular IAP elements, and the infectious human endogenous retrovirus HERV-K are restricted by both murine and human APOBEC3 proteins in an ex vivo assay for infectivity, with evidence in most cases of strand-specific G-to-A editing of the proviruses, with the expected signatures. In silico analysis of the naturally occurring genomic copies of the corresponding endogenous elements performed on the mouse and human genomes discloses "traces" of APOBEC3-editing, with the specific signature of the murine APOBEC3 and human APOBEC3G enzymes, respectively, and to a variable extent depending on the family member. These results indicate that the IAPE and HERV-K elements, which can only replicate via an extracellular infection cycle, have been restricted at the time of their entry, amplification and integration into their target host genomes by definite APOBEC3 proteins, most probably acting in evolution to limit the mutagenic effect of these endogenized extracellular parasites.


Assessing autistic traits: cross-cultural validation of the social responsiveness scale (SRS).
The Social Responsiveness Scale (SRS) is a quantitative measure of autistic traits in 4- to 18-year-olds, which has been used in behavior-genetic, epidemiological and intervention studies. The US standardization demonstrated a single-factor structure and good to excellent psychometric properties. The cross-cultural validity of the German adaptation of the parent-report SRS in a sample of N=1,436 children and adolescents: 838 typically developing and 527 clinical participants (160 with autism spectrum disorders (ASDs)) was examined. Internal consistency (0.91-0.97), test-retest reliability (0.84-0.97), interrater reliability (0.76 and 0.95) and convergent validity with the Autism Diagnostic Observation Schedule as well as the Autism Diagnostic Interview-Revised and Social Communication Questionnaire (0.35-0.58) were satisfactory to good. The SRS total score discriminated between ASD and other mental disorders. SRS scores proved to be sufficiently independent of general psychopathology. Principal component analyses yielded single-factor solutions for the normative and clinical subsamples. In addition, construct validity was ensured by consistent correlations with the Vineland Adaptive Behavior Scales, the Child Behavior Checklist and the Junior Temperament and Character Inventory. Normative SRS total scores for girls and boys as well as values for ASD were lower in the German sample, while scores for conduct disorder and attention deficit hyperactivity/conduct disorder combined were higher. Generally, cross-cultural validity of the SRS seems to be sufficiently assured for a large European sample. However, some discrepancies regarding SRS normative and clinical raw score distributions, reliability and validity findings are critically discussed.


Functional neuroplasticity in response to cerebello-thalamic injury underpins the clinical presentation of tremor in multiple sclerosis.
Tremor is present in almost half of multiple sclerosis (MS) patients. The lack of understanding of its pathophysiology is hampering progress in development of treatments. To clarify the structural and functional brain changes associated with the clinical phenotype of upper limb tremor in people with MS. Fifteen healthy controls (46.1 ± 15.4 years), 27 MS participants without tremor (46.7 ± 11.6 years) and 42 with tremor (46.6 ± 11.5 years) were included. Tremor was quantified using the Bain score (0-10) for overall severity, handwriting and Archimedes spiral drawing. Functional magnetic resonance imaging activations were compared between participants groups during performance of a joystick task designed to isolate tremulous movement. Inflammation and atrophy of cerebello-thalamo-cortical brain structures were quantified. Tremor participants were found to have atrophy of the cerebellum and thalamus, and higher ipsilateral cerebellar lesion load compared to participants without tremor (p < 0.020). We found higher ipsilateral activation in the inferior parietal lobule, the premotor cortex and supplementary motor area in MS tremor participants compared to MS participants without tremor during the joystick task. Finally, stronger activation in those areas was associated with lower tremor severity. Subcortical neurodegeneration and inflammation along the cerebello-thalamo-cortical and cortical functional neuroplasticity contribute to the severity of tremor in MS.


Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors.
A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics, and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4 mg/m(2). Dose escalation in cohorts of at least three patients proceeded according to the worst toxicity observed in the previous cohort. Twenty-eight patients were treated with 72 courses of ES-285 across eight dose levels. No dose-limiting toxicities were seen between 4 and 128 mg/m(2). Two of four patients treated at 256 mg/m(2) had dose-limiting reversible grade 3 transaminitis; one patient at 256 mg/m(2) also had transient grade 3 central neurotoxicity. One of three patients subsequently treated at 200 mg/m(2) died following drug-related central neurotoxicity. Other toxicities included phlebitis, nausea, fatigue, and fever. Pharmacokinetic studies indicated dose proportionality with high volume of distribution (median V(ss) at 256 mg/m(2) was 2,389 liters; range, 1,615-4,051 liters) and long elimination half life (median t(1/2) at 256 mg/m(2) was 28 h; range, 21-32 h). The three patients with dose-limiting toxicity had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Disease stabilization for 6 to 18 weeks was recorded in nine patients. Using this schedule, 128 mg/m(2) was considered safe and feasible. At this dose, pharmacologically relevant concentrations of the drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential mechanistic relevance.


International framework for examination of the cervical region for potential of Cervical Arterial Dysfunction prior to Orthopaedic Manual Therapy intervention.
A consensus clinical reasoning framework for best practice for the examination of the cervical spine region has been developed through an iterative consultative process with experts and manual physical therapy organisations. The framework was approved by the 22 member countries of the International Federation of Orthopaedic Manipulative Physical Therapists (October 2012). The purpose of the framework is to provide guidance to clinicians for the assessment of the cervical region for potential of Cervical Arterial Dysfunction in advance of planned management (inclusive of manual therapy and exercise interventions). The best, most recent scientific evidence is combined with international expert opinion, and is presented with the intention to be informative, but not prescriptive; and therefore as an aid to the clinician's clinical reasoning. Important underlying principles of the framework are that 1] although presentations and adverse events of Cervical Arterial Dysfunction are rare, it is a potentially serious condition and needs to be considered in musculoskeletal assessment; 2] manual therapists cannot rely on the results of one clinical test to draw conclusions as to the presence or risk of Cervical Arterial Dysfunction; and 3] a clinically reasoned understanding of the patient's presentation, including a risk:benefit analysis, following an informed, planned and individualised assessment, is essential for recognition of this condition and for safe manual therapy practice in the cervical region. Clinicians should also be cognisant of jurisdictionally specific requirements and obligations, particularly related to patient informed consent, when intending to use manual therapy in the cervical region.


Effects of antioxidant supplements on cancer prevention: meta-analysis of randomized controlled trials.
This meta-analysis aimed to investigate the effect of antioxidant supplements on the primary and secondary prevention of cancer as reported by randomized controlled trials. We searched Medline (PubMed), Excerpta Medica database, and the Cochrane Review in October 2007. Among 3327 articles searched, 31 articles on 22 randomized controlled trials, which included 161 045 total subjects, 88 610 in antioxidant supplement groups and 72 435 in placebo or no-intervention groups, were included in the final analyses. In a fixed-effects meta-analysis of all 22 trials, antioxidant supplements were found to have no preventive effect on cancer [relative risk (RR) 0.99; 95% confidence interval (CI) 0.96-1.03). Similar findings were observed in 12 studies on primary prevention trials (RR 1.00; 95% CI 0.97-1.04) and in nine studies on secondary prevention trials (RR 0.97; 95% CI 0.83-1.13). Further, subgroup analyses revealed no preventive effect on cancer according to type of antioxidant, type of cancer, or the methodological quality of the studies. On the other hand, the use of antioxidant supplements significantly increased the risk of bladder cancer (RR 1.52; 95% CI 1.06-2.17) in a subgroup meta-analysis of four trials. The meta-analysis of randomized controlled trials indicated that there is no clinical evidence to support an overall primary and secondary preventive effect of antioxidant supplements on cancer. The effects of antioxidant supplements on human health, particularly in relation to cancer, should not be overemphasized because the use of those might be harmful for some cancer.


Ankle arthroplasty using three generations of metal and ceramic prostheses.
Ankle arthroplasties using metal and polyethylene prostheses were done on 28 patients (30 ankles) with painful osteoarthritis or rheumatoid arthritis between 1975 and 1980. Significant loosening and subsidence of the metal prostheses occurred in most patients, and ceramic prostheses were introduced in 1980. Ceramic prostheses with or without cement were used to replace 60 ankles in 56 patients with painful arthritis between 1980 and 1991. Revision surgery was required for five patients (five ankles) during the followup period (mean, 12 years 6 months). Loosening and subsidence of the prostheses were seen in 50% of patients within 5 years after the index procedure. As a result, a new design of bead-formed alumina coated with hydroxyapatite was used. A tibial prosthesis fixed to the posterior cortex of the tibia with a screw was used from 1991. These new ceramic prostheses were used to replace 70 ankles in 62 patients between 1991 and 2000. Thirty-six patients (36 ankles) with a mean age of 71 years (range, 50-87 years) had osteoarthritis, and 26 patients (31 ankles) with a mean age of 60 years (range, 41-76 years) had rheumatoid arthritis. During followup, with an average of 5 years 2 months, three patients (three ankles) required revision surgery (one for infection, two for talar necrosis). Overall results for patients with osteoarthritis were excellent in 21 ankles, good in 10 ankles, fair in two, ankles and poor in zero ankles. Results in patients with rheumatoid arthritis were excellent in five ankles, good in 16 ankles, fair in three ankles, and poor in two. In the intermediate study, 29 patients (31 ankles; 91.2%) with osteoarthritis and 19 patients (21 ankles; 76.9%) with rheumatoid arthritis were satisfied with the short-time results of arthroplasty.


Proteomic-coupled-network analysis of T877A-androgen receptor interactomes can predict clinical prostate cancer outcomes between White (non-Hispanic) and African-American groups.
The androgen receptor (AR) remains an important contributor to the neoplastic evolution of prostate cancer (CaP). CaP progression is linked to several somatic AR mutational changes that endow upon the AR dramatic gain-of-function properties. One of the most common somatic mutations identified is Thr877-to-Ala (T877A), located in the ligand-binding domain, that results in a receptor capable of promiscuous binding and activation by a variety of steroid hormones and ligands including estrogens, progestins, glucocorticoids, and several anti-androgens. In an attempt to further define somatic mutated AR gain-of-function properties, as a consequence of its promiscuous ligand binding, we undertook a proteomic/network analysis approach to characterize the protein interactome of the mutant T877A-AR in LNCaP cells under eight different ligand-specific treatments (dihydrotestosterone, mibolerone, R1881, testosterone, estradiol, progesterone, dexamethasone, and cyproterone acetate). In extending the analysis of our multi-ligand complexes of the mutant T877A-AR we observed significant enrichment of specific complexes between normal and primary prostatic tumors, which were furthermore correlated with known clinical outcomes. Further analysis of certain mutant T877A-AR complexes showed specific population preferences distinguishing primary prostatic disease between white (non-Hispanic) vs. African-American males. Moreover, these cancer-related AR-protein complexes demonstrated predictive survival outcomes specific to CaP, and not for breast, lung, lymphoma or medulloblastoma cancers. Our study, by coupling data generated by our proteomics to network analysis of clinical samples, has helped to define real and novel biological pathways in complicated gain-of-function AR complex systems.


Analysis of bile acids in human biological samples by microcolumn separation techniques: A review.
Bile acids are a group of compounds essential for lipid digestion and absorption with a steroid skeleton and a carboxylate side chain usually conjugated to glycine or taurine. Bile acids are regulatory molecules for a number of metabolic processes and can be used as biomarkers of various disorders. Since the middle of the twentieth century, the detection of bile acids has evolved from simple qualitative analysis to accurate quantification in complicated mixtures. Advanced methods are required to characterize and quantify individual bile acids in these mixtures. This article overviews the literature from the last two decades (2000-2020) and focuses on bile acid analysis in various human biological samples. The methods for sample preparation, including the sample treatment of conventional (blood plasma, blood serum, and urine) and unconventional samples (bile, saliva, duodenal/gastric juice, feces, etc.) are shortly discussed. Eventually, the focus is on novel analytical approaches and methods for each particular biological sample, providing an overview of the microcolumn separation techniques, such as high-performance liquid chromatography, gas chromatography, and capillary electrophoresis, used in their analysis. This is followed by a discussion on selected clinical applications.


Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia.
The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders.


Visual Cone Arrestin 4 Contributes to Visual Function and Cone Health.
Visual arrestins (ARR) play a critical role in shutoff of rod and cone phototransduction. When electrophysiological responses are measured for a single mouse cone photoreceptor, ARR1 expression can substitute for ARR4 in cone pigment desensitization; however, each arrestin may also contribute its own, unique role to modulate other cellular functions. A combination of ERG, optokinetic tracking, immunohistochemistry, and immunoblot analysis was used to investigate the retinal phenotypes of Arr4 null mice (Arr4-/-) compared with age-matched control, wild-type mice. When 2-month-old Arr4-/- mice were compared with wild-type mice, they had diminished visual acuity and contrast sensitivity, yet enhanced ERG flicker response and higher photopic ERG b-wave amplitudes. In contrast, in older Arr4-/- mice, all ERG amplitudes were significantly reduced in magnitude compared with age-matched controls. Furthermore, in older Arr4-/- mice, the total cone numbers decreased and cone opsin protein immunoreactive expression levels were significantly reduced, while overall photoreceptor outer nuclear layer thickness was unchanged. Our study demonstrates that Arr4-/- mice display distinct phenotypic differences when compared to controls, suggesting that ARR4 modulates essential functions in high acuity vision and downstream cellular signaling pathways that are not fulfilled or substituted by the coexpression of ARR1, despite its high expression levels in all mouse cones. Without normal ARR4 expression levels, cones slowly degenerate with increasing age, making this a new model to study age-related cone dystrophy.


Khamiras, a natural cardiac tonic: An overview.
The Unani system of Medicine (Unanipathy), which originated in Greece, is based on the principles proposed by Galen, a Greek practitioner. Since then, many Arab and Persian scholars have contributed to the system. Among them Ibn-e-Sina, an Arab philosopher and Physicist who wrote 'Kitab-al-shifa' are worth mentioning. This system has an extensive and inspiring record in India. It was introduced in India around the tenth century A.D with the spread of Islamic civilization. At present, Unanipathy has become an important part of the Indian system of Medicine. Unani medicines have been used since ancient times, as medicines for the treatment of various ailments. In spite of the great advances observed in modern medicine in recent decades, Unani drugs still make an important contribution to healthcare. The Unani system of medicine is matchless in treating chronic diseases like arthritis, asthma, mental, cardiac, and digestive disorders, urinary infections, and sexual diseases. The medicines administered go well with the temperament of the patient, thus speeding up the process of recovery and also reducing the risk of drug reaction. The Unani system of medicine recognizes the influence of the surroundings and ecological conditions on the state of health of human beings. The system aims at restoring the equilibrium of various elements and faculties of the human body. It has laid down six essential prerequisites for the prevention of diseases and places great emphasis, on the one hand, on the maintenance of proper ecological balance, and on the other, on keeping water, food, and air free from pollution. These essentials, known as 'Asbab-e-Sitta Zarooriya', are air, food, and drink, bodily movement and repose, psychic movement and repose, sleep and wakefulness, and excretion and retention. The Unani system is a secular system in temperament and is popular among the masses. In Unani medicine, although the general preference is for single drugs, compound formulations are also used in the treatment of various complex and chronic disorders. In the light of the present knowledge, this review is a small effort to discuss the efficacious nature of 'Khamira', a semi-solid preparation, which is traditionally used for cardiac ailments, such as, palpitations, weakness of the heart, and so on. On the basis of their constituents these are named as, Khamira Aabresham, Khamira Gaozaban, Khamira Marwareed, and so on. Khameeras are also used as general tonics for other vital organs like the liver and brain. In view of the increasing number of cardiac diseases, a thorough evaluation of this ancient work on Khamira is of special significance.


Chronic granulomatous mastitis: review of 26 cases with special reference to chronic lobular mastitis.
Twenty six cases of chronic granulomatous mastitis are reported in a 5 year period and the slides are reviewed. They are sub-classified into Chronic lobular mastitis (CLM), Plasma cell mastitis and subareolar granuloma. There are 10 cases each of CLM and plasma cell mastitis and one of subareolar granuloma. All the three conditions are associated with duct ectasia. Fat necrosis and infective granulomas were 2 each and one of foreign body granuloma. These lesions can be easily differentiated by histology. While most of the CLM occurred in younger age group, plasma cell mastitis is seen in older women. Histologically, there is a florid inflammatory cell reaction of the stroma with dilatation and destruction of some ducts, with microabscess formation. In plasma cell mastitis, the lesion is more chronic with predominance of plasma cells and involutionary changes of the ducts are seen.


Is kinetic polymer arrest very specific to multiwalled carbon nanotubes?
In this study we have assessed, using dielectric relaxation spectroscopy (DRS), the confinement effects of the more mobile chain in partially miscible polymeric blends of PS/PVME (polystyrene/poly(vinyl methyl ether)) in the presence of anisotropically shaped MWCNTs (multiwalled carbon nanotubes). To understand if this confinement effect is very specific to MWCNTs, the characteristic dimensions of which are often close to the radius of gyration of the polymeric chains, a few other particles like spherical silver, stacked clay tactoids and platy graphene sheets at similar weight fractions were also incorporated and systematically studied. The DRS studies reveal that the more mobile chain (here PVME) experiences possibly two different environments in the presence of frozen PS and more importantly in the presence of MWCNTs at temperatures close to and not so far from the blend Tg. The presence of bimodal relaxations with a weak temperature independent faster relaxation in the blends is composition dependent (PS rich blends). Assuming that there are no chemical interactions of PVME with the particles, these confinement effects seem to be very specific to MWCNTs as the bimodal relaxations were completely absent in the case of other nanoparticles. In the case of polymer blends, when two different chains are brought together, a loss in the deformational entropy is expected due to the excluded volume interaction and chain connectivity effects. In the presence of nanoparticles, especially MWCNTs, the polymer coils are subjected to perturbation leading to entropic loss in the system, which determine the miscibility in the blends. The configurational entropy near glass transition was assessed to understand the improved miscibility due to MWCNTs in this particular blend. The length of cooperativity suggests a cooperative motion of PS and PVME over shorter length scales in the case of MWCNTs as compared to other particles. This also hints at perturbed PVME motion in the network of MWCNTs. Taken together, our study reveals that the kinetic PVME arrest results in two different environments and is dependent on the effective concentration of MWCNTs in the blends.


Recent advances in hemophilia B therapy.
Hemophilia B is a hereditary bleeding disorder caused by the deficiency in coagulation factor IX. Understanding coagulation and the role of factor IX as well as patient population and diagnosis are all critical factors in developing treatment strategies and regimens for hemophilia B patients. Current treatment options rely on protein replacement therapy by intravenous injection, which have markedly improved patient lifespan and quality of life. However, issues with current options include lack of patient compliance due to needle-based administration, high expenses, and potential other complications (e.g., surgical procedures, inhibitor formation). As a result, these treatment options are also limited to developed countries. Recent advantages in hemophilia B treatment have focused on addressing these pain points. Emerging commercial products based on modified factor IX aim to reduce injection frequency. Exploratory research efforts have focused on novel drug delivery systems for orally administered treatment and gene therapy as a potential cure. Such alternative treatment methods are promising options for hemophilia B patients worldwide.


Efficacy and safety profile of long-term exposure to lenalidomide in patients with recurrent multiple myeloma.
Lenalidomide in combination with dexamethasone (Len/Dex) is indicated for patients with recurrent/refractory multiple myeloma (RRMM) who were treated with 1 prior therapy until evidence of disease progression. The objective of the current study was to determine the efficacy and safety profile of long-term exposure to Len/Dex. A total of 50 patients with RRMM who were treated with long-term Len for ≥ 2 years from 2 Intergroupe Francophone du Myélome (IFM) centers (Lille and Nancy) were included in the current study. The median age of the patients was 58 years, with 30% of the patients aged >65 years, 49% having an International Staging System stage of 2 and 3, 12% having severe renal insufficiency, and 8% demonstrating an adverse result on fluorescence in situ hybridization. Approximately 56% of the patients received treatment with Len/Dex for ≥ 3 years. The median duration of treatment with Len/Dex was 3 years (range, 2 years-7 years). The response rates for partial response or better and very good partial response or better for the overall cohort were 96% and 74%, respectively, which is similar to patients exposed to Len for ≥ 3 years. With a median follow-up of 4 years, 19 (38%) patients had stopped treatment with Len/Dex. The time to disease progression rate at 37 months was 78% and 91%, respectively, in patients exposed to Len for 2 years to <3 years and for ≥ 3 years (P=025). The safety profile was manageable, similar to that of Len when administered for a shorter period of time; 16% of patients had grade 3 to 4 neutropenia, 6% had thrombopenia, 6% had anemia, and 20% experienced thromboembolic events, all of venous type. The annual incidence rate of second primary malignancy was 1.96% in the current series. The results of the current study confirmed that the Len/Dex combination is feasible for long-term use in patients with RRMM, with a significant benefit noted in terms of time to disease progression for prolonged treatment with Len/Dex.


Asymmetric 1,3-dipolar cycloadditions of acrylamides.
This critical review, which is relevant to researchers in synthetic organic chemistry, focuses on asymmetric 1,3-dipolar cycloadditions with acrylamides. The use of chiral acrylamides as dipolarophiles leads to high levels of stereocontrol, due to conformational constraint in the acrylamides. Employment of chiral tertiary acrylamides containing nitrogen heterocycles is particularly effective in controlling the stereoselectivity. Following a general overview of 1,3-dipolar cycloadditions, the main body of the review focuses on asymmetric 1,3-dipolar cycloadditions of acrylamides with nitrile oxides, nitrones, diazoalkanes and azomethine ylides, with particular emphasis on the rationale for the observed stereocontrol (215 references).


Adeno-associated virus serotype 8 (AAV8) delivery of recombinant A20 to skeletal muscle reduces pathological activation of nuclear factor (NF)-κB in muscle of mdx mice.
Duchenne muscular dystrophy (DMD) is a genetic muscle disease caused by the absence of a functional dystrophin protein. Lack of dystrophin protein disrupts the dystrophin-glycoprotein complex causing muscle membrane instability and degeneration. One of the secondary manifestations resulting from lack of functional dystrophin in muscle tissue is an increased level of cytokines that recruit inflammatory cells, leading to chronic upregulation of the nuclear factor (NF)-κB. Negative regulators of the classical NF-κB pathway improve muscle health in the mdx mouse model for DMD. We have previously shown in vitro that a negative regulator of the NF-κB pathway, A20, plays a role in muscle regeneration. Here, we show that overexpression of A20 by using a muscle-specific promoter delivered with an adeno-associated virus serotype 8 (AAV8) vector to the mdx mouse decreases activation of the NF-κB pathway in skeletal muscle. Recombinant A20 expression resulted in a reduction in number of fibers with centrally placed nuclei and a reduction in the number of T cells infiltrating muscle transduced with the AAV8-A20 vector. Taken together, we conclude that overexpression of A20 in mdx skeletal muscle provides improved muscle health by reduction of chronic inflammation and muscle degeneration. These results suggest A20 is a potential therapeutic target to ameliorate symptoms of DMD.


Mycobacteria in Crohn's disease: DNA probes identify the wood pigeon strain of Mycobacterium avium and Mycobacterium paratuberculosis from human tissue.
Mycobacterium paratuberculosis is known to cause Johne's disease, a granulomatous ileitis in ruminants, and may be involved in some cases of Crohn's disease. Like M. paratuberculosis, the wood pigeon strain of Mycobacterium avium may also show mycobactin dependence on primary isolation that is attenuated on further subculturing. A wood pigeon strain, M. avium restriction fragment length polymorphism (RFLP) type A/I, is also capable of causing granulomatous ileitis in experimental animal models but is not known to cause disease in humans. M. avium RFLP type A is associated with disease in immunocompromised hosts. Three DNA probes, pMB22 and the two subclones pMB22/S4 and pMB/S12, were found to be capable of distinguishing among M. paratuberculosis, M. avium type A, and M. avium type A/I (wood pigeon strain) on the basis of RFLPs. These DNA probes were used to identify two mycobacterial isolates (M. paratuberculosis and M. avium type A/I, wood pigeon strain) derived from the intestinal tissues of two patients with Crohn's disease. In addition, the wood pigeon strain of M. avium was identified from a patient with ulcerative colitis, and M. avium RFLP type A was identified from a patient with colonic carcinoma. This is the first time that M. avium A/I (wood pigeon strain) is known to have been isolated from human tissue. There are too few isolates to speculate about the etiological significance of mycobacteria and inflammatory bowel disease, but it is reasonable to conjecture that M. paratuberculosis may be responsible for some cases of Crohn's disease and that the wood pigeon strain of M. avium may also be an inflammatory bowel disease pathogen in humans.


Prediction of incidence and bio-psycho-socio-cultural risk factors of post-partum depression immediately after birth in an Iranian population.
Post-partum depression (PPD) is the most prevalent mental problem associated with childbirth. The purpose of the present study was to determine the incidence of early PPD and possible relevant risk factors among women attending primary health centers in Mazandaran province, Iran for the first time. A longitudinal cohort study was conducted among 2279 eligible women during weeks 32-42 of pregnancy to determine bio-psycho-socio-cultural risk factors of depression at 2 weeks post-partum using the Iranian version of the Edinburgh Postnatal Depression Scale (EPDS). Univariate and hierarchical multiple logistic regression models were used for data analysis. Among 1,739 mothers whose EPDS scores were ≤ 12 during weeks 32-42 of gestation and at the follow-up study, the cumulative incidence rate of depression was 6.9% (120/1,739) at 2 weeks post-partum. In the multivariate model the factor that predicted depression symptomatology at 2 weeks post-partum was having psychiatric distress in pregnancy based on the General Health Questionnaire (GHQ) (OR = 1.06, (95% CI: 1.04-1.09), p = 0.001). The risk of PPD also lower in those with sufficient parenting skills (OR = 0.78 (95% CI: 0.69-0.88), p = 0.001), increased marital satisfaction (OR = 0.94 (95% CI: 0.9-0.99), p = 0.03), increased frequency of practicing rituals (OR = 0.94 (95% CI: 0.89-0.99), p = 0.004) and in those whose husbands had better education (OR = 0.03 (95% CI: 0.88-0.99), p = 0.04). The findings indicated that a combination of demographic, sociological, psychological and cultural risk factors can make mothers vulnerable to PPD.


Novel surgical approach for axillary hidradenitis suppurativa using a bilayer dermal regeneration template: a retrospective case study.
Hidradenitis suppurativa (HS) is a chronic debilitating disease of apocrine gland-bearing skin characterized by recurrent abscesses with subsequent rupture, scarring, and draining sinus tracts, most frequently affecting the axillary, inguinal, and anogenital regions. Conservative and temporizing treatment methods have been used to treat mild to moderate disease, but wide local excision of affected tissue is necessary for advanced disease. This creates a large soft tissue defect for which there is no consensus for reconstruction. Recovery is hampered by disease recurrence, tissue necrosis, and reoperation. The authors have described in this case study an alternative surgical approach to treat severe HS. All surgical procedures were performed by dedicated burn surgeons at a regional burn center using a two-stage surgical approach. The first stage is a wide local excision of all affected axillary tissue with immediate placement of a bilayer dermal regeneration template to cover the defect. This is secured with a negative pressure wound therapy dressing. The second stage uses a thin split thickness skin graft to close the wound. Results of four patients are presented. There were no recurrences of HS. Two patients required reoperations to address granulation tissue overgrowth and small areas of autograft loss. One patient experienced skin substitute loss as a result of infection. Inadequate excision of HS is the leading cause of disease recurrence. Using a bilayer dermal regeneration template with subsequent skin graft, surgeons can be aggressive in their excision of HS, achieving satisfactory functional and cosmetic results and minimizing axillary recurrence.


Three-dimensionally printed biological machines powered by skeletal muscle.
Combining biological components, such as cells and tissues, with soft robotics can enable the fabrication of biological machines with the ability to sense, process signals, and produce force. An intuitive demonstration of a biological machine is one that can produce motion in response to controllable external signaling. Whereas cardiac cell-driven biological actuators have been demonstrated, the requirements of these machines to respond to stimuli and exhibit controlled movement merit the use of skeletal muscle, the primary generator of actuation in animals, as a contractile power source. Here, we report the development of 3D printed hydrogel "bio-bots" with an asymmetric physical design and powered by the actuation of an engineered mammalian skeletal muscle strip to result in net locomotion of the bio-bot. Geometric design and material properties of the hydrogel bio-bots were optimized using stereolithographic 3D printing, and the effect of collagen I and fibrin extracellular matrix proteins and insulin-like growth factor 1 on the force production of engineered skeletal muscle was characterized. Electrical stimulation triggered contraction of cells in the muscle strip and net locomotion of the bio-bot with a maximum velocity of ∼ 156 μm s(-1), which is over 1.5 body lengths per min. Modeling and simulation were used to understand both the effect of different design parameters on the bio-bot and the mechanism of motion. This demonstration advances the goal of realizing forward-engineered integrated cellular machines and systems, which can have a myriad array of applications in drug screening, programmable tissue engineering, drug delivery, and biomimetic machine design.


"Descubriendo Soluciones Juntos"-An argument for adapting problem-solving training for Latinx care partners after traumatic brain injury (TBI).
This commentary demonstrates the need for culturally adapted interventions to support informal caregivers (care partners) of adults with traumatic brain injuries (TBI), proposes and supports an evidence-based intervention, Problem-Solving Training (PST), uniquely suitable for cultural adaptation for Latinx care partners, and describes several considerations and concrete suggestions for initial cultural adaption of PST for Latinx care partners of adults with TBI. Caregiving among Latinxs is rooted in cultural values and norms that may facilitate or challenge family coping and adaptation after TBI in the United States. Evidence-based interventions to address emotional distress, health, and caregiver burden are needed for Latinx care partners, but must first be translated and adapted to address language and cultural values. Compared with other cognitive and behavioral evidence-based interventions, PST is ideal for cultural adaptation, as the problem-solving process is driven by, and therefore sensitive and responsive to, care partners and their individual values and situations. Adapting evidence-based problem-solving interventions like PST ("Descubriendo Soluciones Juntos") to be culturally tailored and culturally sensitive for Spanish-speaking Latinx care partners of adults with TBI could reduce existing health disparities and improve the health, well-being, and quality of life of these care partners. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Evidence of an amnesia-like cued-recall memory impairment in nondementing idiopathic Parkinson's disease.
Medicated, non-dementing mild-to-moderate Parkinson's disease (PD) patients usually show recall/recollection impairments but have only occasionally shown familiarity impairments. We aimed to assess two explanations of this pattern of impairment. Recollection typically improves when effortful planning of encoding and retrieval processing is engaged. This depends on prefrontally-dependent executive processes, which are often disrupted in PD. Relative to an unguided encoding and retrieval of words condition (C1), giving suitable guidance at encoding alone (C2) or at encoding and retrieval (C3) should, if executive processes are disrupted, improve PD recollection more than control recollection and perhaps raise it to normal levels. Familiarity, being a relatively automatic kind of memory, whether impaired or intact, should be unaffected by guidance. According to the second explanation, PD deficits are amnesia-like and caused by medial temporal lobe dysfunction and although poorer recollection, which is caused by hippocampal disruption, may be improved by guidance, it should not improve more than control recollection. Familiarity impairment will also occur if the perirhinal cortex is disrupted, but will be unimproved by guidance. Without guidance, recollection/recall was impaired in thirty PD patients relative to twenty-two healthy controls and remained relatively equally impaired when full guidance was provided (C1 vs C3), both groups improving to broadly the same extent. Although impaired, and markedly less so than recollection, familiarity was not improved by guidance in both groups. The patients showed elevated rates of subclinical depressive symptoms, which weakly correlated with recall/recollection in all three conditions. PD executive function was also deficient and correlated with unguided/C1 recollection only. Our results are consistent with a major cause of the patients' recall/recollection impairments being hippocampal disruption, probably exacerbated by subclinical depressive symptoms. However, the results do not exclude a lesser prefrontal cortex contribution because patient executive functions were impaired and correlated solely with unguided overall recollection.


Dual-color co-filamentation in Argon.
We investigate both experimentally and theoretically the mechanisms driving the co-filamentation of two ultrashort laser pulses at 800 and 400 nm in Argon. The cross-Kerr lens and cross-phase modulation between the two filaments of different colors bridging both the continuum spectra and the plasma channels induced by the individual pulses. This dual-color filamentation also results in the simultaneous generation of two few-cycle pulses at both 800 and 400 nm, providing a potential way to generate attosecond pulses.


Ankle injury rehabilitation (AIR): a feasibility randomised controlled trial comparing functional bracing to plaster cast in the treatment of adult ankle fractures.
Approximately 9% of a trauma surgeon's workload in the UK is managing ankle fractures. Following an ankle fracture immobilisation with a plaster cast or removable orthotic is usual. The aim of this research was to assess the feasibility of a large multi-centre randomised controlled trial (RCT) to evaluate the difference between plaster cast and a removable orthotic for the management of adults with an ankle fracture. A feasibility randomised controlled trial was undertaken in a UK trauma hospital in adults with an ankle fracture for which the treating clinician would consider plaster cast a reasonable management option. Exclusions included open or pathological fracture, unable to adhere to trial procedures, had other lower limb injury or required close contact casting. Participants were randomised using an independent telephone service to receive either plaster cast or removable orthotic. The primary outcome was to determine the recruitment and follow-up rates at 6 weeks, 3 and 6 months to assess the feasibility of a full RCT. Eighty five eligible patients presented during the 10-month recruitment period, 50 consented. Two patients were randomised who did not fulfil the eligibility criteria (protocol deviations), and 1 patient from each group crossed over. Follow-up at each time point was 92% at 6 weeks; 74% at 3 months and 83% at 6 months. Recruitment and follow-up data demonstrated feasibility of conducting a larger-scale randomised controlled trial. The distributional properties of the patient-reported outcome measures will be used to determine future sample sizes. This study is registered with the ISRCTN (ISRCTN17809322), assigned 5 November 2015 and approved by the NRES Committee (The Black Country, 15/WM/0340), protocol version 2.0 (17 November 2015). It is co-sponsored by the University Hospitals Coventry and Warwickshire NHS Trust and University of Warwick and funded by the NIHR Research for Patient Benefit (PB-PG-0614-34,009). The trial sponsors have no direct involvement in any aspects of study design, conduct or decision to submit the report for publication.


Cone Photoreceptor Cell Segmentation and Diameter Measurement on Adaptive Optics Images Using Circularly Constrained Active Contour Model.
Cone photoreceptor cells can be noninvasively imaged in the living human eye by using nonconfocal adaptive optics scanning ophthalmoscopy split detection. Existing metrics, such as cone density and spacing, are based on simplifying cone photoreceptors to single points. The purposes of this study were to introduce a computer-aided approach for segmentation of cone photoreceptors, to apply this technique to create a normal database of cone diameters, and to demonstrate its use in the context of existing metrics. Cone photoreceptor segmentation is achieved through a circularly constrained active contour model (CCACM). Circular templates and image gradients attract active contours toward cone photoreceptor boundaries. Automated segmentation from in vivo human subject data was compared to ground truth established by manual segmentation. Cone diameters computed from curated data (automated segmentation followed by manual removal of errors) were compared with histology and published data. Overall, there was good agreement between automated and manual segmentations and between diameter measurements (n = 5191 cones) and published histologic data across retinal eccentricities ranging from 1.35 to 6.35 mm (temporal). Interestingly, cone diameter was correlated to both cone density and cone spacing (negatively and positively, respectively; P < 0.01 for both). Application of the proposed automated segmentation to images from a patient with late-onset retinal degeneration revealed the presence of enlarged cones above individual reticular pseudodrusen (average 23.0% increase, P < 0.05). CCACM can accurately segment cone photoreceptors on split detection images across a range of eccentricities. Metrics derived from this automated segmentation of adaptive optics retinal images can provide new insights into retinal diseases.


Relationships Between Weight, Physical Activity, and Back Pain in Young Adult Women.
Back pain causes enormous financial and disability burden worldwide, which could potentially be reduced by understanding its determinants to develop effective prevention strategies. Our aim was to identify whether modifiable risk factors, weight and physical activity, are predictive of back pain in young adult women.Women born between 1973 and 1978 were randomly selected from the national health insurance scheme database to participate in The Australian Longitudinal Study of Women's Health. Self-reported data on back pain in the last 12 months, weight, height, age, education status, physical activity, and depression were collected in 2000, 2003, 2006, 2009, and 2012. In 2000, 9688 women completed the questionnaire and 83% completed follow-up 12 years later.At baseline, median age was 24.6 years and 41% had self-reported back pain. For every 5 kg higher weight at baseline, there was a 5% (95% confidence interval [CI] 4%-6%) increased risk of back pain over the next 12 years. Higher weight at each survey also predicted back pain risk 3 years later (P < 0.001). The effects of weight on back pain were most significant in those with BMI ≥25 kg/m and were observed at all levels of physical activity. Inadequate physical activity and depression were independent predictors of back pain over the following 12 years (both P < 0.001), after adjusting for age, weight, height, and education status.Back pain is common in community-based young adult women. Higher weight, inadequate levels of physical activity, and depression were all independent predictors of back pain over the following decade. Furthermore, the adverse effects of weight on back pain were not mitigated by physical activity. Our findings highlight the role of both higher weight and physical inactivity in back pain among young women and suggest potential opportunities for future prevention.


Foot-and-mouth disease virus serotype O phylodynamics: genetic variability associated with epidemiological factors in Pakistan.
One of the most challenging aspects of foot-and-mouth disease (FMD) control is the high genetic variability of the FMD virus (FMDV). In endemic settings such as the Indian subcontinent, this variability has resulted in the emergence of pandemic strains that have spread widely and caused devastating outbreaks in disease-free areas. In countries trying to control and eradicate FMD using vaccination strategies, the constantly evolving and wide diversity of field FMDV strains is an obstacle for identifying vaccine strains that are successful in conferring protection against infection with field viruses. Consequently, quantitative knowledge on the factors that are associated with variability of the FMDV is prerequisite for preventing and controlling FMD in the Indian subcontinent. A hierarchical linear model was used to assess the association between time, space, host species and the genetic variability of serotype O FMDV using viruses collected in Pakistan from 2005 to 2011. Significant (P<0.05) amino acid and nucleotide variations were associated with spatial distance, but not with differences in host species, which is consistent with the frequent multi-species infection of this serotype O FMDV. Results from this study will contribute to the understanding of FMDV variability and to the design of FMD control strategies in Pakistan. Viruses sequenced here also provide the earliest reported isolate from the Pan Asia II(ANT-10) sublineage, which has caused several outbreaks in the Middle East and spread into Europe (Bulgaria) and Africa (Libya).


Real-time and low-cost sensing technique based on photonic bandgap structures.
A technique for the development of low-cost and high-sensitivity photonic biosensing devices is proposed and experimentally demonstrated. In this technique, a photonic bandgap structure is used as transducer, but its readout is performed by simply using a broadband source, an optical filter, and a power meter, without the need of obtaining the transmission spectrum of the structure; thus, a really low-cost system and real-time results are achieved. Experimental results show that it is possible to detect very low refractive index variations, achieving a detection limit below 2×10(-6) refractive index units using this low-cost measuring technique.


Association between route of illicit drug administration and hospitalizations for infective endocarditis.
This study examined the association between the route of drug administration and being hospitalized for infective endocarditis among 4817 treatment-seeking illicit drug users in Finland. Cox regression models were used to examine the association between the route of drug administration and infective endocarditis hospitalization, adjusted for age, gender, and homelessness. Cases of infective endocarditis as a primary/main diagnosis were tracked using the 10th version of the International Classification of Disease code I33. In all, 47 persons had a primary diagnosis of infective endocarditis. These 47 persons contributed a total of 95 hospitalizations and their total length of hospital stay was 1393 days. There was a statistically significant difference in hospitalizations between injectors and non-injectors (Log-Rank test p = 0.018). Univariate Cox model showed that injectors had higher hazard or risk for infective endocarditis hospitalization compared to non-injectors (hazard ratio: 2.04, 95% confidence interval: 1.12-3.73, p = 0.020). After adjusting for age, gender, and homelessness in the multivariate model, the elevated hazard among injectors compared to non-injectors remained statistically significant with adjusted hazard ratio of 2.12 (95% confidence interval: 1.11-4.07, p = 0.024). The study findings suggested a need to boost harm reduction measures targeting high-risk injecting and other health behaviors among injecting drug users in order to reduce their hospitalizations for infective endocarditis.


Ulcer site and complications: relation to Helicobacter pylori infection and NSAID use.
The aim of this study was to investigate the relationship between the presence and location of ulcers, H. pylori infection, NSAID use, and major upper gastrointestinal tract bleeding. We studied 100 consecutive patients with duodenal ulcers and 145 consecutive patients with benign gastric ulcers. Ninety-nine percent of the duodenal ulcer patients and 92% of the gastric ulcer patients had H. pylori infection; all gastric ulcer patients without H. pylori infection were using NSAIDs. Gastric ulcers in patients with H. pylori infection who were not using NSAIDs were more likely to be on the lesser curvature (85%) than ulcers in NSAID users who had no H. pylori infection (35%) (p < 0.01). Conversely, only 5% of gastric ulcers in H. pylori-positive patients who were not using NSAIDs were on the greater curvature, compared to 45% in H. pylori-negative NSAID users (p < 0.01), and 23% in patients with both possible etiologies. The frequency of NSAID use was very high in patients presenting with upper gastrointestinal tract bleeding: 21 of 25 with gastric ulcers (84%) and 13 of 21 with duodenal ulcers (62%; p < 0.01 for each, compared to bleeding without taking NSAIDs). Overall, 74% of patients with upper gastrointestinal hemorrhage from peptic ulcer were taking NSAIDs. The prevalence of H. pylori infection was similar among the ulcer patients presenting with and without upper gastrointestinal tract bleeding. The location of a gastric ulcer on the greater curvature, and presentation with upper gastrointestinal tract bleeding, are separate and valuable clues to the involvement of NSAIDs. NSAID use may now be responsible for most bleeding complications of ulcer disease, regardless of H. pylori status.


Effect of a beverage fortified with evaporated sugarcane juice on hemoglobin levels in preschool children.
The study objective was to measure the effect of consumption of a beverage mixed with a high-iron sweetener (evaporated sugarcane juice known as rapadura) on hemoglobin levels in preschool children, and to compare it with the effect of consuming the same beverage sweetened with refined sugar. Research consisted of a 12-week randomized, controlled double-blind trial conducted in 2007 at a state-run school in Sobral, Brazil, among children aged 2-3 years. The study sample was divided into two groups-one consuming cashew juice mixed with 25 g of rapadura and 40 mg of ascorbic acid (per 200-mL serving), and another consuming the same quantity of juice and ascorbic acid sweetened with 25 g of standard refined sugar. A significant statistical increase in hemoglobin was observed in the group consuming the rapadura-fortified beverage. It was therefore concluded that consumption of rapadura increased hemoglobin and thus reduced iron deficiency anemia in preschool children.


Exome Sequencing of Cell-Free DNA from Metastatic Cancer Patients Identifies Clinically Actionable Mutations Distinct from Primary Disease.
The identification of the molecular drivers of cancer by sequencing is the backbone of precision medicine and the basis of personalized therapy; however, biopsies of primary tumors provide only a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. A liquid biopsy, in the form of cell-free DNA (cfDNA) sequencing, has the potential to capture the inter- and intra-tumoral heterogeneity present in metastatic disease, and, through serial blood draws, track the evolution of the tumor genome. In order to determine the clinical utility of cfDNA sequencing we performed whole-exome sequencing on cfDNA and tumor DNA from two patients with metastatic disease; only minor modifications to our sequencing and analysis pipelines were required for sequencing and mutation calling of cfDNA. The first patient had metastatic sarcoma and 47 of 48 mutations present in the primary tumor were also found in the cell-free DNA. The second patient had metastatic breast cancer and sequencing identified an ESR1 mutation in the cfDNA and metastatic site, but not in the primary tumor. This likely explains tumor progression on Anastrozole. Significant heterogeneity between the primary and metastatic tumors, with cfDNA reflecting the metastases, suggested separation from the primary lesion early in tumor evolution. This is best illustrated by an activating PIK3CA mutation (H1047R) which was clonal in the primary tumor, but completely absent from either the metastasis or cfDNA. Here we show that cfDNA sequencing supplies clinically actionable information with minimal risks compared to metastatic biopsies. This study demonstrates the utility of whole-exome sequencing of cell-free DNA from patients with metastatic disease. cfDNA sequencing identified an ESR1 mutation, potentially explaining a patient's resistance to aromatase inhibition, and gave insight into how metastatic lesions differ from the primary tumor.


Neonatal maturation of the hypercapnic ventilatory response and central neural CO2 chemosensitivity.
The ventilatory response to CO2 changes as a function of neonatal development. In rats, a ventilatory response to CO2 is present in the first 5 days of life, but this ventilatory response to CO2 wanes and reaches its lowest point around postnatal day 8. Subsequently, the ventilatory response to CO2 rises towards adult levels. Similar patterns in the ventilatory response to CO2 are seen in some other species, although some animals do not exhibit all of these phases. Different developmental patterns of the ventilatory response to CO2 may be related to the state of development of the animal at birth. The triphasic pattern of responsiveness (early decline, a nadir, and subsequent achievement of adult levels of responsiveness) may arise from the development of several processes, including central neural mechanisms, gas exchange, the neuromuscular junction, respiratory muscles and respiratory mechanics. We only discuss central neural mechanisms here, including altered CO2 sensitivity of neurons among the various sites of central CO2 chemosensitivity, changes in astrocytic function during development, the maturation of electrical and chemical synaptic mechanisms (both inhibitory and excitatory mechanisms) or changes in the integration of chemosensory information originating from peripheral and multiple central CO2 chemosensory sites. Among these central processes, the maturation of synaptic mechanisms seems most important and the relative maturation of synaptic processes may also determine how plastic the response to CO2 is at any particular age.


Assessment of dynamic structural instabilities across 24 cubic inorganic halide perovskites.
Metal halide perovskites are promising candidates for next-generation photovoltaic and optoelectronic applications. The flexible nature of the octahedral network introduces complexity when understanding their physical behavior. It has been shown that these materials are prone to decomposition and phase competition, and the local crystal structure often deviates from the average space group symmetry. To make stable phase-pure perovskites, understanding their structure-composition relations is of central importance. We demonstrate, from lattice dynamics calculations, that the 24 inorganic perovskites ABX3 (A = Cs, Rb; B = Ge, Sn, Pb; X = F, Cl, Br, I) exhibit instabilities in their cubic phase. These instabilities include cation displacements, octahedral tilting, and Jahn-Teller distortions. The magnitudes of the instabilities vary depending on the chemical identity and ionic radii of the composition. The tilting instabilities are energetically dominant and reduce as the tolerance factor increases, whereas cation displacements and Jahn-Teller type distortions depend on the interactions between the constituent ions. We further considered representative tetragonal, orthorhombic, and monoclinic perovskite phases to obtain phonon-stable structures for each composition. This work provides insights into the thermodynamic driving force of the instabilities and will help guide computer simulations and experimental synthesis in material screening.


Degenerative lumbar stenosis: diagnosis and management.
Degenerative lumbar stenosis is a common cause of disabling back and lower extremity pain among older persons. The process usually begins with degeneration of the intervertebral disks and facet joints, resulting in narrowing of the spinal canal and neural foramina. Associated factors may include a developmentally narrow spinal canal and degenerative spinal instability. Nonoperative management includes restriction of aggravating activities, physical therapy, and anti-inflammatory medications. If nonoperative treatment has failed, surgical treatment may be appropriate. Decompression should be performed so as to address all clinically relevant neural elements while maintaining spinal stability. If instability is present, autogenous intertransverse bone grafting is recommended. There may be an advantage to augmenting some of these procedures with internal fixation. Surgical success rates as high as 85% have been reported, but may be compromised by inadequate decompression, inadequate stabilization, or medical comorbidities. Short-term follow-up data indicate that operative management provides more effective relief than nonoperative treatment, but prospective studies comparing the effects of nonoperative and operative interventions on the long-term natural history of lumbar spinal stenosis are needed.


Induction of antitumor immunity with combination of HER2/neu DNA vaccine and interleukin 2 gene-modified tumor vaccine.
The therapeutic effects of both cytokine-secreting tumor vaccine and DNA vaccine were studied using mouse MBT-2 bladder cancer cells as a model. Cytokine-secreting MBT-2 cells were obtained by infecting cells with retroviral particles containing interleukin (IL) 2-, IL-4-, or granulocyte-macrophage colony-stimulating factor (GM-CSF)-expression vector. The MBT-2-IL-2 cells were not tumorigenic in syngenic C3H mice at all. Tumor formation decreased significantly for the MBT-2-GM-CSF cells. MBT-2-IL-2, -IL-4, and -GM-CSF cells were killed by irradiation and tested as tumor vaccines. The irradiated MBT2-IL-2 cells could complete protect mice from the growth of the preexisting tumor cells, and the immune memory lasted for 8 months. On the other hand, irradiated MBT-2-IL-4 and MBT-2-GM-CSF cells were less effective. When the loading tumor mass increased, all tumor vaccines lost protective effects. DNA vaccine encoding the tumor antigen neu was additionally tested to improve the therapeutic efficacy. Coinjection of 60 microg pSV-neu DNA was effective in enhancing the antitumor effects of MBT2-IL-2; however, DNA vaccine alone cannot prevent the progression of the preexisting tumor. Immunohistochemical analysis of tumor infiltrate revealed massive increase of CD4+ lymphoid cells in the group of mice treated with both DNA vaccine and IL-2-secreted tumor vaccine. Western blotting demonstrated the presence of anti-neu antibody in the serum from immunized mice. In contrast, combination of DNA vaccine and MBT-2-GM-CSF has no additive effect. The results indicate the combination of DNA vaccine and IL-2-secreting tumor vaccine can additionally improve therapeutic efficacy, and the efficacy is correlated with the increase of CD4+ T lymphocytes and anti-neu antibody.


Aquaculture fouling: Efficacy of potassium monopersulphonate triple salt based disinfectant (Virkon® Aquatic) against Ciona intestinalis.
With the increasing spread of invasive marine species and their detrimental effects on aquaculture operations globally, mitigation strategies need to be optimized to mitigate economic impacts. The efficacy of a potassium monopersulphonate triple salt based disinfectant used in the aquaculture industry (Virkon® Aquatic at 0.5-5%) was evaluated against the solitary tunicate Ciona intestinalis, as well as the susceptibility of three different age groups of C. intestinalis to the treatment and the effect of the disinfectant on mussel mortality. Younger C. intestinalis were most affected by all treatments, and almost all immersion applications significantly decreased the biomass of C. intestinalis compared to untreated plates. Disinfectant solutions of ≥ 1% reduced biomass below pre-treatment levels. Mussel mortality was low, especially for solutions <3%. C. intestinalis should be treated 4 weeks post-settlement to maximize antifouling treatment effects. Immersion in 3% disinfectant for 30 s reduced the biomass of C. intestinalis by up to 89% and would be feasible in field applications using existing treatment equipment.


Recovery of Repressed Memories in Fibromyalgia Patients Treated With Hyperbaric Oxygen - Case Series Presentation and Suggested Bio-Psycho-Social Mechanism.
Fibromyalgia Syndrome (FMS) is a condition considered to represent a prototype of central sensitization syndrome, characterized by chronic widespread pain and along with symptoms of fatigue, non-restorative sleep and cognitive difficulties. FMS can be induced by trauma, infection or emotional stress with cumulative evidence that dissociation is relatively frequent in FMS patients. Two randomized controlled trials have shown that hyperbaric oxygen therapy (HBOT) can induce neuroplasticity and be effective in patients suffering from FMS. In this paper we present, for the first time, case series of female fibromyalgia patients who, in the course of HBOT, suddenly recalled repressed traumatic memories of childhood sexual abuse (CSA). The surfacing of the repressed (dissociative) memories decades after the sexual abuse events was sudden and utterly surprising. No psychological intervention was involved. As the memories surfaced, the physical pain related to FMS subsided. In one patient who had brain single photon emission CT (SPECT) before and after HBOT, the prefrontal cortex appeared suppressed before and reactivated after. The 3 cases reported in this article are representative of a total of nine fibromyalgia patients who experienced a retrieval of repressed memory during HBOT. These cases provide insights on dissociative amnesia and suggested mechanism hypothesis that is further discussed in the article. Obviously, prospective studies cannot be planned since patients are not aware of their repressed memories. However, it is very important to keep in mind the possibility of surfacing memories when treating fibromyalgia patients with HBOT or other interventions capable of awakening dormant brain regions.


Embedded feature ranking for ensemble MLP classifiers.
A feature ranking scheme for multilayer perceptron (MLP) ensembles is proposed, along with a stopping criterion based upon the out-of-bootstrap estimate. To solve multi-class problems feature ranking is combined with modified error-correcting output coding. Experimental results on benchmark data demonstrate the versatility of the MLP base classifier in removing irrelevant features.


Fabrication of Janus particles composed of poly (lactic-co-glycolic) acid and hard fat using a solvent evaporation method.
The feasibility of fabricating Janus particles based on phase separation between a hard fat and a biocompatible polymer was investigated. The solvent evaporation method used involved preparing an oil-in-water (o/w) emulsion with a mixture of poly (lactic-co-glycolic) acid (PLGA), hard fat, and an organic solvent as the oil phase and a polyvinyl alcohol aqueous solution as the water phase. The Janus particles were formed when the solvent was evaporated to obtain certain concentrations of PLGA and hard fat in the oil phase, at which phase separation was estimated to occur based on the phase diagram analysis. The hard fat hemisphere was proven to be the oil phase using a lipophilic dye Oil Red O. When the solvent evaporation process was performed maintaining a specific volume during the emulsification process; Janus particles were formed within 1.5 h. However, the formed Janus particles were destroyed by stirring for over 6 h. In contrast, a few Janus particles were formed when enough water to dissolve the oil phase solvent was added to the emulsion immediately after the emulsification process. The optimized volume of the solvent evaporation medium dominantly formed Janus particles and maintained the conformation for over 6 h with stirring. These results indicate that the formation and stability of Janus particles depend on the rate of solvent evaporation. Therefore, optimization of the solvent evaporation rate is critical to obtaining stable PLGA and hard fat Janus particles.


Mycobacterium kansasii infection of the spine in a patient with sarcoidosis: a case report and literature review.
Mycobacterium kansasii is an acid-fast bacillus most commonly associated with pulmonary pathology. Infection of the spine is exceedingly rare, with just three reported cases, two of which were in human immunodeficiency virus and acquired immunodeficiency syndrome patients. This case report presents a case of vertebral osteomyelitis secondary to M. kansasii infection and reviews existing literature on this pathogen. The patient, a 37-year-old male with sarcoidosis, sustained a M. kansasii infection of the spine, resulting in vertebral osteomyelitis of L1 and L2 and discitis of the L1-L2 disc. This finding was confirmed by bone and intervertebral disc biopsy. Initially, the patient was thought to have a compression fracture of L2. However, the decision to perform a biopsy was made because of the patient's persistent febrile episodes and magnetic resonance imaging findings. The patient did not have any neurological deficits. He was successfully treated with antimicrobials, with no recurrent symptoms at 2-year follow-up. This case is the first reported case of a M. kansasii infection of the spine in a patient with sarcoidosis.


Subtypes of human immunodeficiency virus type 1 and disease stage among women in Nairobi, Kenya.
In sub-Saharan Africa, where the effects of human immunodeficiency virus type 1 (HIV-1) have been most devastating, there are multiple subtypes of this virus. The distribution of different subtypes within African populations is generally not linked to particular risk behaviors. Thus, Africa is an ideal setting in which to examine the diversity and mixing of viruses from different subtypes on a population basis. In this setting, it is also possible to address whether infection with a particular subtype is associated with differences in disease stage. To address these questions, we analyzed the HIV-1 subtype, plasma viral loads, and CD4 lymphocyte levels in 320 women from Nairobi, Kenya. Subtype was determined by a combination of heteroduplex mobility assays and sequence analyses of envelope genes, using geographically diverse subtype reference sequences as well as envelope sequences of known subtype from Kenya. The distribution of subtypes in this population was as follows: subtype A, 225 (70.3%); subtype D, 65 (20.5%); subtype C, 22 (6.9%); and subtype G, 1 (0.3%). Intersubtype recombinant envelope genes were detected in 2.2% of the sequences analyzed. Given that the sequences analyzed represented only a small fraction of the proviral genome, this suggests that intersubtype recombinant viral genomes may be very common in Kenya and in other parts of Africa where there are multiple subtypes. The plasma viral RNA levels were highest in women infected with subtype C virus, and women infected with subtype C virus had significantly lower CD4 lymphocyte levels than women infected with the other subtypes. Together, these data suggest that women in Kenya who are infected with subtype C viruses are at more advanced stages of immunosuppression than women infected with subtype A or D. There are at least two models to explain the data from this cross-sectional study; one is that infection with subtype C is associated with a more rapid disease progression, and the second is that subtype C represents an older epidemic in Kenya. Discriminating between these possibilities in a longitudinal study will be important for increasing our understanding of the role of specific subtypes in the transmission and pathogenesis of HIV-1.


Adversities and mental health needs of pregnant adolescents in Kenya: identifying interpersonal, practical, and cultural barriers to care.
Adolescent pregnancies present a great public health burden in Kenya and Sub-Saharan Africa (UNFPA, Motherhood in Childhood: Facing the challenge of Adolescent Pregnancy, 2013). The disenfranchisement from public institutions and services is further compounded by cultural stigma and gender inequality creating emotional, psychosocial, health, and educational problems in the lives of vulnerable pregnant adolescents (Int J Adolesc Med Health 15(4):321-9, 2003; BMC Public Health 8:83, 2008). In this paper we have applied an engagement interview framework to examine interpersonal, practical, and cultural challenges faced by pregnant adolescents. Using a qualitative study design, 12 pregnant adolescents (ages 15-19) visiting a health facility's antenatal services in Nairobi were interviewed. All recruited adolescents were pregnant for the first time and screened positive on the nine-item Patient Health Questionnaire (PHQ-9) with 16% of 176 participants interviewed in a descriptive survey in the same Kangemi primary health facility found to be severely depressed (Osok et al., Depression and its psychosocial risk factors in pregnant Kenyan adolescents: a cross-sectional study in a community health Centre of Nairobi, BMC Psychiatry, 2018 18:136 https://doi.org/10.1186/s12888-018-1706-y). An engagement interview approach (Social Work 52(4):295-308, 2007) was applied to elicit various practical, psychological, interpersonal, and cultural barriers to life adjustment, service access, obtaining resources, and psychosocial support related to pregnancy. Grounded theory method was applied for qualitative data sifting and analysis (Strauss and Corbin, Basics of qualitative research, 1990). Findings revealed that pregnant adolescents face four major areas of challenges, including depression, anxiety and stress around the pregnancy, denial of the pregnancy, lack of basic needs provisions and care, and restricted educational or livelihood opportunities for personal development post pregnancy. These challenges were related both to existing social and cultural values/norms on gender and traditional family structure, as well as to service structural barriers (including prenatal care, mental health care, newborn care, parenting support services). More importantly, dealing with these challenges has led to negative mental health consequences in adolescent pregnant girls, including feeling insecure about the future, feeling very defeated and sad to be pregnant, and feeling unsupported and disempowered in providing care for the baby. Findings have implications for service planning, including developing more integrated mental health services for pregnant adolescents. Additionally, we felt a need for developing reproductive education and information dissemination strategies to improve community members' knowledge of pregnant adolescent mental health issues.


Field triage systems: methodologies from the literature.
The primary goal of the Neely Conference project is to work toward defining a set of research criteria for medical necessity in emergency medical services (EMS). This paper reviews the extant literature on triage and nontransport decisions made in the field by EMS personnel, with emphasis on the methodologies that have been used to date. Two types of medical necessity standards are considered. First, there are triage criteria for determining whether a given patient requires EMS transport to the hospital, or whether an alternative might be appropriate. These triage criteria might be incorporated into protocols that field personnel could apply on scene to determine the best disposition for a given patient. Second, there are the outcome measures against which the decisions made by the field personnel are judged. In some cases, the outcome measure is the judgment of a reviewing emergency physician or nurse, while in others specific outcome measures are used to judge the performance of the criteria and the decision making of the field providers. While review of the literature shows that no "standard" set of triage criteria have been generated or validated in determining medical necessity in EMS, there are certain themes that emerge from the literature, and these themes can likely form the basis of a consensus on elements of a medical necessity criteria that need to be validated and refined. These may include (for triage criteria) vital signs, chief complaints, and physical exam findings, and (for outcome measures) hospital admission, critical events, death, and diagnosis.


rs2735383, located at a microRNA binding site in the 3'UTR of NBS1, is not associated with breast cancer risk.
NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3'-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936-1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969-1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905-1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.


Differentiating impulsive and premeditated aggression: self and informant perspectives among adolescents with personality pathology.
Previous research has articulated the conceptual differentiation of impulsive and premeditated aggression. Little, if any, of this research has examined personological differences among adolescents with aggression-oriented pathology, and little, if any, has examined both self and informant perspectives. The current study examined such differentiation within a Conduct Disorder population in which normal and pathological personality characteristics were examined via self- and informant-report. Results indicated the two forms of aggression were independent: high impulsive aggression was associated with high Neuroticism, but high premeditated aggression was associated with low Agreeableness and high Extraversion. Overall, adolescents high in impulsive aggression had a pattern of personality characteristics that are seen as socially-detached and emotionally volatile. In contrast, adolescents high in premeditated aggression had a pattern of characteristics seen as egocentric and socially-engaged but without concern for others. The results have implications for the social and motivational mechanisms producing the two forms of aggression.


Attitudes Toward Gay Men and Lesbian Women Moderate Heterosexual Adults' Subjective Stress Response to Witnessing Homonegativity.
Minority stress theory posits that members of a stigmatized group, such as sexual minorities (lesbian, gay, bisexual, and other non-heterosexual individuals), are particularly subject to ill effects of minority-specific events (stressors), including overt homonegativity. Although adverse effects of homonegativity are well documented for sexual minorities, little is known about effects of witnessing homonegativity on heterosexual individuals. As a growing number of heterosexual individuals hold accepting views of sexual minority individuals, some detrimental effects of homonegativity may extend to heterosexual individuals. For example, prior studies demonstrate that when racial majority-group members witness discrimination against minority-group members, they may experience stress response, particularly if they hold positive attitudes toward the minority-group. In this experimental study, 263 heterosexual adults (Mage = 34.47 years, SD = 9.67, 51.7% female) were randomized to either witness homonegativity or to a control condition. Participants rated subjective stress on a 0-100 visual analogue scale both immediately before and after the film-based induction. Participants also completed a measure of their attitudes toward gay men and lesbian women. Moderation analyses indicated that participants who were more accepting of gay men and lesbian women experienced greater stress after the induction than those with less accepting views. Implications and limitations of these findings are discussed.


Nifedipine protects small intestine from cyclosporine-induced hemodynamic and functional impairment.
We have previously shown that cyclosporine (CsA) causes intestinal hemodynamic and functional impairments. In this study, we evaluated whether nifedipine protects the small intestine from such toxic side effects. Isogeneic small intestinal transplantation was performed in rats which then received one of the following two-week treatments: olive oil, 0.15 ml/kg/day i.m. as vehicle controls in group 1; nifedipine, 1 mg/kg/day i.m. in group 2; CsA, 15 mg/kg/day i.m. in group 3; and both nifedipine and CsA in group 4. Vascular resistance, whole tissue blood flow and its mucosal and serosal/muscularis distributions in both graft and recipient residual native intestines, and absorptive function were determined. The data showed that two-week treatment with CsA resulted in a marked elevation of vascular resistance from 51.0 +/- 6.8 to 72.4 +/- 11.1 U/g in the native whole tissue and from 53.7 +/- 7.2 to 78.2 +/- 12.1 U/g in the graft whole tissue, and decreases in blood flow from 1.59 +/- 0.26 to 1.11 +/- 0.17 ml/g/min in the native whole tissue and from 1.50 +/- 0.21 to 1.03 +/- 0.18 ml/g/min in the graft whole tissue and absorption from 227 +/- 36 to 166 +/- 26 mg glucose/dl. Mucosa was preferentially affected, while serosal/muscularis layers remained relatively unchanged. When nifedipine was concomitantly used with CsA, vascular resistance and blood flow values in the mucosal layer and whole intestinal tissue as well as absorptive function showed no significant differences from the baseline data. The changes observed in denervated grafts and recipient native intestines were similar. We conclude that nifedipine is effective in protecting both graft and native small intestines from CsA-induced toxicity in the rat.


Do spirituality and religiosity help in the management of cravings in substance abuse treatment?
The purpose of this study was to examine the relationship of spirituality, religiosity and self-efficacy with drug and/or alcohol cravings. A cross-sectional survey was completed by 77 male participants at an Australian Salvation Army residential rehabilitation service in 2007. The survey included questions relating to the participants' drug and/or alcohol use and also measures for spirituality, religiosity, cravings, and self-efficacy. The sample included participants aged between 19 and 74 years, with more than 57% reporting a diagnosis for a mental disorder and 78% reporting polysubstance misuse with alcohol most frequently endorsed as the primary drug of concern (71%). Seventy-five percent of the clients reported that spirituality and religious faith were useful components of the treatment program. A multivariate multiple regression analysis identified that spirituality and self-efficacy have significant relationships with cravings. Self-efficacy mediated the relationship between spirituality and drug and/or alcohol cravings. The limitations of this study included its cross-sectional design and a sample that was drawn from a faith-based program. Future research would benefit from the longitudinal examination of the relationship between spirituality, self-efficacy, and cravings; the exploration of a broader range of client-specific and interpersonal variables; and the inclusion of a control group from a secular treatment facility.