The role of quantitative myocardial contrast echocardiography in the study of coronary microcirculation in athlete's heart.
Quantitative myocardial contrast echocardiography was performed with harmonic power Doppler analysis using the background subtraction and Levovist (Schering AG, Berlin, Germany) as contrast agent in a triggered modality. Quantitative analysis of echocontrast was performed offline with PC software, obtaining the transit curves of microbubbles through the coronary capillary system. Coronary microcirculation in athletes showed a behavior substantially comparable with control participants, although at a higher level. Training determines a physiologic left ventricular hypertrophy that counterbalances the dilatation in the left ventricular chambers because of the higher blood volume in athletes compared with control participants. Angiogenesis and several functional adaptations (relaxation of small coronary arteries, increased production of nitric oxide by the coronary endothelium, or both), represent the potential mechanisms that allow an optimal distribution of oxygen and of substrates to the hypertrophied myocardium of the athletes.


3-Year Outcomes of the DKCRUSH-V Trial Comparing DK Crush With Provisional Stenting for Left Main Bifurcation Lesions.
The present study aimed to investigate the difference in target lesion failure (TLF) at 3 years after double kissing (DK) crush stenting versus provisional stenting (PS) for unprotected left main distal bifurcation (UPLMb) lesions. The multicenter and randomized DKCRUSH-V (Double Kissing Crush versus Provisional Stenting for Left Main Distal Bifurcation Lesions: The DKCRUSH-V Randomized Trial) study showed fewer 1-year TLF after DK crush for UPLMb lesions compared with PS. The study reports the 3-year clinical outcome of the DKCRUSH-V study. A total of 482 patients with UPLMb lesions who were randomly assigned to either the DK crush group (DK group) or PS group in the DKCRUSH-V study were followed for 3 years. The primary endpoint was the occurrence of a TLF at 3 years. Stent thrombosis (ST) was the safety endpoint. Patients were classified by lesion's complexity and NERS (New Risk Stratification) II or SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) score. At 3 years, TLF occurred in 41 (16.9%) patients in the PS group and in 20 (8.3%) patients in the DK group (p = 0.005), mainly driven by increased target vessel myocardial infarction (5.8% vs. 1.7%; p = 0.017) and target lesion revascularization (10.3% vs. 5.0%; p = 0.029). Definite or probable ST rate at 3 years was 4.1% in the PS group and 0.4% in the DK group (p = 0.006). Notably, DK crush was associated with a significant reduction in both primary and secondary endpoints for patients with complex lesions or at high risk. Provisional stenting for UPLMb lesions was associated with significantly increased rates of TLF and ST over 3 years of follow-up. Further randomized study is warranted to confirm the benefits of DK crush stenting for complex UPLMb lesions. (Double Kissing and Double Crush versus Provisional T Stenting Technique for the Treatment of Unprotected Distal Left Main True Bifurcation Lesions: A Randomized, International, Multi-center Clinical Trial; ChiCTR-TRC-11001213).


Habituation reveals fundamental chromatic mechanisms in striate cortex of macaque.
Prolonged viewing of a chromatically modulated stimulus usually leads to changes in its appearance, and that of similar stimuli. These aftereffects of habituation have been thought to reflect the activity of two populations of neurons in visual cortex that have particular importance in color vision, one sensitive to red-green modulation, the other to blue-yellow, but they have not been identified. We show here, in recordings from macaque primary visual cortex (V1), that prolonged exposure to chromatic modulation reveals two fundamental mechanisms with distinctive chromatic signatures that match those of the mechanisms identified by perceptual observations. In nearly all neurons, these mechanisms contribute to both excitation and to regulatory gain controls, and as a result their habituation can have paradoxical effects on response. The mechanisms must be located near the input layers of V1, before their distinct chromatic signatures diffuse. Our observations suggest that the fundamental mechanisms do not give rise to two distinct L-M and S chromatic pathways. Rather, the mechanisms are better understood as stages in the elaboration of chromatic tuning, expressed in varying proportions in all cells in V1 (and beyond), and made accessible to physiological and perceptual investigation only through habituation.


Transcription regulation of the nir gene cluster encoding nitrite reductase of Paracoccus denitrificans involves NNR and NirI, a novel type of membrane protein.
The nirIX gene cluster of Paracoccus denitrificans is located between the nir and nor gene clusters encoding nitrite and nitric oxide reductases respectively. The NirI sequence corresponds to that of a membrane-bound protein with six transmembrane helices, a large periplasmic domain and cysteine-rich cytoplasmic domains that resemble the binding sites of [4Fe-4S] clusters in many ferredoxin-like proteins. NirX is soluble and apparently located in the periplasm, as judged by the predicted signal sequence. NirI and NirX are homologues of NosR and NosX, proteins involved in regulation of the expression of the nos gene cluster encoding nitrous oxide reductase in Pseudomonas stutzeri and Sinorhizobium meliloti. Analysis of a NirI-deficient mutant strain revealed that NirI is involved in transcription activation of the nir gene cluster in response to oxygen limitation and the presence of N-oxides. The NirX-deficient mutant transiently accumulated nitrite in the growth medium, but it had a final growth yield similar to that of the wild type. Transcription of the nirIX gene cluster itself was controlled by NNR, a member of the family of FNR-like transcriptional activators. An NNR binding sequence is located in the middle of the intergenic region between the nirI and nirS genes with its centre located at position -41.5 relative to the transcription start sites of both genes. Attempts to complement the NirI mutation via cloning of the nirIX gene cluster on a broad-host-range vector were unsuccessful, the ability to express nitrite reductase being restored only when the nirIX gene cluster was reintegrated into the chromosome of the NirI-deficient mutant via homologous recombination in such a way that the wild-type nirI gene was present directly upstream of the nir operon.


Abnormalities in structural covariance of cortical gyrification in schizophrenia.
The highly convoluted shape of the adult human brain results from several well-coordinated maturational events that start from embryonic development and extend through the adult life span. Disturbances in these maturational events can result in various neurological and psychiatric disorders, resulting in abnormal patterns of morphological relationship among cortical structures (structural covariance). Structural covariance can be studied using graph theory-based approaches that evaluate topological properties of brain networks. Covariance-based graph metrics allow cross-sectional study of coordinated maturational relationship among brain regions. Disrupted gyrification of focal brain regions is a consistent feature of schizophrenia. However, it is unclear if these localized disturbances result from a failure of coordinated development of brain regions in schizophrenia. We studied the structural covariance of gyrification in a sample of 41 patients with schizophrenia and 40 healthy controls by constructing gyrification-based networks using a 3-dimensional index. We found that several key regions including anterior insula and dorsolateral prefrontal cortex show increased segregation in schizophrenia, alongside reduced segregation in somato-sensory and occipital regions. Patients also showed a lack of prominence of the distributed covariance (hubness) of cingulate cortex. The abnormal segregated folding pattern in the right peri-sylvian regions (insula and fronto-temporal cortex) was associated with greater severity of illness. The study of structural covariance in cortical folding supports the presence of subtle deviation in the coordinated development of cortical convolutions in schizophrenia. The heterogeneity in the severity of schizophrenia could be explained in part by aberrant trajectories of neurodevelopment.


Social information-processing and coping in adolescent females diagnosed with an eating disorder: toward a greater understanding of control.
The objective of this study was to examine differences in social information-processing and coping strategies between adolescent females in treatment for an eating disorder and asymptomatic peers. Adolescent females in treatment for an eating disorder (n = 50) were compared to asymptomatic control participants (n = 59) on a measure of social information-processing. Participants were presented with 4 hypothetical, ambiguous social dilemmas in which the intent of a peer provocateur was unclear. Questions followed each dilemma assessing intent attributions, the participant's emotional reaction, the intensity of the emotion, and coping strategies. The participants in treatment for an eating disorder were significantly more likely to perceive hostile intent from a peer provocateur, reported a greater intensity of negative emotions, and identified a significantly greater number of avoidant coping strategies. Specifically, the eating disorder group identified significantly more intrapunitive avoidant coping strategies that reflect maladaptive and self-destructive means of coping with distressing events. Results indicate social cognitive processing biases and maladaptive coping strategies may be instrumental in perceived loss of control and influence the development/maintenance of eating disorders.


Using differential mobility spectrometry to measure ion solvation: an examination of the roles of solvents and ionic structures in separating quinoline-based drugs.
Understanding the mechanisms and energetics of ion solvation is critical in many scientific areas. Here, we present a methodlogy for studying ion solvation using differential mobility spectrometry (DMS) coupled to mass spectrometry. While in the DMS cell, ions experience electric fields established by a high frequency asymmetric waveform in the presence of a desired pressure of water vapor. By observing how a specific ion's behavior changes between the high- and low-field parts of the waveform, we gain knowledge about the aqueous microsolvation of that ion. In this study, we applied DMS to investigate the aqueous microsolvation of protonated quinoline-based drug candidates. Owing to their low binding energies with water, the clustering propensity of 8-substituted quinolinium ions was less than that of the 6- or 7-substituted analogues. We attribute these differences to the steric hinderance presented by subtituents in the 8-position. In addition, these experimental DMS results were complemented by extensive computational studies that determined cluster structures and relative thermodynamic stabilities.


Auto-titrating continuous positive airway pressure treatment for obstructive sleep apnoea after acute quadriplegia (COSAQ): study protocol for a randomized controlled trial.
Quadriplegia is a severe, catastrophic injury that predominantly affects people early in life, resulting in lifelong physical disability. Obstructive sleep apnoea is a direct consequence of quadriplegia and is associated with neurocognitive deficits, sleepiness and reduced quality of life. The usual treatment for sleep apnoea is nasal continuous positive airway pressure (CPAP); however, this is poorly tolerated in quadriplegia. To encourage patients to use this therapy, we have to demonstrate that the benefits outweigh the inconvenience. We therefore propose a prospective, multinational randomized controlled trial of three months of CPAP for obstructive sleep apnoea after acute quadriplegia. Specialist spinal cord injury centres across Australia, New Zealand, the UK and Canada will recruit medically stable individuals who have sustained a (new) traumatic quadriplegia (complete or incomplete second cervical to first thoracic level lesions). Participants will be screened for obstructive sleep apnoea using full, portable sleep studies. Those with an apnoea hypopnoea index greater than 10 per hour will proceed to an initial three-night trial of CPAP. Those who can tolerate CPAP for at least 4 hours on at least one night of the initial trial will be randomized to either usual care or a 3-month period of auto-titrating CPAP. The primary hypothesis is that nocturnal CPAP will improve neuropsychological functioning more than usual care alone. The secondary hypothesis is that the magnitude of improvement of neuropsychological function will be predicted by the severity of baseline sleepiness measures, sleep fragmentation and sleep apnoea. Neuropsychological tests and full polysomnography will be performed at baseline and 3 months with interim measures of sleepiness and symptoms of autonomic dysfunction measured weekly. Spirometry will be performed monthly. Neuropsychological tests will be administered by blinded assessors. Recruitment commenced in July 2009. The results of this trial will demonstrate the effect of nocturnal CPAP treatment of obstructive sleep apnoea in acute quadriplegia. If CPAP can improve neurocognitive function after injury, it is likely that rehabilitation and subsequent community participation will be substantially improved for this group of predominantly young and severely physically disabled people. Australian New Zealand Clinical Trial Registry ACTRN12605000799651.


Mn ions pass through calcium channels. A possible explanation.
The divalent transition-metal cations Fe, Co, and Ni were used to test the hypothesis that Mn ions pass through calcium channels because Mn ions have a relatively low energy of hydration. The test ions were applied to the bath and comparisons were made of their effects on Ca or Mn spikes elicited from myoepithelial cells of the proventriculus of the polychaete worm Syllis spongiphila. Control experiments showed that (a) results obtained using deoxygenated solutions (required to stabilize Fe2+ ions) could be compared with those using solutions containing oxygen, and (b) the test cations did not measurably affect the electrical coupling between cells. Ca spikes were reversibly abolished by the test cations in the order of effectiveness: Fe (16.1 mM +/- 1.0, SE; n = 15) = Co (14.6 mM +/- 0.8; n = 27) less than Ni (8.3 mM +/- 0.7; n = 16). The test cations diminished Mn spikes by decreasing maximum rates of rise (Fe = Co less than Ni) and overshoot amplitudes (Fe less than Co less than Ni). The test cations also increased the current intensity required for Ca (Fe = Co less than Ni) or Mn spike initiation (Fe less than Co less than Ni). Since the energies of hydration of Fe, Co, and Ni increase stepwise from that of Mn, and the effectiveness of these ions in diminishing Ca and Mn spikes increased in the order Fe less than or equal to Co less than Ni, these data support the hypothesis that Mn ions pass through Ca channels because they shed waters of hydration relatively easily. An additional observation was that, at below-blocking concentrations, the test cations caused decreased duration of Mn spikes and increased duration of Ca spikes.


Epidemiology of cancer in end-stage renal disease dialysis patients: a national cohort study in Taiwan.
The incidence and mortality of site-specific cancers in patients with end-stage renal disease (ESRD) on maintenance dialysis have been rarely studied for Asian populations. We tapped Taiwan`s National Health Insurance Research Database to identify and recruit patients starting maintenance dialysis between 1999 and 2004. They were followed from initiation of dialysis until death, discontinuation of dialysis, or the end of 2008. We calculated the survival rate and mortality risk of dialysis patients with cancer. Of 40,833 dialysis patients, 2352 (5.8%) had been newly diagnosed with cancer. Being older, being male, and having chronic liver disease were factors associated with a higher risk for new cancer in ESRD dialysis patients. In men, liver cancer (20.63%) was the most frequent, followed by cancers of the bladder (16.88%) and kidney (11.61%). In women, bladder cancer (25.57%) was the most frequent, followed by cancers of the kidney (16.31%) and breast (11.20%). The 5-year survival rates for kidney and bladder cancer were higher than for other cancers; the survival rates for lung, stomach, and liver cancer were lower. In conclusion, the distribution of site-specific cancer was different between men and women in patients with ESRD on dialysis. More attention should be paid to teaching dialysis patients how to avoid the well-known cancer risks and carcinogens and individualized regular cancer screenings.


Farnesyltransferase inhibitors in myelodysplastic syndrome.
The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematological malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two non-peptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy with overall response rates of 30%, with complete remissions in about 15%. Dose-limiting side effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated with primarily diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this, significant clinical efficacy of the FTIs in MDS, on par with that of currently available chemotherapeutic agents, has been observed, leading to further development of this new class of drugs in MDS and AML.


Pediatric diffuse intrinsic pontine glioma: can optimism replace pessimism?
Pediatric diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis that has not seen a change in outcome despite multiple clinical trials. Possible reasons for failure to make progress in this aggressive childhood brain tumor include: poor understanding of the underlying molecular biology due to lack of access to tumor material; absence of accurate and relevant DIPG preclinical models for drug development; ill-defined therapeutic targets for novel agents; and inadequate drug delivery to the brainstem. This review will demonstrate that systematic studies to identify solutions for each of these barriers is starting to deliver progress that can turn pessimism to optimism in DIPG.


2,5-diketopiperazines as neuroprotective agents.
2,5-diketopiperazines are the simplest cyclic peptides found in nature, commonly biosynthesized from amino acids by different organisms, and represent a promising class of biologically active natural products. Their peculiar heterocyclic structure confers high stability against the proteolysis and constitutes a structural requirement for the active intestinal absorption. Furthermore, the diketopiperazine-based motif is considered as a novel brain shuttle for the delivery of drugs with limited ability to cross the blood-brain barrier (BBB) and can be proposed as an ideal candidate for the rational development of new therapeutic agents. Although these cyclic peptides have been known since the beginning of the 20th century, only recently have they attracted substantial interest with respect to the wide spectrum of their biological properties, including antitumor, antiviral, antifungal, antibacterial and antihyperglycemic activities. In addition to these, the most challenging function of the diketopiperazine derivatives is related with their remarkable neuroprotective and nootropic activity. The aim of the present paper is to provide an overview of the two major classes of diketopiperazines, the TRH-related and the unsaturated derivatives both characterized by a significant ability to protect against neurotoxicity in several experimental models. The neuroprotective profile of these compounds suggests that they may have a future utility in the therapy of neuronal degeneration in vivo, potentially through several different mechanisms.


Coexisting difficulties and couple therapy outcomes: psychopathology and intimate partner violence.
Couples presenting for treatment of relationship distress often experience additional problems, including individual psychopathology and intimate partner violence (IPV). Both issues are associated with current and future poor relationship functioning in nontreatment samples, but relatively little is understood about their association with initial presentation and outcomes in couple therapy. The current study examined these associations in a sample of 177 heterosexual couples who received therapy at two Veteran's Affairs clinics. Unlike most studies of couple therapy outcomes, couples were not excluded from treatment specifically because of high levels of psychopathology or IPV. Results of Actor Partner Interdependence Model (APIM) analyses revealed actor and partner effects of depression, actor effects of anxiety, and partner effects of IPV on initial relationship satisfaction, such that greater coexisting difficulties were associated with poorer initial satisfaction. However, improvement in relationship satisfaction over the course of therapy was not associated with psychopathology, and, contrary to hypothesis, was positively associated with men's IPV prior to treatment, even when initial level of satisfaction was controlled. The results suggest that coexisting symptoms of psychopathology or IPV may not necessarily interfere with therapy outcomes and, indeed, therapy may have positive effects for couples with these problems.


Productivity losses associated with diabetes in the US.
The objective of this study was to estimate the cost of productivity losses in the U.S. attributable to diabetes, with regard to specific demographic and disease-related characteristics in the U.S.. We used the 1989 National Health Interview Survey, a random survey of individuals in the U.S. that included a diabetes supplement. Data on individuals were obtained for labor force participation, hours of work, demographic and occupational characteristics, self-reported health status, and several variables that indicated the presence, duration, and severity (complications) of diabetes. Using multivariate regression analyses, we estimated the association of independent variables (e.g., demographics, health, and diabetes status) with labor force participation, hours of work lost, and the economic value of lost work attributable to diabetes and its complications and duration. In general, the presence of diabetes and complications were found to be related to workforce participation variables. The magnitude of the lost-productivity costs depended on personal characteristics and on the presence and status of diabetes. In general, the loss of yearly earnings amounted to about a one-third reduction in earnings and ranged from $3,700 to $8,700 per annum. Diabetes has a considerable net effect on earnings, and the complications and duration of diabetes have compound effects. Our findings have implications for the cost-effectiveness of diabetes control; the presence of complicating factors is the single most important predictive factor in lost productivity costs attributable to diabetes, and thus the avoidance or retardation of complications will have an impact on indirect health-related costs.


Mycobacterium bovis bacille Calmette Guerin infection of human neutrophils induces CXCL8 secretion by MyD88-dependent TLR2 and TLR4 activation.
To investigate the potential role of neutrophils in initiation of immune responses to mycobacteria, we have characterized the response of human neutrophils to infection with Mycobacterium bovis bacille Calmette Guerin, the BCG vaccine. BCG induced transcription and secretion of the chemokine CXCL8, by signalling through Toll-like receptors TLR2 and TLR4, in conjunction with the adaptor protein myeloid differentiation factor 88 (MyD88). Blocking of responses with antibodies revealed a difference in the kinetics of signalling through the different TLRs. Anti-TLR2 antibody blocked the early phase of CXCL8 and MyD88 induction. Anti-TLR4 antibody blocked the late phase of induction occurring 2 h after infection. The existence of a TLR/MyD88 pathway for recognition and response to mycobacterial ligands provides neutrophils with the ability to drive the recruitment and activation of inflammatory cells during the early phase of mycobacterial infection and immunization.


A case of macroprolactinoma with subclinical growth hormone production.
We describe a rare case of macroprolactinoma with subclinically synchronous growth hormone (GH) production. A 59-year-old man with a giant adenoma in his pituitary had elevated serum prolactin (PRL) and insulin-like growth factor (IGF)-I levels, despite normal levels of basal GH. Serum GH levels were paradoxically increased in response to an intravenous administration of thyrotropin-releasing hormone (TRH). Prolonged exposure to glucose as a result of oral glucose tolerance testing (oGTT) failed to decrease GH levels. Two-week treatment with cabergoline, a dopamine D2 receptor agonist, decreased serum PRL and GH levels, and size of the tumor. Immunohistochemistry and in situ hybridization revealed PRL-producing cells capable of synchronous GH production. Acidophilic stem cell adenoma may be responsible for these phenomena. The nature of high proliferation and invasive tumor growth should be kept in mind when managing patients with this cell type of adenoma. IGF-I levels should be followed in PRLoma, even when basal GH levels are within the normal range, because mixed PRL- and GH-producing tumors would lie underneath. Further endocrinological examinations such as TRH test and oGTT are recommended when elevated IGF-I levels are detected.


Private water distribution as a potential everyday risk: The case of Goba, Dar es Salaam.
A large number of peri-urban settlements in developing countries, including Goba in Tanzania, fall short of government supplied water. The inability of the Government to budget and prioritise its budget poses a serious problem to meet the water demand, a few residents in peri-urban settlements use other sources of water, including groundwater. However, the quality and suitability safety of such groundwater are questionable. This research of Goba settlement was undertaken to explore the reality of what happens and how problems can be resolved. The research methodology deployed in-depth interviews, physical observations, photographing and mapping and analysing and testing various water samples in a laboratory. From the study several conclusions could be drawn: most of the current laws relating to groundwater and sanitation were violated, the distribution of water to neighbours compounded problems. The major diseases typhoid, diarrhoea and dysentery were common. People themselves can take the necessary precaution by the choice of locating waste water so that it does not contaminate, boiling drinking water, etc. The devolution of the power from the Central Government and Ministries to District and down to the wards would go a long way to bring public/private partnership to be meaningful. The evidence from Goba points to the prevailing situation and what could be done to bring improvements.


The sequential determination model of hematopoiesis.
Analysis of hematopoietic development has for decades been central to understanding lineage diversification. Some models consider hematopoietic commitment to be random, and branching lineage maps often include an early myeloid or lymphoid bifurcation. However, the existence of joint lymphoid or myeloid intermediate progenitors argues against both. One of us earlier proposed the sequential determination (SD) model, which features a limited and stepwise set of binary choices across the full hematopoietic spectrum. This model arose from observations that hematopoietic progenitors show preferences for particular associations of lineage potentials--indicating that these linked fates are neighbours developmentally. An updated SD model complemented by several recently recognized processes--spatiotemporal fluctuations in transcription factor concentrations, asymmetric cell division, and Notch signalling--still offers a sound summary of hematopoiesis.


Insulin signaling in health and disease.
The molecular mechanisms of cellular insulin action have been the focus of much investigation since the discovery of the hormone 100 years ago. Insulin action is impaired in metabolic syndrome, a condition known as insulin resistance. The actions of the hormone are initiated by binding to its receptor on the surface of target cells. The receptor is an α2β2 heterodimer that binds to insulin with high affinity, resulting in the activation of its tyrosine kinase activity. Once activated, the receptor can phosphorylate a number of intracellular substrates that initiate discrete signaling pathways. The tyrosine phosphorylation of some substrates activates phosphatidylinositol-3-kinase (PI3K), which produces polyphosphoinositides that interact with protein kinases, leading to activation of the kinase Akt. Phosphorylation of Shc leads to activation of the Ras/MAP kinase pathway. Phosphorylation of SH2B2 and of Cbl initiates activation of G proteins such as TC10. Activation of Akt and other protein kinases produces phosphorylation of a variety of substrates, including transcription factors, GTPase-activating proteins, and other kinases that control key metabolic events. Among the cellular processes controlled by insulin are vesicle trafficking, activities of metabolic enzymes, transcriptional factors, and degradation of insulin itself. Together these complex processes are coordinated to ensure glucose homeostasis.


[The immune state against yellow fever vaccinal virus (17D) in 2 populations of Bahia State, Brazil].
The occurrence of cases of yellow fever (YF) and also the extensive distribution of A. aegypti in Brazil, inspired a study about the estimate of immunity against vaccinal virus (17D) among the residents at two cities of the Bahia State, Ipupiara (n = 461) and Prado (n = 228). At this non-endemic area of YF, the search for serology antibody against 17D (Ab17D) and 18 another arbovirus was made thereby hemagglutination inhibition (HI). Only 1.2% (8/689) showed Ab17D, six of those with monotypic sort. The heterotypic sort for flavivirus (FLV) was interpreted as associated to immunity against 17D too, being much frequent in Prado (30.3%) than in Ipupiara (23.2%). The age > or = 50 years and residence in another states were related to seropositive for FLV, the same way that vaccination's history (17D). However, the history of vaccination presented low percentages of sensibility (< or = 45.4%) and predictive-positive value (< or = 38.4%), but high specificity (> or = 70.8%) and predictive-negative value (> or = 78.8%). Therefore, the frequency of residents with Ab17D was low (1.2%), although the higher frequency (25.5%) of antibody FLV carrier's, what signifies that 26.7% of the studied population should present protection against the YF virus.


Structural and functional basis of VLDLR receptor usage by Eastern equine encephalitis virus.
The very low-density lipoprotein receptor (VLDLR) is comprised of eight LDLR type A (LA) domains and supports entry of distantly related Eastern equine encephalitis (EEEV) and Semliki Forest (SFV) alphaviruses. Here, by resolving multiple cryo-electron microscopy structures of EEEV-VLDLR complexes and performing mutagenesis and functional studies, we show that EEEV uses multiple sites (E1/E2 cleft and E2 A domain) to engage different LA domains simultaneously. However, no single LA domain is necessary or sufficient to support efficient EEEV infection, highlighting complexity in domain usage. Whereas all EEEV strains show conservation of two VLDLR binding sites, the EEEV PE-6 strain and other EEE complex members feature a single amino acid substitution that mediates binding of LA domains to an additional site on the E2 B domain. These structural and functional analyses informed the design of a minimal VLDLR decoy receptor that neutralizes EEEV infection and protects mice from lethal challenge.


BlenderPhotonics: an integrated open-source software environment for three-dimensional meshing and photon simulations in complex tissues.
Rapid advances in biophotonics techniques require quantitative, model-based computational approaches to obtain functional and structural information from increasingly complex and multiscaled anatomies. The lack of efficient tools to accurately model tissue structures and subsequently perform quantitative multiphysics modeling greatly impedes the clinical translation of these modalities. Although the mesh-based Monte Carlo (MMC) method expands our capabilities in simulating complex tissues using tetrahedral meshes, the generation of such domains often requires specialized meshing tools, such as Iso2Mesh. Creating a simplified and intuitive interface for tissue anatomical modeling and optical simulations is essential toward making these advanced modeling techniques broadly accessible to the user community. We responded to the above challenge by combining the powerful, open-source three-dimensional (3D) modeling software, Blender, with state-of-the-art 3D mesh generation and MC simulation tools, utilizing the interactive graphical user interface in Blender as the front-end to allow users to create complex tissue mesh models and subsequently launch MMC light simulations. Here, we present a tutorial to our Python-based Blender add-on-BlenderPhotonics-to interface with Iso2Mesh and MMC, which allows users to create, configure and refine complex simulation domains and run hardware-accelerated 3D light simulations with only a few clicks. We provide a comprehensive introduction to this tool and walk readers through five examples, ranging from simple shapes to sophisticated realistic tissue models. BlenderPhotonics is user friendly and open source, and it leverages the vastly rich ecosystem of Blender. It wraps advanced modeling capabilities within an easy-to-use and interactive interface. The latest software can be downloaded at http://mcx.space/bp.


Exploring fullerene derivatives for optoelectronic applications: synthesis and characterization study.
In this study, we conducted a comprehensive investigation of newly synthesized fullerene derivatives developed for potential application in perovskite solar cells (PSCs). We explored three novel dihydrofuran-fused C60 fullerene derivatives (13, 14, and 15) that were specifically designed to enhance solubility and interaction with the substrate, fluorine-doped tin oxide (FTO). A comparative analysis was performed, with reference to the widely used phenyl-C61-butyric acid methyl ester (PCBM) and compound 12, from which 13, 14, and 15 are derived, to assess the impact of sugar units on materials properties. The synthesized compounds demonstrated significant solubility in common organic solvents, a critical factor in their potential application in wet-processed PSCs. Our investigation included electrochemical property analysis, thin film deposition, surface characterization, and electrochemical impedance spectroscopy (EIS). EIS measurements unveiled key insights into charge transfer properties at the electrode/electrolyte interface, making the compounds attractive candidates for electron transport layers (ETLs) in PSCs.


Vascular endothelial growth factor acts primarily via platelet-derived growth factor receptor α to promote proliferative vitreoretinopathy.
Proliferative vitreoretinopathy (PVR) is a nonneovascular blinding disease and the leading cause for failure in surgical repair of rhegmatogenous retinal detachments. Once formed, PVR is difficult to treat. Hence, there is an acute interest in developing approaches to prevent PVR. Of the many growth factors and cytokines that accumulate in vitreous as PVR develops, neutralizing vascular endothelial growth factor (VEGF) A has recently been found to prevent PVR in at least one animal model. The goal of this study was to test if Food and Drug Administration-approved agents could protect the eye from PVR in multiple animal models and to further investigate the underlying mechanisms. Neutralizing VEGF with aflibercept (VEGF Trap-Eye) safely and effectively protected rabbits from PVR in multiple models of disease. Furthermore, aflibercept reduced the bioactivity of both experimental and clinical PVR vitreous. Finally, although VEGF could promote some PVR-associated cellular responses via VEGF receptors expressed on the retinal pigment epithelial cells that drive this disease, VEGF's major contribution to vitreal bioactivity occurred via platelet-derived growth factor receptor α. Thus, VEGF promotes PVR by a noncanonical ability to engage platelet-derived growth factor receptor α. These findings indicate that VEGF contributes to nonangiogenic diseases and that anti-VEGF-based therapies may be effective on a wider spectrum of diseases than previously appreciated.


Explaining computation of predictive values: 2 x 2 table versus frequency tree. A randomized controlled trial [ISRCTN74278823].
Involving patients in decision making on diagnostic procedures requires a basic level of statistical thinking. However, innumeracy is prevalent even among physicians. In medical teaching the 2 x 2 table is widely used as a visual help for computations whereas in psychology the frequency tree is favoured. We assumed that the 2 x 2 table is more suitable to support computations of predictive values. 184 students without prior statistical training were randomised either to a step-by-step self-learning tutorial using the 2 x 2 table (n = 94) or the frequency tree (n = 90). During the training session students were instructed by two sample tasks and a total of five positive predictive values had to be computed. During a follow-up session 4 weeks later participants had to compute 5 different tasks of comparable degree of difficulty without having the tutorial instructions at their disposal. The primary outcome was the correct solution of the tasks. There were no statistically significant differences between the two groups. About 58% achieved correct solutions in 4-5 tasks following the training session and 26% in the follow-up examination. These findings do not support the hypothesis that the 2 x 2 table is more valuable to facilitate the calculation of positive predictive values than the frequency tree.


Lipoprotein (a) levels in end-stage renal failure and renal transplantation.
Some previous studies have documented an increase in lipoprotein (a) [Lp(a)] levels in renal diseases. Here, we report data in subjects with end-stage renal failure treated with hemodialysis (HD) or with continuous ambulatory peritoneal dialysis (CAPD) and in renal transplant recipients (RTR), compared with a group of normolipidemic controls (C). Lp(a) levels were significantly increased in HD and CAPD patients in comparison with C, while they were only slightly increased in RTR. Both HD and CAPD patients showed Lp(a) levels higher than in RTR, but no difference was found between the subjects of the two dialysis procedures. The prevalence of Lp(a) levels > 25 mg/dl was significantly higher in HD and CAPD patients, but not in RTR, in comparison with C. Moreover, Lp(a) levels did not change after HD. When patients were divided according to their fasting lipid levels in normolipidemics and hyperlipoproteinemics, no difference was found for Lp(a) levels in any group. Mechanisms underlying the increase in Lp(a) levels in these patients are not known. It is possible to suggest an active role of the kidney in the Lp(a) metabolism or that uremic plasma contains some factors affecting Lp(a) metabolism.


[Steri's graffiti of Palermo and medical knowledges].
The graffiti left by prisoners in the Inquisition gaols of Palermo's represent a testimony of the historical period between 1600 to 1793. In that period, by order of the viceroy Caracciolo, all the testimonies were removed at the same time in which the Inquisition court was suppressed. In this work the historical subdivision between sacred and profane themes is analyzed with the purpose to study human body in an anthropological key as a language in condition of limited freedom and under torture. Many of the profane graffiti are devoted to medical knowledge suggesting that doctors were involved in the activities of this religious court likewise happened in civil courts. Giovanni Filippo Ingrassia, the well-known proto-medical physician of the kingdom, in his treatise, wrote in 1578 and entitled Methodus dandi relationes ... reports many examples of the role of medical doctors in attesting fitness to torture of inquired people or the necessity of graduating torture when they were hill or in a morbid conditions.


Total hip arthroplasty in a patient with congenital insensitivity to pain: a case report.
Congenital insensitivity to pain, a rare neurological entity, is characterized by varying degrees of sensory loss and autonomic dysfunction. Orthopedic manifestations of congenital insensitivity to pain include delayed diagnosis of fractures, nonunions, malunions, Charcot arthropathy, acro-osteolysis, avascular necrosis, osteomyelitis, heterotopic ossification and joint dislocations. We here report the case of a patient with congenital insensitivity to pain who had multiple lower extremity fractures at varying intervals, the most recent being a femoral neck fracture managed by total hip replacement. To the best of our knowledge, this is the first report of cementless hip arthroplasty in such a patient. A 37-year-old Caucasian woman was admitted to our hospital complaining of painless swellings in her lower limb and limping. She had been diagnosed with multiple lower extremity fractures at different times. On physical examination, we found multiple perioral mucosal ulcers, shortening of her nails and acro-osteolysis, a prematurely aged facial appearance, undersized skeletal structure, Charcot arthropathy of her right ankle, anosmia, insensitivity to temperature differences and evidence of mild intellectual disability. A right subtrochanteric femur fracture was treated with an intramedullary nail. Eighteen months later, she presented with similar symptoms and we diagnosed a right femoral neck fracture. We removed the nail and performed cementless total right hip arthroplasty. Congenital insensitivity to pain is a rare condition that is associated with severe orthopedic problems. This case report, which will be of particular interest to orthopedic surgeons, presents several difficulties in the management of patients with congenital insensitivity to pain and notes the importance of close follow-up and early recognition of complications. Cementless total hip arthroplasty may be a good therapeutic option for femoral neck fracture in these patients.


International Union of Pharmacology. XLIII. Compendium of voltage-gated ion channels: transient receptor potential channels.
The transient receptor potential (TRP) proteins are six transmembrane-containing subunits that combine to form cation-selective ion channels. TRP channels are present in yeast, Drosophila, Caenorhabditis elegans, and mammals. They are widely distributed and sense local changes in stimuli ranging from light to temperature and osmolarity. Mammals contain at least 22 distinct genes encoding these ion channels. This summary article presents an overview of the molecular relationships among the TRP channels and a standard nomenclature for them, which is derived from the IUPHAR Compendium of Voltage-Gated Ion Channels. The complete Compendium, including data tables for each member of the TRP channel family, can be found at http://www.iuphar-db.org/iuphar-ic/.


Trends in Australian children traveling to school 1971-2003: burning petrol or carbohydrates?
To determine how Australian children traveled to and from school between 1971 and 2003. The 1971 (n=4284), 1981 (n=4936), 1991 (n=662) and 1999-2003 (n=816) Household Travel Surveys from the New South Wales Government Department of Planning were used to determine the mode of transport kids (5-14 years) took to and from school in the area of Sydney (Australia). The results showed that the percentage of children aged 5-9 that walked to school was 57.7, 44.5, 35.3 and 25.5 in 1971, 1981, 1991 and 1999-2003, respectively. The percentage of children aged 5-9 that were driven to school by car in the four surveys was 22.8, 37.3, 53.9 and 66.6, respectively. The results for children aged 10-14 were similar, walking decreased from 44.2% to 21.1% and car use increased from 12.2% to 47.8% over the study period. Similar results were found for travel from school and there were no major differences between boys and girls. Between 1971 and 2003, Australian children's mode of travel to and from school has markedly shifted from active (walking) to inactive (car) modes.


Herpes simplex infection in a juvenile orangutan (Pongo pygmaeus pygmaeus).
A juvenile orangutan (Pongo pygmaeus pygmaeus) died after 8 days of diarrhea and vomiting. Necropsy showed petechial hemorrhages in the skin, the myocardium, and the peritoneal membranes. The lungs were hyperemic and edematous, and the liver and spleen were enlarged. Histologic changes consisted of interstitial pneumonia, hepatitis, and splenic hyperplasia. Numerous eosinophilic intranuclear inclusion bodies were visible in pulmonary epithelial cells, hepatocytes, and splenic endothelial cells. Electron microscopic examination revealed herpesvirus in hepatocyte nuclei. Polymerase chain reaction of liver tissue demonstrated the presence of a herpes simplex virus-1.


Cytotoxic T-lymphocytes from HIV-infected individuals recognize an activation-dependent, non-polymorphic molecule on uninfected CD4+ lymphocytes.
Correlation of lysis of autologous CD4+ target cells by cytotoxic lymphocytes from HIV-seropositive patients to target activation, viral replication, and major histocompatibility complex (MHC) restriction. Twenty-two HIV-infected patients were evaluated for lysis of activated CD4+ cells, concurrent with measurement of proliferation of the target cells, and with viral replication. Titrated standard 51Cr-release assays for specific effector-to-target cell recognition, blocking antibodies and cell depletion for cell characterization, incorporation of [3H]-thymidine for proliferation, and p24 antigen capture assays for viral replication. HIV-infected patients had cytotoxic lymphocytes capable of recognizing activated CD4+ target cells in a non-MHC-restricted manner. The lysis depended on the degree of target activation, and was independent of viral replication. This cytolytic activity is unique to HIV-infected patients, and is suggestive of activation-induced cell death that may contribute to the progressive depletion of CD4+ lymphocytes during HIV pathogenesis.


Type 2 diabetes: perceptions of quality of life and attitudes towards diabetes from a gender perspective.
To compare obese and normal-weight people with type 2 diabetes (T2DM), with a focus on their attitudes towards the disease, quality of life (QoL) and treatment from a gender perspective. Two hundred and eighty-seven people with T2DM participated in a cross-sectional study. Health-related quality of life (HRQL) data from the Medical Outcomes Short Form Study 36 (SF 36), Well-Being Questionnaire (W-BQ12), Diabetes Attitude Scale (DAS) and Diabetes Treatment Satisfaction Questionnaire (DTSQs) were used. The results are presented descriptively. The Mann-Whitney U-test was conducted to examine differences between normal-weight and obese diabetics and between women and men. The results of this study show that there was a gender difference in the perception of QoL; obese females with diabetes experienced more limitations in daily life due to physical and emotional problems than obese males with diabetes. Obese men had reduced physical and vitality scores compared to normal-weight individuals. Compared to normal-weight females with diabetes, obese women had lower vitality scores, more body pain and more severe physical impacts. The negative emotional impact for obese females with diabetes was also demonstrated by the results of the W-BQ12 questionnaire. Obese females with diabetes felt that the disease was more overwhelming and difficult to handle in comparison to obese males with diabetes. There was no difference between the groups in terms of how they experienced treatment. There was a gender difference in the perceptions of QoL of people with T2DM. There was also a difference between the QoL of obese and normal-weight people with T2DM, as the obese may suffer from underlying depression. Further investigations are needed for health professionals to be able to meet the unique needs of each specific diabetic group.


Prediction of Chemoresistance in Women Undergoing Neo-Adjuvant Chemotherapy for Locally Advanced Breast Cancer: Volumetric Analysis of First-Order Textural Features Extracted from Multiparametric MRI.
To assess correlations between volumetric first-order texture parameters on baseline MRI and pathological response after neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (BC). 69 patients with locally advanced BC candidate to neoadjuvant chemotherapy underwent MRI within 4 weeks from the start of therapeutic regimen. T2, DWI, and DCE sequences were analyzed and maps were generated for Apparent Diffusion Coefficient (ADC), T2 signal intensity, and the following dynamic parameters: k-trans, peak enhancement, area under curve (AUC), time to maximal enhancement (TME), wash-in rate, and washout rate. Volumetric analysis of these parameters was performed, yielding a histogram analysis including first-order texture kinetics (percentiles, maximum value, minimum value, range, standard deviation, mean, median, mode, skewness, and kurtosis). Finally, correlations between these values and response to NAC (evaluated on the surgical specimen according to RECIST 1.1 criteria) were assessed. Out of 69 tumors, 33 (47.8%) achieved complete pathological response, 26 (37.7%) partial response, and 10 (14.5%) no response. Higher levels of AUCmax (p value = 0.0338), AUCrange (p value = 0.0311), and TME75 (p value = 0.0452) and lower levels of washout10 (p value = 0.0417), washout20 (p value = 0.0138), washout25 (p value = 0.0114), and washout30 (p value = 0.05) were predictive of noncomplete response. Histogram-derived texture analysis of MRI images allows finding quantitative parameters predictive of nonresponse to NAC in women affected by locally advanced BC.


Power handling capability of Faraday rotation isolators for CO(2) laser radars.
Faraday rotation isolators for CO(2) laser radars must be capable of handling substantial average power loads without degrading the beam quality or experiencing thermal runaway. For this reason, the semiconductorbased isolators, which are of promise for applications at 10.6 microm, must be cooled. This creates radial temperature gradients and, in conjunction with a nonuniform beam pattern, may lead to severe wavefront aberrations. It is the purpose of this paper to formulate simple procedures for assessing the impact of such aberrations in a cw regime and to provide a prescription on how to proceed in the context of designing or evaluating Faraday rotators for CO(2) laser systems. If it is a good approximation to describe the beam-induced temperature rise by means of a fourth-order even polynomial, the degradation in beam quality originates entirely from the quartic term deltaT(4)rho(4). Specifically, it is the spherical aberration factor S = deltaT(4) radicalvar[rho(4)] that best describes the combined impact of temperature profile and beam shape. The heat flow equation for cw-loaded, edge-cooled, or face-cooled cylindrical Faraday rotator elements can be formulated in a simple nondimensional manner, which demonstrates that (a) temperature variations causing optical distortion scale with betaP/K, i.e., linearly with the deposited power per unit path length and inversely with the thermal conductivity; (b) in a transmission mode of operation with edge cooling and no thermal runaway, the power handling capability is independent of the aperture diameter; and (c), in a double-pass reflection mode of operation that takes advantage of a face-cooled back surface, a significant reduction of the distortion requires Nusselt numbers of at least 10, which leads to a new figure of merit for characterizing the performance of Faraday rotator material candidates. Edge-cooled optical isolators described in the published literature then provide cases for exercising the formalism and demonstrating its effectiveness. Finally, the authors examine the InSb free-carrier Faraday rotator developed at Case Western Reserve University and evaluate its surface-cooling requirement in light of specific design objectives.


Differentiation and maturation of zebrafish dorsal root and sympathetic ganglion neurons.
The trunk neural crest of vertebrate embryos gives rise to dorsal root ganglion (DRG) sensory neurons and autonomic sympathetic neurons, among other derivatives. We have examined the development of DRG and sympathetic neurons during development in the zebrafish. We found that sensory neurons differentiate rapidly and that their overt neuronal differentiation significantly precedes that of sympathetic neurons in the trunk. Sympathetic neurons in different regions differentiate at different times. The most rostral population, which we call the cervical ganglion, differentiates several days before trunk sympathetic neurons. After undergoing overt neuronal differentiation, sympathetic neurons subsequently express the adrenergic differentiation markers dopamine beta-hydroxylase and tyrosine hydroxylase. A second population of adrenergic nonneuronal cells initially localized with cervical sympathetic neurons appears to represent adrenal chromaffin cells. In more mature fish, these cells were present in clusters within the kidneys. Individual DRG and sympathetic ganglia initially contain few neurons. However, the number of neurons in DRG and sympathetic ganglia increases continuously at least up to 4 weeks of age. Analysis of phosphohistone H3 expression and bromodeoxyuridine incorporation studies suggests that the increases in DRG and sympathetic ganglion neuronal cell number are due wholly or in part to the division of neuronal cells within the ganglia.


TMEM16A calcium-activated chloride currents in supporting cells of the mouse olfactory epithelium.
Glial-like supporting (or sustentacular) cells are important constituents of the olfactory epithelium that are involved in several physiological processes such as production of endocannabinoids, insulin, and ATP and regulation of the ionic composition of the mucus layer that covers the apical surface of the olfactory epithelium. Supporting cells express metabotropic P2Y purinergic receptors that generate ATP-induced Ca2+ signaling through the activation of a PLC-mediated cascade. Recently, we reported that a subpopulation of supporting cells expresses also the Ca2+-activated Cl- channel TMEM16A. Here, we sought to extend our understanding of a possible physiological role of this channel in the olfactory system by asking whether Ca2+ can activate Cl- currents mediated by TMEM16A. We use whole-cell patch-clamp analysis in slices of the olfactory epithelium to measure dose-response relations in the presence of various intracellular Ca2+ concentrations, ion selectivity, and blockage. We find that knockout of TMEM16A abolishes Ca2+-activated Cl- currents, demonstrating that TMEM16A is essential for these currents in supporting cells. Also, by using extracellular ATP as physiological stimuli, we found that the stimulation of purinergic receptors activates a large TMEM16A-dependent Cl- current, indicating a possible role of TMEM16A in ATP-mediated signaling. Altogether, our results establish that TMEM16A-mediated currents are functional in olfactory supporting cells and provide a foundation for future work investigating the precise physiological role of TMEM16A in the olfactory system.


Dapagliflozin and saxagliptin tablets for adults with type 2 diabetes.
Saxagliptin (a dipeptidyl peptidase-4 inhibitor, DPP-4i) and dapagliflozin (a sodium-glucose cotransporter type 2 inhibitor, SGLT2i) improve glucose control in type 2 diabetes (T2D) through different potentially complementary mechanisms, thus offering the opportunity for a combined therapy. Area covered: The characteristics of the saxagliptin/dapagliflozin combination are analysed, focusing on: 1) pharmacokinetic and pharmacodynamic properties; 2) efficacy and safety in phase III trials with concurrent and sequential add-on therapy; and 3) potential use in clinical practice, including in special populations (cardiovascular disease, heart failure, chronic kidney disease, elderly). Expert commentary: Conclusions drawn from clinical trials investigating combination with the separate drugs are considered to apply to the fixed-dose combination (FDC) that demonstrates bioequivalence. Dual saxagliptin/dapagliflozin therapy is more potent than either monotherapy and can be used as an initial combination or a stepwise sequential approach. Dual therapy is generally well tolerated and may be used in special populations, with some limitations because of the presence of dapagliflozin. However, the latter may offer some advantages because of multiple effects attributed to SGLT2i. The best place of this dual combination for the management of T2D and the profile of patients who will make the most of this combined therapy remains to be defined.


Differences in the acute response of the various segments ofrat intestine to treatment with the intestinal carcinogen, methylazoxymethanol acetate.
Previous work has shown that single injections of methylazoxymethanol acetate in rats induce tumors predominantly in the colon, occasionally in the duodenum, and rarely in the jejunum and ileum. These studies describe the acute pathological and biochemical, alterations induced by this carcinogen in the different segments of rat small intestine and colon. Karyorrhexis was found in crypts of duodenum, cecum, and all segments of colon at 6 hr after treatment. Much of the cellular debris was removed by 24 hr, although mitoses did not return to normal levels until the third day after treatment. No pathological alterations were found in jejunum or ileum, even as late as 24 hr after treatment. Studies of DNA synthesis at 24 hr after treatment indicated that jejunum and ileum were much less affected than were duodenum, cecum, or colon. In contrast, 5-fluorouracil and nitrogen mustard, agents that can inhibit proliferating cells but are not known to be intestinal carcinogens, affected all of the segments equally. The results indicate that a correlation exists between those segments of intestine acutely affected by methylazoxymethanol acetate and the sites of eventual tumor development. The level of deacetylase activity in the various intestinal segments did not correlate with sensitivity to methylazoxymethanol acetate-induced inhibition of DNA synthesis. We also found that methylazoxy-methanol acetate inhibited DNA synthesis in the duodenum and colon in rats with cannulated bile ducts. These data indicate that the carcinogen does not require biliary transport to the intestinal lumen to exert its biological effects. Mechanisms that might account for the observed selectivity in action of methylazoxymethanol acetate in the various rat intestinal segments are discussed.


State-level variation in opioid prescribing after knee arthroscopy among the opioid-naïve in the USA: 2015-2019.
It has been established that most patients prescribed opioids after minor surgery have tablets left over, better understanding the variation in opioid prescribing and variation in dosage of the prescription could guide efforts to reduce prescribing. This study describes the state-level variation in opioid prescribing after a knee arthroscopy among opioid-naïve patients. Retrospective cohort study. Commercial insurance claims data. 98 623 individual across the USA with commercial insurance who were opioid-naïve and had a knee arthroscopy between 2015 and 2019. Patients who filled an opioid prescription within 3 days of a knee arthroscopy. Opioid prescriptions were measured as a pharmacy claim for filling an opioid within 3 days of a knee arthroscopy. We measured the patient and state-level opioid prescribing rate, tablet count, morphine milligram equivalent dose per prescription and risk-adjusted predicted opioid quantity. Overall, 72% of patients filled an opioid prescription with a median tablet count of 40 and median morphine milligram equivalent of 250. Patients with an invasive procedure (27.9% vs 22.4%; p<0.001), higher education level (p<0.001) and fewer comorbidities (0.9 vs 1.2, p<0.001) had higher rates of opioid prescribing. The prescribing rate in the highest state, Nebraska (85%), was double the prescribing rate in the lowest state, South Dakota (40%). Comparing the casemix adjusted expected prescribing rate to the observed prescribing rate displayed that 18 states had observed prescribing rates that were higher than their expected prescribing rates. Wide variation in the likelihood of receiving a prescription, depending on state of residence, was observed. The dosages prescribed were high and have been associated with transition to long-term use. These findings suggest that there is substantial opportunity for the development of guidelines to reduce variability in opioid prescribing for this common ambulatory procedure.


Distribution and release of human pancreatic polypeptide.
A simple and reliable radioimmunoassay has been developed for a new gut hormone, HPP. In the primate 93% of the total PP was found in the pancreas with a small amount throughout the remaining gastrointestinal tract. HPP has been shown to be produced by a number of pancreatic apudomas and their metastases. The immunoreactive PP from these tumours and from normal pancreas was chromatographically indistinguishable from the pure peptide. The plasma PP concentration rose rapidly after a meal in normal subjects and was still raised six hours later. Fasting plasma PP levels in patients with PP cell containing pancreatic endocrine tumours were higher than even the postprandial level in normal subjects. PP measurements is thus useful in diagnosis of pancreatic endocrine tumours.


[Functionality and everyday suitability of commercially wristwear products for frail older people - a comparative product testing].
There is a wide range of smartwatches and emergency watches on the market that are specifically designed for older people. The products are freely available, which is why there is an urgent need for information about the reliability and functionality of the products among potential users, but also health professionals and decision-makers. As part of a systematic product comparison test, the functionality and quality of seven smartwatches were investigated. Four watches for seniors, one watch for adults and two watches for children, but with comparable functionalities, were included in the test. For the test, real-life situations were simulated and, in addition to emergency calls, GPS tracking, fall detection and geofencing, the battery life, call quality, stability/robustness of the products and service/support were evaluated. From the total number of points, a grade was determined based on the German school grading system (1 = very good to 6 = insufficient). All smartwatches evaluated were rated at least "3-satisfactory". The two best-rated watches received a score of 1.8. The differences were particularly evident in the emergency call functionality, battery life, precision of the tracking function, and service/support. The call quality, with one exception, and the stability/robustness were consistently rated as "1-very good". Three watches in the test were able to detect falls with variable results. The functionality and usability of the tested products differed considerably. A focus on a few main functions can even provide added value for older, frail people. Continuous comparative testing of products for this target group with new and updated products is desirable.


Disaccharidase activity in the intestinal tissue of broilers infected with coccidia.
Maltase and sucrase activities were measured in the intestine of broilers inoculated with sporulated coccidial oocysts. Infection with Eimeria acervulina, E. maxima, E. necatrix, and E. brunetti decreased disaccharidase activity in the intestinal region in which maximum infection was found compared with the activity in uninoculated controls. The maximum reduction occurred on the first or second day of patency followed by a rapid recovery in activity. Disaccharidase activity was inversely proportional to the inoculum dose.


Complex samples logistic regression analysis of predictors of the current use of modern contraceptive among married or in-union women in Sierra Leone: Insight from the 2013 demographic and health survey.
Non-use of modern contraceptives among married or in-union women aged 15 to 49 years is a demographic and public health challenge. Studies on the predictors of contraceptive use among women in Sierra Leone are few, more than two decades old, and not nationally representative. This study aims to fill this gap by estimating the prevalence and the predictors of the current use of modern contraceptives among married or in-union women in Sierra Leone. This is a population-based study that used the 2013 Sierra Leone Demographic and Health Survey (SDHS) dataset. We performed complex samples logistic regression with 9,111 reproductive-age women. The analysis was done using the IBM SPSS Statistics version 21, and statistical significance was pegged at p≤0.01 and p≤0.05. The outcome of interest is the current use of modern contraceptives among reproductive-age married or in-union women in Sierra Leone, measured as 'Yes' (currently using a modern method) and 'No' (using a folkloric method, traditional method, and no method). About 18.1% of reproductive-age women were currently using a modern contraceptive. The study found the following sociodemographic factors as positive correlates: being within the age group of 20-24 years [AOR = 1.52, CI: 1.05, 2.19], 25-29 years [AOR = 1.57, CI: 1.10, 2.19], 30-34 years [AOR = 2.31, CI: 1.59, 3.36], 35-39 years [AOR = 1.89, CI: 1.33, 2.70], 40-44 years [AOR = 1.68, CI: 1.12, 2.52], obtaining either a primary [AOR = 1.40, CI: 1.14, 1.71] or secondary level education [AOR = 1.34, CI: 1.02, 1.74], belonging to the category of women that condemned wife beating under only one condition [AOR = 1.37, CI: 1.03, 1.78], under two conditions [AOR = 1.45, CI: 1.08, 1.93], under three conditions [AOR = 1.73, CI: 1.28, 2.35], under four conditions [AOR = 1.91, CI: 1.34, 2.72], and under five conditions [AOR = 1.41, CI: 1.07, 1.85], having the ability to refuse sex [AOR = 1.46, CI: 1.23, 1.76], ever heard family planning on the radio [AOR = 1.30, CI: 1.08, 1.58], being sexually active four weeks prior to the survey [AOR = 3.90, CI: 3.14, 4.84], ever taken an HIV test [AOR = 1.67, CI: 1.39, 2.02], ever visited a health facility in the last 12 months [AOR = 1.73, CI: 1.44, 2.09], dwelling in a richer household [AOR = 1.32, CI: 1.01, 1.72], and dwelling in an urban area [AOR = 1.44, CI: 1.14, 1.81]. Exposure to family planning through print media (newspaper/magazine) was negatively associated with current use of modern contraceptive [AOR = 0.60, CI: 0.37, 0.96]. The study provided in-depth insight into the sociodemographic predictors of the current use of modern contraceptives among married or in-union women in Sierra Leone. The study underscored the need to promote the protective factors of the current use of modern contraceptives and address the risk factors of the low prevalence of modern contraceptive use through policies, programs, and interventions in Sierra Leone.


Effects of oxidative treatment techniques on molecular size distribution of humic acids.
In this study ultrafiltration has been used for the fractionation of humic acid samples. Humic acids were treated in a sequential oxidation system in which ozonation was followed by photocatalytic oxidation using TiO2. Evaluation of the spectroscopic characteristics of the oxidized and fractionated humic acid samples have shown that molecular size distribution ranges shift to lower molecular sizes depending on the oxidation stages. Applied ozone dosage and irradiation time during the photocatalysis stage are the factors affecting the molecular size distribution in the treated humic acid samples. Formation of lower molecular weight compounds during the ozonation stage resulted in increased degradation rates during the photocatalysis stage.


Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis recognize an elastinolytic enzyme.
The target antigen of anti-neutrophil cytoplasm antibodies (ACPA; also known as ANCA) was isolated by affinity chromatography from supernatants of human neutrophils, stimulated with phorbol ester to induce degranulation. Sequence analysis of the antigen revealed 17 NH2-terminal amino acids (IVGGHEAQPHIRPIYMA), which have considerable sequence homology with known serine proteinases. Investigation of the enzymatic activity showed that the antigen is a neutral serine proteinase that is able to cleave elastin. Since the molecular weight of the antigen, its substrate specificity, and its inhibitor profile reported in this study are identical with those reported recently for proteinase 3, we conclude that ACPA are most probably directed against proteinase 3.


Altered reward value of carbohydrate snacks for female smokers withdrawn from nicotine.
Discontinuing nicotine intake usually results in weight gain partially due to heightened energy intake from between-meal snacks. This experiment tested the hypothesis that the reinforcing value of palatable carbohydrate-rich snacks increases for female smokers during nicotine deprivation. Eighteen smokers and 18 nonsmokers completed a concurrent-schedules operant computer task on two separate days. Smokers were bioverified abstinent at the second testing. The operant task allowed participants to earn points redeemable for either carbohydrate snacks or money on concurrent variable-ratio schedules of reinforcement. There were five different probabilities of earning points redeemable for snacks (8%, 16%, 25%, 50%, 75%), while the probability of earning points redeemable for money remained fixed at 25%. Reward value of snacks was measured by switch point: the reinforcement ratio at which the effort required to earn snacks exceeded their value to the respondent, as signified by a shift to working for money. Results showed that smokers undergoing nicotine deprivation persisted in working for snacks into leaner reinforcement schedules than nonsmokers (P=.026). Furthermore, nicotine deprivation increased smokers' allocation of effort to earn snack foods relative to their own behavior when smoking (P=.006). Variation in palatability or hunger did not explain these differences in snack reward value. Findings indicate that nicotine deprivation is associated with a heightened reward value of appealing snack foods for female smokers.


Sirtuin3 rs28365927 functional variant confers to the high risk of non-alcoholic fatty liver disease in Chinese Han population.
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition associated with aging, insulin resistance, metabolic syndrome, genetic factors and more. Although genetic traits are among the most important risks factors for NAFLD, the understanding of their influence is still quite limited. The present study aimed at identifying novel single nucleotide polymorphisms (SNPs) that may confer a risk for NAFLD in the Han Chinese population. Based on the "two-hit hypothesis", candidate SNPs, including Sirtuin3 rs28365927, were genotyped by MassARRAY in B-type ultrasonography-proven NAFLD patients (n = 292) and healthy controls (n = 387). In a model analysis of individuals matched based on gender and age that compared 223 NAFLD and 223 non-NAFLD patients, the rs28365927 GA + AA genotype was a significant risk factor for the development of NAFLD in a dominant model. Rs28365927 was significantly associated with a higher NAFLD risk in both an additive model (A vs G) and genotypic model (GA vs GG). Among the NAFLD patients, serum levels of total bilirubin (TBIL), DBIL direct bilirubin (DBIL) and glutamic-pyruvic transaminase (ALT) in rs28365927 A allele carriers (GA + AA) were 11.1, 14.7 and 41.5% higher, respectively, than in non-carriers (GG). Furthermore, among the NAFLD patients, the carriers of Rs28365927 allele A were positively correlated with higher ALT levels. Sirtuin3 rs28365927 functional variant confers to the high risk of non-alcoholic fatty liver disease in Chinese Han population. The rs28365927 A allele significantly increased the ALT levels of NAFLD patients.


Measured body mass index, body weight perception, dissatisfaction and control practices in urban, low-income African American adolescents.
Current understanding of the associations between actual body weight status, weight perception, body dissatisfaction, and weight control practices among low-income urban African American adolescents is limited. The knowledge can help direct future intervention efforts. Cross-sectional data including measured weight and height and self-reported weight status collected from 448 adolescents in four Chicago Public Schools were used. The prevalence of overweight and obesity (BMI > or = 85th percentile) was 39.8%, but only 27.2% considered themselves as obese, although 43.4% reported trying to lose weight. Girls were more likely to express weight dissatisfaction than boys, especially those with BMI > or = 95th percentile (62.9% vs. 25.9%). BMI > or = 85th percentile girls were more likely to try to lose weight than boys (84.6% vs. 66.7%). Among all adolescents, 27.2% underestimated and 67.2% correctly judged their own weight status. Multinomial logistic models show that those with BMI > or = 85th percentile, self-perceived as obese, or expressed body dissatisfaction were more likely to try to lose weight; adjusted odds ratios and 95% confidence intervals were 4.52 (2.53-8.08), 18.04 (7.19-45.30), 4.12 (1.64-10.37), respectively. No significant differences were found in diet and physical activity between those trying to lose weight and those not trying, but boys who reported trying to lose weight still spent more television time (P < 0.05). Gender differences in weight perception, body dissatisfaction, and weight control practices exist among African American adolescents. One-third did not appropriately classify their weight status. Weight perception and body dissatisfaction are correlates of weight control practices. Adolescents attempting to lose weight need be empowered to make adequate desirable behavioral changes.


Sources of variance of downwelling irradiance in water.
The downwelling irradiance in water is highly variable due to the focusing and defocusing of sunlight and skylight by the wave-modulated water surface. While the time scales and intensity variations caused by wave focusing are well studied, little is known about the induced spectral variability. Also, the impact of variations of sensor depth and inclination during the measurement on spectral irradiance has not been studied much. We have developed a model that relates the variance of spectral irradiance to the relevant parameters of the environmental and experimental conditions. A dataset from three German lakes was used to validate the model and to study the importance of each effect as a function of depth for the range of 0 to 5 m.


Determining the Optimal Restricted Driving Zone Using Genetic Algorithm in a Smart City.
Traffic control is one of the most challenging issues in metropolitan cities with growing populations and increased travel demands. Poor traffic control can result in traffic congestion and air pollution that can lead to health issues such as respiratory problems, asthma, allergies, anxiety, and stress. The traffic congestion can also result in travel delays and potential obstruction of emergency services. One of the most well-known traffic control methods is to restrict and control the access of private vehicles in predetermined regions of the city. The aim is to control the traffic load in order to maximize the citizen satisfaction given limited resources. The selection of restricted traffic regions remains a challenge because a large restricted area can reduce traffic load but with reduced citizen satisfaction as their mobility will be limited. On the other hand, a small restricted area may improve citizen satisfaction but with a reduced impact on traffic congestion or air pollution. The optimization of the restricted zone is a dynamic multi-regression problem that may require an intelligent trade-off. This paper proposes Optimal Restricted Driving Zone (ORDZ) using the Genetic Algorithm to select appropriate restricted traffic zones that can optimally control the traffic congestion and air pollution that will result in improved citizen satisfaction. ORDZ uses an augmented genetic algorithm and determinant theory to randomly generate different foursquare zones. This fitness function considers a trade-off between traffic load and citizen satisfaction. Our simulation studies show that ORDZ outperforms the current well-known methods in terms of a combined metric that considers the least traffic load and the most enhanced citizen satisfaction with over 30.6% improvements to some of the comparable methods.


Fabrication of FITC-doped silica nanoparticles and study of their cellular uptake in the presence of lectins.
Fluorescent silica nanoparticles are reported to be highly stable and biocompatible materials with high water solubility, which make them ideal candidates for biological applications. These nanoparticles can also be modified with biocompatible and targeting moieties and can be used for a variety of in vitro and in vivo applications, such as targeting, particle tracking, cargo carrier, and as contrast agents. In this study, fluorescent dye-doped silica nanoparticles were prepared by a modified Stöber method. The nanoparticles produced were surface functionalized with amine moieties for their conjugation with glucose-derived and galactose-based residues. The amine, glucose-derived, and galactose-based functionalized fluorescent silica nanoparticles were analyzed for their physiochemical properties such as sizes, polydispersities, organic layer content, and surface chemistries. The nanoparticles produced were then studied for their interactions with carbohydrate-specific lectins. These lectin bioconjugates have helped in understanding their interactions with cell-surface receptors. As expected, galactose-functionalized nanoparticles were found to specifically interact with RCA120 , as compared to other nanoparticles. These specific interactions of galactose-lectin conjugates were further studied on the hepatocytes cell surface in vitro. The aggregation of galactose-lectins conjugates on the plasma membrane was possibly due to the specific interactions of carbohydrates with cell-surface glycoproteins, hence preventing the uptake of these nanoparticles. The study has provided an interesting approach to mark the cell-surface glycoproteins with fluorescent probes using a combination of lectin-carbohydrate conjugates.


Comprehensive evaluation of protein-coding sORFs prediction based on a random sequence strategy.
Background: Small open reading frames (sORFs) with protein-coding ability present unprecedented challenge for genome annotation because of their short sequence and low expression level. In the past decade, only several prediction methods have been proposed for discovery of protein-coding sORFs and lack of objective and uniform negative datasets has become an important obstacle to sORFs prediction. The prediction efficiency of current sORFs prediction methods needs to be further evaluated to provide better research strategies for protein-coding sORFs discovery. Methods: In this work, nine mainstream existing methods for predicting protein-coding potential of ORFs are comprehensively evaluated based on a random sequence strategy. Results: The results show that the current methods perform poorly on different sORFs datasets. For comparison, a sequence based prediction algorithm trained on prokaryotic sORFs is proposed and its better prediction performance indicates that the random sequence strategy can provide feasible ideas for protein-coding sORFs predictions. Conclusions: As a kind of important functional genomic element, discovery of protein-coding sORFs has shed light on the dark proteomes. This evaluation work indicates that there is an urgent need for developing specialized prediction tools for protein-coding sORFs in both eukaryotes and prokaryotes. It is expected that the present work may provide novel ideas for future sORFs researches.


Identification of widespread adenosine nucleotide binding in Mycobacterium tuberculosis.
Computational prediction of protein function is frequently error-prone and incomplete. In Mycobacterium tuberculosis (Mtb), ~25% of all genes have no predicted function and are annotated as hypothetical proteins, severely limiting our understanding of Mtb pathogenicity. Here, we utilize a high-throughput quantitative activity-based protein profiling (ABPP) platform to probe, annotate, and validate ATP-binding proteins in Mtb. We experimentally validate prior in silico predictions of >240 proteins and identify 72 hypothetical proteins as ATP binders. ATP interacts with proteins with diverse and unrelated sequences, providing an expanded view of adenosine nucleotide binding in Mtb. Several hypothetical ATP binders are essential or taxonomically limited, suggesting specialized functions in mycobacterial physiology and pathogenicity.


Ongoing ostomy self-care challenges of long-term rectal cancer survivors.
Surgical treatment for rectal cancer (RC) can result in an intestinal ostomy that requires lifelong adaptation and investment of physical, cognitive, and financial resources. However, little is known about the extent of ongoing challenges related to ostomy self-care among long-term RC survivors. We analyzed the prevalence of self-reported ostomy self-care challenges and the physical and environmental factors that can support or undermine ostomy self-care. We mailed surveys to long-term (≥ 5 years post-diagnosis) RC survivors, including 177 adults with ostomies who were members of integrated health systems in northern California, Oregon, and Washington State. Potential participants were identified through tumor registries. Data were also extracted from electronic health records. The response rate was 65%. The majority of respondents were male (67%), and the mean age was 75 years. Sixty-three percent of respondents reported at least one ostomy self-care challenge. The most common challenges were leakage or skin problems around the ostomy and needing to change the pouching system too frequently. Twenty-two percent reported difficulty caring for their ostomy. Younger age and higher BMI were consistently related to ostomy self-care challenges. The majority of RC survivors reported ostomy-related self-care challenges, and 31% experienced problems across multiple domains of ostomy self-care. In addition, most survivors reported significant physical challenges that could lead to ostomy-related disability. Although the participants surveyed had access to ostomy care nurses, the care gaps we found suggest that additional work is needed to understand barriers to ostomy care, reduce unmet needs, and improve well-being among this group.


Swedish version of measuring cultural awareness in nursing students: validity and reliability test.
Nearly 20 % of the Swedish population is foreign-born. Increased exposure of patients from diverse cultures means there is an urgent need to address their unique requirements and provide optimal health care to a diverse population. Nursing schools thus have an important goal of educating nurses to ensure they are culturally competent. Culturally competent care improves safety and equity for patients. To measure cultural awareness among nursing students in Sweden, the aim of this study was to translate, adapt and test the validity and reliability of the Swedish version of a cultural awareness scale which has not previously been tested. A total of 158 nursing students from three universities in Sweden completed the 36-item questionnaire on cultural awareness. Verification of face and content validity and a translation/reverse translation process were first carried out. The results indicate that one item (no 13) caused weak reliability and validity, and therefore it was removed. The reliability test result (with 35 items) showed Cronbach's Alpha ranged from 0.60 to 0.87. The Model ChiSq group fit for five factors was 50.44 (31.27-77.06; Df = 5; p < 0.001), and the RMSEA was 0.24 (C.I 95 % = 0.18-0.30). The findings of the validity and reliability tests revealed that the CAS-scale for the 35 items is valid and reliable for use with Swedish nursing students. However, the CAS should be further tested in larger and more diverse samples of nursing students before being used in different socio-cultural settings.


Upregulation of DNA repair genes and cell extrusion underpin the remarkable radiation resistance of Trichoplax adhaerens.
Trichoplax adhaerens is the simplest multicellular animal with tissue differentiation and somatic cell turnover. Like all other multicellular organisms, it should be vulnerable to cancer, yet there have been no reports of cancer in T. adhaerens or any other placozoan. We investigated the cancer resistance of T. adhaerens, discovering that they are able to tolerate high levels of radiation damage (218.6 Gy). To investigate how T. adhaerens survive levels of radiation that are lethal to other animals, we examined gene expression after the X-ray exposure, finding overexpression of genes involved in DNA repair and apoptosis including the MDM2 gene. We also discovered that T. adhaerens extrudes clusters of inviable cells after X-ray exposure. T. adhaerens is a valuable model organism for studying the molecular, genetic, and tissue-level mechanisms underlying cancer suppression.


Unique Electronic Structures of the Highly Ruffled Hemes in Heme-Degrading Enzymes of Staphylococcus aureus, IsdG and IsdI, by Resonance Raman and Electron Paramagnetic Resonance Spectroscopies.
Staphylococcus aureus uses IsdG and IsdI to convert heme into a mixture of staphylobilin isomers, 15-oxo-β-bilirubin and 5-oxo-δ-bilirubin, formaldehyde, and iron. The highly ruffled heme found in the heme-IsdI and IsdG complexes has been proposed to be responsible for the unique heme degradation products. We employed resonance Raman (RR) and electron paramagnetic resonance (EPR) spectroscopies to examine the coordination and electronic structures of heme bound to IsdG and IsdI. Heme complexed to IsdG and IsdI is coordinated by a neutral histidine. The trans ligand is hydroxide in the ferric alkaline form of both proteins. In the ferric neutral form at pH 6.0, heme is six-coordinated with water as the sixth ligand for IsdG and is in the mixture of the five-coordinated and six-coordinated species for IsdI. In the ferrous CO-bound form, CO is strongly hydrogen bonded with a distal residue. The marker lines, ν2 and ν3, appear at frequencies that are distinct from other proteins having planar hemes. The EPR spectra for the ferric hydroxide and cyanide states might be explained by assuming the thermal mixing of the d-electron configurations, (dxy)2(dxz,dyz)3 and (dxz,dyz)4(dxy)1. The fraction for the latter becomes larger for the ferric cyanide form. In the ferric neutral state at pH 6.0, the quantum mechanical mixing of the high and intermediate spin configurations might explain the peculiar frequencies of ν2 and ν3 in the RR spectra. The heme ruffling imposed by IsdG and IsdI gives rise to unique electronic structures of heme, which are expected to modulate the first and subsequent steps of the heme oxygenation.


Development of the mandibular skeleton in the embryonic chick as evaluated using the DNA-inhibiting agent 5-fluoro-2'-deoxyuridine.
Mandibular development was examined in embryonic chicks following administration of 5-fluoro-2'-deoxyuridine (FUDR, 0.001-1.0 microgram/egg), an inhibitor of both DNA synthesis and of cell division. FUDR was injected in ovo at one of three developmental stages corresponding to 1) the migration of mandible-destined, midbrain-level neural crest cells (Hamburger and Hamilton [H.H.] stage 10); 2) midway through the epithelial-mesenchymal interaction required to initiate mandibular osteogenesis (H.H. stage 22), which is also after the epithelial-neural crest cell interaction required for the initiation of chondrogenesis in Meckel's cartilage; and 3) when prechondroblasts of Meckel's cartilage are beginning to differentiate (H.H. stage 25). Micromelia was induced following the administration of FUDR at either H.H. stages 22 or 25 but not when FUDR was given at H.H. stage 10. Although the micromelic mandibles were shorter than normal, Meckel's cartilage and the mandibular membrane bones both differentiated and grew along the full proximodistal length of the shortened mandibles. In contrast to the situation previously described by Ferguson for alligator embryos exposed to FUDR, the migration of neural crest cells in the embryonic chick was not inhibited by FUDR. In contrast to the situation previously described for rat embryos exposed to FUDR, differentiation of Meckel's cartilage was not inhibited in embryonic chicks exposed to FUDR. Differentiation of the membrane bones was also normal following either in ovo administration of FUDR or when mandibular processes were maintained in FUDR in vitro. Therefore, FUDR does not produce micromelia in the embryonic chick by interfering with the epithelial-mesenchymal/neural crest cell interactions, which are prerequisites or differentiation of cartilage or bone, nor by inhibiting the differentiation of chondrogenic or osteogenic mesenchymal cells after completion of these tissue interactions. Neither did the growth-inhibiting action of FUDR result from an inhibition of growth of Meckel's cartilage during the several days following initial chondrogenic differentiation. Rather, subsequent growth of the entire mandibular process was delayed. This mechanism of action differs from that in the alligator embryo, in which FUDR inhibits mandibular growth by removing mandible-destined, migrating neural crest cells, and in the rat, in which FUDR inhibits the differentiation of Meckel's cartilage but catch-up growth restores growth of the mandible to normal.


Macrophage activity and clinical immunology. Origin and kinetics of mononuclear phagocytes.
The origin and kinetics of mononuclear phagocytes can only be studied after the cells have been properly characterized. The basis for such a characterization on morphological, cytochemical, functional, and immunological grounds has been discussed. The production and kinetics of mononuclear phagocytes during the normal steady state have been described and compared with the effect of an acute inflammatory stimulus on these parameters. The influence of hydrocortisone and azathioprine was also studied in this connection. The increased production and monocytosis seen during an acute inflammatory response have been shown to be regulated by a humoral factor. The concept of the mononuclear phagocyte system was also discussed and an outline of the participation of mononuclear phagocytes in pathological processes put forward.


Disseminated hemorrhagic leukoencephalomyelitis with localized herpes simplex brain stem infection.
A case of widespread hemorrhagic and perivenous demyelinative leukoencephalomyelitis complicating a localized herpes simplex virus (HSV) brain stem infection is reported in a 28-year-old man. The presence of the virus is documented immunohistochemically and ultrastructurally. The spinal trigeminal tract at the level of the medulla oblongata contained viral antigen in the neurons, glia and in the vascular walls, including a few endothelial cells. The foci of demyelination showed deposits of gamma globulins and slight inflammatory infiltrations; the virus was absent from these lesions. It is postulated that HSV entered the central nervous system through the trigeminal nerve. Focal expression of the viral antigen on the endothelium in a sensitized host was the likely precipitating factor in the hyperacute autoimmune reaction, resulting in the widespread hemorrhagic and demyelinating lesions in the central nervous system.


Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning.
Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features.


A practical guide to monitoring for adverse drug reactions during antihypertensive drug therapy.
Monitoring of patients taking antihypertensive treatment can identify potential adverse drug reactions (ADRs). However, published guidelines give divergent or incomplete recommendations on monitoring for ADRs. Using a predetermined strategy, we undertook a systematic review to identify hypertension guidelines published from January 2001 to October 2011 with recommendations for monitoring for ADRs. We screened 88 abstracts and 187 web-based guidelines, and identified 19 published guidelines on monitoring the biochemical effects of antihypertensive drug therapy. We then produced a set of practical clinical guidelines, synthesized from those recommendations. Our recommendations are designed to provide efficient monitoring. They reduce the number of tests to a minimum consistent with safe practice and align monitoring schedules, so that creatinine, potassium and sodium concentrations are measured at the same times in all cases. The instructions for biochemical monitoring in current guidelines differ greatly, both in the extent of advice and in the detail provided. The current lack of consistent and workable instructions poses serious difficulties for practitioners. The recommendations distilled from this systematic review should help practitioners when they monitor therapy with antihypertensive drugs.


Alpine Skiing With total knee ArthroPlasty (ASWAP): symmetric loading during skiing.
The aim of this pilot study was to determine the pressure distribution, symmetry of load between operated (OP) and non-operated (NOP) leg, and pain level during alpine skiing in participants with unilateral total knee arthroplasty (TKA). The responses of the dependent variables were analyzed following a 10-week guided skiing intervention of 2-3 days of skiing per week. Ground reaction force (GRF) was recorded bilaterally and was determined for 13 participants with TKA (65 ± 4 years) at pre- and post-test. Additionally, pain perception was determined using a numeric rating scale in the OP leg at both test sessions and after each skiing day. No statistical differences were observed between OP and NOP legs for peak and average GRF as well as the asymmetry indices at pre-test. Pain perception was low and was not increased as a consequence of the skiing intervention. In conclusion, alpine skiing did not lead to increased or decreased loading of the OP leg compared with the NOP leg. Therefore, alpine skiing may be allowed for patients with skiing experience and a good clinical outcome.