Hypertrophic cardiomyopathy: pathological features and molecular pathogenesis.
Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic cardiac disorder with various genotypic and phenotypic manifestations, and is often a diagnostic challenge. Although more than forty years have passed since the first description of HCM, a variety of mutations in genes encoding sarcomeric proteins, that cause the disease have been defined by laboratory and clinical studies over the past few years. The fact that HCM is the most common cause of sudden death in young competitive athletes and that, it is actually an important cause of morbidity and mortality in people of all ages, has made the researchers to concentrate more on the molecular basis and treatment strategies of the disease. This study aims to summarize both pathological features and rapidly evolving molecular genetics of HCM, and so to understand this not infrequently seen, complex disorder better.


Regulation of CDX4 gene transcription by HoxA9, HoxA10, the Mll-Ell oncogene and Shp2 during leukemogenesis.
Cdx and Hox proteins are homeodomain transcription factors that regulate hematopoiesis. Transcription of the HOX and CDX genes decreases during normal myelopoiesis, but is aberrantly sustained in leukemias with translocation or partial tandem duplication of the MLL1 gene. Cdx4 activates transcription of the HOXA9 and HOXA10 genes, and HoxA10 activates CDX4 transcription. The events that break this feedback loop, permitting a decreased Cdx4 expression during normal myelopoiesis, were previously undefined. In the current study, we find that HoxA9 represses CDX4 transcription in differentiating myeloid cells, antagonizing activation by HoxA10. We determine that tyrosine phosphorylation of HoxA10 impairs transcriptional activation of CDX4, but tyrosine phosphorylation of HoxA9 facilitates repression of this gene. As HoxA9 and HoxA10 are phosphorylated during myelopoiesis, this provides a mechanism for differentiation stage-specific Cdx4 expression. HoxA9 and HoxA10 are increased in cells expressing Mll-Ell, a leukemia-associated MLL1 fusion protein. We find that Mll-Ell induces a HoxA10-dependent increase in Cdx4 expression in myeloid progenitor cells. However, Cdx4 decreases in a HoxA9-dependent manner on exposure of Mll-Ell-expressing cells to differentiating cytokines. Leukemia-associated, constitutively active mutants of Shp2 block cytokine-induced tyrosine phosphorylation of HoxA9 and HoxA10. In comparison with myeloid progenitor cells that are expressing Mll-Ell alone, we find increased CDX4 transcription and Cdx4 expression in cells co-expressing Mll-Ell plus constitutively active Shp2. Increased Cdx4 expression is sustained on exposure of these cells to differentiating cytokines. Our results identify a mechanism for increased and sustained CDX4 transcription in leukemias co-overexpressing HoxA9 and HoxA10 in combination with constitutive activation of Shp2. This is clinically relevant, because MLL1 translocations and constitutive Shp2 activation co-exist in human myeloid leukemias.


Casting a wider net: Immunosurveillance by nonclassical MHC molecules.
Most studies of T lymphocytes focus on recognition of classical major histocompatibility complex (MHC) class I or II molecules presenting oligopeptides, yet there are numerous variations and exceptions of biological significance based on recognition of a wide variety of nonclassical MHC molecules. These include αβ and γδ T cells that recognize different class Ib molecules (CD1, MR-1, HLA-E, G, F, et al.) that are nearly monomorphic within a given species. Collectively, these T cells can be considered "unconventional," in part because they recognize lipids, metabolites, and modified peptides. Unlike classical MHC-specific cells, unconventional T cells generally exhibit limited T-cell antigen receptor (TCR) repertoires and often produce innate immune cell-like rapid effector responses. Exploiting this system in new generation vaccines for human immunodeficiency virus (HIV), tuberculosis (TB), other infectious agents, and cancer was the focus of a recent workshop, "Immune Surveillance by Non-classical MHC Molecules: Improving Diversity for Antigens," sponsored by the National Institute of Allergy and Infectious Diseases. Here, we summarize salient points presented regarding the basic immunobiology of unconventional T cells, recent advances in methodologies to measure unconventional T-cell activity in diseases, and approaches to harness their considerable clinical potential.


Genetic variation of HvCBF genes and their association with salinity tolerance in Tibetan annual wild barley.
The evaluation of both the genetic variation and the identification of salinity tolerant accessions of Tibetan annual wild barley (hereafter referred to as Tibetan barley) (Hordeum vulgare L. ssp. Spontaneum and H. vulgare L. ssp. agriocrithum) are essential for discovering and exploiting novel alleles involved in salinity tolerance. In this study, we examined tissue dry biomass and the Na(+) and K(+) contents of 188 Tibetan barley accessions in response to salt stress. We investigated the genetic variation of transcription factors HvCBF1, HvCBF3 and HvCBF4 within these accessions, conducting association analysis between these three genes and the respective genotypic salt tolerance. Salt stress significantly reduced shoot and root dry weight by 27.6% to 73.1% in the Tibetan barley lines. HvCBF1, HvCBF3 and HvCBF4 showed diverse sequence variation in amplicon as evident by the identification of single nucleotide polymorphisms (SNPs) and 3, 8 and 13 haplotypes, respectively. Furthermore, the decay of Linkage disequilibrium (LD) of chromosome 5 was 8.9 cM (r(2)<0.1). Marker bpb-4891 and haplotype 13 (Ps 610) of the HvCBF4 gene were significantly (P<0.05) and highly significantly (P<0.001) associated with salt tolerance. However, HvCBF1 and HvCBF3 genes were not associated with salinity tolerance. The accessions from haplotype 13 of the HvCBF4 gene showed high salinity tolerance, maintaining significantly lower Na(+)/K(+) ratios and higher dry weight. It is thus proposed that these Tibetan barley accessions could be of value for enhancing salinity tolerance in cultivated barley.


Development and homeostasis of the sebaceous gland.
The important role of epidermal appendages especially the sebaceous gland has only recently been recognized. In particular, it has been convincingly shown that normal development and maintenance of the sebaceous gland are required for skin homeostasis since atrophic sebaceous glands and disturbances in sebaceous lipid composition result in major defects of the physiological barrier and maintenance of the skin. Consequently, it is important to unravel the signaling network controlling proper sebaceous lineage differentiation in mammalian skin and to understand the underlying mechanisms leading to severe skin diseases, including abnormal proliferation and differentiation of the gland, defects of the lipid metabolism and barrier, as well as sebaceous tumor formation. Over the last years, results from transgenic and knock out mouse models manipulating distinct signaling pathways in the skin as well as the detailed analysis of human sebaceous gland-derived cell lines provided new insights into crucial mediators balancing proliferation and differentiation of the sebaceous gland. Here, we discuss our current knowledge of in vivo mechanisms of sebaceous gland development, maintenance and disorders and highlight recent contributions to the field of sebaceous gland biology.


Photosynthesis, photorespiration and productivity of wheat and soybean genotypes.
The results of the numerous measurements obtained during the last 40 years on gas exchange rate, photosynthetic carbon metabolism by exposition in ¹⁴CO₂ and activities of primary carbon fixation enzyme, ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBPC/O), in various wheat and soybean genotypes grown over a wide area in the field and contrasting in photosynthetic traits and productivity are presented in this article. It was established that high productive wheat genotypes (7-9 t ha⁻¹) with the optimal architectonics possess higher rate of CO₂ assimilation during the leaf ontogenesis. Along with the high rate of photosynthesis, high values of photorespiration are characteristic for the high productive genotypes. Genotypes with moderate (4-5 t ha⁻¹) and low (3 t ha⁻¹) grain yield are characterized by relatively low rates of both CO₂ assimilation and photorespiration. A value of photorespiration constitutes 28-35% of photosynthetic rate in contrasting genotypes. The activities of RuBPC and RuBPO were changing in a similar way in the course of the flag leaf and ear elements development. High productive genotypes are also characterized by a higher rate of biosynthesis and total value of glycine-serine and a higher photosynthetic rate. Therefore, contrary to conception arisen during many years on the wastefulness of photorespiration, taking into account the versatile investigations on different aspects of photorespiration, it was proved that photorespiration is one of the evolutionarily developed vital metabolic processes in plants and the attempts to reduce this process with the purpose of increasing the crop productivity are inconsistent.


Radiotherapy for Adult Soft Tissue Sarcomas of the Head and Neck.
Surgery followed by postoperative radiation therapy (RT) is the standard of care for soft tissue sarcomas (STS) of the head and neck that are high grade or have close or positive margins. The authors retrospectively reviewed adult patients with head and neck STS treated with RT at a single institution between 1981 and 2017. All patients who were 19 years and older with STS of the head and neck-excluding rhabdomyosarcoma, angiosarcoma, and Ewing tumors-were included in this study. Toxicity was graded using Common Terminology Criteria for Adverse Events (CTCAE), version 4. Among 34 patients with head and neck STS treated with postoperative RT (33) or primary RT (1) who met the inclusion criteria, the median age at diagnosis was 45 years (range, 20 to 83). Overall, 37% had T1 tumors, 50% had high-grade histology (grade 3), and 26% had microscopically positive margins. The median RT dose was 65 Gy to the primary site; 29% received elective nodal irradiation. The median follow-up for living patients was 16.6 years (range, 0.6 to 30). At 5 and 10 years, the local control rates were 88% and 80%, the regional control rates were 97% and 97%, the freedom from distant metastases rates were 100% and 100%, the cause-specific survival rates were 88% and 81%, and the overall survival rates were 85% and 69%. Two patients (6%) developed late grade 3+ complications. Our study demonstrates that surgery and radiotherapy for STS of the head and neck have excellent disease outcomes.


Prevalence and Distribution of Anti-Amoebic IgG Antibody among Orang Asli (Aborigines) in Peninsular Malaysia.
Entamoeba species are commonly detected in stool samples of Orang Asli due to their substandard living conditions and poor hygiene. Among the Entamoeba spp., Entamoeba histolytica is the only known primary pathogenic species. This study determined the prevalence and distribution of anti-amoebic IgG antibody among Orang Asli in Peninsular Malaysia. The results would reflect the prevalence of amoebiasis in the population. This study analysed a total of 375 serum samples from archives of two Orang Asli projects conducted between 2011 and 2014. They were from six different states in Malaysia, namely Johor, Kedah, Kelantan, Pahang, Perak, and Selangor. Anti-amoebic IgG antibody was detected using an enzymelinked immunosorbent assay (ELISA) with crude soluble antigen produced from axenically grown E. histolytica trophozoites. From the analysis, the overall seropositivity was approximately 71% (266/375), while the seropositivity rates for each of the three Orang Asli tribes i.e. Senoi, Negrito and Proto-Malay, were 66% (137/208), 92% (103/112), and 43% (17/ 41) respectively. Orang Asli from Kedah [95% (52/55)] showed the highest seropositivity, followed by Kelantan [79% (54/68)], Perak [73% (78/107)], Pahang [60% (57/95)], Selangor [56% (14/25)], and Johor [48% (10/21)]. Orang Asli from rural [76% (192/254)] and peripheral urban [65% (69/106)] areas showed significantly higher seropositivity (p=0.002) than those from urban areas [36% (4/11)]. The high prevalences of anti-amoebic IgG antibody in these Orang Asli populations comprised both active and past infections. This study provides current insights of amoebiasis in selected Orang Asli settlements in Peninsular Malaysia. The high seropositivity of anti-amoebic IgG antibody suggests that the settlements are endemic for amoebiasis and there is a high risk of acquiring E. histolytica infection among the dwellers.


Opioid Prescription Following Wrist and Ankle Fracture Fixation in Scotland-Tradition Prevails.
The American 'opioid crisis' is rapidly spreading internationally. Perioperative opioid use increases the risk of long-term opioid use. We review opioid use following wrist and ankle fracture fixation across Scotland, establishing prescribing patterns and associations with patient, injury, or perioperative factors. Six Scottish orthopedic units contributed. A total of 598 patients were included. Patient demographics were similar across all sites. There was variation in anesthetic practice, length of stay, and AO fracture type (p < 0.01). For wrist fractures, 85.6% of patients received a discharge opioid prescription; 5.0% contained a strong opioid. There was no significant variation across the six units in prescribing practice. For ankle fractures, 82.7% of patients received a discharge opioid prescription; 17% contained a strong opioid. Dundee and Edinburgh used more strong opioids; Inverness and Paisley gave the least opioids overall (p < 0.01). Younger patient age, location, and length of stay were independent predictors of increased prescription on binary regression. Despite variability in perioperative practices, discharge opioid analgesic prescription remains overwhelmingly consistent. We believe that the biggest influence lies with the prescriber-institutional 'standard practice'. Education of these prescribing clinicians regarding the risk profile of opioids is key to reducing their use following surgery, thus lowering long-term opioid dependence.


Trends in admission rates and in-hospital stay for venous thromboembolism.
Acute venous thromboembolism leads to significant morbidity and mortality. Advances in pharmacotherapy facilitate outpatient care in low-risk acute venous thromboembolism. The proportion of hospitalized acute venous thromboembolism cases and the average length of stay are not known. We sought to identify predictors of hospitalization, changes in hospitalization rates and length of stay of acute venous thromboembolism over a decade in Alberta, Canada. Using linked administrative health databases, we identified adult patients diagnosed primarily with acute venous thromboembolism between April 2002 and March 2012. We measured trends using Poisson regression, adjusted length of stay using analysis of covariance. We identified predictors of hospitalization using multivariate logistic regression. 8198 out of 31,656 acute venous thromboembolism cases were hospitalized. The overall venous thromboembolism admission rates ranged between 23.7% and 27.8% with no evident temporal trend (P=0.10). The average admission rate was 51.9% for pulmonary embolism and 16.1% for deep vein thrombosis. The mean length of stay for deep vein thrombosis and pulmonary embolism remained unchanged with an adjusted mean for venous thromboembolism of 6.9±1.0days. Higher Charlson index, older age, male gender, pulmonary embolism at presentation and multiple comorbidities were associated with hospitalization. Hospitalization was associated with 30-day mortality (odds ratio:2.8, 95% CI: 2.2-3.5) whereas the length of stay was not (odds ratio:1.0, 95% CI: 0.99-1.0). Hospitalization rates and mean length of stay for acute venous thromboembolism did not change significantly between 2002 and 2012. Advances in pharmacotherapy have not yet reduced hospitalization rates or length of stay for venous thromboembolism.


Mouse primordial germ cells produce cysts that partially fragment prior to meiosis.
Mammalian germ cells divide mitotically and form nests of associated cells just prior to entering meiosis. At least some nests contain germline cysts that arise by synchronous, incomplete mitotic divisions, but others may form by aggregation. To systematically investigate early murine germ cell development, we lineage marked the progeny of individual, newly arrived primordial germ cells in the E10.5 gonad. All the marked germ cells initially develop into clones containing two, four or eight cells, indicating cyst formation. Surprisingly, growing cysts in both sexes partially fragment into smaller cysts prior to completion and associate with cysts from unrelated progenitors. At the time divisions cease, female clones comprise five cysts on average that eventually give rise to about six primordial follicles. Male cyst cells break apart and probably become spermatogonial stem cells. Thus, cysts are invariant units of mouse germ cell development and cyst fragmentation provides insight into the amplification of spermatogonial stem cells and the origin of primordial follicles.


[Non-neurologic manifestations in hypoxic-ischemic disease in newborn infants].
The aim of this work is to determine the most important factors related with to the appearance of systemic abnormalities in hypoxic-ischemic illness after neonatal asphyxia. A total of 145 full-terms neonates affected by hypoxic-ischemic encephalopathy (HIE), were studied. Forty-seven infants (32.4%) presented systemic abnormalities (arterial hypotension and acute renal failure, pulmonary abnormalities or necrotizing enterocolitis). A relationship between the presence of HIE and the appearance of extra-neurological abnormalities was found (p = 0.0174). An increase in erythroblasts was related with to the appearance of extra-neurological abnormalities (p = 0.0127).


Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons.
A number of compounds related to TEA(+) (tetraethylammoniumion) were injected into squid axons and their effects on g(K) (the potassium conductance) were determined. In most of these ions a quaternary nitrogen is surrounded by three ethyl groups and a fourth group that is very hydrophobic. Several of the ions cause inactivation of g(K), a type of ionic gating that is not normally seen in squid axon; i.e., after depolarization g(K) increases and then spontaneously decreases to a small fraction of its peak value even though the depolarization is maintained. Observations on the mechanism of this gating show that (a) QA (quaternary ammonium) ions only enter K(+) channels that have open activation gates (the normal permeability gates). (b) The activation gates of QA-occluded channels do not close readily. (c) Hyperpolarization helps to clear QA ions from the channels. (d) Raising the external K(+) concentration also helps to clear QA ions from the channels. Observations (c) and (d) strongly suggest that K(+) ions traverse the membrane by way of pores, and they cannot be explained by the usual type of carrier model. The data suggest that a K(+) pore has two distinct parts: a wide inner mouth that can accept a hydrated K(+) ion or a TEA(+)-like ion, and a narrower portion that can accept a dehydrated or partially dehydrated K(+) ion, but not TEA(+).


Virion envelope content, infectivity, and neutralization sensitivity of simian immunodeficiency virus.
A truncating E767stop mutation was introduced into the envelope glycoprotein of simian immunodeficiency virus (SIV) strain SIV239-M5 (moderately sensitive to antibody-mediated neutralization and lacking five sites for N-linked carbohydrate attachment) and strain SIV316 (very sensitive to neutralization, with eight amino acid changes from the neutralization-resistant parental molecular clone, SIV239). The truncating mutation increased Env content in virions, increased infectivity, and decreased sensitivity to antibody-mediated neutralization in both strains. However, the magnitude of the effect on infectivity and neutralization sensitivity differed considerably between the two strains. In the context of strain SIV239-M5, truncation increased Env content in virions approximately 10-fold and infectivity in a reporter cell assay 24-fold. The truncated SIV239-M5 was only slightly more resistant to neutralization by polyclonal monkey sera and by monoclonal antibodies than SIV239-M5 with a full-length envelope glycoprotein. In the context of strain SIV316, truncation increased infectivity a dramatic 480-fold, while envelope content in virions was increased only about 14-fold. This dramatic increase in infectivity cannot be simply explained by the increase in envelope content and is likely due to an increase in inherent infectivity, i.e., infectivity per spike, that results from truncation. The truncated SIV316 was extremely resistant to antibody-mediated neutralization. In fact, it was not neutralized by any of the antibodies tested. When increasing amounts of SIV316 envelope glycoprotein (full length) were provided in trans to SIV316, infectivity was increased and sensitivity to neutralization was decreased, but to nowhere near the degree that was obtained when truncated SIV316 envelope glycoprotein was used. Truncated forms of SIV239 and SIV239-M5 required higher levels of soluble CD4 for inhibition of infection than their nontruncated forms; truncated SIV316 did not. Our results suggest that envelope content in SIV virions, infectivity, and resistance to antibody-mediated neutralization can be increased not only by truncation of the cytoplasmic domain but also by provision of excess envelope in trans. The striking increase in infectivity that results from truncation in the context of SIV316 appears to be due principally to an increase in inherent infectivity per spike.


Pertussis Antibody Concentrations in Infants Born Prematurely to Mothers Vaccinated in Pregnancy.
Maternal antenatal pertussis-containing vaccination is recommended for the prevention of neonatal pertussis, but the ability of maternal vaccination to protect premature infants is unknown. We hypothesized that that infants born prematurely to antenatally vaccinated women would have higher pertussis antibody concentrations than those born to unvaccinated women. Mothers had been offered a combined tetanus, diphtheria, 5-component acellular pertussis, inactivated polio vaccine from 28 weeks' gestation as part of their routine antenatal care. Premature infants of vaccinated and unvaccinated mothers enrolled in a randomized controlled trial of pneumococcal conjugate vaccine schedules had antibody concentrations (pertussis toxin, filamentous hemoagglutinin [FHA], and fimbriae 2 and 3) measured at 2 months (before primary vaccination), 5 months (1 month after primary vaccination), and 12 months of age. Mothers of 31 (19%) of 160 premature infants had received combined tetanus, diphtheria, 5-component acellular pertussis, inactivated polio vaccine in pregnancy. Compared with infants of unvaccinated mothers, those born to vaccinated mothers had significantly higher antibody concentrations at 2 months for all measured vaccine antigens (P < .001). The number of days between maternal vaccination and delivery and immunoglobulin G concentration at 2 months of age was positively correlated for pertussis toxin (P = .011) and FHA (P = .001). After primary immunization, infants of vaccinated mothers had significantly lower antibody concentrations for FHA (P = .003) compared with infants of unvaccinated mothers; these differences had resolved by 12 months of age. Maternal vaccination administered early in the third trimester may provide protection for infants born prematurely.


Tetrahydrocurcumin is more effective than curcumin in preventing azoxymethane-induced colon carcinogenesis.
Tetrahydrocurcumin (THC), a major metabolite of curcumin (CUR), has been demonstrated to be anti-cancerogenic and anti-angiogenic and prevents type II diabetes. In this present study, we investigated the chemopreventive effects and underlying molecular mechanisms of dietary administration of CUR and THC in azoxymethane (AOM)-induced colon carcinogenesis in mice. All mice were sacrificed at 6 and 23 wk, and colonic tissue was collected and examined. We found that dietary administration of both CUR and THC could reduce aberrant crypt foci and polyps formation, while THC showed a better inhibitory effect than CUR. At the molecular level, results from Western blot analysis and immunohistochemistry staining showed that dietary CUR and THC exhibited anti-inflammatory activity by decreasing the levels of inducible NOS and COX-2 through downregulation of ERK1/2 activation. In addition, both dietary CUR and THC significantly decreased AOM-induced Wnt-1 and β-catenin protein expression, as well as the phosphorylation of GSK-3β in colonic tissue. Moreover, dietary feeding with CUR and THC markedly reduced the protein level of connexin-43, an important molecule of gap junctions, indicating that both CUR and THC might interfer with the intercellular communication of crypt cells. Taken together, these results demonstrated for the first time the in vivo chemopreventive efficacy and molecular mechanisms of dietary THC against AOM-induced colonic tumorigenesis.


Proximal balloon-guided catheter with flow inversion vs. distal filter protection during the carotid stent placement, a seven years experience in a Colombian reference center.
The carotid stent placement as a therapeutic option for carotid stenosis has been increasing among years; therefore, studies are required to evaluate the security and efficacy of its materials. The purpose of this study was to evaluate the distal filter and the proximal balloon-guided catheter with flow inversion as protection devices during carotid angioplasty and stenting. This is a retrospective, observational study of patients diagnosed with carotid stenosis treated with angioplasty between January 1, 2014, and June 30, 2020; we analyzed a radiology service database to compare the distal filter and the proximal balloon-guided catheter as protection devices during angioplasty. One hundred seventy-five angioplasties were performed, the distal filter was the most prevalent embolic protection device used (66%), patients baseline characteristics did not differ between groups with different embolic protection devices, except for history of dyslipidemia (p < 0.000). As well, we did not find any significant differences between the groups in the device related complications, intervention time (p = 0.140), unrelated complications (p = 0.693) and functional independence at 90 days (p = 0.096). In our study the proximal balloon-guided catheter and the distal filter protection device as protection devices during the carotid stenting didn't show significant differences regarding complications related to the system.


MAGI3 Suppresses Glioma Cell Proliferation via Upregulation of PTEN Expression.
To investigate the role and molecular mechanism of membrane-associated guanylate kinase inverted 3 (MAGI3) in glioma cell proliferation. The expression levels of MAGI3 and PTEN were assessed in glioma samples by Western blotting. MAGI3 was stably transfected into C6 glioma cells to obtain C6-MAGI3 cells. Then, the proliferation, the expression levels of MAGI3 and PTEN, and Akt phosphorylation were evaluated in C6 and C6-MAGI3 cells. Xenograft tumor models were established by subcutaneous injection of C6 and C6-MAGI3 cells into nude mice, and the growth rates of xenografts in the mice were compared. The potential role of MAGI3 expression in PI3K/Akt signaling activation was further investigated by examining the correlation between MAGI3 expression and the expression of PI3K/Akt signaling downstream target genes in a glioma dataset using gene set enrichment analysis (GSEA). Expression levels of MAGI3 and PTEN were significantly downregulated in gliomas. Overexpression of MAGI3 in the glioma C6 cell line upregulated PTEN protein expression, inhibited the phosphorylation of Akt, and suppressed cell proliferation. MAGI3 overexpression also inhibited the growth of C6 glioma tumor xenografts in nude mice. Analysis based on the GEO database confirmed the negative correlation between activation of PI3K/Akt pathway and MAGI3 mRNA levels in human glioma samples. The loss of MAGI3 expression in glioma may enhance the proliferation of glioma cells via downregulation of PTEN expression, leading to the activation of the PI3K/Akt pathway. MAGI3 is a potential glioma suppressor.


Endoscopic control of upper gastrointestinal bleeding.
One important objective in managing patients with upper gastrointestinal hemorrhage is to control the bleeding until the patient's condition is stable and definitive therapy can be carried out. Endoscopic techniques are now available to attain this goal. Endoscopic sclerosis has become an accepted treatment for bleeding esophageal varices, especially in patients with Child's class B or C cirrhosis. Control of nonvariceal bleeding by endoscopic techniques is now feasible and involves laser photocoagulation and electrocoagulation. Clinical experience with endoscopic laser photocoagulation has demonstrated that it can successfully arrest bleeding in gastric and duodenal ulcers. Endoscopic electrocoagulation has been successful in stopping bleeding from Mallory-Weiss tears, acute gastric erosions, and gastric, duodenal and stomal ulcers. Use of an endoscopic heater probe, now in the development stage, to control bleeding gastric and duodenal ulcers will be an important addition.


Doctors or technicians: assessing quality of medical education.
Medical education institutions usually adapt industrial quality management models that measure the quality of the process of a program but not the quality of the product. The purpose of this paper is to analyze the impact of industrial quality management models on medical education and students, and to highlight the importance of introducing a proper educational quality management model. Industrial quality management models can measure the training component in terms of competencies, but they lack the educational component measurement. These models use performance indicators to assess their process improvement efforts. Researchers suggest that the performance indicators used in educational institutions may only measure their fiscal efficiency without measuring the quality of the educational experience of the students. In most of the institutions, where industrial models are used for quality assurance, students are considered as customers and are provided with the maximum services and facilities possible. Institutions are required to fulfill a list of recommendations from the quality control agencies in order to enhance student satisfaction and to guarantee standard services. Quality of medical education should be assessed by measuring the impact of the educational program and quality improvement procedures in terms of knowledge base development, behavioral change, and patient care. Industrial quality models may focus on academic support services and processes, but educational quality models should be introduced in parallel to focus on educational standards and products.


Mycosis fungoides associated with dystrophic xanthomatosis.
A 59-year-old man with no evidence or history of hyperlipidemia had a dystrophic xanthoma, an accumulation of lipid-rich foam cells in an area of damaged or abnormal skin, that was associated with untreated mycosis fungoides (MF). The patient was subsequently treated with whole-body electron beam therapy. This association of MF and dystrophic xanthoma illustrates histiocyte and xanthoma cell interaction in MF, a cutaneous T-cell lymphoma. Xanthomas may be a cutaneous sign of an underlying lymphoproliferative or myeloproliferative disease in normolipemic patients.


Immunologic mechanisms of cardiac transplant rejection.
The successful application of cardiac transplantation as a useful therapeutic procedure has been the result of improved surgical techniques and the effective immunosuppression of cardiac rejection. Despite the improvements that have led to the successful application of cardiac transplantation, there are important limitations in our understanding and ability to manipulate the immune-mediated rejection of the donor heart by the host. Methods that allow for improved preservation of the donor heart are necessary to provide the opportunity to match more carefully the donor and recipient for histocompatibility antigens that stimulate rejection of the graft. Clinical data in humans and experimental studies in animals demonstrate that the rejection of the heart is stimulated by a wide variety of histocompatibility antigens, many of which may be neutralized by donor-recipient matching. The immunologic mechanisms that influence the survival of the graft include (1) hyperacute rejection of the graft by recipient antibody directed against foreign antigens of the donor heart, (2) T lymphocyte-mediated acute cellular rejection of the graft, and (3) chronic rejection of the graft associated with the emergence of cardiac graft arteriosclerosis in otherwise successful long-term graft recipients. An increased understanding of these processes will provide opportunities to improve cardiac transplant outcome.


Precision medicine in myeloid malignancies.
Myeloid malignancies have always been at the forefront of an improved understanding of the molecular pathogenesis of cancer. In accordance, over the last years, basic research focusing on the aberrations underlying malignant transformation of myeloid cells has provided the basis for precision medicine approaches and subsequently has led to the development of powerful therapeutic strategies. In this review article, we will recapitulate what has happened since in the 1980s the use of all-trans retinoic acid (ATRA), as a first targeted cancer therapy, has changed one of the deadliest leukemia subtypes, acute promyelocytic leukemia (APL), into one that can be cured without classical chemotherapy today. Similarly, imatinib, the first molecularly designed cancer therapy, has revolutionized the management of chronic myeloid leukemia (CML). Thus, targeted treatment approaches have become the paradigm for myeloid malignancy, but many questions still remain unanswered, especially how identical mutations can be associated with different phenotypes. This might be linked to the impact of the cell of origin, gene-gene interactions, or the tumor microenvironment including the immune system. Continuous research in the field of myeloid neoplasia has started to unravel the molecular pathways that are not only crucial for initial treatment response, but also resistance of leukemia cells under therapy. Ongoing studies focusing on leukemia cell vulnerabilities do already point to novel (targetable) "Achilles heels" that can further improve myeloid cancer therapy.


Cancer-related knowledge, attitudes, and risk perception among 6 grade students in Jordan.
Elementary schools in Jordan have included health education material in curricula to promote healthy lifestyles among younger school children. However, the relation between healthy lifestyles and the prevention of chronic diseases such as cancer has not been an explicit component in school curricula of younger age groups. We sought to explore the level of knowledge among 6th grade students as well as their attitudes with respect to cancer. This comes as part of a pilot project to develop an educational series on cancer prevention that aims to meet knowledge gaps specific to the community of students in this age group in Jordan. A questionnaire composed of items measuring knowledge about cancer and cancer prevention through healthy practices, attitudes towards cancer, and intentions to engage in healthy behaviors was developed. Questionnaires previously used in similar age groups elsewhere were used as a reference. Our questionnaire was reviewed and approved by the Ministry of Education - School Health & Nutrition Department. Sixth graders in a convenience sample of four schools selected by the Ministry of Education completed the self-administered questionnaire. Ninety-six 6th graders from four schools answered the baseline survey, but 28% of the surveys were excluded from the analysis (data quality problems) leaving 69 student participants. In the original sample of 96 students, 48 (69.6%) were girls. Among the 69 student participants, 67 (97.1%) had heard of cancer, but fewer than 44 (63.8% knew it was not a contagious disease. Regarding fear, 29 (42%) would not play with a cancer patient. Concerning prevention of the most prevalent cancers in Jordan as research has shown that certain risk factors increase the chance that a person will develop cancer. The most common risk factors are smoking, Poor diet, lack of physical activity, or being overweight, 25 (36.2%) knew breast cancer was preventable, and 28 (40.6%) and 24 (34.8%) knew this regarding lung and colorectal cancers, respectively. About 40 (57.8%) students identified healthy dietary behaviors (e.g., low fat, low sugar), but only six could identify the ideal frequency for exercise (60 minutes daily). Fifty-eight (84.1%) agreed that cigarettes harmed the health. However, only 21 (30.4%) found it easy to avoid exposure to secondhand smoke. Nine (13%) reported smoking water pipes, but only one reported smoking cigarettes. Forty-eight (69.6%) and 47 (68.1%) agreed that daily physical activity and healthy eating were important, respectively. Fifty-two (75.4%) students found it easy to eat healthy at home, but only 37 (53.6%) found it easy to do so at school. Finally, 63 (91.3%) students wanted to learn more about cancer. Although a significant number of our sample of students has heard about cancer and students exhibit some knowledge regarding healthy practices, our results show that knowledge gaps exist with regard to the nature of cancer as a noncontagious disease, the preventability of specific cancers, and the link between specific risk factors and cancer.


Understanding the mechanochemical synthesis of the perovskite LaMnO3 and its catalytic behaviour.
Mechanochemistry offers a solventless, 'waste free' route to preparing metal oxide catalysts, however, there is limited information on the chemical steps involved. In this work, the perovskite LaMnO3 has been successfully synthesized via mechanochemistry from metal oxide powders, La2O3 and Mn2O3, at room temperature, using a planetary ball mill. Separate ex situ'time slices' were taken during the milling procedure to provide insights into the underlying chemistry. The crystalline material was assessed using XRD, which identified 100% perovskite phase after 3 h of milling. Conversely, characterization by X-ray absorption spectroscopy (XAS) at both the Mn K-edge and La L3-edge provides a very different picture. The XAS data shows that there are significant structural alterations as early as 30 min of milling, with the La precursor dispersed over Mn2O3. Increasing milling time then allows for mechanical activation of both precursors and the formation of powdered LaMnO3, with no calcination step required. The XAS highlights that there is a significant amount of amorphous, oxygen deficient, content even when XRD has identified 100% perovskite phase. The samples were tested for the decomposition of the environmental pollutant N2O; at a milling time of 3 h, the LaMnO3 catalyst displays a much early onset production of N2 compared to a traditional sol-gel synthesized LaMnO3, resulting from increased oxygen deficiency at the surface, confirmed by XPS and STEM-EELS. This is an encouraging sign that mechanochemical routes can be harnessed to provide a sustainable route to preparing mixed metal oxide catalysts with enhanced catalytic performance.


Adipose tissue metabolism in humans determined by vein catheterization and microdialysis techniques.
A technique for catheterization of a vein draining abdominal subcutaneous tissue and a microdialysis technique that allows measurements of intercellular water concentrations in adipose tissue in humans have recently been described. In the present study, we compare the two techniques during an oral glucose load. In addition a technique using microdialysis for measurement of tissue oxygen and carbon dioxide tensions is described. Microdialysis and vein catheterization were performed in the same region on the abdomen, and the subcutaneous adipose tissue blood flow was measured by the local 133Xe washout method. The results show that subcutaneous adipose tissue gas tensions are on level with gas tensions measured in abdominal venous blood. Comparison of metabolite concentrations measured in the venous blood and venous blood concentrations calculated from microdialysis data shows that there is good agreement between the concentrations obtained by the two techniques with respect to glucose and glycerol, whereas lactate concentrations are very different. With regard to substrate fluxes calculated by Fick's principle, the catheterization technique is probably the most reliable, considering the numerous assumptions on which calculations of venous concentrations from microdialysis data are based. Advantages and disadvantages of the two techniques are discussed.


Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke.
Background and Purpose- We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke. Methods- We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy. Results- All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post-in-clinic therapy (difference, 2.3 points; CI, -1.8 to 6.4; P=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI, -1.4 to 11.5; P=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS ( P<0.05). Conclusions- VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02243020.


Does the singlet minus triplet spectrum with major photobleaching band near 680-682 nm represent an intact reaction center of Photosystem II?
We use both frequency- and time-domain low-temperature (5-20 K) spectroscopies to further elucidate the shape and spectral position of singlet minus triplet (triplet-bottleneck) spectra in the reaction centers (RCs) of Photosystem II (PSII) isolated from wild-type Chlamydomonas reinhardtii and spinach. It is shown that the shape of the nonresonant transient hole-burned spectrum in destabilized RCs from C. reinhardtii is very similar to that typically observed for spinach. This suggests that the previously observed difference in transient spectra between RCs from C. reinhardtii and spinach is not due to the sample origin but most likely due to a partial destabilization of the D1 and D2 polypeptides. This supports our previous assignments that destabilized RCs (referred to as RC680) (Acharya, K. et al. J. Phys. Chem. B 2012, 116, 4860-4870), with a major photobleaching band near 680-682 nm and the absence of a photobleaching band near 673 nm, do not represent the intact RC residing within the PSII core complex. Time-resolved absorption difference spectra obtained for partially destabilized RCs of C. reinhardtii and for typical spinach RCs support the above conclusions. The absence of clear photobleaching bands near 673 and 684 nm (where the PD1 chlorophyll and the active pheophytin (PheoD1) contribute, respectively) in picosecond transient absorption spectra in both RCs studied in this work indicates that the cation can move from the primary electron donor (ChlD1) to PD1 (i.e., PD1ChlD1(+)PheoD1(-) → PD1(+)ChlD1PheoD1(-)). Therefore, we suggest that ChlD1 is the major electron donor in usually studied destabilized RCs (with a major photobleaching near 680-682 nm), although the PD1 path (where PD1 serves as the primary electron donor) is likely present in intact RCs, as discussed in Acharya, K. et al. J. Phys. Chem. B 2012, 116, 4860-4870.


MITF reprograms the extracellular matrix and focal adhesion in melanoma.
The microphthalmia-associated transcription factor (MITF) is a critical regulator of melanocyte development and differentiation. It also plays an important role in melanoma where it has been described as a molecular rheostat that, depending on activity levels, allows reversible switching between different cellular states. Here, we show that MITF directly represses the expression of genes associated with the extracellular matrix (ECM) and focal adhesion pathways in human melanoma cells as well as of regulators of epithelial-to-mesenchymal transition (EMT) such as CDH2, thus affecting cell morphology and cell-matrix interactions. Importantly, we show that these effects of MITF are reversible, as expected from the rheostat model. The number of focal adhesion points increased upon MITF knockdown, a feature observed in drug-resistant melanomas. Cells lacking MITF are similar to the cells of minimal residual disease observed in both human and zebrafish melanomas. Our results suggest that MITF plays a critical role as a repressor of gene expression and is actively involved in shaping the microenvironment of melanoma cells in a cell-autonomous manner.


Effects of cafestol and kahweol from coffee grounds on serum lipids and serum liver enzymes in humans.
The diterpenes cafestol and kahweol are present in unfiltered coffee in oil droplets and floating fines. They elevate serum cholesterol and alanine aminotransferase (ALT). We measured fines in coffee brews, and examined diterpene availability from spent grounds in healthy volunteers. Turkish or Scandinavian boiled coffee contained 2-5 g fines/L and French press coffee contained 1.5 g fines/L. An intake of 8 g fine grounds/d for 3 wk increased cholesterol by 0.65 mmol/L (95% CI 0.41-0.89 mmol/L) and ALT by 18 U/L (95% CI 4-32 U/L) relative to control subjects (n = 7/group). In a crossover study (n = 15), mean serum cholesterol was 4.9 mmol/L after consumption of both fine and coarse grounds for 10 d (P = 0.43). Serum ALT activities were 29 U/L on fine and 21 U/L on coarse grounds (P = 0.02). Floating fines could contribute substantially to the hyperlipidemic and ALT-elevating effect of unfiltered coffee. Diterpene measurements in coffee brews should include the contribution of fines.


Limited junctional diversity in kappa light chains. Junctional sequences from CD43+B220+ early B cell progenitors resemble those from peripheral B cells.
Among all adult T and B cell Ag receptor chains, only Ig light chains lack N regions. It is thought that this is due to the fact that light chain genes rearrange after heavy chain genes, and that terminal deoxynucleotidyl transferase, the enzyme that adds N regions, is not longer expressed at that stage. However, this concept has been challenged recently by the demonstration that 3 to 10% of B cell precursors (CD43+B220+) appear to rearrange their light chains at approximately the same time as they undergo VH-->DJ rearrangements. To examine N region addition in B cell precursors undergoing early kappa-chain rearrangement, we PCR amplified rearranged V kappa 21 genes from the CD43+B220+ bone marrow cells and compared them to sequences obtained from whole bone marrow and spleen. Unexpectedly, all three populations showed approximately 10% N region containing junctions, most consisting of only one N nucleotide. Thus, even the B cell precursors that rearrange light chains at this early stage of development lack much N region diversity. Twelve percent of the sequences unambiguously contained P regions, which were from 1 to 5 nucleotides in length. All but 2 of the 41 productive rearrangements had the commonly observed CDR3 length of nine amino acids. Many (71%) of the sequences were out of frame. CDR3 length was very restricted in nonproductive rearrangements too, and deletion of nucleotides from V kappa and J kappa gene segments was limited. Thus, even at the level of nonproductive rearrangements, junctional diversity is minimal for kappa-chains.


Using Tox21 High-Throughput Screening Assays for the Evaluation of Botanical and Dietary Supplements.
Introduction: Recent nationwide surveys found that natural products, including botanical dietary supplements, are used by ∼18% of adults. In many cases, there is a paucity of toxicological data available for these substances to allow for confident evaluations of product safety. The National Toxicology Program (NTP) has received numerous nominations from the public and federal agencies to study the toxicological effects of botanical dietary supplements. The NTP sought to evaluate the utility of in vitro quantitative high-throughput screening (qHTS) assays for toxicological assessment of botanical and dietary supplements. Materials and Methods: In brief, concentration-response assessments of 90 test substances, including 13 distinct botanical species, and individual purported active constituents were evaluated using a subset of the Tox21 qHTS testing panel. The screen included 20 different endpoints that covered a broad range of biologically relevant signaling pathways to detect test article effects upon endocrine activity, nuclear receptor signaling, stress response signaling, genotoxicity, and cell death signaling. Results and Discussion: Botanical dietary supplement extracts induced measurable and diverse activity. Elevated biological activity profiles were observed following treatments with individual chemical constituents relative to their associated botanical extract. The overall distribution of activity was comparable to activities exhibited by compounds present in the Tox21 10K chemical library. Conclusion: Botanical supplements did not exhibit minimal or idiosyncratic activities that would preclude the use of qHTS platforms as a feasible method to screen this class of compounds. However, there are still many considerations and further development required when attempting to use in vitro qHTS methods to characterize the safety profile of botanical/dietary supplements.


[IR-luminescence of low-stability aqueous structures (theory and experiment)].
The effect of IR luminescence in liquid water was registered. A theory was suggested according to which the bands of IR luminescence are related to the presence of clusters (clathrates) in water. The effect arises in water exposed to low-intensity electromagnetic oscillations. Under strong exposure, the decomposition of luminescent structures takes place. A quantitative theory was proposed and the spectrum of water luminescence for the region of strain oscillations was calculated. A good agrement between the theory and experimental data was obtained.


Effect of shipping and chromium supplementation on performance, immune response, and disease resistance of steers.
Forty-eight Angus crossbred steers (263 +/- 2 kg initial BW) were blocked by weight and randomly assigned within weight group to treatment. Treatments consisted of control or .4 mg of supplemental Cr as Cr-nicotinic acid complex/kg of DM. Steers were fed diets containing 90% corn silage (DM basis) and 10% of a soybean meal-mineral-vitamin supplement. After 56 d on the dietary treatment, half of the steers in each treatment were transported 343 km and unloaded in an unfamiliar location. The next day, d 58, shipped steers were returned to the feedlot (50 km). On d 58 after shipped steers were returned to the feedlot, all steers were inoculated with infectious bovine rhinotracheitis virus (IBRV) intranasally. Average daily gain from d 0 to 80 was increased (P < .10) by supplemental Cr. There was a shipping x time interaction for serum cortisol concentrations. Shipping increased (P < .02) serum cortisol on d 58, but 7 d after transport there were no effects of shipping on serum cortisol. Transportation increased (P < .05) the ratio of neutrophils to lymphocytes. Supplemental Cr did not affect rectal temperature after the IBRV challenge or the antibody response to IBRV or porcine red blood cells. Immunoglobulin G antibody response to porcine red blood cells was decreased (P < .09) by shipping. Supplemental Cr as Cr-nicotinic acid improved ADG of growing steers, regardless of whether they had been stressed by shipping. Supplemental Cr did not affect any of the immune responses that were measured.


Sjögren's syndrome: managed care data from a large United States population highlight real-world health care burden and lack of treatment options.
To better understand the real-world characteristics and costs of Sjögren's syndrome (SS). Analysing the MarketScan Commercial Claims database from Jan. 1, 2006 to Dec. 31, 2011, we identified 10,414 patients ≥18 years old newly diagnosed with SS. Patient characteristics, drugs (commonly used for SS), resource utilisation, and medical costs were evaluated for 12 months pre- and post-diagnosis. Mean age was 55 years; 90% were female. At diagnosis, SS patients were most often seen by rheumatologists (39%) or internists (14.2%); the most common concurrent autoimmune conditions were rheumatoid arthritis (17.9%) and systemic lupus erythematosus (14.6%). Other common comorbidities were hypertension (37.6%), osteoarthritis (31.4%), and hyperlipidaemia/dyslipidaemia (30.3%). Post diagnosis of SS, claims for myocardial infarction and coronary artery bypass graft doubled. Medications of interest prescribed post-diagnosis were eye/mouth drugs (32.2%) and synthetic immunosuppressants (32.1%). Biologic drugs were prescribed to a minority (TNF inhibitors, ~5.0%; non-TNF inhibitors, 1%). Of note, prescriptions for all systemic immunotherapies (synthetic and biologic) were significantly lower in the subgroup without concurrent autoimmune disease, and 15.1% of the overall population had no SS-related prescriptions. Post diagnosis, total medical resource utilisation and total medical costs increased (1.2 and 1.4-fold, respectively). In this retrospective, real-world analysis, medical claims in the first year after SS diagnosis revealed that cardiovascular (CV) events increased and all-cause healthcare costs grew by 40%. Pharmacologic management consisted primarily of low potency immunomodulation and symptomatic treatments. Systemic disease-modifying therapies were used mostly in patients who had another concurrent autoimmune disease, suggesting a lack of treatment options for SS.


Colonic alpha 2-adrenoceptor-mediated responses in the pony.
The motor responses of the caecum and colon to stimulation of alpha 2-adrenoceptors by xylazine and detomidine at the recommended dose levels of 0.6 and 0.1 mg/kg were investigated in three ponies. The motor changes of the left ventral colon induced by continuous intra-arterial infusion of a prostaglandin (PGF2 alpha) were used to assess the relative inhibitory effects of xylazine and detomidine in a colic model. The administration of alpha 2-agonists inhibited the spiking activity on the whole of the large intestine for 20-30 min (xylazine) or 2-3 h (detomidine). However, the detomidine-induced inhibition was preceded by a short period of increased smooth muscle basal tone as indicated by strain-gauge force transducer measurements. This pattern of activity was neither reversed nor prevented by the administration of tolazoline (10 micrograms/kg/min) intra-arterially. In contrast, inhibition of the colonic phasic and tonic motor activity by alpha 2-adrenoceptor stimulation was reversed competitively by tolazoline. The intra-arterial infusion of prostaglandin F2 alpha (10 micrograms/kg/min) induced prolonged and sustained spiking activity that might be related to signs of mild colic. Detomidine, and to a lesser extent xylazine, relaxed the whole of the large intestine and this was accompanied by alleviation of the signs of visceral pain.


Determination of pesticide residues in wine by SPME and GC/MS for consumer risk assessment.
An analytical procedure applying solid phase microextraction (SPME) combined with gas chromatography/ mass spectrometry (GC/MS) for the detection of pesticide residues in wine was performed for the determination of 14 of the pesticides most frequently used on grapes (insecticides, fungicides, herbicides). As SPME combines the possibility of a single-step extraction with other advantages (short sampling times, solvent-free procedure, speedy extraction, low cost and simplicity) it could be successfully used either for screening or routine analysis for detecting pesticides of different chemical classes in wines, even at trace levels. The analytical procedure performed showed minimum detectable quantities ranging from 0.10 microgram/l to 6.0 micrograms/l and precision from 9.7% to 18% (as relative standard deviation of 1 microgram/l levels), assuring high sensitivity and precision of analysis. Twenty-one wine samples (10 white wines and 11 red wines) available on the Italian market were analysed with the procedure described and about 57% were positive for one or more pesticides. An approach for consumer risk assessment on the basis of the data obtained was proposed for further assessments of the daily dietary intake of pesticides through wine.


MTHFR genotype and differential evolution of metabolic parameters after initiation of a second generation antipsychotic: an observational study.
Most second-generation antipsychotics (SGAs) induce metabolic disturbances, but large differences exist in the degree to which individual patients develop these. Little is known about genetic factors associated with differential liability. Cross-sectional studies suggested an association between polymorphisms in 5,10-methylenetetraydrofolate reductase (MTHFR) and metabolic syndrome in patients with schizophrenia. This study aimed to assess whether the C677T (rs1801133) or A1298C (rs1801131) polymorphism in the MTHFR gene predict differential evolution of metabolic parameters over the course of a 3-month follow-up period after initiation of an SGA. One hundred and four patients with schizophrenia initiated on a SGA were measured at baseline, 6 weeks and 3 months. MTHFR A1298C, but not C677T, genotype predicted pos-baseline increases in weight [beta=2.5, standard error (SE)=0.92, P=0.006], waist circumference (beta=2.0, SE=1.0, P=0.050), fasting glucose (beta=2.8, SE=1.2, P=0.024) and glucose at 120 min during the Oral Glucose Tolerance Test (beta=10.7, SE=4.5, P=0.018) following a de novo metabolic challenge with a specific SGA. A1298C allele carriers consistently displayed the most unfavorable evolution of metabolic parameters. Thus, MTHFR A1298C genotype may explain part of the individual liability to metabolic disturbances in patients with schizophrenia.


Sensory processing in the deep spinal dorsal horn of neurokinin-1 receptor knockout mice.
The neurokinin-1 receptor and its primary ligand, substance P, are widely recognized as contributing to the spinal processing of nociceptive stimuli, yet the specific function of the neurokinin-1 receptor remains unclear. To better clarify these functions, the authors examined the neurophysiologic responses of L4-L5 neurons in the deep dorsal horn to acute mechanical, thermal, and electrical stimuli in knockout and wild-type mice. In addition, the capacity of knockout and wild-type mice to show wind-up to repeated C-fiber stimuli and to show sensitization after cutaneous mustard oil was assessed. A total of 68 nociceptive neurons (35 in knockout, 33 in wild type) in laminae III-V were studied. No differences in the acute responses of neurons in knockout and wild-type mice to graded mechanical, thermal, or electrical stimuli or in the acute responses to mustard oil were observed. However, wind-up to repeated electrical stimulation at C-fiber intensity was significantly attenuated in the knockout mice compared with wild type controls. In addition, mustard oil-induced mechanical hypersensitivity was significantly reduced in the knockout mice. These results indicate that neurokinin-1 receptors do not play a significant role in the responses of nociceptive neurons in the deep spinal dorsal horn to acute noxious mechanical, thermal, electrical, or chemical stimuli. On the other hand, neurokinin-1 receptors are critical for the central hyperexcitability that is observed in these neurons with repeated C-fiber inputs and to the central sensitization induced by topical mustard oil application.


Evaluation of the Performance of the IDvet IFN-Gamma Test for Diagnosis of Bovine Tuberculosis in Spain.
In Spain, the national bovine tuberculosis (bTB) eradication program is based on yearly skin testing of every ≥6 weeks old animal using the single or comparative tuberculin test and parallel use of the interferon-gamma (IFN-γ) assay as an ancillary diagnostic test in infected herds. There are several versions of the latter. Recently, a new commercial IDvet IFN-γ assay has been authorized for use in the program, but there is limited scientific evidence about its performance in different epidemiological settings. Therefore, two studies to evaluate the performance of the IDvet assay were conducted. In study 1, a concordance analysis between the new IDvet and the Bovigam IFN-γ assay in use in Spain for over 10 years was conducted. In study 2, results from the IDvet assay when applied in tandem with a single intradermal tuberculin (SIT) test were used to evaluate the concordance between both tests and to estimate their sensitivity (Se) and specificity (Sp) using a Bayesian latent-class model. Field data from cattle herds located in Madrid and Castilla y Leon (Spain) were collected. For study 1, herd selection was based on a high expected prevalence of reactors to the IFN-γ assay, while herds were selected at random to estimate Se and Sp of the new IDvet assay in study 2. Agreement between the results obtained with both kits for IFN-γ assay was poor (Kappa = 0.20), and a receiver operating characteristic (ROC) analysis indicated a low Se of the new IDvet relative to the Bovigam in a heavily bTB infected population. The Bayesian latent-class analysis estimated the Se of the IDvet assay to be 36.7% [95% probability posterior interval (PPI) 14.7-78.8%] with estimated Sp close to 100% when the cut-off recommended by the manufacturer (35) was applied. At the alternative cut-off values of 16 and 4, the estimated Se of the IDvet assay increased to 49.0% (PPI: 24.8-94.1%) and 56.0% (PPI: 30.8-96.3%), respectively, while maintaining a high specificity. The results suggest that the new IDvet assay may have lower sensitivity than the Bovigam for diagnosis of bTB in cattle herds in Spain, and that adjusting its cut-off might be considered.


Withaferin a alters intermediate filament organization, cell shape and behavior.
Withaferin A (WFA) is a steroidal lactone present in Withania somnifera which has been shown in vitro to bind to the intermediate filament protein, vimentin. Based upon its affinity for vimentin, it has been proposed that WFA can be used as an anti-tumor agent to target metastatic cells which up-regulate vimentin expression. We show that WFA treatment of human fibroblasts rapidly reorganizes vimentin intermediate filaments (VIF) into a perinuclear aggregate. This reorganization is dose dependent and is accompanied by a change in cell shape, decreased motility and an increase in vimentin phosphorylation at serine-38. Furthermore, vimentin lacking cysteine-328, the proposed WFA binding site, remains sensitive to WFA demonstrating that this site is not required for its cellular effects. Using analytical ultracentrifugation, viscometry, electron microscopy and sedimentation assays we show that WFA has no effect on VIF assembly in vitro. Furthermore, WFA is not specific for vimentin as it disrupts the cellular organization and induces perinuclear aggregates of several other IF networks comprised of peripherin, neurofilament-triplet protein, and keratin. In cells co-expressing keratin IF and VIF, the former are significantly less sensitive to WFA with respect to inducing perinuclear aggregates. The organization of microtubules and actin/microfilaments is also affected by WFA. Microtubules become wavier and sparser and the number of stress fibers appears to increase. Following 24 hrs of exposure to doses of WFA that alter VIF organization and motility, cells undergo apoptosis. Lower doses of the drug do not kill cells but cause them to senesce. In light of our findings that WFA affects multiple IF systems, which are expressed in many tissues of the body, caution is warranted in its use as an anti-cancer agent, since it may have debilitating organism-wide effects.


Effects of growth hormone on fuel utilization and muscle glycogen synthase activity in normal humans.
To examine the insulin antagonistic effects of growth hormone (GH), seven healthy subjects underwent, in random order, two 5-h euglycemic clamp studies with moderate hyperinsulinemia. A GH infusion (45 ng.kg-1.min-1) was given throughout one of the studies. GH inhibited the insulin-stimulated glucose disposal by 27% from 4.4 +/- 0.7 to 3.3 +/- 0.4 mg.kg-1.min-1 (P less than 0.02) and raised the nonprotein energy expenditures (NPEE) from 18.7 +/- 0.5 to 20.5 +/- 0.3 kcal.kg-1.24 h-1 (P less than 0.03). Lipid oxidation contributed 71.7 +/- 5.6% of NPEE during the GH infusion as compared with 48.7 +/- 5.2% during the control clamp (P less than 0.02). In skeletal muscle biopsies, insulin binding to wheat germ agglutinin-purified insulin receptors and insulin receptor kinase activity were unaffected by GH infusion. Glycogen synthase activation by insulin was inhibited by 41% during the GH clamp (fractional velocity 14.1 +/- 2.5 vs. 8.3 +/- 1.4%, P less than 0.03). In conclusion, GH 1) increases energy expenditures and inhibits glucose oxidation in favor of an increased lipid oxidation, and 2) inhibits insulin-mediated activation of the glycogen synthase in skeletal muscle biopsies by a mechanism distal to insulin receptor binding and kinase activity.


Modeling Alzheimer's disease in primary neurons reveals DNA damage response coupled with MAPK-DLK signaling in wild-type tau-induced neurodegeneration.
Alzheimer's disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed wild-type human tau in primary mouse neurons and characterized the subsequent cellular and molecular changes. RNAseq profiling and functional investigation were performed as well. A direct comparison with a mutant human tau was conducted in detail. We observed substantial axonal degeneration and cell death associated with wild-type tau, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) were effective in alleviating wild-type human tau-induced neurodegeneration. In contrast, mutant P301L human tau was less toxic to neurons, despite causing comparable DNA damage. Axonal DLK activation induced by wild-type tau potentiated the impact of DNA damage response, resulting in overt neurotoxicity. We have established a cellular tauopathy model highly relevant to AD and identified a functional synergy between DNA damage response and the MAPK-DLK axis in the neuronal degenerative process.


Coronary hemodynamics and myocardial metabolism during and after pacing stress in normal humans.
We investigated coronary hemodynamics, myocardial utilization of circulating substrates (by coronary sinus catheterization), and overall use of oxidative fuels (by regional indirect calorimetry) in healthy adults during incremental atrial pacing (up to 159 +/- 9 beats/min), and during 25 min of recovery. Great cardiac vein flow (thermodilution) increased from 52 +/- 9 to 115 +/- 15 ml/min (P less than 0.001) with pacing; myocardial O2 uptake (301 +/- 53 to 593 +/- 71 mumol/min, P less than 0.001) and CO2 production (225 +/- 37 to 518 +/- 66 mumol/min, P less than 0.005) paralleled the pacing-induced rise in rate-pressure product (9.4 +/- 0.9 to 21.1 +/- 1.1 mmHg.beat. min-1.10(-3), P less than 0.001). During recovery, all the above variables returned to base line within 5 min, but myocardial O2 extraction remained depressed (67 +/- 2 vs. 71 +/- 3%, P less than 0.05). Circulating glucose uptake rose linearly with pacing (P less than 0.05) and remained above base line throughout recovery. By contrast, free fatty acid (FFA) uptake (10 mumol/min) did not increase with pacing and fell during recovery (P less than 0.01). Calorimetry, however, showed that net lipid oxidation exceeded FFA uptake throughout the study, whereas net carbohydrate oxidation was small at base line, rose significantly at maximal pacing (62% of myocardial energy output), and remained above base line during recovery (32% of energy output). In the basal state as well as during recovery, myocardial uptake of glucose equivalents (lactate plus glucose plus pyruvate) was in excess of carbohydrate oxidation, indicating nonoxidative disposal of these substrates.(ABSTRACT TRUNCATED AT 250 WORDS)


Therapeutic health effects of ginger (Zingiber officinale): updated narrative review exploring the mechanisms of action.
Ginger (Zingiber officinale) has been investigated for its potentially therapeutic effect on a range of chronic conditions and symptoms in humans. However, a simplified and easily understandable examination of the mechanisms behind these effects is lacking and, in turn, hinders interpretation and translation to practice, and contributes to overall clinical heterogeneity confounding the results. Therefore, drawing on data from nonhuman trials, the objective for this narrative review was to comprehensively describe the current knowledge on the proposed mechanisms of action of ginger on conferring therapeutic health effects in humans. Mechanistic studies support the findings from human clinical trials that ginger may assist in improving symptoms and biomarkers of pain, metabolic chronic disease, and gastrointestinal conditions. Bioactive ginger compounds reduce inflammation, which contributes to pain; promote vasodilation, which lowers blood pressure; obstruct cholesterol production, which regulates blood lipid profile; translocate glucose transporter type 4 molecules to plasma membranes to assist in glycemic control; stimulate fatty acid breakdown to aid weight management; and inhibit serotonin, muscarinic, and histaminergic receptor activation to reduce nausea and vomiting. Additional human trials are required to confirm the antimicrobial, neuroprotective, antineoplastic, and liver- and kidney-protecting effects of ginger. Interpretation of the mechanisms of action will help clinicians and researchers better understand how and for whom ginger may render therapeutic effects and highlight priority areas for future research.


Sources of variance in ocular microtremor.
This study presents a preliminary investigation of the sources of variance in the measurement of ocular microtremor frequency in a normal population. When the results from both experienced and relatively inexperienced operators are pooled, factors that contribute significantly to the total variance include the measurement procedure (p < 0.001), day-to-day variations within subjects (p < 0.001), and inter-subject differences (p < 0.01). Operator experience plays a role in determining the measurement precision: the intra-subject coefficient of variation is about 5% for a very experienced operator, and about 14% for a relatively inexperienced operator.


High power density vertical-cavity surface-emitting lasers with ion implanted isolated current aperture.
We report on GaAs-based high power density vertical-cavity surface-emitting laser diodes (VCSELs) with ion implanted isolated current apertures. A continuous-wave output power of over 380 mW and the power density of 4.9 kW/cm2 have been achieved at 15 °C from the 100-μm-diameter aperture, which is the highest output characteristic ever reported for an ion implanted VCSEL. A high background suppression ratio of over 40 dB has also been obtained at the emission wavelength of 970 nm. The ion implantation technique provides an excellent current isolation in the apertures and would be a key to realize high power output from a VCSEL array.


Human CD1d knock-in mouse model demonstrates potent antitumor potential of human CD1d-restricted invariant natural killer T cells.
Despite a high degree of conservation, subtle but important differences exist between the CD1d antigen presentation pathways of humans and mice. These differences may account for the minimal success of natural killer T (NKT) cell-based antitumor therapies in human clinical trials, which contrast strongly with the powerful antitumor effects in conventional mouse models. To develop an accurate model for in vivo human CD1d (hCD1d) antigen presentation, we have generated a hCD1d knock-in (hCD1d-KI) mouse. In these mice, hCD1d is expressed in a native tissue distribution pattern and supports NKT cell development. Reduced numbers of invariant NKT (iNKT) cells were observed, but at an abundance comparable to that in most normal humans. These iNKT cells predominantly expressed mouse Vβ8, the homolog of human Vβ11, and phenotypically resembled human iNKT cells in their reduced expression of CD4. Importantly, iNKT cells in hCD1d knock-in mice exert a potent antitumor function in a melanoma challenge model. Our results show that replacement of mCD1d by hCD1d can select a population of functional iNKT cells closely resembling human iNKT cells. These hCD1d knock-in mice will allow more accurate in vivo modeling of human iNKT cell responses and will facilitate the preclinical assessment of iNKT cell-targeted antitumor therapies.


Mexico's path towards the Sustainable Development Goal for health: an assessment of the feasibility of reducing premature mortality by 40% by 2030.
The United Nations Sustainable Development Goal for health (SDG3) poses complex challenges for signatory countries that will require clear roadmaps to set priorities over the next 15 years. Building upon the work of the Commission on Investing in Health and published estimates of feasible global mortality SDG3 targets, we analysed Mexico's mortality to assess the feasibility of reducing premature (0-69 years) mortality and propose a path to meet SDG3. We developed a baseline scenario applying 2010 age-specific and cause-specific mortality rates from the Mexican National Institute of Statistics and Geography (INEGI) to the 2030 UN Population Division (UNPD) population projections. In a second scenario, INEGI age-specific and cause-specific trends in death rates from 2000 to 2014 were projected to 2030 and adjusted to match the UNPD 2030 mortality projections. A third scenario assumed a 40% reduction in premature deaths across all ages and causes. By comparing these scenarios we quantified shortfalls in mortality reductions by age group and cause, and forecasted life expectancy pathways for Mexico to converge to better performing countries. UNPD-projected death rates yield a 25·9% reduction of premature mortality for Mexico. Accelerated reductions in adult mortality are necessary to reach a 40% reduction by 2030. Mortality declines aggregated across all age groups mask uneven gains across health disorders. Injuries, particularly road traffic accidents and homicides, are the main health challenge for young adults (aged 20-49 years) whereas unabated diabetes mortality is the single most important health concern for older adults (aged 50-69 years). Urgent action is now required to control non-communicable diseases and reduce fatal injuries in Mexico, making a 40% reduction in premature mortality by 2030 feasible and putting Mexico back on a track of substantial life expectancy convergence with better performing countries. Our study provides a roadmap for setting national health priorities. Further analysis of the equity implications of following the suggested pathway remains a subject of future research. Mexico's Ministry of Health, University of California, San Francisco, and Bill & Melinda Gates Foundation.


A novel Asp380Ala mutation in the GLC1A/myocilin gene in a family with juvenile onset primary open angle glaucoma.
Glaucoma describes a clinically and genetically heterogeneous group of diseases that result in optic neuropathy and progressive loss of visual fields. A gene for juvenile onset primary open angle glaucoma JOAG) has recently been mapped to 1q21-31. Mutations in the trabecular meshwork induced glucocorticoid response gene (TIGR, also known as myocilin or the GLC1A locus) have been found to cause both juvenile and later onset primary open angle glaucoma. Family TCD-POAG1 is a Spanish kindred, which segregates JOAG in an autosomal dominant fashion. This family was found to be linked to the previously identified GLC1A locus on chromosome 1q. Direct sequencing of the TIGR/myocilin gene showed a heterozygous A to C transition in codon 380, resulting in the substitution of alanine for aspartic acid (Asp380Ala). This substitution created a StyI restriction site, which segregated with the JOAG phenotype and permitted rapid screening of all members of the family. This restriction site was not present in 60 controls.


Uptake of immunisations in low birthweight infants.
The timing of immunisations for preterm infants is controversial. Because of the statement by the British Paediatric Association/Joint Committee on Vaccination and Immunisation Liaison group that immunisations should normally begin three months after the date of birth, the records of all infants born in 1984 and currently (June 1986) resident in the London Borough of Newham were studied to find out if this recommendation was being implemented. Subjects were divided into groups by birth weight and where possible by gestational age. Cumulative uptakes by age of any component of the first and third triple immunisations, and of the pertussis component, were plotted separately. Comparison of uptake of the first course showed a considerable initial delay for infants weighing less than 2000 g at birth compared with heavier babies, but by 18 months the coverage was almost identical. This difference was not evident for the third course. A similar delay was apparent when infants of 37 weeks' gestation or less were compared with babies born at full term, though recording of gestational age was incomplete. Final overall uptake was poor for all groups. Differences among groups in numbers consenting were not an important factor. Informing those responsible for giving the immunisations of these findings has stimulated their interest in improving practice by implementing the recommendations.


Dyskeratosis congenita: molecular insights into telomerase function, ageing and cancer.
Dyskeratosis congenita (DC) is a severe, inherited, bone marrow failure syndrome, with associated cutaneous and noncutaneous abnormalities. DC patients also show signs of premature ageing and have an increased occurrence of cancer. DC can originate through: (1) mutations in DKC1, which result in X-linked recessive DC; (2) mutations in the RNA component of telomerase (TERC), which result in autosomal dominant DC (AD-DC); and (3) mutations in other, currently uncharacterized, genes, which result in autosomal recessive DC (AR-DC). As DKC1 encodes dyskerin, a protein component of small nucleolar ribonucleoprotein (snoRNP) particles, which are important in ribosomal RNA processing, DC was initially described as a disorder of defective ribosomal biogenesis. Subsequently, dyskerin and TERC were shown to closely associate with each other in the telomerase complex, and DC has since come to be regarded as a telomerase deficiency disorder characterised by shorter telomeres. These findings demonstrate the importance of telomerase in humans and highlight how its deficiency (through DKC1 and TERC mutations) results in multiple abnormalities including premature ageing, bone marrow failure and cancer. Identification of the gene(s) involved in AR-DC will help to define the pathophysiology of DC further, as well as expand our insights into telomere function, ageing and cancer.


Phenotypic Characterization of 2D and 3D Prostate Cancer Cell Systems Using Electrical Impedance Spectroscopy.
Prostate cancer is the second leading cause of death in men. A challenge in treating prostate cancer is overcoming cell plasticity, which links cell phenotype changes and chemoresistance. In this work, a microfluidic device coupled with electrical impedance spectroscopy (EIS), an electrode-based cell characterization technique, was used to study the electrical characteristics of phenotype changes for (1) prostate cancer cell lines (PC3, DU145, and LNCaP cells), (2) cells grown in 2D monolayer and 3D suspension cell culture conditions, and (3) cells in the presence (or absence) of the anti-cancer drug nigericin. To validate observations of phenotypic change, we measured the gene expression of two epithelial markers, E-cadherin (CDH1) and Tight Junction Protein 1 (ZO-1). Our results showed that PC3, DU145, and LNCaP cells were discernible with EIS. Secondly, moderate phenotype changes based on differences in cell culture conditions were detected with EIS and supported by the gene expression of CDH1. Lastly, we showed that EIS can detect chemoresistant-related cell phenotypes with nigericin drug treatment. EIS is a promising label-free tool for detecting cell phenotype changes associated with chemoresistance. Further development will enable the detection and characterization of many other types of cancer cells.


Distribution of technetium 99m-labeled red blood cells during isoflurane anesthesia in ferrets.
To address the physiologic mechanism of isoflurane-associated reduction in hematologic variables in ferrets. 6 young adult female ferrets. Distribution of 99mTc-labeled autologous erythrocytes was measured by serial in vivo imaging. Data were recorded in 4 ferrets, using a gamma camera, immediately prior to anesthesia, 15 minutes after 2% isoflurane anesthesia in O2 via endotracheal tube, 1 minute prior to and throughout a 10-minute phenylephrine infusion, 20 and 40 minutes after termination of the phenylephrine infusion, and 45 minutes after termination of anesthesia. Blood indices were also measured at times that paralleled those for imaging. One ferret served as a conscious control (no anesthetic administration), and another as an isoflurane control (no phenylephrine administration). In ferrets under anesthesia, splenic radioactivity increased from baseline of 10.2 +/- 2.0% to 38.4 +/- 3.2% (mean +/- SEM; P < 0.05) of the injected dose. Splenic radioactivity decreased to 13.4 +/- 3.8% of the injected dose during phenylephrine infusion and to near baseline for the recovery image. Splenic radioactivity in the conscious control remained constant throughout the study, whereas that of the anesthetized control was persistently increased throughout administration of isoflurane. Percentage reduction of the 15-minute sample values, compared with baseline values for all hematologic indices, was: RBC count, 33% (P < 0.05); hemoglobin concentration, 34% (P < 0.05); hematocrit, 35% (P < 0.05); and plasma protein concentration, 20% (P < 0.05). All RBC variables returned to within 7 to 14% of baseline by 45 minutes after termination of anesthesia. Isoflurane anesthesia causes splenic sequestration of RBC in ferrets that is partially reversed by phenylephrine infusion or termination of anesthesia. Thus, investigators and clinicians should be cautious when interpreting hematologic findings in isoflurane-anesthetized ferrets, and accordingly, fluid treatment and transfusion should be planned.


Separation of Alcaligenes eutrophus cells containing Poly(3-hydroxybutyrate) from fermentation broth with pretreatment using Al- and Fe-based coagulants.
Alcaligenes eutrophus containing intracellular poly(3-hydroxybutyrate) was recovered from fermentation broth by centrifugation and filtration after pretreatment with Al- and Fe-based coagulants. Coagulation efficiency was largely affected by pH, and the optimum pH's for cell recovery were about 4.6-5.6 for the Al-based coagulants and about 5-8 for the Fe-based coagulants. Ammonium ions that combined with metals to form complex compounds increased the coagulant requirement, and the additional requirement of coagulant was found to be proportional to the ammonium concentration. In addition, various ligands in addition to ammonium ions contained in the culture medium interfered with the coagulation reaction and increased the coagulant requirement also. The coagulant requirement increased with the cell concentration regardless of coagulant type. The polymeric coagulants such as PACS, Hi-PAX, and Ferix-3 were more effective than nonpolymeric coagulants of aluminum sulfate and ferrous sulfate. The optimum dosages of the coagulants tested were determined over a broad range of cell concentration of 20.5-210 g/L. It was observed that the energy requirement for centrifugation could be greatly reduced with cell coagulation.


Lower extremity muscle functions during full squats.
The purpose of this research was to determine the functions of the gluteus maximus, biceps femoris, semitendinosus, rectus femoris, vastus lateralis, soleus, gastrocnemius, and tibialis anterior muscles about their associated joints during full (deep-knee) squats. Muscle function was determined from joint kinematics, inverse dynamics, electromyography, and muscle length changes. The subjects were six experienced, male weight lifters. Analyses revealed that the prime movers during ascent were the monoarticular gluteus maximus and vasti muscles (as exemplified by vastus lateralis) and to a lesser extent the soleus muscles. The biarticular muscles functioned mainly as stabilizers of the ankle, knee, and hip joints by working eccentrically to control descent or transferring energy among the segments during scent. During the ascent phase, the hip extensor moments of force produced the largest powers followed by the ankle plantar flexors and then the knee extensors. The hip and knee extensors provided the initial bursts of power during ascent with the ankle extensors and especially a second burst from the hip extensors adding power during the latter half of the ascent.


Effect of brassinolide on gene expression in elongating soybean epicotyls.
We have studied the effect of brassinolide (BR), a plant steroidal lactone, on the expression of auxin-regulated genes in soybean (Glycine max L. cv Williams 82) epicotyls. BR caused up to 4-fold increases in epicotyl length during extended assays at 10(-7)m, in the absence of added auxin. Structurally related steroids failed to induce elongation or to alter the BR effect. Northern blot analysis, using sequences corresponding to auxin-regulated genes as probes, has shown that the molecular mechanism of BR-induced elongation is likely to differ from that of auxin-induced elongation in this system. BR does not rapidly induce members of the GH, SAUR, or JCW auxin-inducible gene families before the onset of elongation. BR enhances SAUR and GH1 transcripts after 18 h but has no effect on JCW1 or GH3 transcripts at any time examined. We have shown by two-dimensional gel analysis of in vitro translated mRNA that a submicromolar concentration of BR alters the pattern of gene expression in elongating soybean epicotyls.


AME seminar program in the United States: genesis, goals, and cost-benefit reflections.
The practicing physician's requirement for continuing postgraduate medical education is generally accepted and has generated a number of postgraduate education programs. In 1960, the FAA inaugurated a seminar program to serve the special educational needs of its approximately 7,500 designated Aviation Medical Examiners. These doctors, the majority of whom are civilian physicians representing almost every specialty, are charged with issuing or withholding the pilot's medical license to fly. Under the administration of coauthor Harris, the AME Seminar Program undergoes modification and change as improvements are suggested by accrued experience. Evaluation of data acquired from a variety of sources indicates that the AME does, in fact, need refresher training in civil aviation medicine. In helping fulfill that need, the AME Seminar Program is working effectively.


Customizing properties of β-chitin in squid pen (gladius) by chemical treatments.
The squid pen (gladius) from the Loligo vulgaris was used for preparation of β-chitin materials characterized by different chemical, micro- and nano-structural properties that preserved, almost completely the macrostructural and the mechanical ones. The β-chitin materials obtained by alkaline treatment showed porosity, wettability and swelling that are a function of the duration of the treatment. Microscopic, spectroscopic and synchrotron X-ray diffraction techniques showed that the chemical environment of the N-acetyl groups of the β-chitin chains changes after the thermal alkaline treatment. As a consequence, the crystalline packing of the β-chitin is modified, due to the intercalation of water molecules between β-chitin sheets. Potential applications of these β-chitin materials range from the nanotechnology to the regenerative medicine. The use of gladii, which are waste products of the fishing industry, has also important environmental implications.


Photo-thermal measurement of absorptance losses, temperature induced wavefront deformation and compaction in DUV-optics.
A measurement system for quantitative registration of transient and irreversible lens effects in DUV optics induced by absorbed UV laser radiation was developed. It is based upon a strongly improved Hartmann-Shack wavefront sensor with an extreme sensitivity of approximately lambda/10000 rms @ 193nm, accomplishing precise on-line monitoring of wavefront deformations of a collimated test laser beam transmitted through the laser-irradiated site of a sample. Caused by the temperature dependence of the refractive index as well as thermal expansion, the initially plane wavefront of the test laser is distorted into a convex or concave lens, depending on sign and magnitude of index change and expansion. This transient wavefront distortion yields a quantitative measure of the absorption losses in the sample. In the case of fused silica, an additional permanent change indicates irreversible material compaction. Results for both fused silica and CaF(2) are presented and compared.


A conventional surgical approach for removal of an ectopic tooth in the nasal cavity.
A 40-year-old female patient presented to ears, nose and throat complaining of cacosmia and discharge from the left maxillary sinus. Her CT scan revealed an ectopic supplemental nasal tooth which could not be removed by nasoendoscopy. Therefore, a conventional intraoral surgical approach was taken. In this case, we discuss the indications for conventional surgical removal of teeth from the nasal cavity when a nasoendoscopic approach is not possible. We highlight the potential pitfalls of both conventional and nasoendoscopic approaches, including some essential considerations when treatment planning these cases.


Genome-Wide Association Study of Male Sexual Orientation.
Family and twin studies suggest that genes play a role in male sexual orientation. We conducted a genome-wide association study (GWAS) of male sexual orientation on a primarily European ancestry sample of 1,077 homosexual men and 1,231 heterosexual men using Affymetrix single nucleotide polymorphism (SNP) arrays. We identified several SNPs with p < 10-5, including regions of multiple supporting SNPs on chromosomes 13 (minimum p = 7.5 × 10-7) and 14 (p = 4.7 × 10-7). The genes nearest to these peaks have functions plausibly relevant to the development of sexual orientation. On chromosome 13, SLITRK6 is a neurodevelopmental gene mostly expressed in the diencephalon, which contains a region previously reported as differing in size in men by sexual orientation. On chromosome 14, TSHR genetic variants in intron 1 could conceivably help explain past findings relating familial atypical thyroid function and male homosexuality. Furthermore, skewed X chromosome inactivation has been found in the thyroid condition, Graves' disease, as well as in mothers of homosexual men. On pericentromeric chromosome 8 within our previously reported linkage peak, we found support (p = 4.1 × 10-3) for a SNP association previously reported (rs77013977, p = 7.1 × 10-8), with the combined analysis yielding p = 6.7 × 10-9, i.e., a genome-wide significant association.


[Interaction of neuronal NOS and catecholamines in regulation of expression of proteins of apoptosis by vasopressinergic hypothalamic neurons].
The work studied vasopressinergic neurons of hypothalamic supraoptic and paravenricular nuclei of the wild type mice and the neuronal nitric oxide synthase (nNOS) gene knockouted mice at a decrease of the brain catecholamine (CA) level caused by administration of the blocker of activity of tyrosine hydroxylase alpha-methyl-paratyrosine (alpha-MPT) and at the CA level decrease on the background of functional activity of the vasopressinergic neurons caused by dehydration of animals. There were analyzed changes in the number of neurons in both magnocellular hypothalamic nuclei expressing proapoptotic proteins caspase-8 and caspase-9, p53, and antiapoptotic protein Bcl-2. The disturbance of the CA-ergic innervation was shown to be a strong damaging factor leading to apoptosis of neurons regardless of the presence of nNOS in the cells. However, at disturbance of the CA-ergic innervation due to the 5-day mouse dehydration, no death of neurons by apoptosis was revealed. Thus, it is possible that functional activation prevents the hypothalamic vasopressinergic neurons from death at a decrease of the CA level in brain. The main difference of the nNOS gene knockouts is the absence of activation of the Bcl-2 expression under all used actions. This confirms our suggestion about interaction of CA and NO in triggering of expression of the antiapoptotic protein Bcl-2.


An improved in vivo neutron activation system for measuring kidney cadmium.
An in vivo neutron activation system for measuring kidney cadmium has been redesigned, firstly to reduce ambient dose levels and, secondly, to improve the cadmium signal to neutron dose ratio by modifying the neutron spectrum from 238Pu/Be, by interposing a beryllium premoderator. The ambient dose was reduced by a factor of seven. The overall system performance (lower limit of detection for a given dose) was improved by 40-50%. This 238Pu/Be based system now performs as well as or better than analogous 252Cf systems, without the drawback of the relatively short half life of 252Cf.


Cohnella endophytica sp. nov., a novel endophytic bacterium isolated from bark of Sonneratia apetala.
A Gram-stain-positive, aerobic, rod-shaped, endospore-forming bacterium, designated strain M2MS4P-1T, was isolated from surface-sterilized bark of Sonneratiaapetala sampled in Guangxi, China. The bacterium was characterized by a polyphasic approach to determine its taxonomic position. 16S rRNA gene sequence comparisons revealed that strain M2MS4P-1T belonged to the genus Cohnella and was most closely to Cohnella luojiensis HY-22RT (98.4 % similarity). The average nucleotide identity value and estimated DDH value between strain M2MS4P-1T and the type strain of C. luojiensis HY-22RT were 79.2 and 20.1 %, respectively. Neither substrate nor aerial mycelia were formed, and no diffusible pigments were observed on the media tested. Strain M2MS4P-1T grew in the pH range 6.0-9.0 (optimum, pH 7.0-8.0), at temperatures between 10-37 °C (30 °C) and in 0-1 % (w/v) NaCl (0 %). The predominant isoprenoid quinone in strain M2MS4P-1T was menaquinone-7. The major fatty acids were anteiso-C15 : 0 and iso-C16 : 0. The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, lysyl-phosphatidylglycerol, four unidentified aminophospholipids and two unidentified phospholipids. The DNA G+C content was 51.5 mol%. According to the phylogenetic, phenotypic and chemotaxonomic evidence, strain M2MS4P-1T was clearly distinguishable from other species with validly published names in the genus Cohnella and should therefore be classified as a novel species, for which we suggest the name Cohnellaendophytica sp. nov. The type strain is M2MS4P-1T (=KCTC 43011T=CGMCC 1.13745T).


Diagnosis and treatment of acute phlegmonous gastritis: A case report.
Acute phlegmonous gastritis (PG) is a rare and often fatal condition mainly characterized by severe bacterial infection of the gastric wall. Case reports of PG over the past century average about 1 per year. Early diagnosis and immediate treatment are crucial to achieve positive outcomes. A 47-year-old man was referred to our hospital because of abdominal pain, high fever, and vomiting for 4 days, with aggravation for 24 hours. Physical examination revealed epigastric abdominal pain, rebound pain, and abdominal wall tightness. Abdominal CT showed thickening of the stomach wall with edema and gas. On the basis of symptoms and CT imaging findings, the patient was diagnosed with acute PG. Antibiotic therapy and operation. The patient immediately underwent an operation after conservative treatment using antibiotics proved ineffective. The whole stomach was obviously swollen, and the anterior side and posterior wall of the stomach were nigrescent necrotic. Hence, total gastrectomy was performed followed by reconstruction (roux-en-y), and pus that accumulated in the stomach wall was cultured. At postoperative broad-spectrum antibiotic coverage, the patient finally recovered. Acute PG is a rare infection of the gastric wall especially after antibiotic treatment. Given the fast progression of this disease, early recognition and immediate action are crucial to achieve positive outcomes.