Temporal changes in the corpus luteum during early pregnancy reveal regulation of pathways that enhance steroidogenesis and suppress luteolytic mechanisms†.
Although rescue of the corpus luteum (CL) is required for pregnancy, luteal function during maternal recognition of pregnancy remains largely unexplored. CL were collected from pregnant cattle on days 14, 17, 20, and 23, to encompass the maternal recognition of pregnancy period. Next-generation sequencing was used to profile mRNA abundance during this time, while tandem mass spectrometry and nanostring technology were used to profile proteins and miRNA, respectively. A total of 1157 mRNA were differentially abundant, while 27 miRNA changed, and 29 proteins tended to change. mRNA that increased were regulators of interferon signaling and DNA repair, while those that decreased were associated with luteolytic processes, such as calcium signaling and matrix metallopeptidase (MMP) signaling, indicating inhibition of these processes. One of these, MMP12, was regulated by prostaglandin F2A in vitro. mRNA that were maximally abundant on day 20 were primarily associated with immune processes. Two of these, C-C motif chemokine ligand 1 and NFKB inhibitor alpha, were regulated by interferon tau in vitro. MiRNA that increased were predicted to inhibit phosphatidylinositol signaling, while those that decreased may be negative regulators of steroidogenesis. One protein that was greater on day 20 than on day 14 was aldehyde dehydrogenase 1 family member A1 (ALDH1A1), which synthesizes retinoic acid. Pharmacological inhibition of this enzyme, or of retinoic acid receptor signaling, led to suppression of progesterone production in vitro. Overall, these data indicate that there are changes in the CL of pregnancy that are important for continued luteal function.


Family physicians' knowledge of risk factors for cervical cancer.
A woman's risk for cervical cancer has been used by physicians to guide the initiation and frequency of a Pap smear. The aim of this study was to determine family physicians' knowledge of risk factors for cervical cancer and perceived importance of risk in screening women. The self-administered questionnaire was mailed to 5000 randomly selected active members of the American Academy of Family Physicians (AAFP). Data from 2748 usable questionnaires indicated the mean number of risks considered for cervical cancer was 4.5. Physician's age and the number of reported risks were inversely correlated (p = 0.0001). Female physicians reported significantly more risk factors than male physicians (p = 0.05). The number of Pap smears performed per month was positively correlated with the number of risk factors reported (p = 0.001). Only 10% of the physicians indicated that they perform a Pap smear at the same interval regardless of the risk of the woman. This sample of family physicians has a limited understanding of the risk factors for cervical cancer. This was true regardless of the age, gender, training, race, geographic location, or practice setting of the responding physician. Yet the usual practice of screening for cervical cancer reported by these physicians would suggest that knowledge and use of risk factors would be a critical aspect of screening for cervical cancer.


Perforation of metastatic melanoma to the small bowel with simultaneous gastrointestinal stromal tumor.
The gastrointestinal tract (GIT) is a common site of metastases for malignant melanoma. These metastatic tumors are often asymptomatic. We describe a case of a 58-year-old male who presented with a sudden onset of generalized abdominal pain. The patient's past medical history was significant for lentigo melanoma of the right cheek. Laparotomy was performed and two segments of small bowel, one with a perforated tumor, the other with a non-perforated tumor, were removed. Histology and immunohistochemical staining revealed the perforated tumor to be a metastatic malignant melanoma and the non-perforated tumor was found to be a gastrointestinal stromal tumor (GIST). The patient was discharged 7 d postoperatively. To the best of our knowledge, this is the first reported case in the literature of a simultaneous metastatic malignant melanoma and a GIST. Surgical intervention is warranted in patients with symptomatic GIT metastases to improve the quality of life or in those patients with surgical emergencies.


The prognostic value of quantitative diffusion-weighted MRI after pediatric cardiopulmonary arrest.
The prognostic value of quantitative diffusion-weighted magnetic resonance imaging (DWI MRI) in predicting neurologic outcomes after pediatric cardiopulmonary arrest (CPA) has not been determined. The aim of this study was to identify a DWI MRI threshold for brain volume percent that correlates with neurologic outcome in children who remain comatose or display significant neurologic deficits immediately after resuscitation from CPA. This single-center retrospective study analyzed DWI MRIs of pediatric patients who remained neurologically impaired after CPA. Any MRI obtained within 2 weeks after CPA was analyzed. The apparent diffusion coefficient (ADC) value of each voxel within the brain was determined. Percentage brain volume with voxels below each ADC threshold between 300 and 1200 × 10-6 mm2/s with a step of 50 were calculated. Area under the receiver operating characteristics curve (AUC) was used to identify optimal DWI MRI thresholds for brain volume percent most predictive of poor neurologic outcome. The primary outcome measure was neurologic outcome 6-months after CPA based on Pediatric Cerebral Performance Category (PCPC) score. Poor neurologic outcome was defined as PCPC score of 3-6, or a worsening from baseline score ≥1 if baseline PCPC score was ≥3. Twenty-six patients were included in this study. The median age was 8.5 years (2.2-14) and median time from CPA to MRI was 4 days (2-7). Two ADC thresholds for brain volume percent had the largest AUC for predicting poor neurologic outcome. An ADC threshold of <600 × 10-6 mm2/s in ≥7% of brain volume; and <650 × 10-6 mm2/s in ≥11% of brain volume both demonstrated a specificity of 1.0 (0.76-1.0, 95% CI) and a sensitivity of 0.8 (0.44-0.96, 95% CI) for poor outcome. In pediatric patients who remain comatose or have significant neurologic deficits after CPA, quantitative DWI MRI correlates with neurologic outcome. Both an ADC threshold of <600 × 10-6 mm2/s in ≥7% of brain volume and <650 × 10-6 mm2/s in ≥11% of brain volume are highly specific for predicting poor neurologic outcome. A prospective trial to validate these thresholds is needed.


Clinical implications of numeracy: theory and practice.
Low numeracy is pervasive and constrains informed patient choice, reduces medication compliance, limits access to treatments, impairs risk communication, and affects medical outcomes; therefore, it is incumbent upon providers to minimize its adverse effects. We provide an overview of research on health numeracy and discuss its implications in clinical contexts. Low numeracy cannot be reliably inferred on the basis of patients' education, intelligence, or other observable characteristics. Objective and subjective assessments of numeracy are available in short forms and could be used to tailor health communication. Low scorers on these assessments are subject to cognitive biases, irrelevant cues (e.g., mood), and sharper temporal discounting. Because prevention of the leading causes of death (e.g., cancer and cardiovascular disease) depends on taking action now to prevent serious consequences later, those low in numeracy are likely to require more explanation of risk to engage in prevention behaviors. Visual displays can be used to make numerical relations more transparent, and different types of displays have different effects (e.g., greater risk avoidance). Ironically, superior quantitative processing seems to be achieved by focusing on qualitative gist and affective meaning, which has important implications for empowering patients to take advantage of the evidence in evidence-based medicine.


A laboratory-based study to assess the performance of surgical gloves.
The inherent tear resistance and elasticity of latex and the touch sensitivity it provides has made it the traditional material of choice for surgical gloves, protecting both health care workers and patients from the transmission of bloodborne infections. Although increased incidence of latex allergy has led to increased use of nonlatex surgical gloves, the effectiveness of these gloves as a barrier to infection has not been examined thoroughly. This laboratory-based study compared the performance of latex and nonlatex surgical gloves in a simulated stress protocol. The propensity of surgical gloves to fail was dependent on glove material, manufacturer, and stress. Nonlatex neoprene and nitrile gloves were comparable to latex and can provide a good alternative to latex for allergic patients and health care workers. In this study, isoprene was found to be inferior to latex and other nonlatex materials. The presence or absence of glove powder had no significant influence on the probability of glove failure.


A more sustainable isothiocyanate synthesis by amine catalyzed sulfurization of isocyanides with elemental sulfur.
Isothiocyanates (ITCs) are typically prepared using amines and highly toxic reagents such as thiophosgene, its derivatives, or CS2. In this work, an investigation of a multicomponent reaction (MCR) using isocyanides, elemental sulfur and amines revealed that isocyanides can be converted to isothiocyanates using sulfur and catalytic amounts of amine bases, especially DBU (down to 2 mol%). This new catalytic reaction was optimized in terms of sustainability, especially considering benign solvents such as Cyrene™ or γ-butyrolactone (GBL) under moderate heating (40 °C). Purification by column chromatography was further optimized to generate less waste by maintaining high purity of the product. Thus, E-factors as low as 0.989 were achieved and the versatility of this straightforward procedure was shown by converting 20 different isocyanides under catalytic conditions, while obtaining moderate to high yields (34-95%).


ANTXR1 Intronic Variants Are Associated with Fetal Hemoglobin in the Arab-Indian Haplotype of Sickle Cell Disease.
Disease severity of sickle cell anemia is highly variable, and it is commonly accepted that fetal hemoglobin (HbF) levels play a major role as an ameliorating factor. Investigation of genetic variants have identified several genes to be the principal influencers of HbF regulation. Here, we further elucidated the association of rs4527238 and rs35685045 of ANTXR1 genes in the context of HbF level variance in sickle cell anemia patients of the Arab-Indian haplotype. Samples from 630 sickle cell anemia patients were analyzed for the mutations at 2 specific locations of the ANTXR1 gene by TaqMan®-based real-time PCR. The CC genotype (p = 0.018) of rs4527238 and the TT genotype (p = 0.048) of rs35685045 of ANTXR1 were found to be significantly associated with low HbF expression. The frequency of the CC genotype of rs4527238 was observed to be high in the low HbF patient group compared to the high HbF group (p = 0.009). Likewise, the frequency of the TT genotype of rs35685045 was also high among the low HbF group (p = 0.017). The ANTXR1 genetic mutations and the association with HbF expression in the Arab-Indian haplotype sickle cell patients revealed that the ANTXR1 gene may be a major HbF modulator leading to potential therapeutic options that should be further explored.


Glucose monitoring in fission yeast via the Gpa2 galpha, the git5 Gbeta and the git3 putative glucose receptor.
The fission yeast Schizosaccharomyces pombe responds to environmental glucose by activating adenylate cyclase. The resulting cAMP signal activates protein kinase A (PKA). PKA inhibits glucose starvation-induced processes, such as conjugation and meiosis, and the transcription of the fbp1 gene that encodes the gluconeogenic enzyme fructose-1,6-bisphosphatase. We previously identified a collection of git genes required for glucose repression of fbp1 transcription, including pka1/git6, encoding the PKA catalytic subunit, git2/cyr1, encoding adenylate cyclase, and six "upstream" genes required for adenylate cyclase activation. The git8 gene, identical to gpa2, encodes the alpha subunit of a heterotrimeric guanine-nucleotide binding protein (Galpha) while git5 encodes a Gbeta subunit. Multicopy suppression studies with gpa2(+) previously indicated that S. pombe adenylate cyclase activation may resemble that of the mammalian type II enzyme with sequential activation by Galpha followed by Gbetagamma. We show here that an activated allele of gpa2 (gpa2(R176H), carrying a mutation in the coding region for the GTPase domain) fully suppresses mutations in git3 and git5, leading to a refinement in our model. We describe the cloning of git3 and show that it encodes a putative seven-transmembrane G protein-coupled receptor. A git3 deletion confers the same phenotypes as deletions of other components of the PKA pathway, including a germination delay, constitutive fbp1 transcription, and starvation-independent conjugation. Since the git3 deletion is fully suppressed by the gpa2(R176H) allele with respect to fbp1 transcription, git3 appears to encode a G protein-coupled glucose receptor responsible for adenylate cyclase activation in S. pombe.


[Endoscopic and pathological characteristics of gastric cancer in a Peruvian public hospital].
The endoscopic and pathological characteristics of gastric cancer in Luis N. Sáenz National Hospital between 2008 and 2013. retrospective cross-sectional observational study. We reviewed the endoscopic reports of patients older than 30 years, we studied the histological diagnosis of gastric adenocarcinoma, pathological variables such as histological type, presence of H. pylori and complete and incomplete intestinal metaplasia. 92 cases of gastric adenocarcinoma were identified. Average prevalence 0.6%, 0.34% in 2009 and 0.82% in 2013; 62% male, 38% female, age less than 55 years 16%, greater than 76 years 42%; endoscopic presentation Borrmann III 57%, II 16.3%, IV 15%, V 7.6%, I 3.3%; 8 times most frequent presentations distal the proximal v, 75% histologic intestinal type, H. pylori in 50% cases, intestinal metaplasia in 40% of cases of gastric cancer. We found high prevalence of gastric cancer. Common in males, and in people over 76, more frequent endoscopic presentation was Borrmann III, the presence of H. pylori and incomplete intestinal metaplasia associated with intestinal cancer type.


The mathematical limits of genetic prediction for complex chronic disease.
Attempts at predicting individual risk of disease based on common germline genetic variation have largely been disappointing. The present paper formalises why genetic prediction at the individual level is and will continue to have limited utility given the aetiological architecture of most common complex diseases. Data were simulated on one million populations with 10 000 individuals in each populations with varying prevalences of a genetic risk factor, an interacting environmental factor and the background rate of disease. The determinant risk ratio and risk difference magnitude for the association between a gene variant and disease is a function of the prevalence of the interacting factors that activate the gene, and the background rate of disease. The risk ratio and total excess cases due to the genetic factor increase as the prevalence of interacting factors increase, and decrease as the background rate of disease increases. Germline genetic variations have high predictive capacity for individual disease only under conditions of high heritability of particular genetic sequences, plausible only under rare variant hypotheses. Under a model of common germline genetic variants that interact with other genes and/or environmental factors in order to cause disease, the predictive capacity of common genetic variants is determined by the prevalence of the factors that interact with the variant and the background rate. A focus on estimating genetic associations for the purpose of prediction without explicitly grounding such work in an understanding of modifiable (including environmentally influenced) factors will be limited in its ability to yield important insights about the risk of disease.


The bone morphogenetic protein pathway is inactivated in the majority of sporadic colorectal cancers.
The finding of bone morphogenetic protein (BMP) receptor 1a mutations in juvenile polyposis suggests that BMPs are important in colorectal cancer (CRC). We investigated the BMP pathway in sporadic CRC. We investigated BMP receptor (BMPR) expression using immunoblotting and sequenced BMPR2 in CRC cell lines. We assessed the expression of BMPRs, SMAD4, and pSMAD1/5/8 in 72 sporadic CRCs using a tissue microarray and immunohistochemistry. We assessed the effect of reintroduction of wild-type BMPR2 on BMP pathway activity and the effect of wild-type or mutated BMPR2 3' untranslated region (UTR) sequences on protein expression by attachment to pCMV-Luc. BMPR2 and SMAD4 protein expression is abrogated in microsatellite unstable (MSI) and microsatellite stable (MSS) cell lines, respectively. BMPR2 3'UTR is mutated in all MSI and in none of the MSS cell lines. Mutant BMPR2 3'UTR sequences reduced luciferase expression 10-fold compared with wild-type BMPR2 3'UTR. BMPR2 expression is impaired more frequently in MSI CRCs than MSS (85% vs 29%; P < .0001) and shows a mutually exclusive pattern of impaired expression compared with SMAD4. Nine of 11 MSI cancers with impaired expression of BMPR2 have microsatellite mutations. The BMP pathway is inactivated, as judged by nuclear pSMAD1/5/8 expression, in 70% of CRCs, and this correlates with BMPR and SMAD4 loss. Our data suggest that the BMP pathway is inactivated in the majority of sporadic CRCs. In MSI CRC this is associated predominantly with impaired BMPR2 expression and in MSS CRC with impaired SMAD4 expression.


Benthic habitat mapping of Plazh Gradina - Zlatna ribka (Black Sea) and Karpathos and Saria Islands (Mediterranean Sea).
Habitat mapping is nеcessary for the efficient conservation and protection of marine ecosystems. In addition, it is a requirement for EU Member States as stated in the European Union (EU) Habitats Directive (92/43/EEC), as well as necessary for the achievement and maintenance of 'good environmental status (GES)' of benthic marine habitats in the framework of the EU Marine Strategy Framework Directive (2008/56/EC). This study provides baseline information on the marine benthic habitats of Sozopol Bay (Black Sea) and Karpathos and Saria Islands (Mediterranean Sea). These two Natura 2000 sites were selected as study sites of the RECONNECT project, which aimed at creating a transnational cooperative network to confront the environmental threats of ecosystems with a high natural and cultural interest, by the establishment of common practices and a joint regional strategy. The specific objective was to map the marine habitats using a defined a priori classification (EUNIS), with the ultimate purpose of supporting government marine spatial planning, management and decision-making processes through the development of a Decision Support System.


Combination chemotherapy of Hodgkin disease in children.
MOPP chemotherapy program was employed in 20 children with advanced Hodgkin disease (stages III and IV). Complete remissions were achieved in 13 patients (65%)within an average duration rate of 17.1 months varying from 2 to 40 months. If thses only one patient developed recurrency and died 10 months after the onset of treatment. The remaining 12 children are alive and well; an average survival rate since the onset of MOPP chemotherapy being 20 months. The patients with partial remission died from further progression of the disease within the period from 2 to 15 months. The study showed that histological type and mode of previous treatment had an influence on the results of chemotherapy used. The complications of MOPP chemotherapy were insignificant and easily controlled.


Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy.
SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A, which encodes the voltage-gated sodium channel NaV1.6. To date, it is unclear if and how inhibitory interneurons, which express NaV1.6, influence disease pathology. Using both sexes of a transgenic mouse model of SCN8A epileptic encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of WT SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational modeling and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A epileptic encephalopathy, but epilepsy in general.SIGNIFICANCE STATEMENTSCN8A epileptic encephalopathy is a devastating neurological disorder that results from de novo mutations in the sodium channel isoform Nav1.6. Inhibitory neurons express NaV1.6, yet their contribution to seizure generation in SCN8A epileptic encephalopathy has not been determined. We show that mice expressing a human-derived SCN8A variant (R1872W) selectively in somatostatin (SST) interneurons have audiogenic seizures. Physiological recordings from SST interneurons show that SCN8A mutations lead to an elevated persistent sodium current which drives initial hyperexcitability, followed by premature action potential failure because of depolarization block. Furthermore, chemogenetic activation of WT SST interneurons leads to audiogenic seizure activity. These findings provide new insight into the importance of SST inhibitory interneurons in seizure initiation, not only in SCN8A epileptic encephalopathy, but for epilepsy broadly.


Maternal fluoxetine treatment in the postpartum period: effects on platelet serotonin and plasma drug levels in breastfeeding mother-infant pairs.
Postpartum major depression, a frequently (10%) occurring complication of childbirth, adversely affects the mother's functioning, the mother-infant relationship, and the child's subsequent development and propensity for later psychopathology. Although selective serotonin reuptake inhibitors (SSRIs) are effective in treating postpartum depression, concerns have been raised regarding their use in lactating women. Although plasma drug levels of infants who are exposed to SSRIs through breast milk are low compared with those typically seen in patients, infant levels in some reports do seem to be at or near the drugs' reported affinities (K(D)s) and IC(50)s for inhibition at the serotonin (5-hydroxytryptamine [5-HT]) transporter. The impact of central serotonin 5-HT modulation by SSRIs during critical periods of brain development is unknown. These concerns have led our group to examine whether exposure through breast milk has a discernible effect on platelet 5-HT uptake. Taking advantage of the similarities between platelet and neuronal serotonin transporters, we previously used measurements of platelet 5-HT before and during maternal sertraline treatment to determine the degree of 5-HT transporter blockade in breastfed infants. We found that infants who were exposed to sertraline through their mothers' breast milk experienced little to no change in platelet 5-HT levels, suggestive of minimal effects on peripheral and central 5-HT transporter blockade. Compared with sertraline and most other SSRIs, fluoxetine and its active metabolite, norfluoxetine, have substantially longer plasma half-lives, and both compounds have been found in measurable quantities in plasma of nursing infants. Thus, to extend our previous work in this area, we measured platelet 5-HT levels and plasma drug levels in breastfeeding mother-infant pairs before and during maternal treatment with fluoxetine. Maternal and infant transporter blockade was assessed by measurement of platelet 5-HT in 11 breastfeeding mother-infant pairs before and after 4 to 12 weeks of maternal fluoxetine (20-40 mg/d) treatment for postpartum depression. The study was approved by the Human Investigation Committee of Yale University School of Medicine, and each mother (mean age: 34.5 years; standard deviation [SD]: 5.3) gave written informed consent. Whole-blood 5-HT levels and plasma fluoxetine and norfluoxetine levels were determined by high-performance liquid chromatography. Five mothers were taking 20 mg of fluoxetine daily, 4 were taking 30 mg daily, and 2 were taking 40 mg daily. Mean infant age at the start of the study was 16.8 (SD: 8.8) weeks. All infants except 1 were <6 months of age and 4 were <3 months of age when their mothers began treatment. Six infants were breastfed exclusively; the remaining were breastfed between 3 and 8 times daily and were given supplemental feedings. Mean maternal postexposure 5-HT levels of 22.9 ng/mL (SD: 12.5) were markedly lower than mean preexposure (baseline) levels of 156.6 ng/mL (SD: 71.4; paired t = 6.9, df = 10). In contrast, the mean infant pre- and postexposure 5-HT concentrations of 217.1 (SD: 66.5) and 229.9 (SD: 83.5) ng/mL, respectively, were similar (paired t = -0.24, df = 10). However, the 1 infant with measurable plasma fluoxetine had a substantial decline in 5-HT to 40% of baseline. In samples obtained from the same infant 4 months later, plasma drug levels were undetectable (<1 ng/mL) and the platelet serotonin levels were no longer reduced (12% increase from baseline). The marked declines (to 9%-28% of baseline) in platelet 5-HT concentrations seen in mothers who were treated with the SSRI fluoxetine were similar to those observed in our study of sertraline in breastfeeding and other previous studies. In contrast, all but 1 infant experienced little or no decline in whole-blood (platelet) 5-HT concentrations after exposure to fluoxetine through breast milk. The substantial drop in platelet 5-HT seen in 1 infant and the coupling of this drop with measurable plasma fluoxetine leves drop with measurable plasma fluoxetine level raises some concern. Possible reasons for the infant's measurable plasma fluoxetine level include his mother's high plasma drug level and his being breastfed exclusively. However, the observations may be coincidental, and the infant experienced no discernible adverse effects. These data suggest that most infants may continue to breastfeed without experiencing meaningful changes in platelet 5-HT transport while their mothers are treated with 20 to 40 mg of fluoxetine daily. Given the limited data regarding occurrence and extent of SSRI exposure and the uncertainties concerning the possible effects of exposure, it is premature to propose treatment guidelines. Our own advice to women who are thinking of combining breastfeeding and SSRI treatment will weigh a range of factors, including severity of postpartum depression, any demonstrated preferential response to a specific SSRI, and the mother's commitment to breastfeeding. Additional research is needed to establish more definitively the frequency of physiologically meaningful infant SSRI exposure during breastfeeding and to determine the behavioral consequences of such exposure.


Epidemiological typing and prevalence of integrons in multiresistant Acinetobacter strains.
Seventy-seven Acinetobacter isolates were recovered from patients in a Korean hospital during the period from November to December 1998. The isolates were genotyped using randomly amplified polymorphic DNA (RAPD) analysis for epidemiological relationship, and investigated for antibiotic susceptibility and presence of integrons. Sixty-nine Acinetobacter baumannii isolates were distributed into five groups by RAPD profiles, with 5, 1, 60, 2 and 1 in each group. The major RAPD group of 60 isolates was further divided into six subgroups by antibiograms. Eight isolates belonging to Acinetobacter DNA group 13TU were distributed among six RAPD groups. Seventy-three of the Acinetobacter isolates were resistant to eight or more of the antibiotics tested. Integrase genes were detected in 66 of the 69 A. baumannii (96%) and in 5 of the 8 Acinetobacter DNA group 13TU isolates (63%). The intI1 and intI2 genes were found in 63 and 8 isolates, respectively. The intI3 gene was not detected. All integron-carrying isolates were resistant to multiple antibiotics. All strains isolated from more than one patient carried integrons. According to the results, the presence of integrons was significantly (p<0.01) associated with multiple antibiotic resistance and nosocomial spread in Acinetobacter strains.


Neuropathology of suicide. A review and an approach.
Neuropathology is one approach to the effort to elucidate the pathophysiology of suicide. Initial neurochemical studies focusing on the roles of serotonin (5-HT) and noradrenaline (NE) abnormalities in brains of suicide victims have been somewhat inconsistent. More recently developed methodologies, including quantitative receptor autoradiography, immunoblotting, immunohistochemistry, cell morphometry, in situ hybridization, Northern analysis, solution hybridization/RNase protection assay, reverse transcriptase polymerase chain reaction, and genotyping, which have already been applied successfully in studies of other disorders of brain structure or function, are now increasingly being adopted for postmortem studies of suicide. These new strategies are adding convergent evidence for brain 5-HT and NE dysfunction in the etiology of suicide susceptibility, refining the neuroanatomical localization of this dysfunction, and in addition, implicating heretofore unsuspected candidate neurotransmitter systems in the neuropathological substrates of suicide susceptibility. It is argued here that the confluence of the availability of suitable postmortem samples and this augmentation of our armamentarium of techniques promises the attainment of important new insights into the biological underpinnings of suicide from postmortem research. It is to be hoped that this new knowledge might inspire novel pharmacotherapeutic strategies for the prevention of suicide.


Enhanced alloresponse to platelet transfusion due to immune dysregulation following ablative chemotherapy in mice.
Alloimmunization is common following platelet transfusion and can result in negative outcomes for recipients such as refractoriness to subsequent transfusions and rejection of transplants. Healthy people do not receive blood transfusions, and the diseases and therapies that result in a need to transfuse have significant impacts on the immunological environment to which these alloantigens are introduced. Ablative chemotherapies are common among platelet recipients and have potent immunological effects. In this study, we modeled the impact of chemotherapy on the alloresponse to platelet transfusion. As chemotherapies are generally regarded as immunosuppressive, we hypothesized that that they would result in a diminished alloresponse. Mice were given a combination chemotherapeutic treatment of cytarabine and doxorubicin followed by transfusion of allogeneic platelets, and compared to controls given no treatment, chemotherapy alone, or transfusion alone. Alloantibody responses were measured 2 weeks after transfusion, and cellular responses and growth factors were monitored over time. Contrary to our hypothesis, we found that chemotherapy led to increased alloantibody responses to allogeneic platelet transfusion. This enhanced response was antigen-specific and was associated with increased CD4+ and CD8+ T cell responses. Chemotherapy led to rapid lymphocyte depletion followed by reconstitution, non-specific activation of transitional B cells with the highest levels of activation in the least mature subsets, and increased serum levels of B cell activating factor (BAFF). These data suggest that ablative chemotherapy can increase the risk of alloimmunization and, if confirmed clinically, that additional measures to protect these patient populations may be warranted.


Attention Deficit Hyperactivity Disorder and oxidative stress: A short term follow up study.
In this study, we aimed to investigate total antioxidative status (TAS) and total oxidative status (TOS) of plasma and antioxidant enzymes such as paraoxonase (PON), stimulated paraoxonase (SPON), arylesterase (ARES) and thiols in plasma of children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD). In the second step. this study aimed to reveal the possible effects of ADHD treatment on these parameters. Fifty-six patients with ADHD and 52 healthy controls were involved in this study. Venous blood samples were collected and oxidative and antioxidative parameter's were studied. In the second phase of the study, blood samples were taken from patients using medication. Pre-treatment oxidative stress index (OSI) values and the plasma TOS levels of the patients with ADHD were statistically higher than those of the control group. The plasma thiol levels of the patients with ADHD were significantly lower than the control group. The post-treatment plasma antioxidative parameter's levels were significantly higher than the pre-treatment levels. The post-treatment oxidative stress index value was significantly lower than the pre-treatment value. Therefore, oxidative metabolism was found to be impaired in children and adolescents with ADHD. It was also determined that methylphenidate repairs the oxidative balance by increasing antioxidant defence mechanisms.


Comparative Analysis between Podography and Radiography in the Management of Idiopathic Clubfeet by Ponseti Technique.
Idiopathic clubfoot is one of the most common and oldest congenital foot anomalies. There are controversies regarding its optimum management protocol and methodologies to be employed for its functional outcome evaluation. This paper attempts to propose a simple, reasonable and easily reproducible technique of podography for clinical and functional evaluation of clubfoot treated by the popular Ponseti technique. To compare the Foot Bimalleolar (FBM) angle method (podography) and radiography with respect to management of idiopathic clubfoot by Ponseti's Technique and its functional evaluation. Sixty feet of 48 patients with idiopathic clubfoot deformity were assessed in terms of FBM by podography (foot print on paper and FBM angle drawing) and radiologically; before starting treatment, after 6 weeks and at 6 monthly intervals with a maximum follow up period of 4.8 years (Range 1.2 to 4.8 years). Mean age at start of treatment was 1.5 years (2 months to 2.5 years). Functional evaluation was done by Magone's scoring system. After treatment, 92 percent patients had good correction (FBM greater than 70 degrees) which correlated well with post treatment Magone's score of greater than 80 (good to excellent) in nearly 85 percent of cases. Radiologically, talocalcaneal angles in both the views improved in only 60 percent of cases. Radiological criteria show inconsistent correlation with functional outcome for feet treated by Ponseti's Technique. Podography (FBM angle analysis) is a very simple, objective, cost effective, radiation free, easily reproducible and highly reliable clinical criterion for the assessment of deformity correction in club foot by Ponseti's Technique with an excellent correlation with functional outcome.


The Profunda Artery Perforator Flap: A Versatile Option for Head and Neck Reconstruction.
Although the profunda artery perforator flap has gained popularity in breast reconstruction, it has not been well described for reconstruction of head and neck defects. The authors report their experience with free profunda artery perforator flaps in postoncologic head and neck reconstruction. A retrospective review of all free profunda artery perforator flaps used for head and neck reconstruction from 2016 to 2019 was performed. Overall, 61 profunda artery perforator flap reconstructions were performed: 45 single independent flaps, 12 in conjunction with a second free flap, and four in combination with two other free flaps. The profunda artery perforator flaps were most commonly used for reconstruction of the tongue (n = 19), cheek (n = 11), parotid (n = 10), and maxilla (n = 6). The profunda artery perforator flaps averaged 7.1 × 12.1 × 1.9 cm, with a mean pedicle length of 11.5 cm. The A, B, and C perforators were located at mean distances of 7.4 cm (range, 4 to 11.5 cm), 11.7 cm (range, 8 to 18 cm), and 16.1 cm (range, 14 to 20.5 cm) from the pubic tubercle along the axis of the adductor longus muscle and 7.9 cm (range, 7 to 11cm), 7.6 cm (range, 7 to 15.5 cm), and 7.2 cm (range, 6 to 16 cm) posterior and perpendicular to the axis. There were three partial flap losses. Eight patients (13 percent) had recipient-site complications necessitating operative intervention: four for vascular compromise of the profunda artery perforator flap, two for hematoma evacuation, and two for infection. Donor-site complications were noted in seven patients (11 percent), two of whom required operative intervention. The profunda artery perforator flap is a versatile and reliable flap with consistent anatomy and a low complication rate. The profunda artery perforator flap seems to be a reasonable alternative for reconstruction of head and neck defects. Therapeutic, IV.


Report on Mortality from Gluteal Fat Grafting: Recommendations from the ASERF Task Force.
Gluteal fat grafting is among the fastest growing aesthetic procedures in the United States and around the world. Given numerous anecdotal and published reports of fatal and nonfatal pulmonary fat embolism resulting from this procedure, the Aesthetic Surgery Education and Research Foundation (ASERF) formed a Task Force to study this complication. To determine the incidence of fatal and nonfatal pulmonary fat embolism associated with gluteal fat grafting and provide recommendations to decrease the risks of the procedure. An anonymous web-based survey was sent to 4843 plastic surgeons worldwide. Additional data on morbidity and mortality was collected through confidential interviews with plastic surgeons and medical examiners, public records requests for autopsy reports in the United States, and through the American Association for the Accreditation of Ambulatory Surgical Facilities (AAAASF). Six hundred and ninety-two (692) surgeons responding to the survey reported 198,857 cases of gluteal fat grafting. Over their careers, surgeons reported 32 fatalities from pulmonary fat emboli as well as 103 nonfatal pulmonary fat emboli. Three percent (3%) of respondents experienced a patient fatality and 7% of respondents reported at least one pulmonary fat embolism in a patient over their careers. Surgeons reporting the practice of injecting into the deep muscle experienced a significantly increased incidence rate of fatal and nonfatal pulmonary fat emboli. Twenty-five fatalities were confirmed in the United States over the last 5 years through of autopsy reports and interviews with surgeons and medical examiners. Four deaths were reported from 2014 to 2015 from pulmonary fat emboli in AAAASF facilities. Despite the growing popularity of gluteal fat grafting, significantly higher mortality rates appear to be associated with gluteal fat grafting than with any other aesthetic surgical procedure. Based on this survey, fat injections into the deep muscle, using cannulae smaller than 4 mm, and pointing the injection cannula downwards should be avoided. More research is necessary to increase the safety of this procedure.


mRNA cap-binding protein: cloning of the gene encoding protein synthesis initiation factor eIF-4E from Saccharomyces cerevisiae.
We have isolated genomic and cDNA clones encoding protein synthesis initiation factor eIF-4E (mRNA cap-binding protein) of the yeast Saccharomyces cerevisiae. Their identity was established by expression of a cDNA in Escherichia coli. This cDNA encodes a protein indistinguishable from purified eIF-4E in terms of molecular weight, binding to and elution from m7GDP-agarose affinity columns, and proteolytic peptide pattern. The eIF-4E gene was isolated by hybridization of cDNA to clones of a yeast genomic library. The gene lacks introns, is present in one copy per haploid genome, and encodes a protein of 213 amino acid residues. Gene disruption experiments showed that the gene is essential for growth.


The phosphatidylcholine transfer protein StarD7 is important for myogenic differentiation in mouse myoblast C2C12 cells and human primary skeletal myoblasts.
StarD7 is a phosphatidylcholine (PC)-specific lipid transfer protein essential for the maintenance of mitochondrial PC composition, morphogenesis, and respiration. Here, we studied the role of StarD7 in skeletal myoblast differentiation using mouse myoblast C2C12 cells and human primary myoblasts. Immunofluorescence and immuno-electron microscopy revealed that StarD7 was distributed in the cytosol, inner mitochondria space, and outer leaflet of the outer mitochondrial membrane in C2C12 cells. Unlike human kidney embryonic cell line HEK293 cells, the mitochondrial proteinase PARL was not involved in the processing and maturation of StarD7 in C2C12 cells. StarD7 was constantly expressed during myogenic differentiation of C2C12 cells. The siRNA-mediated knockdown of StarD7 in C2C12 cells and human primary myoblasts significantly impaired myogenic differentiation and reduced the expression of myomaker, myomerger and PGC-1α. The reduction in mitochondrial PC levels and oxygen consumption rates, decreased expression of myomaker, myomerger and PGC-1α, as well as impaired myogenic differentiation, were completely restored when the protein was reintroduced into StarD7-knockout C2C12 cells. These results suggest that StarD7 is important for skeletal myogenesis in mammals.


Bovine viral diarrhea virus contamination of nutrient serum, cell cultures and viral vaccines.
Bovine viral diarrhea virus (BVDV) infection is common in the bovine population. Infection in utero leads to virus and antibody contamination of the fetal bovine serum used in cell cultures. These contaminants can interfere with diagnosis of viral infection. The high frequency of virus and antibody detection in individual animal or small pool samples suggests that any large pool of unscreened sera will be contaminated. Infection of cell cultures with BVDV can lead to interference with the growth of other viruses. Vaccine produced on contaminated cells may in turn be contaminated, leading to seroconversion or disease in the vaccine. The safety, purity, and efficacy of viral vaccines require BVDV testing of ingredients, cell substrates and final product. Methods for detection of BVDV in nutrient serum, cell cultures, seed viruses, and viral vaccines, and the frequency of their detection at the National Veterinary Services Laboratories are discussed.


Cellulitis caused by Roseomonas mucosa in a child: a case report.
Roseomonas mucosa (R. mucosa) is a pink-pigmented, Gram-negative short rod bacterium. It is isolated from moist environments and skin, resistant to multiple drugs, including broad-spectrum cephalosporins, and a rare cause of infection with limited reports. R. mucosa mostly causes catheter-related bloodstream infections, with even fewer reports of skin and soft tissue infections. A 10-year-old boy received topical steroid treatment for sebum-deficient eczema. A few days before the visit, he was bitten by an insect on the front of his right lower leg and scratched it due to itching. The day before the visit, redness, swelling, and mild pain in the same area were observed. Based on his symptoms, he was diagnosed with cellulitis. He was treated with sulfamethoxazole/trimethoprim, and his symptoms improved. Pus culture revealed R. mucosa. We report a rare case of cellulitis caused by R. mucosa. Infections caused by rare organisms that cause opportunistic infections, such as R. mucosa, should be considered in patients with compromised skin barrier function and regular topical steroid use. Gram stain detection of organisms other than Gram-positive cocci should be considered.


Clinical and molecular genetic analysis of a new mutation in children with Wolfram syndrome: a case report.
A 12‑year‑old Chinese girl presented with gradual vision loss and insulin‑dependent diabetes mellitus and was suspected to suffer from Wolfram syndrome (WFS). A series of clinical examinations were performed, as well as direct DNA sequencing to screen the entire coding region of the WFS1 gene in the patient's family, including her parents and a brother. Ophthalmological examination revealed counting fingers/10 cm in the right eye and hand motions/10 cm in the left eye. Ophthalmoscopical examination identified bilateral optic atrophy without any signs of diabetic retinopathy. A hearing test was performed and revealed that the hearing ability for high frequency sounds was decreased. Urinary output in 24 h was >5,000 ml. In addition, a base substitution at c.2411T>C (Leu804Pro) in exon 8 was identified which was homozygous with the patient and heterozygous with the healthy parents and the brother. In the present case, a neuroophthalmology consult performed in the early stages of the disease was crucial for early diagnosis. In addition, this case study highlights the importance of performing a hearing test as well as collecting and analyzing 24‑h urine output in patients presenting with juvenile diabetes mellitus patients and optic atrophy without any signs of diabetic retinopathy.


[One hundred years of the Association of Surgeons in the Netherlands. III. Gastrointestinal surgery].
On 27 February 1989 the Nederlandse Vereniging voor Gastro-Intestinale Chirurgie [Netherlands Association for Gastrointestinal Surgery] was founded. The aim--improvement of quality by integrating scientific and clinical work--was already formulated 10 years previously by the Gastrointestinal Surgery Working Group. The integration proceeded carefully; the Netherlands Association for Gastrointestinal Surgery began as a chapter of the Association of Surgeons in the Netherlands and as a working group within the Dutch Gastroenterology Association. Meanwhile new techniques have been investigated and introduced and surgical oncology is a growing area of collaboration with the Dutch Association for Surgical Oncology. In the future minimally invasive interventions and robot surgery will come to the fore, reflux disease and inflammatory bowel diseases will decrease as an operative indication and early diagnosis will play a greater role.


Thyroid and celiac diseases autoantibodies in patients with adult chronic idiopathic thrombocytopenic purpura.
The association of chronic idiopathic thrombocytopenic purpura (cITP) and thyroid autoimmune diseases (TAD) is a known but an uncommon condition. Celiac disease (CD), which is characterized by malabsorption and villous atrophy that occur as a consequence of the ingestion of wheat gluten may also be related to other autoimmune disorders. In this study, we investigated the prevalence of thyroid anti-microsomal (TAMA) and anti-thyroglobulin (TATA) auto antibodies, anti-gliadin (AGA) IgG, IgA, anti-endomisium (EMA) IgG and IgA antibodies in 74 patients with cITP and in 162 healthy controls. TATA positivity was found in 29, and TAMA positivity in 19 out of 74 patients; and in 16 and 18 out of 162 controls respectively (p < 0.0001 and p = 0.005, respectively). TAD was diagnosed in 29 of cITP patients. AGA IgG positivity was found in 17, and IgA was present in five out of 74 patients; and AGA IgG was found in 19, and IgA was detected in 4 out of 162 controls (p = 0.032 and p = 0.143, respectively). EMA IgG positivity was found in six out of 74 patients and in nine out of 162 control subjects (p = 0.566). EMA IgA positivity was found in two out of 74 patients and in one out of 162 controls (p = 0.232). We showed that the prevalence of TAD and related autoantibodies are higher in patients with cITP. We suggest that, patients with cITP should be followed up for development of TAD. In addition, all CD related auto antibodies were found to be more frequent in patients with cITP, but only the AGA IgG reached to the clinical significance. None of the CD related auto antibody positive patients developed clinically manifested CD. Large-scale designed studies are needed to clarify the long-term impact and importance of these CD related auto antibodies in patients with cITP.


Vagal afferent transmission in the NTS mediating reflex responses of the rat esophagus.
In urethan-anesthetized rats, esophageal distension evoked volume-dependent reflex contractions with phase-locked multiunit discharges in the central subnucleus of the solitary tract complex (NTSC) and the nucleus ambiguus. During blockade of solitarial, but not peripheral, muscarinic cholinoceptors, the volume-response relationship of reflex contractions was shifted rightward with a depression in pressure wave amplitude. Concurrently, premotor NTSC responses were attenuated and nucleus ambiguus activity was abolished during esophagomotor inhibition. Both NTSC discharges and reflex responses were eliminated, or strongly inhibited, during blockade of excitatory amino acid receptors (EAARs) with 6-cyano-7-nitroquinoxaline-2,3-dione, gamma-glutamylglycine or 2-amino-7-phosphonoheptanoate. In brain stem slice preparations, whole cell recordings in the NTSC region revealed fast excitatory postsynaptic potentials (EPSPS) with spikes in response to electrical stimulation of the solitary tract. Although spiking was facilitated by muscarine, EPSPS were resistant to cholinoceptor antagonists but sensitive to EAAR blockers. We conclude that esophageal vagal afferents excite ipsilateral NTSC interneurons via activation of glutamate receptors of the DL-alpha-amino-3-hydroxy-5-methylisoxazole-propionic acid and N-methyl-D-aspartate subtypes. Cholinergic input to the NTSC probably derives from propriobulbar sources and serves to modulate the responsiveness of reflex interneurons.


Safety and Efficacy of Medical Cannabis in Autism Spectrum Disorder Compared with Commonly Used Medications.
Objective: The objective of this study was to evaluate the safety and efficacy of medications commonly used in autism spectrum disorder (ASD) and compare this to what current research has shown regarding medical cannabis use in this population. Methods: Searches were performed to collect information surrounding currently used medications and their safety and efficacy profiles, biologic plausibility of cannabis use for symptoms of ASD, and studies detailing cannabis' safety and efficacy profile for use in the ASD population. Results were used to compare medications to cannabis as a proposed treatment. Results: The heterogeneity of ASD produces great difficulties in finding appropriate treatment, leading to many medication changes or treatment trials throughout a patient's life. Commonly prescribed medications display varying levels of efficacy, safety, and tolerability between patients and symptoms targeted. Some of the most common side effects cited are also considered the most troubling symptoms associated with ASD; aggression, anxiety, irritability, and a negative effect on cognition, leading many patients to discontinue use as the side effects outweigh benefits. Recent case reports and retrospective studies have displayed the potential efficacy, safety, and tolerability of cannabidiol (CBD)-rich medical cannabis use for treating both core symptoms of ASD and many comorbid symptoms such as irritability and sleep problems. Studies have also identified circulating endocannabinoids as a possible biomarker for ASD, providing another possible method of diagnosis. Conclusions: Currently, there are no approved medications for the core symptoms of ASD and only two medications Food and Drug Administration approved for associated irritability. Prescribed medications for symptoms associated with ASD display varying levels of efficacy, safety, and tolerability among the heterogeneous ASD population. At the time of this study there are no published placebo-controlled trials of medical cannabis for ASD and the observational studies have limitations. CBD-rich medical cannabis seems to be an effective, tolerable, and relatively safe option for many symptoms associated with ASD, however, the long-term safety is unknown at this time.


Electrochemical deposition of platinum within nanopores on silicon: drastic acceleration originating from surface-induced phase transition.
An electrochemical reaction within nanopores is remarkably decelerated once a diffusion-limited condition is reached due to the difficulty in supply of reactants from the bulk. Here, we report a powerful method of overcoming this problem for electrochemical deposition of platinum within nanopores formed on silicon. We made the pore wall surface of the silicon electrode hydrophobic by covering it with organic molecules and adopted platinum complex ions with sufficiently large sizes. Such ions, which are only weakly hydrated, are excluded from the bulk aqueous electrolyte solution to the surface and rather hydrophobic in this sense. When the ion concentration in the bulk was gradually increased, at a threshold the deposition behavior exhibited a sudden change, leading to drastic acceleration of the electrochemical deposition. Using our statistical-mechanical theory for confined molecular liquids, we show that this change originates from a surface-induced phase transition: The space within nanopores is abruptly filled with the second phase within which the ion concentration is orders of magnitude higher. When the affinity of the surface with water was gradually reduced with fixing the ion concentration, qualitatively the same transition phenomenon was observed, which can also be elucidated by our theory. The utilization of the surface-induced phase transition sheds new light on the design and control of a chemical reaction in nanospace.


Associations of serious mental illness with earnings: results from the WHO World Mental Health surveys.
Burden-of-illness data, which are often used in setting healthcare policy-spending priorities, are unavailable for mental disorders in most countries. To examine one central aspect of illness burden, the association of serious mental illness with earnings, in the World Health Organization (WHO) World Mental Health (WMH) Surveys. The WMH Surveys were carried out in 10 high-income and 9 low- and middle-income countries. The associations of personal earnings with serious mental illness were estimated. Respondents with serious mental illness earned on average a third less than median earnings, with no significant between-country differences (chi(2)(9) = 5.5-8.1, P = 0.52-0.79). These losses are equivalent to 0.3-0.8% of total national earnings. Reduced earnings among those with earnings and the increased probability of not earning are both important components of these associations. These results add to a growing body of evidence that mental disorders have high societal costs. Decisions about healthcare resource allocation should take these costs into consideration.


Leptomeningeal Metastases in Melanoma Patients: An Update on and Future Perspectives for Diagnosis and Treatment.
Leptomeningeal disease (LMD) is a devastating complication of cancer with a particularly poor prognosis. Among solid tumours, malignant melanoma (MM) has one of the highest rates of metastasis to the leptomeninges, with approximately 10-15% of patients with advanced disease developing LMD. Tumour cells that metastasise to the brain have unique properties that allow them to cross the blood-brain barrier, evade the immune system, and survive in the brain microenvironment. Metastatic colonisation is achieved through dynamic communication between metastatic cells and the tumour microenvironment, resulting in a tumour-permissive milieu. Despite advances in treatment options, the incidence of LMD appears to be increasing and current treatment modalities have a limited impact on survival. This review provides an overview of the biology of LMD, diagnosis and current treatment approaches for MM patients with LMD, and an overview of ongoing clinical trials. Despite the still limited efficacy of current therapies, there is hope that emerging treatments will improve the outcomes for patients with LMD.


Aging exacerbates negative remodeling and impairs endothelial regeneration after balloon injury.
Many older patients, because of their high prevalence of coronary artery disease, are candidates for percutaneous coronary interventions (PCI), but the effects of vascular aging on restenosis after PCI are not yet well understood. Balloon injury to the right carotid artery was performed in adult and old rats. Vascular smooth muscle cell (VSMC) proliferation, apoptotic cell death, together with Akt induction, telomerase activity, p27kip1, and endothelial nitric oxide synthase (eNOS) expression was assessed in isolated arteries. Neointima hyperplasia and vascular remodeling along with endothelial cell regeneration were also measured after balloon injury. Arteries isolated from old rats exhibited a significant reduction of VSMC proliferation and an increase in apoptotic death after balloon injury when compared with adult rats. In the vascular wall of adult rats, balloon dilation induced Akt phosphorylation, and this was barely present in old rats. In arteries from old rats, Akt-modulated cell cycle check points like telomerase activity and p27kip1 expression were decreased and increased, respectively, compared with adults. After balloon injury, old rats showed a significant reduction of neointima formation and an increased vascular negative remodeling compared with adults. These results were coupled by a marked delay in endothelial regeneration in aged rats, partially mediated by a decreased eNOS expression and phosphorylation. Interestingly, chronic administration of L-arginine prevented negative remodeling and improved reendothelialization after balloon injury in aged animals. A decreased neointimal proliferation, an impaired endothelial regeneration, and an increase in vascular remodeling after balloon injury were observed in aged animals. The molecular mechanisms underlying these responses seem to be a reduced Akt and eNOS activity.


Population-level transcriptome sequencing of nonmodel organisms Erynnis propertius and Papilio zelicaon.
Several recent studies have demonstrated the use of Roche 454 sequencing technology for de novo transcriptome analysis. Low error rates and high coverage also allow for effective SNP discovery and genetic diversity estimates. However, genetically diverse datasets, such as those sourced from natural populations, pose challenges for assembly programs and subsequent analysis. Further, estimating the effectiveness of transcript discovery using Roche 454 transcriptome data is still a difficult task. Using the Roche 454 FLX Titanium platform, we sequenced and assembled larval transcriptomes for two butterfly species: the Propertius duskywing, Erynnis propertius (Lepidoptera: Hesperiidae) and the Anise swallowtail, Papilio zelicaon (Lepidoptera: Papilionidae). The Expressed Sequence Tags (ESTs) generated represent a diverse sample drawn from multiple populations, developmental stages, and stress treatments. Despite this diversity, > 95% of the ESTs assembled into long (> 714 bp on average) and highly covered (> 9.6x on average) contigs. To estimate the effectiveness of transcript discovery, we compared the number of bases in the hit region of unigenes (contigs and singletons) to the length of the best match silkworm (Bombyx mori) protein--this "ortholog hit ratio" gives a close estimate on the amount of the transcript discovered relative to a model lepidopteran genome. For each species, we tested two assembly programs and two parameter sets; although CAP3 is commonly used for such data, the assemblies produced by Celera Assembler with modified parameters were chosen over those produced by CAP3 based on contig and singleton counts as well as ortholog hit ratio analysis. In the final assemblies, 1,413 E. propertius and 1,940 P. zelicaon unigenes had a ratio > 0.8; 2,866 E. propertius and 4,015 P. zelicaon unigenes had a ratio > 0.5. Ultimately, these assemblies and SNP data will be used to generate microarrays for ecoinformatics examining climate change tolerance of different natural populations. These studies will benefit from high quality assemblies with few singletons (less than 26% of bases for each assembled transcriptome are present in unassembled singleton ESTs) and effective transcript discovery (over 6,500 of our putative orthologs cover at least 50% of the corresponding model silkworm gene).


Molecular basis for therapeutic decisions in chronic myeloid leukemia patients after allogeneic bone marrow transplantation.
Recent progress in the development of diagnostic techniques has greatly facilitated the monitoring of minimal residual disease (MRD) in patients with chronic myeloid leukemia (CML) after allogeneic bone marrow transplantation (BMT), the only curative treatment for this disease. The presence of the P210(bcr-abl) rearrangement in CML cells has allowed highly sensitive detection of MRD by polymerase chain reaction (PCR). However, complete eradication of the leukemic clone may not be a necessary prerequisite for long-term remission or cure. This observation limits the value of qualitative PCR analysis for prediction of progressive disease and highlights the need to monitor the proliferative activity of the malignant clone in order to permit timely detection of impending relapse and, thus, early therapy. This article discusses the applicability of several molecular methods to the monitoring of treatment efficacy and early assessment of clonal expansion in patients with CML after BMT. It also presents guidelines for clinical use of PCR analyses and the most effective approaches to treat relapsed patients. The authors have been working in this field, both experimentally and at a clinical level, contributing original papers to peer-reviewed journals. The material examined in this review includes articles published in journals covered by MedLine and reviews from journals with a high impact factor. In view of the very limited value of qualitative PCR in detecting CML patients destined to relapse after BMT, several investigators have developed molecular assays that enable the kinetics of MRD to be monitored over time (e.g. quantitative PCR for P210(bcr-abl), PCR analysis of whole blood/lineage-specific chimerism and qualitative PCR for P190(bcr-abl)). These molecular strategies closely trace the kinetics of leukemic regrowth. Disease evolution in relapsed patients is consistently characterized by the sequential detection of increasing P210(bcr-abl) transcript levels, increasing myeloid mixed chimerism and finally, P190(bcr-abl) positivity preceding cytogenetic relapse. A 10-fold or greater increase in the expression of P210(bcr-abl) confirmed by a minimum of three independent quantitative PCR analyses and/or a progressive increase in the percentage of host myeloid cells in three consecutive chimerism analyses and/or P190(bcr-abl) mRNA detection must be regarded as an indication of incipient disease progression and should provide a rationale for initiation of treatment. There are various approaches to the management of the patient who relapses. The first step, if possible, is to reduce or terminate immune suppression. If the patient is not receiving this therapy, he or she can be treated with hydroxyurea or interferon or can be offered a second transplant. However, infusion to the patient of lymphoid cells (DLI) collected from the original donor has the capacity to restore complete remission in 70-80% of cases. Currently, several strategies are being used to minimize the severity of graft-versus-host disease after DLI (optimization of transfused lymphocyte doses, modification of the transfused lymphocyte subsets, administration of lymphocytes in escalating doses or lymphocyte transfection with a suicide gene), to reduce the incidence of marrow aplasia (stem cell support) and to increase the rate of complete responses (cytokines associated with DLI, leukemia-reactive cytotoxic lymphocytes, tyrosine kinase inhibitors or pre-emptive DLI).


Oral health and pediatricians: results of a national survey.
Pediatricians have regular opportunities to perform screening dental examinations on young children and to educate families on preventive oral health. We sought to assess pediatricians' current attitudes and practices related to oral health of children 0-3 years old. A Periodic Survey of Fellows, focused on oral health in pediatricians' office settings, was sent to 1618 postresidency fellows of the American Academy of Pediatrics. The response rate was 68%. More than 90% of pediatricians said that they should examine their patients' teeth for caries and educate families about preventive oral health. However, in practice, only 54% of pediatricians reported examining the teeth of more than half of their 0-3-year-old patients. Four percent of pediatricians regularly apply fluoride varnish. The most common barrier to participation in oral health-related activities in their practices was lack of training, which was cited by 41%. Less than 25% of pediatricians had received oral health education in medical school, residency, or continuing education. Most pediatricians (74%) reported that availability of dentists who accept Medicaid posed a moderate to severe barrier for 0-3-year-old Medicaid-insured patients to obtain dental care. Pediatricians see it within their purview to educate families about preventive oral health and to assess for dental caries. However, many pediatricians reported barriers to fully implementing preventive oral health activities into their practices. Pediatricians and dentists need to work together to improve the quality of preventive oral health care available to all young children.


Sudden cardiac arrest and ventricular arrhythmias following first type I myocardial infarction in the contemporary era.
Myocardial infarction (MI) is associated with an increase in subsequent heart failure (HF), recurrent ischemic events, sudden cardiac arrest, and ventricular arrhythmias (SCA-VA). The primary objective of the study to determine the role of intercurrent HF and ischemic events on the development of SCA-VA following first type I MI. A retrospective cohort study of patients experiencing first type 1 MI in Olmsted County, Minnesota (2002-2012) was conducted by identifying patients using the medical records linkage system (Rochester epidemiology project). Patients aged ≥18 years were followed from the time of MI till death or 31 July, 2017. Intercurrent HF and ischemic events were the primary exposures following MI and their association with outcome SCA-VA was assessed. Eight hundred and sixty-seven patients (mean age was 63 ± 14.5 years; 69% male; 49.8% ST-elevation myocardial infarction) who had their first type I MI during the study period were included. Majority of acute MI patients were revascularized using percutaneous coronary intervention and bypass surgery (628 [72.43%] and 87 [10.03%] respectively). During a mean follow-up of 7.69 ± 4.17 years, HF, recurrent ischemic events and SCA-VA occurred in 155 (17.9%), 245 (28.3%), and 40 (4.61%) patients respectively. Low ejection fraction (adjusted hazard ratio [HR] 0.95; 95% confidence interval [CI], 0.93-0.98; P < .001), intercurrent HF (adjusted HR 3.11; 95% CI, 1.39-6.95; P = .006) and recurrent ischemic events (adjusted HR 3.47; 95% CI, 1.68-7.18; P < .001) were associated with subsequent SCA-VA. SCA-VA occurred in a small proportion of patients after MI and is associated with intercurrent HF and recurrent ischemic events.


Estimation of human gonadal Pu and Ce concentrations from animal data.
Data were obtained from the literature for gonad and body weights and for the Pu or Ce content of the gonads and body at death for several laboratory animal species, five human Pu injection cases, and 731 human adults exposed environmentally to Pu in fallout. Data for Pu concentration in gonads, liver, and bone samples of 59 male and five female occupational Pu cases (including four completely analyzed whole bodies) were obtained from the U.S. Transuranium Registry. A logarithmic function was used to relate fractional Pu or Ce concentration in testes and ovaries to body weight of the animals and to predict fractional Pu or Ce concentrations in human gonads, [Pu]G . PuB-1 = aBWb, where [Pu]G or [Ce]G is the nuclide concentration in gonads (Bq g-1 of wet weight), PuB or CeB is the nuclide content of the body at death, and BW is body weight (kg). The fractional Pu and Ce concentrations in both the testes and ovaries are inverse and nearly linear functions of body weight. The regression lines of fractional Pu or Ce concentration in testes and ovaries have similar slopes (b = -1.07 +/- 0.14); however, the nuclide concentrations (coefficient a) in ovaries are six times greater than in testes. Extrapolation of the animal data yielded fractional Pu concentrations in human testes and ovaries that agree with those calculated for the occupational cases and those recommended by the International Commission on Radiological Protection. The good agreement between the fractional concentrations of Pu and Ce in the testes and in the ovaries suggests that these data can be substituted in metabolic models of chemically similar elements for which gonadal data are scarce.


Application of equilibrium passive sampling to profile pore water and accessible concentrations of hydrophobic organic contaminants in Danube sediments.
Total concentrations of hydrophobic organic contaminants (HOCs) in sediment present a poor quality assessment parameter for aquatic organism exposure and environmental risk because they do not reflect contaminant bioavailability. The bioavailability issue of HOCs in sediments can be addressed by application of multi-ratio equilibrium passive sampling (EPS). In this study, riverbed sediment samples were collected during the Joint Danube Survey at 9 locations along the Danube River in 2013. Samples were ex-situ equilibrated with silicone passive samplers. Desorption isotherms were constructed, yielding two endpoints: pore water (CW:0) and accessible (CAS:0) concentration of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polycyclic aromatic hydrocarbons (PAHs) and polybrominated diphenyl ethers in sediment. CW:0 concentrations of DDT and its breakdown products exhibited elevated levels in the low Danube, with the maximum in the river delta. Other investigated HOCs did not show any clear spatial trends along the river, and only a moderate CW:0 variability. CAS:0 in sediment ranged from 10 to 90% of the total concentration in sediment. CW:0 was compared with freely dissolved concentration in the overlaying surface water, measured likewise by passive sampling. The comparison indicated potential compound release from sediment to the water phase for PAHs with less than four aromatic rings, and for remaining HOCs either equilibrium between sediment and water, or potential compound deposition in sediment. Sorption partition coefficients of HOC to organic carbon correlated well with octanol-water partition coefficients (KOW), showing stronger sorption of PAHs to sediment than that of PCBs and OCPs having equal logKOW. Comparison of CW:0 values with European environmental quality standards indicated potential exceedance for hexachlorobenzene, fluoranthene and benzo[a]pyrene at several sites. The study demonstrates the utility of passive sampling as an innovative approach for risk-oriented monitoring of HOCs in river catchments.


Microarousals during sleep are associated with increased levels of lipids, cortisol, and blood pressure.
Previous work has demonstrated a link between restricted sleep and risk indicators for cardiovascular and metabolic disease, such as levels of cortisol, lipids, and glucose. The present study sought to identify relations between polysomnographic measures of disturbed sleep (frequency of arousals from sleep, total sleep time, and sleep efficiency) and a number of such indicators. A second purpose was to relate the number of arousals to mood, stress, work characteristics, and other possible predictors in daily life. Twenty-four people (10 men, 14 women; mean age 30 years), high vs. low on burnout, were recruited from a Swedish IT company. Polysomnographically recorded sleep was measured at home before a workday. Blood pressure, heart rate, morning blood sample, and saliva samples of cortisol were measured the subsequent working day. They were also recorded for diary ratings of sleep and stress, and a questionnaire with ratings of sleep, stress, work conditions, and mood was completed. A stepwise regression analysis using sleep parameters as predictors brought out number of arousals as the best predictor of morning cortisol (serum and saliva), heart rate, systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein (HDL)-, low-density lipoprotein (LDL)-cholesterol, and LDL/HDL-ratio. Work stress/unclear boundaries between work and leisure time was the best predictor of arousals among the stress variables. Consistent with sleep restriction experiments, sleep fragmentation was associated with elevated levels of metabolic and cardiovascular risk indicators of stress-related disorders. Number of arousals also seems to be related to workload/stress.


Indirect pulp capping and primary teeth: is the primary tooth pulpotomy out of date?
Formocresol pulpotomy (FP) in the United States is most frequently used to treat asymptomatic caries near the pulp in primary teeth. Indirect pulp therapy (IPT) is also indicated and has a significantly higher long-term success. Pulpotomy is thought to be indicated for primary teeth with carious pulp exposures, but research shows the majority of such teeth are nonvital or questionable for treatment with vital pulp therapy. IPT has a significantly higher success in treating all primary first molars, but especially those with reversible pulpitis compared with FP. The purpose of this article was to review the dental literature and new research in vital pulp therapy to determine the following: (1) Is a pulpotomy indicated for a true carious pulp exposure? (2) Is there a diagnostic method to reliably identify teeth that are candidates for vital pulp therapy? (3) Is primary tooth pulpotomy out of date, and should indirect pulp therapy replace pulpotomy?


Optimization in freeze-drying.
The author assumes that success in freeze-drying must be judged in economic terms. Following a summary of the reasons given for adopting freeze-drying, and an historical outline to explain the changing emphasis in the performance requirements of equipment, desirable features in design and operation are reviewed as the basis for a charter for plant manufacturers and an aid to comparison between different types of plant. Ways of appraising value for money are examined and a novel method is proposed for maximizing throughput by optimising the conditions in the freeze-dryer.


A hybrid BCI system combining P300 and SSVEP and its application to wheelchair control.
In this paper, a hybrid brain-computer interface (BCI) system combining P300 and steady-state visual evoked potential (SSVEP) is proposed to improve the performance of asynchronous control. The four groups of flickering buttons were set in the graphical user interface. Each group contained one large button in the center and eight small buttons around it, all of which flashed at a fixed frequency (e.g., 7.5 Hz) to evoke SSVEP. At the same time, the four large buttons of the four groups were intensified through shape and color changes in a random order to produce P300 potential. During the control state, the user focused on a desired group of buttons (target buttons) to evoke P300 potential and SSVEP, simultaneously. Discrimination between the control and idle states was based on the detection of both P300 and SSVEP on the same group of buttons. As an application, this method was used to produce a "go/stop" command in real-time wheelchair control. Several experiments were conducted, and data analysis results showed that combining P300 potential and SSVEP significantly improved the performance of the BCI system in terms of detection accuracy and response time.


Hypomethylation of alphoid DNA and classical satellite DNA on chromosome 1, 9, 16 and Y in extraembryonic tissue.
The pattern of DNA methylation can be analyzed on methaphase chromosomes with fluorescein labeled antibodies against 5-methylcytosine. In human extraembryonic tissue lower overall intensity of immunofluorescence in centromeric chromosomal regions correspond to hypomethylation of the DNA when compared with normal human lymphocytes. Pericentromeric regions on chromosomes 1,9,16 and heterochromatin on chromosome Y, which reveal lower levels of immunofluorescence, are rich in classical satellite DNA type II and III. In our experiment methylation-sensitive restriction enzymes, alphoid and classical satellite DNA probes specific for chromosomes 1,9,16 and Y were used. Southern blot analysis on cells from extraembryonic tissue revealed different extent of hypomethylation in different chromosomal regions. Our results confirm overall and sequence-specific hypomethylation of DNA in cells from extraembryonic tissue in comparison with somatic cells.


Analysis of the Mitochondrial DNA and Its Replicative Capacity in Induced Pluripotent Stem Cells.
The mitochondrial genome resides in the mitochondrion of nearly all mammalian cells. It is important for energy production as it encodes 13 of the key subunits of the electron transfer chain, which generates the vast majority of cellular ATP through the process of oxidative phosphorylation. As cells establish pluripotency, they regulate their mtDNA copy number so that they possess few copies but sufficient that they can be replicated to match the differentiated cell-specific requirements for ATP derived through oxidative phosphorylation. However, the failure to strictly regulate this process prevents pluripotent cells from differentiating. We describe a series of protocols that analyze mtDNA copy number, DNA methylation within the nuclear-encoded mtDNA-specific polymerase, and gene expression of the other factors that drive replication of the mitochondrial genome. We demonstrate how to measure ATP-generating capacity through oxygen respiratory capacity and total cellular ATP and lactate levels. Finally, we also describe how to detect mtDNA variants in pluripotent and differentiating cells using next-generation sequencing protocols and how the variants can be confirmed by high-resolution melt analysis.


Fully automated determination of nicotine and its major metabolites in whole blood by means of a DBS online-SPE LC-HR-MS/MS approach for sports drug testing.
Dried blood spots (DBS) represent a sample matrix collected under minimal-invasive, straightforward and robust conditions. DBS specimens have been shown to provide appropriate test material for different analytical disciplines, e.g., preclinical drug development, therapeutic drug monitoring, forensic toxicology and diagnostic analysis of metabolic disorders in newborns. However, the sample preparation has occasionally been reported as laborious and time consuming. In order to minimize the manual workload and to substantiate the suitability of DBS for high sample-throughput, the automation of sample preparation processes is of paramount interest. In the current study, the development and validation of a fully automated DBS extraction method coupled to online solid-phase extraction using the example of nicotine, its major metabolites nornicotine, cotinine and trans-3'-hydroxycotinine and the tobacco alkaloids anabasine and anatabine is presented, based on the rationale that the use of nicotine-containing products for performance-enhancing purposes has been monitored by the World Anti-Doping Agency (WADA) for several years. Automation-derived DBS sample extracts were directed online to liquid chromatography high resolution/high mass accuracy tandem mass spectrometry, and target analytes were determined with support of four deuterated internal standards. Validation of the method yielded precise (CV <7.5% for intraday and <12.3% for interday measurements) and linear (r(2)>0.998) results. The limit of detection was established at 5 ng mL(-1) for all studied compounds, the extraction recovery ranged from 25 to 44%, and no matrix effects were observed. To exemplify the applicability of the DBS online-SPE LC-MS/MS approach for sports drug testing purposes, the method was applied to authentic DBS samples obtained from smokers, snus users, and e-cigarette users. Statistical evaluation of the obtained results indicated differences in metabolic behavior depending on the route of administration (inhalative versus buccal absorption) in terms of the ratio of nicotine and nornicotine.


Bio-based Large Tablet Controlled-Release Urea: Synthesis, Characterization, and Controlled-Released Mechanisms.
To improve nitrogen (N) use efficiency and minimize environmental pollution caused by fertilizer overuse, novel bio-based large tablet controlled-release urea (LTCRU) was prepared using bio-based coating materials to coat large tablet urea (LTU) derived from urea prills (U). Nano fumed silica (NFS) was added to the bio-based coating materials to improve the slow-release properties. The surface area of the LTU and U was measured by three-dimensional scanning. In comparison to U, LTU had a smaller surface area/weight ratio, which can reduce the coating materials. Scanning electron microscopy analysis showed that the addition of NFS in bio-based coating materials reduced the porosity of the coating shells of LTCRUs and, thus, enhanced the N release longevity of the controlled-released fertilizer. Dependent upon the pores on the coating shells of LTCRU, two N release patterns were revealed. Because of the good release characteristics, the novel LTCRU shows great potential to support sustainable agricultural production.


Effects of vitamin D in the elderly population: current status and perspectives.
Besides its well-known effect on bone metabolism, recent researches suggest that vitamin D may also play a role in the muscular, immune, endocrine, and central nervous systems. Double-blind RCTs support vitamin D supplementation at a dose of 800 IU per day for the prevention of falls and fractures in the senior population. Ecological, case-control and cohort studies have suggested that high vitamin D levels were associated with a reduced risk of autoimmune diseases, type 2 diabetes, cardio-vascular diseases and cancer but large clinical trials are lacking today to provide solid evidence of a vitamin D benefit beyond bone health. At last, the optimal dose, route of administration, dosing interval and duration of vitamin D supplementation at a specific target dose beyond the prevention of vitamin D deficiency need to be further investigated.


Lacking Clarity or Strategic Ambiguity? Comment on "Competing Frames in Global Health Governance: An Analysis of Stakeholder Influence on the Political Declaration on Non-communicable Diseases".
This commentary engages with Suzuki and colleagues' analysis about the ambiguity of multi-stakeholder discourses in the United Nations (UN) Political Declaration of the 3rd High-Level Meeting of the General Assembly on the Prevention and Control of Non-Communicable Diseases (HLM-NCDs), suggesting that blurring between public and private sector in this declaration reflects broader debates about multi-stakeholder partnerships (MSPs) and public-private partnerships (PPPs) in health governance. We argue that the ambiguity between the roles and responsibilities of public and private actors involved may downplay the role (and regulation) of conflicts of interest (COI) between unhealthy commodity industries and public health. We argue that this ambiguity is not simply an artefact of the Political Declaration process, but a feature of multi-stakeholderism, which assumes that commercial actors´ interests can be aligned with the public interest. To safeguard global health governance, we recommend further empirical and conceptual research on COI and how it can be managed.


Comparison of post-marketing surveillance approaches regarding infections related to tumor necrosis factor inhibitors (TNFi's) used in treatment of autoimmune diseases.
Objectives: To examine agreement between the FDA Adverse Event Reporting System (FAERS) and observational studies in common infections for tumor necrosis factor inhibitors (TNFi's). Methods: Using MedDRA® preferred terms, all infection cases in FAERS with each TNFi were retrieved using EvidexTM. Observational studies reporting TNFi-related infections were identified from PubMed (OS-PM) and ClinicalTrials.gov (OS-CT). Infections with a reporting rate of ≥2% (based on percentage of total number of infections) from each data source were compiled. Fleiss's kappa and Cohen's kappa (κ) were calculated to determine agreement across all three sources and between each two sources. Results: A total of 163,789 FAERS infection cases, 53 OS-PM studies and 52 OS-CT studies were identified. The Fleiss' kappa that comparing all 3 data sources demonstrated lack of agreement. Significant moderate agreements were found between FAERS and OS-CT for etanercept and adalimumab, respectively (κ = 0.53, p = 0.02; κ = 0.56, p = 0.02), but no agreements (κ < 0) when comparing FAERS vs. OS-PM or OS-CT vs. OS-PM. Conclusion: For common TNFi-related infections, passive (FAERS) and active (observational studies) pharmacovigilance results are similar between FAERS vs. OS-CT for etanercept and adalimumab but dissimilar across the 3 sources. Our findings suggest incorporating both active and passive pharmacovigilance methods in post-marketing drug safety assessment.


Microhabitat use, trophic patterns, and the evolution of brain structure in African cichlids.
The species assemblages of cichlids in the three largest African Great Lakes are among the richest concentrations of vertebrate species on earth. The faunas are broadly similar in terms of trophic diversity, species richness, rates of endemism, and taxonomic composition, yet they are historically independent of each other. Hence, they offer a true and unique evolutionary experiment to test hypotheses concerning the mutual dependencies of ecology and brain morphology. We examined the brains of 189 species of cichlids from the three large lakes: Victoria, Tanganyika, and Malawi. A first paper demonstrated that patterns of evolutionary change in cichlid brain morphology are similar across taxonomic boundaries as well as across the three lakes [van Staaden et al., 1995 ZACS 98: 165-178]. Here we report a close relationship between the relative sizes of various brain structures and variables related to the utilization of habitat and prey. Causality is difficult to assign in this context, nonetheless, prey size and agility, turbidity levels, depth, and substrate complexity are all highly predictive of variation in brain structure. Areas associated with primary sensory functions such as vision and taste relate significantly to differences in feeding habits. Turbidity and depth are closely associated with differences in eye size, and large eyes are associated with species that pick plankton from the water column. Piscivorous taxa and others that utilize motile prey are characterized by a well developed optic tectum and a large cerebellum compared to species that prey on molluscs or plants. Structures relating to taste are well developed in species feeding on benthos over muddy or sandy substrates. The data militated against the existence of compensatory changes in brain structure. Thus enhanced development of a particular function is generally not accompanied by a parallel reduction of structures related to other modalities. Although genetic and environmental influences during ontogeny of the brain cannot be isolated, this study provides a rich source of hypotheses concerning the way the nervous system functions under various environmental conditions and how it has responded to natural selection.


Comparison the post operative refractive errors in same size corneal transplantation through deep lamellar keratoplasty and penetrating keratoplasty methods after sutures removing in keratoconus patients.
Corneal transplantation is a surgery in which cornea is replaced by a donated one and can be completely penetrating keratoplasty (PK) or included a part of cornea deep lamellar keratoplasty (DLK). Although the functional results are limited by some complications, it is considered as one of the most successful surgeries. This study aimed to compare the refractive errors after same size corneal transplantation through DLK and PK methods in keratoconus patients over 20 years. This descriptive, analytical study was conducted in Feiz Hospital, Sadra and Persian Clinics of Isfahan in 2013-2014. In this study, 35 patients underwent corneal transplantation by PK and 35 patients by DLK, after removing the sutures, the patients were compared in terms of best corrected visual acuity (BCVA) and refractive errors. Data were analyzed using Chi-square and t Student tests by SPSS software. The BCVA mean in DLK and PK groups was 6/10 ± 2/10 and 5/10 ± 2/10, respectively, with no significant difference (P = 0.4). The results showed 9 cases of DLK and 6 cases of PK had normal (8/10 ≤ BCVA) visual acuity (25.7% vs. 17.1%), 24 cases of DLK and 27 cases of PK had mild vision impairment (68.6% vs. 77.1%) and 2 cases of the DLK group and 2 cases of PK had moderate vision impairment, (5.7% vs. 5.7%), there was no significant difference in "BCVA" (P = 0.83). Both methods were acceptably effective in improving BCVA, but according to previous articles (5,9,10) the DLK method due to fewer complications and less risk of rejection was superior to another method and in the absence of any prohibition this method is recommended.


National survey of sensory features in children with ASD: factor structure of the sensory experience questionnaire (3.0).
This national online survey study characterized sensory features in 1,307 children with autism spectrum disorder (ASD) ages 2-12 years using the Sensory Experiences Questionnaire Version 3.0 (SEQ-3.0). Using the SEQ-3.0, a confirmatory factor analytic model with four substantive factors of hypothesized sensory response patterns (i.e., hyporesponsiveness; hyperresponsiveness; sensory interests, repetitions and seeking behaviors; enhanced perception), five method factors of sensory modalities (i.e., auditory, visual, tactile, gustatory/olfactory, vestibular/proprioceptive), and one of social context were tested with good model fit. Child and family characteristics associated with the sensory response patterns were explored. The effect of sensory response patterns on autism severity was tested, controlling for key child and family characteristics. The SEQ-3.0 demonstrates an empirically valid factor structure specific to ASD that considers sensory response patterns, modalities, and social context.


Change in social ties and subsequent mortality in rural elders.
Prior studies assessing social ties and mortality risk in older persons have not considered the dynamic nature of social ties, health, and functional status in this age group. We evaluated the association between change in social ties (assessed in 1982 and 1985) and subsequent mortality through 1993 in a population-based cohort of 2,575 rural persons ages 65-102 years. The same summary measure of social ties was constructed for both interviews and included marital status, number of close friends and relatives, church attendance, and membership in a group. Compared with persons reporting higher levels of social ties at both interviews, a decrease to a low level of social ties was associated with an increased mortality risk for both men [hazard ratio (HR) = 1.8; 95% confidence interval (CI) = 1.2-2.7] and women (HR = 2.1; 95% CI = 1.5-3.0). Lower levels of social ties at both interviews were also associated with greater mortality risk in men (HR = 2.2: 95% CI = 1.5-3.1) and women (HR = 2.2; 95% CI = 1.6-2.9), whereas an increase to a higher level of social ties was not associated with subsequent mortality risk. Adjustment for age, education, smoking status, cognitive function, onset of a major illness, change in physical function, change in self-perceived health status, and change in depressive symptoms eliminated the association between loss of social ties and survival, but both men (HR = 2.3; 95% CI = 1.5-3.5) and women (HR = 1.8; 95% CI = 1.2-2.6) reporting low levels of social ties at both interviews remained at elevated risk. The lack of an association between loss of social ties and mortality risk after adjusting for demographic, health, and functional status variables indicates that these are either confounding or intervening variables in a social ties and mortality association. In contrast, sustained low levels of social ties appear to influence mortality risk independent of these same variables and imply that continued social isolation may be a more important determinant of mortality risk than recent changes in social ties.


Short-Term Homing of Hyaluronan-Primed Cells: Therapeutic Implications for Osteoarthritis Treatment.
The evaluation of key factors modulating cell homing following injection can provide new insights in the comprehension of unsolved biological questions about the use of cell therapies for osteoarthritis (OA). The main purpose of this in vivo study was to investigate the biodistribution of an intra-articular injection of mesenchymal stromal cells (MSCs) and bone marrow concentrate (BMC) in a rabbit OA model and whether the additional use of sodium hyaluronate (HA) could modulate their migration and delay joint degeneration. OA was surgically induced in adult male New Zealand rabbits. A group of animals was used to test the biodistribution of labeled cells alone or with HA at 7 and 14 days to investigate cell migration. The efficacy of treatments was evaluated in other experimental groups at 2 months. Histology and immunohistochemistry for markers identifying anabolic and catabolic processes in the cartilage and meniscus, or macrophage subset population in the synovial membrane, were performed. Kruskal-Wallis test, followed by post hoc Dunn's test, and Spearman's rank-order correlation method were used. MSCs and BMC preferentially migrate toward tissue areas showing OA features in the meniscus and cartilage and in detail near inflammatory zones in the synovial membrane. The combination with HA contributed to boost cell migration toward articular cartilage. In general, both labeled cells combined with HA were found near cell cluster and fissures in the cartilage and meniscus, respectively, and close to areas of synovial membrane showing mainly anti-inflammatory macrophages. A promotion of joint repair was observed at different levels for all treatments, although BMC-HA treatment resulted as the best strategy to support joint repair. This last, displayed a good protein expression of type II collagen in the cartilage, as well as the presence of anti-inflammatory macrophages in the synovial membrane at 2 months from the treatment. Studies tracking cell biodistribution indicate that priming progenitor cells with HA modulated cell homing favoring not only attachment but also their integration within articular cartilage.


Prevention of external ventricular drain--related ventriculitis.
The purpose of this study was to test if a reduction of external ventricular drains (EVD) related ventriculitis could be achieved by a strict protocol of care and if protocol violation was associated with a higher incidence of EVD-related ventriculitis. A written protocol for EVD insertion, nursing and surveillance was implemented. A retrospective comparison of EVD-related ventriculitis incidence was performed between control (161 EVD in 131 patients) and study periods (216 EVD in 175 patients). Risk factor analysis was performed in patients in whom an EVD was inserted during the study period including the relationship between protocol compliance and ventriculitis. A score for the number of protocol violations (absence of hair clipping, absence of a tunnelled EVD, absence of shampooing, incorrect dressing change, inappropriate CSF bag or tap samplings and EVD manipulation) was established for each patient. Incidence of patient-related ventriculitis decreased from 12.2% (1999) down to 5.7% (p<0.05) as well as incidence of EVD-related ventriculitis (9.9% vs 4.6%, p<0.05). During the study period, the only statistically significant risk factors for infection were CSF leak and protocol violations. The mean protocol violation score was 4 times higher in the infected versus the non-infected patients (p<0.0001). Patients with a violation score of 0 or 1 had no infection (EVD duration 2 to 42 days). EVD can be left safely, as long as needed, provided that meticulous care is taken for EVD insertion and nursing. EVD duration seems to have no effect on infection incidence.


Adolescent psychosocial maturity and alcohol use: quantitative and qualitative analysis of longitudinal data.
Based on a psyschosocial developmental framework, this study used a mixed model design, including both quantitative and qualitative methods, to examine the relationship between adolescents' psychosocial maturity and their alcohol use. A sample of 1,198 10th-grade students (51% female) was surveyed and followed up two years later. Both concurrent and longitudinal findings indicated that the more psychosocially mature adolescents were less likely to drink heavily than those who showed less maturity. At age 15 this relationship was even stronger for those whose peers also drank. Further, at age 17, this linear relationship was more pronounced for those who drank less heavily at age 15. Of the three psychosocial competencies examined, the construct of personal meaning was more strongly related to adolescent alcohol use than were the constructs of interpersonal understanding and interpersonal skills. To illustrate this construct, two of the adolescents were interviewed, a girl and a boy, individually at the end of both school years. Thematic and developmental analyses of the interviews revealed individual variations in how the adolescents made meaning of their drinking; these encourage speculations that go beyond the general pattern found in the study.