Influence of diabetes and obesity on ten-year outcomes after coronary artery bypass grafting in the arterial revascularisation trial.
Diabetes and obesity are common conditions which can influence outcomes after coronary artery bypass graft (CABG) surgery. The aim of this study was to evaluate the influence of diabetes and obesity, and their interactions, on ten-year outcomes following CABG. Patients enrolled in the Arterial Revascularisation Trial (ART) were stratified by diabetes and obesity at baseline. Diabetes was further stratified into insulin and non-insulin dependent. The primary outcome was all-cause mortality at 10 years of follow-up. Secondary outcomes were the composite of all-cause mortality, myocardial infarction or stroke at 10 years, and sternal wound complications at 6 months follow-up. A total of 3096 patients were included in the analysis (24% with diabetes, 30% with obesity). Patients in the "diabetes/no obesity" group had a higher risk of all-cause mortality following CABG (adjusted hazard ratio [aHR] 1.33, 95% confidence interval [CI] 1.08-1.64, p = 0.01) compared to the reference group of "no diabetes/no obesity". No excess risk was observed in the "no diabetes/obesity" or "diabetes/obesity" groups. Patients with insulin dependent diabetes had a significantly higher ten-year mortality risk compared to no diabetes (aHR 1.85, 95% CI 1.41-2.44, p = 0.00). Patients in the "diabetes/no obesity" and "diabetes/obesity groups" had a higher risk of sternal wound complications (HR 2.29, 95% CI 1.39-3.79, p < 0.001 and HR 3.21, 95% CI 1.89-5.45, p < 0.001 respectively). The composite outcome results were consistent with the mortality results. Diabetes, especially insulin dependent diabetes, is associated with a higher ten-year mortality risk after CABG, in contrast to obesity which does not appear to increase long term mortality compared to non-obese. The interaction between diabetes and obesity shows an apparent "protective" effect of obesity irrespective of diabetes on mortality. Both conditions are associated with a higher risk of post-operative sternal wound infections.


Efficient Second-Harmonic Generation in Nanocrystalline Silicon Nanoparticles.
Recent trends to employ high-index dielectric particles in nanophotonics are motivated by their reduced dissipative losses and large resonant enhancement of nonlinear effects at the nanoscale. Because silicon is a centrosymmetric material, the studies of nonlinear optical properties of silicon nanoparticles have been targeting primarily the third-harmonic generation effects. Here we demonstrate, both experimentally and theoretically, that resonantly excited nanocrystalline silicon nanoparticles fabricated by an optimized laser printing technique can exhibit strong second-harmonic generation (SHG) effects. We attribute an unexpectedly high yield of the nonlinear conversion to a nanocrystalline structure of nanoparticles supporting the Mie resonances. The demonstrated efficient SHG at green light from a single silicon nanoparticle is 2 orders of magnitude higher than that from unstructured silicon films. This efficiency is significantly higher than that of many plasmonic nanostructures and small silicon nanoparticles in the visible range, and it can be useful for a design of nonlinear nanoantennas and silicon-based integrated light sources.


Expression of connective tissue growth factor in cartilaginous tumors.
Connective tissue growth factor (CTGF) predominantly is expressed in hypertrophic chondrocytes and its specific receptors are demonstrated on chondrocytic cells. Therefore, CTGF may be involved in the proliferation and/or differentiation of cartilage cells. In the current study, CTGF expression was examined both in chondrosarcoma and enchondroma to clarify the relation between the expression of CTGF and the grade of malignancy. The expression of CTGF and proliferating cell nuclear antigen (PCNA) were analyzed immunohistochemically in 34 cartilaginous tumor specimens. Eighteen tumors were determined to be chondrosarcoma including 8 Grade 1 tumors, 6 Grade 2 tumors, and 4 Grade 3 tumors. The percentage of CTGF positive and PCNA positive cells was quantified using at least 500 cells. CTGF was expressed in 70.1% of enchondroma cells, 84.0% of Grade 1 chondrosarcoma cells, 53.7% of Grade 2 tumor cells, and 26.8% of Grade 3 tumor cells (rho = -0.501; P = 0.0053). In chondrosarcoma cases, CTGF expression was correlated closely with tumor grade (rho = -0.920; P = 0.0001). There was a strong correlation between PCNA expression and tumor grade (rho = 0.907; P < 0.0001) and a strong negative correlation between CTGF and PCNA expression (rho = -0.493; P = 0.0061). In chondrosarcoma cases, patients with high expression of CTGF (>/= 30%) showed higher overall survival compared with those with low expression (< 30%) (P = 0.004). The current study revealed a correlation between the histologic grade of chondrosarcoma and prognosis, and the concomitant association between CTGF immunostaining and tumor grade and prognosis. Therefore, immunohistochemical staining with CTGF is a useful procedure for assessing the tumor grade and clinical course in patients with chondrosarcoma.


Why do breast cancer patients report late or abscond during treatment in ghana? A pilot study.
To determine the causes of delayed presentation in breast cancer patients at Korle Bu Teaching Hospital (KBTH), and reasons for patients absconding before and during treatment. Questionnaire survey. Out patient departments and surgical wards of KBTH. Women newly diagnosed with breast cancer and breast cancer patients who previously absconded and were returning for treatment. Sixty six newly-diagnosed patients aged between 20 and 84 (mean 44.8, median 43) years and 35 previous absconders aged 20 to 74 (mean 44.5, median 44) years were interviewed. The causes of delayed presentation were: previous medical consultations 26(29.4%), ignorance 19(28.8%), fear of mastectomy 16(24.2%), herbal treatment 13(19.7%), prayer/prayer camps 13(19.7%) and financial incapability 12(18.2%). Fear of mastectomy 20(57.1%), herbal treatment 13(37.1%), financial incapability 11(31.4%) and prayers/prayer camps 10(28.6%) which were prominent causes of late presentation, were the main reasons for absconding. Newly diagnosed patients had duration of symptoms one week to five years (mean 46, median 34 weeks). Those whose lumps were found by clinical breast examination in the community presented to hospital between six weeks to two years (mean 47, median 39 weeks). Married women were more likely to abscond (p=0.001). There are similar reasons for delayed presentation and absconding among Ghanaian patients. These must be addressed in outreach programmes, and patients must be counselled at time of diagnosis. Dealing with the causes of delayed presentation appears more important than attempts to screen for breast cancer, since patients identified through community screening still present late to hospital.


Guided bone regeneration to repair an osseous defect.
The ultimate goal of orthodontic therapy is to establish functional and esthetic dental relationships in a balanced facial pattern. In patients with compromised periodontal support, the use of multidisciplinary treatment plans is essential in attaining these goals. This case report includes a thorough documentation of the orthodontic and periodontal treatments to demonstrate the effectiveness of guided bone regenerative procedures combined with a bone allograft to aid in correcting a dental malocclusion.


1 alpha, 25-Dihydroxyvitamin D3 specifically induces its own metabolism in a human cancer cell line.
Human breast cancer and malignant melanoma cells possess specific, high affinity receptors for 1 alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3). The replication of these cells is affected by 1,25-(OH)2D3 with a biphasic dose response, i.e. stimulation at low concentration and inhibition at high concentration. Several 1,25-(OH)2D3 metabolites hydroxylated at the 23,24 and 26 carbons have reduced affinity for the receptors but are still able to inhibit cell replication at high concentrations; none of these metabolites are able to stimulate cell growth. In this context, it is of considerable interest that T47-D breast cancer cells in culture actively metabolize 1,25-(OH)2D3 to chloroform- and aqueous-soluble compounds. Based on multiple solvent high pressure liquid chromatography, double label studies, and periodate sensitivity it is apparent that metabolism occurs about the 23,24 and 26,27 carbon atoms. Three metabolites have been tentatively identified as 1,24,25-(OH)3D3 and the 24-oxo derivatives of 1,25-(OH)2D3 and 1,23,25-trihydroxyvitamin D3. Although calcitroic acid may be produced, other aqueous-soluble metabolites with partially intact side chains are major metabolic products. The metabolic activity is low in the 1,25-(OH)2D3-depleted cell and is induced in 3-4 h by a process requiring new protein synthesis. The induction by 1,25-(OH)2D3 is highly specific since 25-OH D3 is quite ineffective. The studies reported here carried out in intact cells in culture demonstrate unequivocally that 1,25-(OH)2D3 metabolism, through chloroform-soluble to aqueous-soluble metabolites, occurs entirely within a proven target cell of 1,25-(OH)2D3 action. Since other 1,25-(OH)2D3 metabolites hydroxylated at the 23,24 and 26 carbons lack the ability to stimulate cell replication, it is hypothesized that the hormone-inducible metabolic activity represents a sensitive mechanism for the control of cellular responsiveness to 1,25-(OH)2D3.


Dimensionality and scale properties of the Edinburgh Depression Scale (EDS) in patients with type 2 diabetes mellitus: the DiaDDzoB study.
Depression is a common complication in type 2 diabetes (DM2), affecting 10-30% of patients. Since depression is underrecognized and undertreated, it is important that reliable and validated depression screening tools are available for use in patients with DM2. The Edinburgh Depression Scale (EDS) is a widely used method for screening depression. However, there is still debate about the dimensionality of the test. Furthermore, the EDS was originally developed to screen for depression in postpartum women. Empirical evidence that the EDS has comparable measurement properties in both males and females suffering from diabetes is lacking however. In a large sample (N = 1,656) of diabetes patients, we examined: (1) dimensionality; (2) gender-related item bias; and (3) the screening properties of the EDS using factor analysis and item response theory. We found evidence that the ten EDS items constitute a scale that is essentially one dimensional and has adequate measurement properties. Three items showed differential item functioning (DIF), two of them showed substantial DIF. However, at the scale level, DIF had no practical impact. Anhedonia (the inability to be able to laugh or enjoy) and sleeping problems were the most informative indicators for being able to differentiate between the diagnostic groups of mild and severe depression. The EDS constitutes a sound scale for measuring an attribute of general depression. Persons can be reliably measured using the sum score. Screening rules for mild and severe depression are applicable to both males and females.


Arginine mutations within a transmembrane domain of Tar, an Escherichia coli aspartate receptor, can drive homodimer dissociation and heterodimer association in vivo.
The interactions between the TM (transmembrane) domains of many membrane proteins are important for their proper functioning. Mutations of residues into positively charged ones within TM domains were reported to be involved in many genetic diseases, possibly because these mutations affect the self- and/or hetero-assembly of the corresponding proteins. To our knowledge, despite significant progress in understanding the role of various amino acids in TM-TM interactions in vivo, the direct effect of positively charged residues on these interactions has not been studied. To address this issue, we employed the N-terminal TM domain of the aspartate receptor (Tar-1) as a dimerization model system. We expressed within the ToxR TM assembly system several Tar-1 constructs that dimerize via polar- or non-polar amino acid motifs, and mutated these by replacement with a single arginine residue. Our results have revealed that a mutation in each of the motifs significantly reduced the ability of the TMs to dimerize. Furthermore, a Tar-1 construct that contained two arginine residues was unable to correctly integrate itself into the membrane. Nevertheless, an exogenous synthetic Tar-1 peptide containing these two arginine residues was able to inhibit in vivo the marked dimerization of a mutant Tar-1 construct that contained two glutamate residues at similar positions. This indicates that hetero-assembly of TM domains can be mediated by the interaction of two oppositely charged residues, probably by formation of ion pairs. This study broadens our knowledge regarding the effect of positively charged residues on TM-TM interactions in vivo, and provides a potential therapeutic approach to inhibit uncontrolled dimerization of TM domains caused by mutations of polar amino acids.


Perforator-based interposition flaps for sustainable scar contracture release: a versatile, practical, and safe technique.
Problematic scar contractures are frequently observed following extensive (burn) wounds. In this study, the authors investigated the applicability of islanded and nonislanded perforator-based interposition flaps as a technique for release of scar contracture. Patients requiring surgery for scar contracture release were included. Preoperatively, a suitable perforator was identified by color Doppler sonography. The flap design was tailored according to the localization of this perforator and the anticipated defect. Flap measurements were obtained intraoperatively and at follow-up. Supple scar tissue was included in the flap design when necessary, to increase the applicability of this concept in extensively burned patients. Flaps were converted into island flaps on indication to circumvent significant kinking of the flap base and compromised tissue perfusion. Twenty-two flaps were performed, of which four were converted into island flaps. All flaps survived, but in four cases necrosis of the tip was observed. After a mean follow-up of 7.8 months, the width and surface area of the flaps had expanded to 123 percent (range, 40 to 311 percent) and 116 percent (range, 60 to 246 percent), respectively. One flap was converted into a full-thickness graft during the initial operation. This concept of perforator-based interposition flaps was found to be a reliable and versatile technique for broad scar contractures. Moreover, it allows intraoperative tailoring, as the flap base can be islanded when indicated. Nevertheless, additional venous outflow is warranted and operative time is saved if the flap base remains intact.


Possible involvement of hic-5, a focal adhesion protein, in the differentiation of C2C12 myoblasts.
Hic-5, a focal adhesion protein, has been implicated in cellular senescence and differentiation. In this study, we examined its involvement in myogenic differentiation. The hic-5 expression level in growing C2C12 myoblasts increased slightly on the first day and then gradually decreased until no hic-5 was detectable after 7 days of differentiation. In vivo, its expression level declined in the thigh and the calf skeletal muscle of mouse embryos after birth. The introduction of an antisense expression vector of hic-5 into C2C12 cells decreased the number of clones expressing the myosin heavy chain (MHC) upon exposure to the differentiation medium. In the cloned cells with low levels of hic-5, the efficiency of myotube formation was significantly reduced. The expression levels of MyoD, myogenin, MHC and p21 were also reduced in these clones. The results suggested that hic-5 plays a role in the initial stage of myogenic differentiation.


Early growth and chronic disease: a public health overview.
Infant and childhood growth result from and reflect a range of influences in pre- and postnatal life. These include nutrition, burden of infection and the psycho-social environment. Nutrition in young children is dependent on individual level factors such as fetal experience, infant feeding and weaning practices, and on societal factors such as education of women and economic conditions. The relationship of early postnatal growth to adult disease may be indicative or causal, and may reveal both biological and sociological processes. Although non-insulin-dependent diabetes mellitus (NIDDM) and obesity are risk factors for ischaemic heart disease, the relationships of these three conditions to infant growth differ. Poor infant growth has been associated with higher levels of NIDDM and ischaemic heart disease, but lower levels of adult obesity. Most research has been of populations living in developed countries at different stages of nutritional transition. However, differences in context are not simply limited to the stage of the nutritional transition. They also need to consider the nature of that transition and its social correlates, which may result in the clustering of aetiological influences such as increased body mass and poverty. The size of effect of the relationship of infant growth to adult disease is important not only to determine its relative aetiological importance but also for its potential for public health policy. Such policy also needs to consider the relationships of infant growth to a range of outcomes, both health and human capital, which are not the subject of this workshop.


Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein(a).
The B apolipoproteins, apo-B48 and apo-B100, are key structural proteins in those classes of lipoproteins considered to be atherogenic [e.g., chylomicron remnants, beta-VLDL, LDL, oxidized LDL, and Lp(a)]. Here we describe the development of transgenic mice expressing high levels of human apo-B48 and apo-B100. A 79.5-kb human genomic DNA fragment containing the entire human apo-B gene was isolated from a P1 bacteriophage library and microinjected into fertilized mouse eggs. 16 transgenic founders expressing human apo-B were generated, and the animals with the highest expression had plasma apo-B100 levels nearly as high as those of normolipidemic humans (approximately 50 mg/dl). The human apo-B100 in transgenic mouse plasma was present largely in lipoproteins of the LDL class as shown by agarose gel electrophoresis, chromatography on a Superose 6 column, and density gradient ultracentrifugation. When the human apo-B transgenic founders were crossed with transgenic mice expressing human apo(a), the offspring that expressed both transgenes had high plasma levels of human Lp(a). Both the human apo-B and Lp(a) transgenic mice will be valuable resources for studying apo-B metabolism and the role of apo-B and Lp(a) in atherosclerosis.


Activation of PERK Elicits Memory Impairment through Inactivation of CREB and Downregulation of PSD95 After Traumatic Brain Injury.
The PKR-like ER kinase (PERK), a transmembrane protein, resides in the endoplasmic reticulum (ER). Its activation serves as a key sensor of ER stress, which has been implicated in traumatic brain injury (TBI). The loss of memory is one of the most common symptoms after TBI, but the precise role of PERK activation in memory impairment after TBI has not been well elucidated. Here, we have shown that blocking the activation of PERK using GSK2656157 prevents the loss of dendritic spines and rescues memory deficits after TBI. To elucidate the molecular mechanism, we found that activated PERK phosphorylates CAMP response element binding protein (CREB) and PSD95 directly at the S129 and T19 residues, respectively. Phosphorylation of CREB protein prevents its interaction with a coactivator, CREB-binding protein, and subsequently reduces the BDNF level after TBI. Conversely, phosphorylation of PSD95 leads to its downregulation in pericontusional cortex after TBI in male mice. Treatment with either GSK2656157 or overexpression of a kinase-dead mutant of PERK (PERK-K618A) rescues BDNF and PSD95 levels in the pericontusional cortex by reducing phosphorylation of CREB and PSD95 proteins after TBI. Similarly, administration of either GSK2656157 or overexpression of PERK-K618A in primary neurons rescues the loss of dendritic outgrowth and number of synapses after treatment with a PERK activator, tunicamycin. Therefore, our study suggests that inhibition of PERK phosphorylation could be a potential therapeutic target to restore memory deficits after TBI.SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is the leading cause of death and disability around the world and affects 1.7 million Americans each year. Here, we have shown that TBI-activated PKR-like ER kinase (PERK) is responsible for memory deficiency, which is the most common problem in TBI patients. A majority of PERK's biological activities have been attributed to its function as an eIF2α kinase. However, our study suggests that activated PERK mediates its function via increasing phosphorylation of CAMP response element binding protein (CREB) and PSD95 after TBI. Blocking PERK phosphorylation rescues spine loss and memory deficits independently of phosphorylation of eIF2α. Therefore, our study suggests that CREB and PSD95 are novel substrates of PERK, so inhibition of PERK phosphorylation using GSK2656157 would be beneficial against memory impairment after TBI.


Outcomes following endoscopic, expanded endonasal resection of suprasellar craniopharyngiomas: a case series.
Craniopharyngiomas are challenging tumors that most frequently occur in the sellar or suprasellar regions. Microscopic transsphenoidal resections with various extensions and variations have been performed with good results. The addition of the endoscope as well as the further expansion of the standard and extended transsphenoidal approaches has not been well evaluated for the treatment of this pathological entity. The authors performed a retrospective review of all patients who underwent a purely endoscopic, expanded endonasal approach (EEA) for the resection of craniopharyngiomas at their institution between June 1999 and February 2006. Endocrine and ophthalmological outcomes, extent of resection, and complications were evaluated. Sixteen patients underwent endoscopic EEA for the resection of craniopharyngiomas. Five patients (31%) presented with recurrent disease. Complete resection was planned in 11 of the 16 patients. Three elderly patients with vision loss underwent planned debulking, 1 patient with vision loss and a moderate-sized tumor had express wishes for debulking, and 1 patient had a separate, third ventricular nodule that was not resected. Of those in whom complete resection was planned, 91% underwent near-total (2/11) or gross-total (8/11) resection. No patient who underwent gross-total resection suffered a recurrence. The mean follow-up period was 34 months. Of the 14 patients who presented with vision loss, 93% had improvement or complete recovery and 1 patient's condition remained stable. No patient experienced visual worsening. Eighteen percent of patients (without preexisting hypopituitarism) developed panhypopituitarism and 8% developed permanent diabetes insipidus. There were no cases of new obesity. The postoperative cerebrospinal fluid leak rate was 58%. All leaks were resolved, and there were no cases of bacterial meningitis. There was 1 vascular injury (posterior cerebral artery perforator branch) resulting in the only new neurological deficit. No patient died. Endoscopic EEA for the resection of craniopharyngiomas provides acceptable results and holds the potential to improve outcomes.


The effect of maternal nutrition level during the periconception period on fetal muscle development and plasma hormone concentrations in sheep.
The effect of maternal nutrition level during the periconception period on the muscle development of fetus and maternal-fetal plasma hormone concentrations in sheep were examined. Estrus was synchronized in 55 Karayaka ewes and were either fed ad libitum (well-fed, WF, n=23) or 0.5×maintenance (under-fed, UF, n=32) 6 days before and 7 days after mating. Non-pregnant ewes (WF, n=13; UF, n=24) and ewes carrying twins (WF, n=1) and female (WF, n=1; UF, n=3) fetuses were removed from the experiment. The singleton male fetuses from well-fed (n=8) and under-fed (n=5) ewes were collected on day 90 of gestation and placental characteristics, fetal BWs and dimensions, fetal organs and muscles weights were recorded. Maternal (on day 7 after mating) and fetal (on day 90 of pregnancy) blood samples were collected to analyze plasma hormone concentrations. Placental characteristics, BW and dimensions, organs and muscles weights of fetuses were not affected by maternal feed intake during the periconception period. Maternal nutrition level did not affect fiber numbers and the muscle cross-sectional area of the fetal longissimus dorsi (LD), semitendinosus (ST) muscles, but the cross-sectional area of the secondary fibers in the fetal LD and ST muscles from the UF ewes were higher than those from the WF ewes (P<0.05). Also, the ratio of secondary to primary fibers in the ST muscle were tended to be lower in the fetuses from the UF ewes (P=0.07). Maternal nutrition level during the periconception period did not cause any significant changes in fetal plasma insulin and maternal and fetal plasma IGF-I, cortisol, progesterone, free T3 and T4 concentrations. However, maternal cortisol concentrations were lower while insulin concentrations were higher in the WF ewes than those in the UF ewes (P<0.05). These results indicate that the reduced maternal feed intake during the periconception period may alter muscle fiber diameter without affecting fiber types, fetal weights and organ developments and plasma hormone concentrations in the fetus.


[Gastroesophageal reflux, pulmonary and gastric function in patients with cystic fibrosis. Results of a randomized trial].
We studied ten patients with Cystic fibrosis. The purposes of this study were to investigate the presence of gastroesophageal reflux and establish the probable association between gastroesophageal reflux and pulmonary and gastric involvement. All 10 patients underwent 24-hour esophageal pH recording, spirometry and gastric function. Abnormal reflux index was found in all these patients. Lung function was pathologic in the 3 older children. There were no relationship between the severity of the gastroesophageal reflux and the degree of pulmonary damage. No patient has gastric acid hypersecretion. Eight of 10 patients had steatorrhea. Our findings confirm the high frequence of gastroesophageal reflux in cystic fibrosis.


Theoretical model for predicting thermoelectric properties of tin chalcogenides.
The global energy crisis demands the search for new materials for efficient thermoelectric energy conversion. Theoretical predictive modelling with experiments can expedite the global search of novel and ecoconscious thermoelectric materials. The efficiency of thermoelectric materials depends upon the thermoelectric figure of merit (ZT). In this perspective, we discuss the theoretical model to calculate thermoelectric properties. Different scattering mechanisms of electrons and phonons are calculated using a simple model for the fast prediction of thermoelectric properties. Thermoelectric properties based on the simple model have shown more than 90% agreement with the experimental values. Possibility to optimize the figure of merit by alloying, defects, nanostructuring and band convergence is also discussed for layered chalcogenides of tin. In the case of doped materials, ion-impurity scattering is found to be dominating over electron-phonon scattering and the power factor can be optimized by tuning the former scattering rate. For phonon transport, alloy scattering is found to be the most dominating among all other scattering mechanisms. Theoretically, it is found that in the temperature range between 300 K and 800 K, SnSe0.70S0.30 has the highest ZT with an efficiency of 17.20% with respect to Carnot efficiency. There could be 53.8% enhancement of the device efficiency in SnSe0.70S0.30 compared to experimentally reported SnSe0.50S0.50 in the medium temperature range (300 K to 800 K). Possible routes to achieve the best ZT in the medium temperature range are also discussed in this perspective.


The epidemiology, pathogenesis, and diagnosis of vulvovaginal candidosis: a mycological perspective.
Vulvovaginal candidosis (VVC) is the second most common cause of vaginitis after bacterial vaginosis, and it is diagnosed in up to 40% of women with vaginal complaints in the primary care setting. Reliable diagnosis of VVC requires a correlation of clinical features with mycological evidence. The mycological methods used for diagnosis include microscopic examination, fungal culture, and antigen tests. Fungal culture can reveal the species of organism(s) responsible for the infection and provide epidemiological data. This report reviews current knowledge about the available diagnostic methods and tests that accurately diagnose VVC, and highlights the importance of fungal culture.


Mesenchymal stem cells (MSCs) as skeletal therapeutics - an update.
Mesenchymal stem cells hold the promise to treat not only several congenital and acquired bone degenerative diseases but also to repair and regenerate morbid bone tissues. Utilizing MSCs, several lines of evidences advocate promising clinical outcomes in skeletal diseases and skeletal tissue repair/regeneration. In this context, both, autologous and allogeneic cell transfer options have been utilized. Studies suggest that MSCs are transplanted either alone by mixing with autogenous plasma/serum or by loading onto repair/induction supportive resorb-able scaffolds. Thus, this review is aimed at highlighting a wide range of pertinent clinical therapeutic options of MSCs in the treatment of skeletal diseases and skeletal tissue regeneration. Additionally, in skeletal disease and regenerative sections, only the early and more recent preclinical evidences are discussed followed by all the pertinent clinical studies. Moreover, germane post transplant therapeutic mechanisms afforded by MSCs have also been conversed. Nonetheless, assertive use of MSCs in the clinic for skeletal disorders and repair is far from a mature therapeutic option, therefore, posed challenges and future directions are also discussed. Importantly, for uniformity at all instances, term MSCs is used throughout the review.


To Evaluate the Role of Positron Emission Tomography-Computerized Tomography in Initial Staging of Carcinoma Breast.
Breast cancer is the most common cancer in urban and second common in rural Indian women. In India, in spite of the best treatment available being given to the patients they lose their lives because of paucity of diagnostic aids and lack of an organized breast cancer screening program. Early detection, accurate staging, and initiation of appropriate therapy are the key factors for improving the treatment outcome and prognosis of the disease for the patients. Traditional staging methods include clinical examination, blood tests, chest X-ray, ultrasound of the abdomen, and/or skeletal survey. As these tests lack sensitivity and specificity, these are being scaled down. The hybrid positron emission tomography-computerized tomography (PET-CT) is a unique tool in the field of imaging modalities that combines the effectiveness of PET and CT. This study was undertaken to assess the efficacy and accuracy of PET-CT as a single-session staging modality in the very initial stage itself and if it can replace the conventional means of staging. This was a cross-sectional study conducted in the Radiotherapy department at GGS Medical College and Hospital Faridkot from March 2014 to October 2015. 52 patients with newly diagnosed and histopathologically proven carcinoma breast were staged by conventional modalities (clinical examination, blood tests, X-ray chest, mammography, ultrasonography abdomen, skeletal survey) and by 18F-fluorodeoxyglucose (18F FDG) PET/CT. PET-CT images were used for the detection, localization, staging of tumors and detection, evaluation, and diagnosis of metastatic lesions, disease burden and organ function along with treatment planning and planning therapeutic procedures. Following the completion of initial study, the results of 18F FDG PET-CT staging in comparison with conventional staging method were assessed. Along with this, the accuracy, changes in staging of cases of carcinoma breast and cost-effectiveness of 18F-FDG PET-CT were also studied. All the pathologic entities identified by conventional imaging were also perceived with 18F-FDG PET/CT. Therefore, we recommend the use of PET/CT as an important imaging modality for initial diagnosis of carcinoma breast.


Renal transplantation and the living donor. Decision and consequences.
Renal transplantation in end-stage renal disease is now an accepted medical procedure but the source and origin of the grafted organ (living donor vs. cadaveric kidney) remain controversial and it appears that each transplant team has to work out its own guidelines. We present the results of questionnaires and interviews of a large number of donors, many of them looking back on their experience with the knowledge that unfortunately, and in the long run, their sacrifice proved to be in vain. All our subjects evaluated their participation as donors in the transplant program in a very positive way. There was general agreement that none of them was significantly harmed by his action and that, in the realms of self-knowledge and feelings of self-worth and self-respect, the act of donorship turned out to be a very positive and very highly valued experience. These donors' opinions and attitudes, their relatively unconflicted conduct, are in sharp contrast with the agonizing appraisal of many a transplant team. It remains the task of the team doctors to weigh and balance risks and advantages of such an intervention and to be the advocate of both the donor and the recipient. It is to them that we offer our findings in the hope that it may help them in that difficult decision-making process.


Human immunodeficiency virus type 1 in Ireland: phylogenetic evidence for risk group-specific subepidemics.
HIV genetic diversity may have an impact on viral pathogenesis, transmission, response to treatment, and vaccine development. Public health surveillance that monitors the frequency and variety of HIV subtypes in a particular region or patient group is vital to successfully control the pandemic. We present the first comprehensive report on HIV diversity in Ireland. This study comprised all new HIV-1 diagnoses that were confirmed in the National Virus Reference Laboratory, University College Dublin, from January 2004 to December 2008. HIV 1 protease and reverse transcriptase sequences were generated using the Siemens Trugene HIV 1 Genotyping System. Subtypes were determined using web-based genotyping tools. There were 1579 new diagnoses [615 (39%) female and 964 (61%) male], of which 1060 had HIV-1 RNA specimens available for sequencing. Of sequenced samples, HIV-1 subtype B accounted for 50% overall, decreasing from 55.1% in 2004 to 49.5% in 2008. In addition, subtype B accounted for more than 80% of Irish-born individuals and more than 90% of Irish-born injection drug users and men who have sex with men. Subtype C was the second most prevalent in the overall cohort, accounting for 25%, although it accounted for only 6.1% of Irish-born individuals, with no evidence of in country transmission. The prevalence of non-subtype B HIV-1 infection in Ireland is increasing. However, these appear primarily to be imported infections not yet circulating within traditional Irish risk groups. Enhanced HIV-1 molecular epidemiology surveillance is required to monitor the spread of HIV-1, to inform future public health policy, and to ultimately control the HIV-1 epidemic in Ireland.


[Changes in immune reactivity of the organism and content of monoaminodicarboxylic acid and their derivatives in brain and spleen].
It is established in experiments with mice that the contrary effects on the immune system caused different changes in the level of monoaminodicarboxylic acids and their derivatives in the brain and spleen structures. While immunostimulation was accompanied by an increase in monoaminocarboxylic acids, immunodepression, on the contrary, was characterized by a decrease in their contents up to the level, which is lower than the initial one. The main task of the investigation was to find out if this correlation is of causal character, which might be indicative of the significance of maintaining the definite level of monoaminodicarboxylic acids and their derivatives in the brain immunocompetent organs for normal functioning of the immune system.


The Periareolar Approach: All Seasons Technique for Multiple Breast Conditions.
The periareolar approach was first introduced by Hollander in 1924 and, since then, numerous contributions have been reported by different authors. Despite all the strengths associated with this versatile technique, the periareolar approach still poses three main problems: large areolar diameter with poor quality scar, flattening of the breast cone, and poor stability of the results. The purpose of this article is to show how this surgical technique, with a good patient selection, can be applied to different situations and obtain excellent results. We performed a retrospective study on 5028 consecutive procedures in 4198 female patients treated with a periareolar approach in two regional institutions between 2008 and 2018. We considered 853 pure mastopexies, 362 breast augmentations, 422 secondary breast augmentations, 402 corrections of stenotic breast, 2921 oncoplastic surgeries, and 68 breast reductions. Postoperative complication, as well as patient and surgeon satisfaction were assessed. Patient and surgeon satisfaction 1 year after the procedure was excellent, and the complication rate was low. When the indication is set correctly, the periareolar approach can obtain excellent results. This versatile technique, initially introduced as a mastopexy technique, has expanded its applications and can now be used for multiple surgical situations.


Immune response of rats to group A streptococcal vaccine.
Adult female Sprague-Dawley rats were hyperimmunized with group A streptococcal vaccine in an attempt to evaluate this species for its immunological responsiveness to the group A streptococcal carbohydrate. Pronounced hyperproteinemia, generally attributable to hypergammaglobulinemia was produced in 30 to 40% of the animals. The immune response of the rats was extremely variable, yielding precipitating antibody concentrations ranging from <0.1 mg per ml to >26 mg per ml. Antibody levels also varied considerably in the same rat at different times during the immunization routine. The highest concentration of precipitating antibody was 26.3 mg per ml. Evidence is presented to suggest the production of antibodies of restricted heterogeneity and the production of non-streptococcal antibodies during the immune response.


Results of intraoperative neurophysiological monitoring in spinal canal surgery.
Spine surgery carries the risk of neurological complications. Neurophysiological intraoperative monitoring (NIOM) plays some role in preventing adverse events. NIOM is a young technique, and because of its costs and additional personnel it requires constant evaluation of indications. Nowadays, it is generally assumed that if available, NIOM should be used in every intracanal surgical procedure. This study aimed to evaluate the efficacy and indications for NIOM in spine surgery in relation to procedure location. Effectiveness of NIOM in spinal canal surgery was evaluated by comparison of the number of neurological complications in patients treated surgically with and without NIOM. A total of 74 consecutive patients were surgically treated for spinal canal pathology at the Department of Neurosurgery, 10th Military Hospital in Bydgoszcz. Thirty-eight patients operated on with the use of NIOM were compared to a historic population of 36 patients treated before the introduction of NIOM. The number of patients with neurological complications was analyzed in three groups based on surgical location: extradural, intradural extramedullary, and intramedullary procedures. Differences between groups were tested with the Fisher exact test. The number of neurological complications was significantly lower in the intramedullary procedure group with NIOM. There was no significant difference in the number of complications in patients undergoing intra- or extradural extramedullary procedures with versus without NIOM. NIOM decreases the risk of neurological complications in spinal cord surgery, but not in extramedullary spinal canal procedures.


Activated ErbB3 Translocates to the Nucleus via Clathrin-independent Endocytosis, Which Is Associated with Proliferating Cells.
Members of the receptor tyrosine kinase family (RTK) have been shown to be present in the nucleus of cells; however, the mechanisms underlying their trafficking to the nucleus, and their relevance once there are poorly understood. In the present study, we focus on the RTK ErbB3 and elucidate the mechanisms regulating its trafficking. We show that heregulin-stimulation induces trafficking of phosphorylated ErbB3 from the plasma membrane to the nucleus via a clathrin-independent mechanism. Nuclear import of ErbB3 occurs via importin β1, which drives the receptor through the nuclear pore complex. In the nucleus, ErbB3 interacts with transcription complexes, and thereby has a role in transcriptional regulation. Our results also demonstrate that ErbB3 nuclear localization is transient as it is exported out of the nucleus by the nuclear receptor protein crm-1. Analysis of normal, regenerating tissues, and tumors showed that ErbB3 nuclear translocation is a common event in proliferating tissues.


Fine mapping two distinct antigenic sites on simian virus 40 (SV40) T antigen reactive with SV40-specific cytotoxic T-cell clones by using SV40 deletion mutants.
The existence of two distinct antigenic sites at the surface of simian virus 40 (SV40)-transformed H-2b cells has been previously demonstrated (A. E. Campbell, L. F. Foley, and S. S. Tevethia, J. Immunol. 130:490-492, 1983) by using two independently isolated SV40-specific cytotoxic T-lymphocyte (CTL) clones, K11 and K19. We identified amino acids in the amino-terminal half of SV40 T antigen that are essential for the recognition of antigenic sites by these CTL clones by using H-2b cells transformed by mutants that produce T antigen truncated from the amino-terminal or carboxy-terminal end or carrying overlapping internal deletions in the amino-terminal regions of SV40 T antigen. The results show that CTL clone K11 failed to recognize and lyse target cells missing SV40 T-antigen amino acids 189 to 211, whereas CTL clone K19 lysed these cells. The cell lines missing SV40 T-antigen amino acids 220 to 223 and 220 to 228 were not lysed by CTL clone K19 but were susceptible to lysis by CTL clone K11. Two other cell lines missing amino acids 189 to 223 and 189 to 228 of SV40 T antigen were not lysed by either of the CTL clones but were lysed by SV40-specific bulk-culture CTL if sufficient amounts of relevant restriction elements were expressed at the cell surface. The SV40 T-antigen amino acids critical for the recognition of an antigenic site by CTL clone K11 were identified to be 193 to 211; 220 to 223 were identified as critical for recognition by CTL clone K19. The deletion of these amino acids from the T antigen resulted in the loss of antigenic sites specific for CTL clones K11 and K19.


Enablers and Barriers to Registered Nurses Expanding Their Scope of Practice in Australia: A Cross-Sectional Study.
A number of resources exist to assist registered nurses in Australia to determine their scope of practice; however, the ability of a professional nurse to expand his or her practice is highly context dependent. This article reports on barriers and enablers to expanding scope of practice, as identified by registered nurses across Australia. A cross-sectional survey administered online in 2016 returned 1,205 useable submissions. Results indicated that nurses wishing to expand their practice felt supported to do so by nursing colleagues and were aware of professional and regulatory documents relating to expanding scope of practice. Less support for this process was evident from other health professionals or employers. Respondents also indicated that they were motivated to expand their scope by professional satisfaction, potential for career advancement, and the desire to meet health service user's needs. The majority of respondents identified barriers to expanding scope of practice, including lack of remuneration and the absence of supportive guidelines. Respondents in the early stage of their careers were more likely to perceive organizational support for expanding their scope of practice. When required to expand their role, the majority of respondents indicated that they had undertaken additional training or accessed various resources to guide them in this process. Barriers to expanding nursing scope of practice can result in underutilization of the one of the greatest resources in the health care system. This article identifies a number of strategies that can facilitate role expansion to ensure that nursing continues to make a significant contribution to positive health service outcomes in Australia.


Dimenhydrinate effect on cerebral oxygen status and salivary chromogranin-A during cognitive tasks.
To investigate the effects of dimenhydrinate on cerebral oxygen status (COS; cerebral oxygenated hemoglobin concentration changes) and salivary chromogranin-A (CgA) during a cognitive test battery, a double-blind, placebo-controlled, randomized, crossover protocol was used to examine the effect of 50 mg of dimenhydrinate or placebo in 12 subjects. This test battery includes tests of both reaction time and fundamental cognitive ability and was used in the assessment of pilots. Poor cognitive performance was observed in the subjects taking dimenhydrinate. We used two-channel near-infrared spectroscopy to investigate the effects of dimenhydrinate on the COS. With the one exception of shifting attention task in the left forehead, no significant difference was found between dimenhydrinate and placebo during the tasks of the test battery. Under placebo treatment, on the other hand, CgA levels were significantly elevated during cognitive testing when compared with baseline. However, CgA levels were not significantly elevated above baseline following dimenhydrinate. The present study is one of the first to demonstrate that the first-generation antihistamine drugs altered the responses of salivary CgA during cognitive tasks. The changes in salivary CgA secretion, as a result of dimenhydrinate administration, may serve as a sensitive biomarker of a psychological status such as a drug-induced sedation during the performance of a cognitive test battery. Further studies, however, are required to examine the usefulness of this sensitive biomarker in investigation of psychological agents during cognitive tasks.


Pathways to meaning: a new approach to studying emotions at work.
Research on the emotional consequences of interactive service work remains inconclusive in large part because scholars have not analyzed the mechanisms that lead frontline employees to adopt the meanings disseminated by their employers. The authors argue that the theoretical framework best suited for remedying this situation is the negotiated order perspective. It suggests that whether employees adopt a corporate-sanctioned meaning, and with what emotional effect, depends on the conjunction of several social conditions. The authors also propose a novel analytical strategy that can identify these conditional pathways and formalize the combinatorial logic of the negotiated order perspective: fuzzy-set techniques. To illustrate the utility of this approach, the article examines a university hospital that has tried to create a more meaningful and emotionally rewarding work environment for its nursing staff. Consistent with expectations, findings show that employees can embrace the same corporate-sanctioned meaning under different sets of conditions and with different emotional consequences.


Use of Health Information Technology by Adults With Diabetes in the United States: Cross-sectional Analysis of National Health Interview Survey Data (2016-2018).
The use of health information technology (HIT) has been proposed to improve disease management in patients with type 2 diabetes mellitus. This study aims to report the prevalence of HIT use in adults with diabetes in the United States and examine the factors associated with HIT use. We analyzed data from 7999 adults who self-reported a diabetes diagnosis as collected by the National Health Interview Survey (2016-2018). All analyses were weighted to account for the complex survey design. Overall, 41.2% of adults with diabetes reported looking up health information on the web, and 22.8% used eHealth services (defined as filled a prescription on the web, scheduled an appointment with a health care provider on the web, or communicated with a health care provider via email). In multivariable models, patients who were female (vs male: prevalence ratio [PR] 1.16, 95% CI 1.10-1.24), had higher education (above college vs less than high school: PR 3.61, 95% CI 3.01-4.33), had higher income (high income vs poor: PR 1.40, 95% CI 1.23-1.59), or had obesity (vs normal weight: PR 1.11, 95% CI 1.01-1.22) were more likely to search for health information on the web. Similar associations were observed among age, race and ethnicity, education, income, and the use of eHealth services. Patients on insulin were more likely to use eHealth services (on insulin vs no medication: PR 1.21, 95% CI 1.04-1.41). Among adults with diabetes, HIT use was lower in those who were older, were members of racial minority groups, had less formal education, or had lower household income. Health education interventions promoted through HIT should account for sociodemographic factors.


Effects of low-wage employment on family well-being.
Assumptions about the processes that link a mother's employment to the development of her child must underlie expectations about how children may fare when their mothers move from welfare dependence into employment. This article explores the idea, mentioned in the research overview by Zaslow and Emig in this journal issue, that the working conditions such as wages, work hours, and task complexity that mothers experience on the job can influence their behavior as parents and shape the home environments they provide for their children. This article discusses the significance of home environments for children's intellectual and emotional development and considers how home surroundings change when mothers begin jobs that are more rewarding or less rewarding. The authors conclude that, while maternal employment is not necessarily harmful, if welfare recipients find only low-wage, stressful jobs, working may prove costly for both family and child well-being. The authors recommend that welfare-to-work programs devote attention to (1) assisting mothers to obtain more complex work at good wages, (2) helping mothers understand the role home environments play in shaping children's development, and (3) encouraging parents to make their children's home surroundings as positive as possible.


5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice.
Intravenous administration of apolipoprotein (apo) A-I complexed with phospholipid has been shown to rapidly reduce plaque size in both animal models and humans. Short synthetic amphipathic peptides can mimic the antiatherogenic properties of apoA-I and have been proposed as alternative therapeutic agents. In this study, we investigated the atheroprotective effect of the 5A peptide, a bihelical amphipathic peptide that specifically effluxes cholesterol from cells by ATP-binding cassette transporter 1 (ABCA1). 5A stimulated a 3.5-fold increase in ABCA1-mediated efflux from cells and an additional 2.5-fold increase after complexing it with phospholipid (1:7 mol/mol). 5A-palmitoyl oleoyl phosphatidyl choline (POPC), but not free 5A, was also found to promote cholesterol efflux by ABCG1. When incubated with human serum, 5A-POPC bound primarily to high-density lipoprotein (HDL) but also to low-density lipoprotein (LDL) and promoted the transfer of cholesterol from LDL to HDL. Twenty-four hours after intravenous injection of 5A-POPC (30 mg/kg) into apoE-knockout (KO) mice, both the cholesterol (181%) and phospholipid (219%) content of HDL significantly increased. By an in vivo cholesterol isotope dilution study and monitoring of the flux of cholesterol from radiolabeled macrophages to stool, 5A-POPC treatment was observed to increase reverse cholesterol transport. In three separate studies, 5A when complexed with various phospholipids reduced aortic plaque surface area by 29 to 53% (n = 8 per group; p < 0.02) in apoE-KO mice. No signs of toxicity from the treatment were observed during these studies. In summary, 5A promotes cholesterol efflux both in vitro and in vivo and reduces atherosclerosis in apoE-KO mice, indicating that it may be a useful alternative to apoA-I for HDL therapy.


Differential effects of human neuromelanin and synthetic dopamine melanin on neuronal and glial cells.
We investigated the effects of neuromelanin (NM) isolated from the human substantia nigra and synthetic dopamine melanin (DAM) on neuronal and glial cell lines and on primary rat mesencephalic cultures. Lactate dehydrogenase (LDH) activity and lipid peroxidation were significantly increased in SK-N-SH cells by DAM but not by NM. In contrast, iron-saturated NM significantly increased LDH activity in SK-N-SH cells, compared with 100 mg/mL ETDA-treated NM containing a low concentration of bound iron. DAM, but not NM, stimulated hydroxyl radical production and increased SK-N-SH cell death via apoptotic-like mechanisms. Neither DAM nor NM induced any changes in the glial cell line U373. 3H-dopamine uptake in primary rat mesencephalic cultures was significantly reduced in DAM-compared with NM-treated cultures, accompanied by increased cell death via an apoptosis-like mechanism. Interestingly, Fenton-induced cell death was significantly decreased in cultures treated with both Fenton reagent and NM, an effect not seen in cultures treated with Fenton reagent plus DAM. These data are suggestive of a protective role for neuromelanin under conditions of high oxidative load. Our findings provide new evidence for a physiological role for neuromelanin in vivo and highlights the caution with which data based upon model systems should be interpreted.


Effects of increasing crude protein level on nitrogen retention and intestinal supply of amino acids in lambs fed diets based on alkaline hydrogen peroxide-treated wheat straw.
The effects of increasing dietary CP level on N retention (Exp. 1) and intestinal supply of amino acids (AA; Exp. 2) were studied in lambs fed diets based on alkaline hydrogen peroxide-treated wheat straw (AHPWS). Soybean meal (SBM) was substituted for corn to increase CP level in both experiments. In Exp. 1, an incomplete design for the two-way elimination of error was used to allot 24 ram lambs (mean BW = 25 kg) within breed to six CP levels (6, 8, 10, 12, 14, and 16% of DM). Neutral detergent fiber digestibility and N retention increased quadratically (P = .06 and P less than .01, respectively) with increasing CP level. Nitrogen retention, expressed as a percentage of N intake, was greatest for lambs fed 12% CP (20.7%) but was greatest for lambs fed 14% CP when expressed as grams per day (4.0 g/d). In Exp. 2, five multicannulated St. Croix lambs (34 kg) were used in a 5 x 5 Latin square design. Treatments were 8.5, 11, 13.5, 16, and 18.5% dietary CP. Chromic oxide was used as a digesta flow marker and purines were used as a bacterial marker. Protein level had no effect on extent of dietary CP degradation in the rumen (69 +/- 3.2%). True ruminal OM digestibility increased (P less than .01) linearly and ruminal fluid NH3 N concentration increased (P less than .01) quadratically with increasing CP level. Total, bacterial, and nonbacterial N and AA flows to the duodenum increased (P less than .05) linearly with increasing CP level. Duodenal AA profile (g/100 g total AA) was altered slightly. The essential AA valine, isoleucine, phenylalanine, lysine, and arginine increased (P less than .05) and methionine decreased (P less than .05) in proportion to other AA with increasing CP level. Flows of all essential AA increased with increasing CP level. Apparent small intestinal N and AA disappearance increased linearly (P less than .05) and apparent total tract N digestibility increased (P less than .01) quadratically with increasing CP level. These data are interpreted to indicate that maximal N retention and fiber digestibility in diets based on AHPWS are obtained at 12% CP, even though the intestinal supply of AA continues to increase with increasing CP level. Supplementation of diets based on AHPWS with an extensively degraded protein source (SBM) does not substantially alter the profile of AA entering the duodenum compared to the AA profile of bacterial protein.


DNA methylation profiles and their relationship with cytogenetic status in adult acute myeloid leukemia.
Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required. We carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients. Our study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature.


Infrared fluorescent detection of D1S80 alleles from blood and body fluid collected on IsoCode devices.
A genetic locus D1S80 (pMCT 118) containing variable number of tandem repeats (VNTR) has been used extensively in forensic analysis and paternity testing. In the current research, DNA was isolated from blood saliva and nasal secretions collected on two types of IsoCode paper-based devices. The D1S80 locus was amplified using PCR technology, and the alleles were separated by gel electrophoresis and then detected using an infrared (IR) fluorescence automated DNA sequencer. IR-labeled amplification products were generated from human genomic DNA using oligonucleotide primers, which were covalently linked to an infrared fluorescent dye (IRD41) at the 5' end. This system combines IR fluorescence chemistry and laser technology, thus eliminating the need for post-electrophoretic gel handling for the detection of the alleles. Real-time detection after separation of the alleles is valuable for visualization of the data. The VNTR alleles are displayed as familiar autoradiogram-like images, which can also be analyzed by computer. Since DNA is eluted from the IsoCode devices only with sterile distilled water and without time-consuming methods of extraction, amplification can be performed from numerous samples within a short period of time.


Systematic Review with Meta-Analysis: Low-Level Alcohol Consumption and the Risk of Liver Cancer.
Multiple meta-analyses and observational studies have reported that alcohol is a risk factor for liver cancer. However, whether there is a safe level of alcohol consumption remains unclear. We performed a systematic review and meta-analysis of the correlation between low-level alcohol consumption and the risk of liver cancer. Nested case-control studies and cohort studies involving the general population published prior to July 2019 were searched. In total, 28 publications (31 cohorts) with 4,899 incident cases and 10,859 liver cancer-related deaths were included. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Compared with those with low levels of alcohol consumption, moderate and heavy drinkers (≥1 drink/day for females and ≥2 drinks/day for males) had pooled ORs of 1.418 (95% CI, 1.192 to 1.687; p<0.001) for liver cancer incidence and 1.167 (95% CI, 1.056 to 1.290; p=0.003) for liver cancer mortality. The pooled OR for liver disease-related mortality for those with more than low levels of alcohol consumption was 3.220 (95% CI, 2.116 to 4.898; p<0.001) and that for all-cause mortality was 1.166 (95% CI, 1.065 to 1.278; p=0.001). The sensitivity analysis showed that none of the studies had a strong effect on the pooled OR. The Egger test, Begg rank correlation test, and the funnel plot showed no overt indication of publication bias. Continuous consumption of more than a low-level of alcohol (≥1 drink/day for females and ≥2 drinks/ day for males) is related to a higher risk of liver cancer.


An in vivo analysis of the vestigial gene in Drosophila melanogaster defines the domains required for Vg function.
Considerable evidence indicates an obligate partnership of the Drosophila melanogaster Vestigial (VG) and Scalloped (SD) proteins within the context of wing development. These two proteins interact physically and a 56-amino-acid motif within VG is necessary and sufficient for this binding. While the importance of this SD-binding domain has been clearly demonstrated both in vitro and in vivo, the remaining portions of VG have not been examined for in vivo function. Herein, additional regions within VG were tested for possible in vivo functions. The results identify two additional domains that must be present for optimal VG function as measured by the loss of ability to rescue vg mutants, to induce ectopic sd expression, and to perform other normal VG functions when they are deleted. An in vivo study such as this one is fundamentally important because it identifies domains of VG that are necessary in the cellular context in which wing development actually occurs. The results also indicate that an additional large portion of VG, outside of these two domains and the SD-binding domain, is dispensable in the execution of these normal VG functions.


The patient-consumer-advocate nexus: the marketing and dissemination of gardasil, the human papillomavirus vaccine, in the United States.
The 2006 availability of Merck's human papillomavirus (HPV) vaccine, Gardasil, in the United States provides an opportunity to examine the pharmaceutical company's creation of patient awareness for one of the most common sexually transmitted infections and its related cancer. In spite of the ubiquity of gynecological screening, prior to the vaccine's dissemination, most U.S. women were not familiar with either the infection or its association with cancer. Merck's role in encouraging a patient advocacy community mimics existing breast cancer patient advocacy culture in the United States while also demonstrating marked popular culture differences between the two women's health concerns and their respective advocacy groups. This article draws on ethnographic fieldwork with an HPV/cervical cancer advocacy organization to demonstrate how the group and its members engaged in an activism of awareness that disavows larger political aims.


Autoimmune diseases of the liver and biliary tract and overlap syndromes in childhood.
Autoimmune liver diseases in childhood includes Autoimmune Hepatitis (AIH) and Primary (Autoimmune) Sclerosing Cholangitis (P(A)SC). Both diseases are characterized by a chronic, immune-mediated liver inflammation involving mainly hepatocytes in AIH and bile ducts in PSC. Both diseases, if untreated, lead to liver cirrhosis. AIH could be classified, according to the autoantibodies pattern, into two subtypes: AIH type 1 presents at any age as a chronic liver disease with recurrent flares occasionally leading to liver cirrhosis and liver failure. Characterizing autoantibodies are anti-nuclear (ANA) and anti-smooth muscle (SMA), usually at high titer (>1:100). These autoantibodies are not specific and probably do not play a pathogenic role. AIH type 2 shows a peak of incidence in younger children, however with a fluctuating course. The onset is often as an acute liver failure. Anti-liver kidney microsome autoantibodies type 1 (LKM1) and/or anti-liver cytosol autoantibody (LC1) are typically found in AIH type 2 and these autoantibodies are accounted to have a potential pathogenic role. Diagnosis of AIH is supported by the histological finding of interface hepatitis with massive portal infiltration of mononuclear cells and plasmocytes. Inflammatory bile duct lesions are not unusual and may suggest features of ''overlap'' with P(A)SC. A diagnostic scoring system has been developed mainly for scientific purposes, but his diagnostic role in pediatric age is debated. Conventional treatment with steroids and azathioprine is the milestone of therapy and it is proved effective. Treatment withdrawal however should be attempted only after several years. Cyclosporin A is the alternative drug currently used for AIH and it is effective as steroids. P(A)SC exhibit a peak of incidence in the older child, typically in pre-pubertal age with a slight predominance of male gender. Small bile ducts are always concerned and the histological picture shows either acute cholangitis (bile duct infiltration and destruction) and/or lesions suggesting chronic cholangitis as well (bile duct paucity and/or proliferation, periductal sclerosis). Small bile ducts damage may be associated, at onset or in the following years, with lesions of larger bile ducts with duct wall irregularities, strictures, dilations, and beading resulting in the characteristic ''bead-on-a-string'' appearance. The ''small duct'' (autoimmune) sclerosing cholangitis is also called autoimmune cholangitis. PSC is strictly associated to a particular form of inflammatory bowel disease (IBD) which shows features not typical of ulcerative colitis neither of Crohn's disease. Symptoms related to IBD often are present at onset (abdominal pain, weight loss, bloody stools) but the liver disease is frequently asymptomatic and it may be discovered fortuitously. Treatment of PSC is particularly challenging. In case of ''small duct'' SC or in case of evidence active inflammation on liver biopsy, immunosuppressive treatment is probably useful while in case of large bile ducts non inflammatory sclerosis, immunosuppression is probably uneffective. Ursodeoxycholic acid, however, may leads to an improvement of liver biochemistry even if there's no evidence that it may alter the course of disease. Thus, liver transplantation, is often necessary in the long term follow-up, even with a risk of disease recurrence. In adjunction to these two main disorders, many patients show an''overlap'' disease with features of both AIH and PSC. In such disorders the immune-mediated damage concerns both the hepatocyte and the cholangiocyte with a continuous clinical spectrum from AIH with minimal bile ducts lesions and PSC with portal inflammation and active inflammatory liver damage.


School-based nutrition programs are associated with reduced child food insecurity over time among Mexican-origin mother-child dyads in Texas Border Colonias.
In 2011, an estimated 50.2 million adults and children lived in US households with food insecurity, a condition associated with adverse health effects across the life span. Relying solely on parent proxy may underreport the true prevalence of child food insecurity. The present study sought to understand mothers' and children's (aged 6-11 y) perspectives and experiences of child food insecurity and its seasonal volatility, including the effects of school-based and summertime nutrition programs. Forty-eight Mexican-origin mother-child dyads completed standardized, Spanish-language food-security instruments during 2 in-home visits between July 2010 and March 2011. Multilevel longitudinal logistic regression measured change in food security while accounting for correlation in repeated measurements by using a nested structure. Cohen's κ statistic assessed dyadic discordance in child food insecurity. School-based nutrition programs reduced the odds of child food insecurity by 74% [OR = 0.26 (P < 0.01)], showcasing the programs' impact on the condition. Single head of household was associated with increased odds of child food insecurity [OR = 4.63 (P = 0.03)]. Fair dyadic agreement of child food insecurity was observed [κ = 0.21 (P = 0.02)]. Obtaining accurate prevalence rates and understanding differences of intrahousehold food insecurity necessitate measurement at multiple occasions throughout the year while considering children's perceptions and experiences of food insecurity in addition to parental reports.


Renovascular Disease Induces Senescence in Renal Scattered Tubular-Like Cells and Impairs Their Reparative Potency.
Scattered tubular-like cells (STCs), dedifferentiated renal tubular epithelial cells, contribute to renal self-healing, but severe injury might blunt their effectiveness. We hypothesized that ischemic renovascular disease (RVD) induces senescence in STC and impairs their reparative potency. CD24+/CD133+ STCs were isolated from swine kidneys after 16 weeks of RVD or healthy controls. To test their reparative capabilities in injured kidneys, control or RVD-STC (5×105) were prelabeled and injected into the aorta of 2 kidneys, 1-clip (2k,1c) mice 2 weeks after surgery. Murine renal function and oxygenation were studied in vivo 2 weeks after injection using micro-magnetic resonance imaging, and fibrosis, tubulointerstitial injury, capillary density, and expression of profibrotic and inflammatory genes ex vivo. STC isolated from swine RVD kidneys showed increased gene expression of senescence and senescence-associated secretory phenotype markers and positive SA-β-gal staining. Delivery of normal pig STCs in 2k,1c mice improved murine renal perfusion, blood flow, and glomerular filtration rate, and downregulated profibrotic and inflammatory gene expression. These renoprotective effects were blunted using STC harvested from RVD kidneys, which also failed to attenuate hypoxia, fibrosis, tubular injury, and capillary loss in injured mouse 2k,1c kidneys. Hence, RVD may induce senescence in endogenous STC and impair their reparative capacity. These observations implicate cellular senescence in the pathophysiology of ischemic kidney disease and support senolytic therapy to permit self-healing of senescent kidneys.


Diagnosis of vesicoureteral reflux according to the 1999 and 2011 guidelines of the Subcommittee on Urinary Tract Infection of the American Academy of Pediatrics.
In 1999, the American Academy of Pediatrics (AAP) recommended perform a renal ultrasonography and avoiding cystourethrography to all infants between 2 and 24 months of age after their first urinary tract infection (UTI). In 2011, the AAP restricted voiding cystourethrography to children with a pathological ultrasonography, recurrent and/ or atypical infections. Our objective was to compare, in patients with vesicoureteral reflux (VUR) and normal renal ultrasonography, the prevalence of a relevant pathology as if patients had been studied as per the 1999 guidelines (for first UTI) or the 2011 guidelines (for recurrent and/or atypical UTI). We conducted a retrospective analysis of patients with UTI, aged between 2 and 24 months old, seen at our department between January 2010 and August 2014 and who had a normal renal ultrasonography and VUR. A relevant pathology was defined as a finding of grade III VUR or higher and/or pathological renal scintigraphy. Forty-five patients (31 girls) were included and were grouped as if they had been treated as per the 1999 or 2011 guidelines. The prevalence of a relevant pathology among patients studied as per the 1999 guidelines (9 out of 24 cases, 3 with atypical UTI) or as per the 2011 guidelines (11 out of 21 cases) was similar (37.5% versus 52%, respectively; p= 0.31). Six patients (25%) with a relevant pathology diagnosed as per the 1999 guidelines would not have been identified in a timely manner with the 2011 version. The prevalence of a relevant pathology identified in children with VUR and normal renal ultrasonography was similar with both guidelines. However, considering the present guidelines, one out of four patients would have been exposed to a delayed or potentially missed diagnosis if recurrence would have been expected to complete the assessment.


Clinical Efficacy of Levothyroxine Sodium plus I 131 in the Treatment of Patients with Thyroidectomy and Its Effect on the Levels of Thyroglobulin and Thyrotropin.
This study was to evaluate the clinical efficacy of levothyroxine sodium tablets combined with I 131 in the treatment of patients after thyroidectomy and the effect on thyroglobulin (Tg) and thyroid stimulating hormone (TSH) levels. 80 patients with differentiated thyroid cancer who required thyroidectomy after surgery between July 2019 and January 2021 were recruited for prospective study, 40 patients in the control group received levothyroxine sodium tablets, and 40 patients in the experimental group received levothyroxine sodium treatment plus I 131 treatment. Treatment effect, serum Tg and TSH levels, and relapse were measured. The removal rate of residual thyroid tissue in the experimental group (87.50%) was significantly higher than that in the control group (57.50%) (P < 0.05). Levothyroxine sodium tablets plus I 131 was associated with a significantly higher efficacy versus levothyroxine sodium tablets (P < 0.05). There were no significant differences in the serum Tg levels between the two groups before treatment (P > 0.05). After treatment, the serum Tg levels in both groups were significantly decreased, and levothyroxine sodium tablets plus I 131 resulted in a significantly lower Tg level versus levothyroxine sodium tablets (P < 0.05). Before treatment, the two groups showed similar TSH levels (P > 0.05). After treatment, patients receiving levothyroxine sodium tablets plus I 131 had a significantly greater increase in the TSH levels versus levothyroxine sodium tablets (P < 0.05). The recurrence rate of the experimental group was lower than that of the control group (P < 0.05). Levothyroxine sodium tablets plus I 131 for post-operative patients with differentiated thyroid cancer enhance the removal rate of residual thyroid tissue, effectively reduce serum Tg level, and increase TSH level, with significant therapeutic effects, low recurrence rates, and a high safety profile.


Changes in cellular distribution of connexins 32 and 26 during formation of gap junctions in primary cultures of rat hepatocytes.
In the adult rat hepatocyte, gap junction proteins consist of connexin 32 (Cx32) and connexin 26 (Cx26). Previously, we reported that both Cx32 and Cx26 were markedly induced and maintained in primary cultures of adult rat hepatocytes. The reappearing gap junctions were accompanied by increases in both the proteins and the mRNAs, and they were well maintained together with extensive gap junctional intercellular communication (GJIC) for more than 4 weeks. In the present study, we examined the cellular location of the gap junction proteins and the structures in the hepatocytes cultured in our system, using confocal laser microscopy and immunoelectron microscopy of cells processed for Cx32 and Cx26 immunocytochemistry and freeze-fracture analysis. In immunoelectron microscopy, the size of Cx32-immunoreactive gap junction structures on the plasma membrane increased with time of culture, and some of them were larger than those in liver sections in vivo. Freeze-fracture analysis also showed that the size of gap junction plaques increased and that the larger gap junction plaques were composed of densely packed particles. These results suggest that in this culture system, not only the synthesis of Cx proteins but also the size of the gap junction plaques was increased markedly. In the adluminal lateral membrane of the cells, Cx32-immunoreactive lines were observed and many small gap junction plaques were closely associated with a more developed tight junction network. In the basal region of the cells, small Cx32- and Cx26-immunoreactive dots were observed in the cytoplasm and several annular structures labeled with the antibody to Cx32 were observed in the cytoplasm. These results indicated the formation and degradation of gap junctions in the cultured hepatocytes.


Variola type IB DNA topoisomerase: DNA binding and supercoil unwinding using engineered DNA minicircles.
Type IB topoisomerases unwind positive and negative DNA supercoils and play a key role in removing supercoils that would otherwise accumulate at replication and transcription forks. An interesting question is whether topoisomerase activity is regulated by the topological state of the DNA, thereby providing a mechanism for targeting the enzyme to highly supercoiled DNA domains in genomes. The type IB enzyme from variola virus (vTopo) has proven to be useful in addressing mechanistic questions about topoisomerase function because it forms a reversible 3'-phosphotyrosyl adduct with the DNA backbone at a specific target sequence (5'-CCCTT-3') from which DNA unwinding can proceed. We have synthesized supercoiled DNA minicircles (MCs) containing a single vTopo target site that provides highly defined substrates for exploring the effects of supercoil density on DNA binding, strand cleavage and ligation, and unwinding. We observed no topological dependence for binding of vTopo to these supercoiled MC DNAs, indicating that affinity-based targeting to supercoiled DNA regions by vTopo is unlikely. Similarly, the cleavage and religation rates of the MCs were not topologically dependent, but topoisomers with low superhelical densities were found to unwind more slowly than highly supercoiled topoisomers, suggesting that reduced torque at low superhelical densities leads to an increased number of cycles of cleavage and ligation before a successful unwinding event. The K271E charge reversal mutant has an impaired interaction with the rotating DNA segment that leads to an increase in the number of supercoils that were unwound per cleavage event. This result provides evidence that interactions of the enzyme with the rotating DNA segment can restrict the number of supercoils that are unwound. We infer that both superhelical density and transient contacts between vTopo and the rotating DNA determine the efficiency of supercoil unwinding. Such determinants are likely to be important in regulating the steady-state superhelical density of DNA domains in the cell.


Rotational responses of vestibular-nerve afferents innervating the semicircular canals in the C57BL/6 mouse.
Extracellular recordings were made from vestibular-nerve afferents innervating the semicircular canals in anesthetized C57BL/6 mice ranging in age from 4-24 weeks. A normalized coefficient of variation was used to divide afferents into regular (CV*<0.1) and irregular (CV*>0.1) groups. There were three overall conclusions from this study. First, mouse afferents resemble those of other mammals in properties such as resting discharge rate and dependence of response dynamics on discharge regularity. Second, there are differences in mouse afferents relative to other mammals that are likely related to the smaller size of the semicircular canals. The rotational sensitivity of mouse afferents is approximately threefold lower than that reported for afferents in other mammals. One consequence of the lower sensitivity is that mouse afferents have a larger linear range for encoding head velocity. The long time constant of afferent discharge, which is a measure of low-frequency response dynamics, is shorter in mouse afferents than in other species. Third, juvenile mice (age 4-7 weeks) appear to lack a class of low-sensitivity, highly irregular afferents that are present in adult animals (age 10-24 weeks). By analogy to studies in the chinchilla, these irregular afferents with low sensitivities for lower rotational frequencies correspond to calyx-only afferents. These findings suggest that, although the calyx ending on to type I hair cells is morphologically complete in mice by the age of about 1 month, the physiological response properties in these juvenile animals are not equivalent to those in adults.


Anesthetic experience using total intra-venous anesthesia for a patient with Wolf-Hirschhorn syndrome -A case report-.
We present here the case of a 33-month-old male patient with Wolf-Hirschhorn syndrome (WHS) and who underwent tympanoplasty and myringotomy. WHS is caused by a rare chromosomal abnormality, which is the deletion of the short arm of chromosome number 4. The typical craniofacial features of WHS patients such as micrognathia, microcephaly and the muscular weakness can make using neuromuscular blocking agents and performing intubation difficult. Moreover, there are a few previous case reports showing that malignant hyperthermia occurred during and after an operation in which the anesthesia was done with inhalation agents, so special anesthetic care is needed when operating on a WHS patient. By carefully intubating the patient and using total intravenous anesthesia, we performed successful anesthesia without any complications. We describe here the anesthetic management of a WHS patient and we review the relevant literature.


Structural determinants of aromatase cytochrome p450 inhibition in substrate recognition site-1.
The porcine gonadal form of aromatase cytochrome P450 (P450arom) exhibits higher sensitivity to inhibition by the imidazole, etomidate, than the placental isozyme. The residue(s) responsible for this functional difference was mapped using chimeragenesis and point mutation analysis of the placental isozyme, and the kinetic analysis was conducted on native and mutant enzymes after overexpression in insect cells. The etomidate sensitivity of the placental isozyme was markedly increased by substitution of the predicted substrate recognition site-1 (SRS-1) and essentially reproduced that of the gonadal isozyme by substitution of SRS-1 and the predicted B helix. A single isoleucine (I) to methionine (M) substitution at position 133 of the placental isozyme (I(133)M) was proven to be the critical residue within SRS-1. Residue 133 is located in the B'-C loop and has been shown to be equally important in other steroid-metabolizing P450s. Single point mutations (including residues 110, 114, 120, 128, 137, and combinations thereof among others) and mutation of the entire B and C helixes were without marked effect on etomidate inhibitory sensitivity. The same mutation (I(133)M) introduced into human P450arom also markedly increased etomidate sensitivity. Mutation of Ile(133) to either alanine (I(133)A) or tyrosine (I(133)Y) decreased apparent enzyme activity, but the I(133)A mutant was sensitive to etomidate inhibition, suggesting that it is Ile(133) that decreases etomidate binding rather than Met(133) increasing enzyme sensitivity. Androstenedione turnover and affinity were similar for the I(133)M mutant and the native placental isozyme. These data suggest that Ile(133) is a contact residue in SRS-1 of P450arom, emphasize the functional conservation that exists in SRS-1 of a number of steroid-hydroxylating P450 enzymes, and suggest that substrate and inhibitor binding are dependent on different contact points to varying degrees.


Effect of long-term amiodarone treatment on thyroid function in euthyroid Japanese patients: a 12-month retrospective analysis.
Amiodarone is an effective antiarrhythmic drug. However, it is associated with changes in thyroid function in euthyroid patients due to its high iodine content and intrinsic drug effects. Studies have been conducted in iodine-deficient and iodine-sufficient countries; however, data from countries with excessive iodine intake are lacking. Thus, this study aimed to evaluate the effect of long-term amiodarone treatment on thyroid function in euthyroid Japanese patients. Japanese adults aged ≥18 years who were treated with amiodarone for at least 90 consecutive days were included in this retrospective chart review. Patients with abnormal thyroid function test results at baseline were excluded. Serial changes in thyroid function tests at baseline and at days 30, 90, 180, 270, and 360 were analyzed using a mixed-effects model for repeated measures. In total, 46 patients with a mean age of 63.7 years were evaluated. The mean TSH level significantly increased from 1.62 μIU/mL at baseline to 3.43, 2.75, 2.84, 2.78, and 2.65 μIU/mL at days 30, 90, 180, 270, and 360, respectively. The mean free T4 level significantly increased from 1.3 ng/dL at baseline to 1.4, 1.5, 1.5, 1.5, and 1.5 ng/dL at days 30, 90, 180, 270, and 360, respectively. The mean free T3 level significantly decreased from 2.8 pg/mL at baseline to 2.4, 2.3, 2.3, 2.4, and 2.4 pg/mL at days 30, 90, 180, 270, and 360, respectively. In conclusion, significant changes in thyroid function persisted not only in the acute phase but also in the chronic phase of long-term amiodarone treatment.


21st century (clinical) decision support in nursing and allied healthcare. Developing a learning health system: a reasoned design of a theoretical framework.
In this paper, we present a framework for developing a Learning Health System (LHS) to provide means to a computerized clinical decision support system for allied healthcare and/or nursing professionals. LHSs are well suited to transform healthcare systems in a mission-oriented approach, and is being adopted by an increasing number of countries. Our theoretical framework provides a blueprint for organizing such a transformation with help of evidence based state of the art methodologies and techniques to eventually optimize personalized health and healthcare. Learning via health information technologies using LHS enables users to learn both individually and collectively, and independent of their location. These developments demand healthcare innovations beyond a disease focused orientation since clinical decision making in allied healthcare and nursing is mainly based on aspects of individuals' functioning, wellbeing and (dis)abilities. Developing LHSs depends heavily on intertwined social and technological innovation, and research and development. Crucial factors may be the transformation of the Internet of Things into the Internet of FAIR data & services. However, Electronic Health Record (EHR) data is in up to 80% unstructured including free text narratives and stored in various inaccessible data warehouses. Enabling the use of data as a driver for learning is challenged by interoperability and reusability.To address technical needs, key enabling technologies are suitable to convert relevant health data into machine actionable data and to develop algorithms for computerized decision support. To enable data conversions, existing classification and terminology systems serve as definition providers for natural language processing through (un)supervised learning.To facilitate clinical reasoning and personalized healthcare using LHSs, the development of personomics and functionomics are useful in allied healthcare and nursing. Developing these omics will be determined via text and data mining. This will focus on the relationships between social, psychological, cultural, behavioral and economic determinants, and human functioning.Furthermore, multiparty collaboration is crucial to develop LHSs, and man-machine interaction studies are required to develop a functional design and prototype. During development, validation and maintenance of the LHS continuous attention for challenges like data-drift, ethical, technical and practical implementation difficulties is required.


Evolutionary response to global change: Climate and land use interact to shape color polymorphism in a woodland salamander.
Evolutionary change has been demonstrated to occur rapidly in human-modified systems, yet understanding how multiple components of global change interact to affect adaptive evolution remains a critical knowledge gap. Climate change is predicted to impose directional selection on traits to reduce thermal stress, but the strength of directional selection may be mediated by changes in the thermal environment driven by land use. We examined how regional climatic conditions and land use interact to affect genetically based color polymorphism in the eastern red-backed salamander (Plethodon cinereus). P. cinereus is a woodland salamander with two primary discrete color morphs (striped, unstriped) that have been associated with macroclimatic conditions. Striped individuals are most common in colder regions, but morph frequencies can be variable within climate zones. We used path analysis to analyze morph frequencies among 238,591 individual salamanders across 1,170 sites in North America. Frequency of striped individuals was positively related to forest cover in populations occurring in warmer regions (>7°C annually), a relationship that was weak to nonexistent in populations located in colder regions (≤7°C annually). Our results suggest that directional selection imposed by climate warming at a regional scale may be amplified by forest loss and suppressed by forest persistence, with a mediating effect of land use that varies geographically. Our work highlights how the complex interaction of selection pressures imposed by different components of global change may lead to divergent evolutionary trajectories among populations.


Dermatomyositis and cancer in Singapore.
Of 12 patients with adult dermatomyositis studied, 5 (41%) had associated malignancies, of which 3 were nasopharyngeal carcinomas. The youngest was a 23-year-old woman. In view of the high incidence of cancer and the predominance of nasopharyngeal carcinoma, malignancy evaluation in Chinese patients from the Far East, 20 years of age or older with dermatomyositis should have extended workups for postnasal cancer. Two patients who had positive antinuclear not have associated cancers. Three patients died of acute myocardial infarction.


Epidemiology and Treatment of Menstrual Migraine and Migraine During Pregnancy and Lactation: A Narrative Review.
The peak prevalence of migraine occurs in women of reproductive age, and women experience a higher burden of migraine symptoms and disability compared to men. This increased burden of migraine in women is related to both developmental and temporally variable activational effects of female sex hormones. Changing levels of female sex hormones affect the expression of migraine during pregnancy, and, to a lesser degree, lactation, and are the mechanism underlying menstrual migraine. This review describes the evidence for sex differences in the expression of migraine across the reproductive epoch; reviews the epidemiology of migraine during pregnancy, lactation, and menses; and summarizes the available evidence for safety and efficacy of acute treatments during pregnancy and lactation and for menstrual migraine. Areas of controversy in treatment of migraine during pregnancy, including the use of magnesium, triptans vs butalbital combination medications, and onabotulinum toxin, are also explored.


Characterization of a vaccinia virus strain used to produce smallpox vaccine in Argentina between 1937 and 1970.
Due to recent political developments, smallpox has re-emerged as a serious threat. We recovered and characterized an old batch of smallpox vaccine, Malbrán strain, produced between 1945 and 1949. The virus was re-isolated and characterized by sequence analysis and biological activity in animals. Phylogenetic analysis using the hemagglutinin and A45R genes showed that the Malbrán strain was closely related to the Lister strain of vaccinia virus. In animals, the Malbrán strain exhibited low pathogenicity, confirming historical records. Mice immunized with the Malbrán strain survived a lethal challenge with cowpox virus. Thus, this strain of vaccinia virus remains a viable candidate as a smallpox vaccine.


Optical recording of electrical activity in intact neuronal networks with random access second-harmonic generation microscopy.
One of the main challenges in understanding the central nervous system is to measure the network dynamics of neuronal assemblies, while preserving the computational role of individual neurons. However, this is not possible with current techniques. In this work, we combined the advantages of second-harmonic generation (SHG) with a random access (RA) excitation scheme to realize a new microscope (RASH) capable of optically recording fast membrane potential events occurring in a wide-field of view. The RASH microscope, in combination with bulk loading of tissue with FM4-64 dye, was used to simultaneously record electrical activity from clusters of Purkinje cells in acute cerebellar slices. Complex spikes, both synchronous and asynchronous, were optically recorded simultaneously across a given population of neurons. Spontaneous electrical activity was also monitored simultaneously in pairs of neurons, where action potentials were recorded without averaging across trials. These results show the strength of this technique in describing the temporal dynamics of neuronal assemblies, opening promising perspectives in understanding the computations of neuronal networks.


Treatment of nursing home-acquired pneumonia.
Pneumonia is an important cause of morbidity and mortality in nursing home residents, with 30-day mortality rates ranging from 10 to 30 percent. Streptococcus pneumoniae is the most common cause of nursing home-acquired pneumonia, although Staphylococcus aureus and gram-negative organisms may be more common in severe cases. Antibiotic therapy for nursing home-acquired pneumonia should target a broad range of organisms, and drug-resistant microbes should be considered when making treatment decisions. In the nursing home setting, treatment should consist of an antipneumococcal fluoroquinolone alone or either a high-dose beta-lactam/beta-lactamase inhibitor or a second- or third-generation cephalosporin, in combination with azithromycin. Treatment of hospitalized patients with nursing home-acquired pneumonia requires broad-spectrum antibiotics with coverage of many gram-negative and gram-positive organisms, including methicillin-resistant S. aureus. Appropriate dosing of antibiotics for nursing home-acquired pneumonia is important to optimize effectiveness and avoid adverse effects. Because many nursing home residents take multiple medications, it is important to consider possible drug interactions.


Long-Term Outcomes for Different Forms of Stress Cardiomyopathy After Surgical Treatment for Subarachnoid Hemorrhage.
Stress-induced cardiomyopathy (SCM) after subarachnoid hemorrhage (SAH) includes predominant apical or basal regional left ventricular dysfunction (RLVD) with concomitant changes in electrocardiogram or increase in cardiac enzymes. We hypothesized that difference in outcome is associated with the type of RLVD after SAH. We studied a single-center retrospective cohort of SAH patients hospitalized between 2000 and 2010 with follow-up until 2013. We classified patients who had an echocardiogram for clinically indicated reasons according to the predominate location of RLVD as classic SCM-apical form and variant SCM-basal form. A Cox proportional hazard model and logistic regression were used to estimate the risk for death and hospital complications associated with different RLVD after adjustment for propensity to undergo echocardiography given clinical characteristics on admission. Among 715 SAH patients, 28% (200/715) had an echocardiogram for clinical evidence of cardiac dysfunction during hospitalization, the most common being acute left ventricular dysfunction, suspected acute ischemic event, changes in electrocardiogram and cardiac enzymes, and arrhythmia. SCM was present in 59 patients (8% of all cohort and 30% of patients with echocardiogram, respectively) with similar distribution of SCM-basal (25/59) and SCM-apical forms (34/59). SAH patients who had an echocardiogram for clinically indicated reasons had a significantly decreased risk-adjusted long-term survival compared with those without an echocardiogram, regardless of the presence of RLVD. SCM-basal form was associated with cardiac complications (odds ratio, 6.1; 99% confidence interval, 1.8-20.2) and severe sepsis (odds ratio, 5.3; 99% confidence interval, 1.6-17.2). SAH patients with echocardiogram for a clinically indicated reason have a decreased long-term survival, regardless of the presence of RLVD. The association between severe sepsis and SCM-basal warrants future studies to determine their potential synergistic effect on left ventricular systolic dysfunction among SAH patients.