Study of warm ischemia followed by reperfusion on a lower limb model in rats: effect of allopurinol and streptokinase.
Prolonged tissue ischemia leads to changes in microcirculation and production of oxygen free radicals. The event eventually responsible for tissue death is the no-reflow phenomenon and its management is a challenge for the surgeon dealing with replantation or transplantation. We introduce a model of warm ischemia and reperfusion of the lower limb of rats with which we studied the effect of allopurinol and streptokinase. Section of the lower limb with preservation of vessels and nerves was performed in 110 rats. Femoral vessels clamped for periods of 0, 2, 4, 6, and 8 hours of ischemia were allowed to reperfuse (groups M0, M2, M4, M6, and M8 respectively). Other groups, E1, E2, and E3, received streptokinase, allopurinol, or a combination of the two drugs after 6 hours of ischemia. Viability rates of the ischemic limbs after 7 days were 100% (M0), 80% (M2), 63.6% (M4), 50% (M6), and 20% (M8). In the experimental groups, E1, E2, and E3, viability rates were 67% (E1), 70% (E2), and 70% (E3). Groups M0, M2, M4, M6, and M8 differed among themselves except for groups M4 and M6. Group E1 had a higher rate of limb viability than M6 (control group) but not than M4. Groups E1, E2 and E3 had higher rates of limb viability than M6 but not than M2 or M4. The results suggest that increased viability of limbs after 6 hours of ischemia occurs when allopurinol or streptokinase is used. The combination of the two drugs does not appear to produce any additional effect.


The significance of multiple, recurrent, and "complex" cardiac myxomas.
We reviewed the Mayo Clinic records of 56 patients who underwent operation for cardiac myxoma and 29 cases in which cardiac myxoma was found at autopsy. Five patients had a "complex" of unusual findings including multiple pigmented skin lesions (lentiginosis), myxoid fibroadenomas of the breast, skin myxomas, and primary pigmented nodular adrenocortical disease (a cause of Cushing's syndrome). Four of these five patients had multiple cardiac myxomas. Three of the four patients who underwent surgical excision of the cardiac myxomas had recurrent myxomas (the only recurrences in our series), and one of these patients had a second recurrence. The occurrence of multiple and recurrent myxomas in patients with the complex was significantly (p less than 0.001) higher than in our 80 patients with sporadic myxomas. The world literature was searched for cases of cardiac myxomas with the unusual associations of the complex, and also for familial, multiple, and recurrent myxomas. A group of patients were identified who had unusual biologic behavior including early development of myxomas, atypical myxoma locations, and a high risk for the development of recurrent myxomas. For these patients, we recommend a thorough search for multiple tumors at operation, close postoperative follow-up, and careful screening of family members.


Janet M. Corrigan, Ph.D.. Interview by Marie E. Sinioris.
The ability of health care purchasers and consumers to make objective evaluations and comparisons of health plan performance is a critical element in achieving competition based on quality and value. The Health Plan Employer Data and Information Set, commonly referred to as HEDIS 2.0, is a step toward making such evaluations and comparisons possible. To get an inside perspective on HEDIS and its implications for health care, QMHC interviewed Janet Corrigan, Ph.D., Vice President, Planning and Development, National Committee for Quality Assurance (NCQA). Dr. Corrigan is in charge of NCQA's efforts to implement and continually improve HEDIS.


Impact of nonionizing electromagnetic radiation on male infertility: an assessment of the mechanism and consequences.
Environment and lifestyle factors are being attributed toward increased instances of male infertility. Rapid technological advancement, results in emission of electromagnetic radiations of different frequency which impacts human both biologically as well as genetically. Devices like cell phone, power line and monitors emit electromagnetic radiation and are a major source of the exposure. Numerous studies describe the detrimental consequence of radiation on physiological parameters of male reproductive system including sperm parameters (morphology, motility, and viability), metabolism and genomic instability. While the thermal and nonthermal interaction of nonionizing radiations with biological tissues can't be ruled out, most studies emphasize the generation of reactive oxygen species. Oxidative stress alters redox equilibrium and disrupts morphology and normal functioning of sperms along with declination of total anti-oxidant capacity. In this paper, we describe a detailed literature review with the intent of analyzing the impact of electromagnetic radiation and understand the consequence on male reproductive system. The underlying mechanism suggesting ROS generation and pathway of action has also been discussed. Additionally, the safety measures while using electronic gadgets and mobile phones has also been presented.


Limitations to the 6-minute walk test in interstitial lung disease and pulmonary hypertension in scleroderma.
To determine factors that influence 6-minute walk distance (6MWD) in patients with scleroderma (systemic sclerosis, SSc)-interstitial lung disease (ILD), SSc-pulmonary hypertension (PH), and idiopathic pulmonary fibrosis (IPF). We retrospectively evaluated all patients with SSc or IPF who performed a 6-minute walk test (6MWT) at a university hospital between 1999 and 2003. Chi-square, ANOVA, simple linear regression, and backwards elimination multivariable regressions were performed. Forty-eight consecutive IPF patients with 6MWT were compared to 33 patients with SSc-ILD, 13 with SSc-PH, 19 with both SSc-ILD and SSc-PH (SSc-Both), and 15 with SSc without ILD or PH (SSc-Neither). Mean 6MWD did not differ between groups. Limitations to 6MWT trended toward dyspnea in IPF and lower extremity pain in SSc. SSc-Both had dyspnea limitation more than other SSc subgroups (p = 0.017). Percentage predicted forced vital capacity (FVC%) and percentage predicted carbon monoxide diffusing capacity (DLCO%) were more strongly predictive of 6MWD in IPF than in SSc; however, exclusion of SSc subjects with pain limitation improved the predictive value. Significant correlates of 6MWD in multivariable analysis differed between subgroups. Pain limitations confound the utility of the 6MWT, particularly in SSc. Pain may cause failure to reach a dyspnea limitation during 6MWT, especially in SSc patients without both ILD and PH. Correlates of 6MWD differ between SSc subgroups and IPF; therefore, the 6MWT distance is not always reflective of the same physiological process. 6MWT interpretation should include consideration of vascular, pulmonary, and musculoskeletal exercise limitations.


Shoulder hemiarthroplasty with concentric glenoid reaming in patients 55 years old or less.
Glenohumeral arthritis in younger individuals is challenging because of the complex pathology, need for extended durability, and high expectations of the patients. Humeral hemiarthroplasty combined with concentric glenoid reaming is a surgical option for the management of glenohumeral arthritis that avoids the risks of glenoid component failure and avoids the challenges of tissue interposition. The results of this procedure in young patients have not been previously reported. Sixty-five shoulders in patients who were 55 years old or less at the time of surgery underwent humeral hemiarthroplasty combined with concentric glenoid reaming and were followed for a minimum of 2 years or until the time of revision surgery. Patient self-assessments of shoulder comfort and function were compared before and after surgery. For 22 of these shoulders, standardized radiographs were available for follow-up evaluation. Nine shoulders required revision surgery. These shoulders had 3 ± 3 prior surgeries, in comparison to 1 ± 1 prior surgeries for the unrevised group. For the 56 unrevised shoulders, the number of Simple Shoulder Test functions that could be performed improved from a mean of 4.1 before surgery to a mean of 9.5 at an average follow-up of 43 months (range, 24-85) (P < .001). For the 22 shoulders with radiographic follow-up, medial glenoid erosion averaged 1.1 mm (range, 0.0-6.3 mm) at an average of 44 months after the procedure. In selected patients 55 years or younger with glenohumeral arthritis, this procedure can provide significant improvement in self-assessed shoulder comfort and function.


An information management system for patients with tuberculosis: usability assessment with end-users.
Information systems with clinical decision support (CDS) offer great potential to assist the co-ordination of patients with chronic diseases and to improve patient care. Despite this, few have entered routine clinical use. Tuberculosis (TB) is an infection of public health importance. It has complex interactions with many comorbid conditions, requires close supervised care and prolonged treatment for effective cure. These features make it suitable for use with an information management system with CDS features. In close consultation with key stakeholders, a clinical application was developed for the management of TB patients in Victoria. A formal usability assessment using semi-structured case-scenario based exercises was performed. Subjects were 12 individuals closely involved in the care of TB patients, including Infectious Diseases and Respiratory Physicians, and Public Health Nurses. Two researchers conducted the sessions, independently analysed responses and discrepancies compared to the voice record for validity. Despite varied computer experience, responses were positive regarding user interface and content. Data location was not always intuitive, however this improved with familiarity of the program. Decision support was considered valuable, with useful suggestions for expansion of these features. Automated reporting for correspondence and notification to the Health Department were felt worth the initial investment in data entry. An important workflow-based issue regarding dismissal of alerts and several errors were detected. Usability assessment validated many design elements of the system, provided a unique insight into workflow issues faced by users and hopefully will impact on its ultimate clinical utility.


Zone 1 Endovascular Balloon Occlusion of the Aorta vs Resuscitative Thoracotomy for Patient Resuscitation After Severe Hemorrhagic Shock.
Aortic occlusion (AO) is a lifesaving therapy for the treatment of severe traumatic hemorrhagic shock; however, there remains controversy whether AO should be accomplished via resuscitative thoracotomy (RT) or via endovascular balloon occlusion of the aorta (REBOA) in zone 1. To compare outcomes of AO via RT vs REBOA zone 1. This was a comparative effectiveness research study using a multicenter registry of postinjury AO from October 2013 to September 2021. AO via REBOA zone 1 (above celiac artery) was compared with RT performed in the emergency department of facilities experienced in both procedures and documented in the prospective multicenter Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery (AORTA) registry. Propensity score matching (PSM) with exact institution matching was used, in addition to subgroup multivariate analysis to control for confounders. The study setting included the ED, where AO via RT or REBOA was performed, and participants were adult trauma patients 16 years or older. AO via REBOA zone 1 vs RT. The primary outcome was survival. Secondary outcomes were ventilation-free days (VFDs), intensive care unit (ICU)-free days, discharge Glasgow Coma Scale score, and Glasgow Outcome Score (GOS). A total of 991 patients (median [IQR] age, 32 [25-48] years; 808 male individuals [81.9%]) with a median (IQR) Injury Severity Score of 29 (18-50) were included. Of the total participants, 306 (30.9%) had AO via REBOA zone 1, and 685 (69.1%) had AO via RT. PSM selected 112 comparable patients (56 pairs). REBOA zone 1 was associated with a statistically significant lower mortality compared with RT (78.6% [44] vs 92.9% [52]; P = .03). There were no significant differences in VFD greater than 0 (REBOA, 18.5% [10] vs RT, 7.1% [4]; P = .07), ICU-free days greater than 0 (REBOA, 18.2% [10] vs RT, 7.1% [4]; P = .08), or discharge GOS of 5 or more (REBOA, 7.5% [4] vs RT, 3.6% [2]; P = .38). Multivariate analysis confirmed the survival benefit of REBOA zone 1 after adjustment for significant confounders (relative risk [RR], 1.25; 95% CI, 1.15-1.36). In all subgroup analyses (cardiopulmonary resuscitation on arrival, traumatic brain injury, chest injury, pelvic injury, blunt/penetrating mechanism, systolic blood pressure ≤60 mm Hg on AO initiation), REBOA zone 1 offered an either similar or superior survival. Results of this comparative effectiveness research suggest that REBOA zone 1 provided better or similar survival than RT for patients requiring AO postinjury. These findings provide the ethically necessary equipoise between these therapeutic approaches to allow the planning of a randomized controlled trial to establish the safety and effectiveness of REBOA zone 1 for AO in trauma resuscitation.


Macroevolutionary Origin and Adaptive Function of a Polymorphic Female Signal Involved in Sexual Conflict.
Intersexual signals that reveal developmental or mating status in females have evolved repeatedly in many animal lineages. Such signals have functions in sexual conflict over mating and can therefore influence sexually antagonistic coevolution. However, we know little about how female signal development modifies male mating harassment and thereby sexual conflict. Here, we combine phylogenetic comparative analyses of a color polymorphic damselfly genus (Ischnura) with behavioral experiments in one target species to investigate the evolutionary origin and current adaptive function of a developmental female color signal. Many Ischnura species have multiple female color morphs, which include a male-colored morph (male mimics) and one or two female morphs that differ markedly from males (heterochrome females). In Ischnura elegans, males and male-mimicking females express a blue abdominal patch throughout postemergence life. Using phenotypic manipulations, we show that the developmental expression of this signaling trait in heterochrome females reduces premating harassment prior to sexual maturity. Across species this signal evolved repeatedly, but in heterochrome females its origin is contingent on the signal expressed by co-occurring male-mimicking females. Our results suggest that the co-option of a male-like trait to a novel female antiharassment function plays a key role in sexual conflict driven by premating interactions.


Total clinical laboratory test volume in Connecticut, 1994-1995.
To measure the volume of clinical laboratory testing in Connecticut during a one-year period. To explore the potential value of such data. Summary and analysis of federal and state clinical laboratory registration/licensure/inspection forms. 2,333 clinical laboratory test facilities registered in Connecticut. The total clinical laboratory output for Connecticut by type of facility and category of technology over a 12-month period. During 1995, 2,333 registered clinical laboratory test facilities performed approximately 65,427,103 analyses in Connecticut. This represents approximately 20 tests per person per year. Thirty-five acute care hospitals performed 59.4%, nine large commercial laboratories 33.2%, 30 small commercial laboratories 1.7%, 1,491 physicians' offices 3.9%, and a miscellaneous group 1% of the tests. Test volumes are further segregated into eight major categories of technology: chemistry 59%, hematology 23.3%, microbiology 5.6%, blood banking 2.9%, coagulation 2.8%, waived tests 2.7%, urine analysis 1.8%, cytology 0.9%, and histology 0.8%. For the first time mechanisms are in place to measure essentially all clinical testing for a given area. With minor changes the data collection system could be greatly improved. The possible uses for such a data bank are discussed.


Bacterial Vector-Borne Plant Diseases: Unanswered Questions and Future Directions.
Vector-borne plant diseases have significant ecological and economic impacts, affecting farm profitability and forest composition throughout the world. Bacterial vector-borne pathogens have evolved sophisticated strategies to interact with their hemipteran insect vectors and plant hosts. These pathogens reside in plant vascular tissue, and their study represents an excellent opportunity to uncover novel biological mechanisms regulating intracellular pathogenesis and to contribute to the control of some of the world's most invasive emerging diseases. In this perspective, we highlight recent advances and major unanswered questions in the realm of bacterial vector-borne disease, focusing on liberibacters, phytoplasmas, spiroplasmas, and Xylella fastidiosa.


IL-37 exerts therapeutic effects in experimental autoimmune encephalomyelitis through the receptor complex IL-1R5/IL-1R8.
Background: Interleukin 37 (IL-37), a member of IL-1 family, broadly suppresses inflammation in many pathological conditions by acting as a dual-function cytokine in that IL-37 signals via the extracellular receptor complex IL1-R5/IL-1R8, but it can also translocate to the nucleus. However, whether IL-37 exerts beneficial actions in neuroinflammatory diseases, such as multiple sclerosis, remains to be elucidated. Thus, the goals of the present study were to evaluate the therapeutic effects of IL-37 in a mouse model of multiple sclerosis, and if so, whether this is mediated via the extracellular receptor complex IL-1R5/IL-1R8. Methods: We used a murine model of MS, the experimental autoimmune encephalomyelitis (EAE). We induced EAE in three different single and double transgenic mice (hIL-37tg, IL-1R8 KO, hIL-37tg-IL-1R8 KO) and wild type littermates. We also induced EAE in C57Bl/6 mice and treated them with various forms of recombinant human IL-37 protein. Functional and histological techniques were used to assess locomotor deficits and demyelination. Luminex and flow cytometry analysis were done to assess the protein levels of pro-inflammatory cytokines and different immune cell populations, respectively. qPCRs were done to assess the expression of IL-37, IL-1R5 and IL-1R8 in the spinal cord of EAE, and in blood peripheral mononuclear cells and brain tissue samples of MS patients. Results: We demonstrate that IL-37 reduces inflammation and protects against neurological deficits and myelin loss in EAE mice by acting via IL1-R5/IL1-R8. We also reveal that administration of recombinant human IL-37 exerts therapeutic actions in EAE mice. We finally show that IL-37 transcripts are not up-regulated in peripheral blood mononuclear cells and in brain lesions of MS patients, despite the IL-1R5/IL-1R8 receptor complex is expressed. Conclusions: This study presents novel data indicating that IL-37 exerts therapeutic effects in EAE by acting through the extracellular receptor complex IL-1R5/IL-1R8, and that this protective physiological mechanism is defective in MS individuals. IL-37 may therefore represent a novel therapeutic avenue for the treatment of MS with great promising potential.


[The practice guideline 'Anxiety disorders' (first revision) from the Dutch College of General Practitioners; a response from the perspective of general practice].
The recommendations provided by the revised guideline 'Anxiety disorders' are well suited to every-day practice. The multidisciplinary approach reflects the increasing cooperation between primary and secondary care in the management of mental-health problems. The description of the various anxiety disorders and the questions that can be asked to elicit the symptoms will facilitate recognition. The indications for treatment with medication are clear: a limited number of antidepressants should be used. Although it is agreed that patient education is an important part of treatment, the guidelines could have described in more detail how this should be done. Cognitive-behavioural techniques may be used but this requires extra training; its effectiveness when used by general practitioners needs further study. This guideline will add to existing knowledge and improve the skills of general practitioners in dealing with anxiety.


Smartphone keyboard dynamics predict affect in suicidal ideation.
While digital phenotyping provides opportunities for unobtrusive, real-time mental health assessments, the integration of its modalities is not trivial due to high dimensionalities and discrepancies in sampling frequencies. We provide an integrated pipeline that solves these issues by transforming all modalities to the same time unit, applying temporal independent component analysis (ICA) to high-dimensional modalities, and fusing the modalities with linear mixed-effects models. We applied our approach to integrate high-quality, daily self-report data with BiAffect keyboard dynamics derived from a clinical suicidality sample of mental health outpatients. Applying the ICA to the self-report data (104 participants, 5712 days of data) revealed components related to well-being, anhedonia, and irritability and social dysfunction. Mixed-effects models (55 participants, 1794 days) showed that less phone movement while typing was associated with more anhedonia (β = -0.12, p = 0.00030). We consider this method to be widely applicable to dense, longitudinal digital phenotyping data.


"If you and I, if we, in this later day, lose that sacred fire . . .": perspective in political interviews.
It is argued in the following that the dialogical complexity of speaker perspective requires a broad empirical analysis. To date, such analyses, particularly of political discourse, have been couched in terms of narrower concepts, such as self-presentation and political positioning or involvement/distancing, and have been typically carried out by means of qualitative methods applied to pronominal usage. The present research applies complementarily both quantitative and qualitative analyses to BBC television interviews of Shimon Peres (January 29, 2001) and of Edward Said (October 18, 2000) by Tim Sebastian in a program entitled HARDtalk. In addition to pronouns, these analyses include a number of other hypothetical indicators of a broad concept of perspective on the part of both interviewer and interviewees: turn-initial words, hesitations, questions, use of yes and no, personal reference utterances (e.g., I think), interjections, number of syllables spoken, and interruptions and overlaps. Quantitative comparisons of interviewer with interviewee revealed important differences on all these measures. Qualitative analyses also confirmed subtle local dynamics of perspective. Accordingly, the findings are interpreted within a general theoretical concept of perspective, derived from Bakhtin's (1981) dialogicity.


Is there a risk of seizures in "preventive" awake surgery for incidental diffuse low-grade gliomas?
Although a large amount of data supports resection for symptomatic diffuse low-grade glioma (LGG), the therapeutic strategy regarding incidental LGG (ILGG) is still a matter of debate. Indeed, early "preventive" surgery has recently been proposed in asymptomatic patients with LGG, after showing that the extent of resection was larger than in symptomatic patients with LGG. However, the quality of life should be preserved by avoiding both neurological deficit and epilepsy. The aim of this study was to determine the risk of seizures related to such a prophylactic surgical treatment in ILGG. The authors report a prospective series of 21 patients with ILGG who underwent awake surgery with a minimum follow-up of 20 months following resection. Data regarding clinicoradiological features, surgical procedures, and outcomes were collected and analyzed. In particular, the eventual occurrence and type of seizures in the intra- and postoperative periods were studied, as follows: early (< 3 months) and long-term (until last follow-up) periods. There were no intraoperative seizures in this series. During the early postoperative period, the authors observed only a single episode of partial seizures in a patient with no antiepileptic drug (AED) prophylaxis-all other patients were given antiepileptic treatment following resection. The AEDs were discontinued in all cases, with a mean delay of 8 months after surgery (range 3-24 months). No patient had permanent neurological deficits. All 21 patients returned to an active familial, social, and professional life (working full time in all cases). Total or even "supratotal" resection (the latter meaning that a margin around the tumor visible on FLAIR-weighted MRI was removed) was achieved in 14 cases (67%). In 7 patients (33%) subtotal resection was performed, with a mean residual tumor volume of 1.5 ml (range 1-7 ml). No oncological treatment was administered in the postsurgical period. The mean follow-up after surgery was 49 months (range 20-181 months). Only 2 patients had seizures during the long-term follow-up. Indeed, due to tumor progression after incomplete resection, seizures occurred in 2 cases, 39 and 78 months postsurgery, leading to administration of AEDs and adjuvant treatment. So far, all patients are still alive and enjoy a normal life. The risk of inducing seizures is very low in ILGG, and it does not represent an argument against early surgery. These data strongly support the proposal of a screening policy for LGG that will evolve toward a preventive treatment in a more systematic manner.


Fetal bradyarrhythmia associated with congenital heart defects - nationwide survey in Japan.
Because there is limited information on fetal bradyarrhythmia associated with congenital heart defects (CHD), we investigated its prognosis and risk factors. In our previous nationwide survey of fetal bradyarrhythmia from 2002 to 2008, 38 fetuses had associated CHD. Detailed clinical data were collected from secondary questionnaires on 29 fetuses from 18 institutions, and were analyzed. The 29 fetuses included 22 with isomerism, 4 with corrected transposition of the great arteries (TGA) and 3 with critical pulmonary stenosis; 14 had complete atrioventricular block (AVB), 8 had second-degree AVB, and 16 had sick sinus syndrome; 5 died before birth, and 10 died after birth (5 in the neonatal period). Neonatal and overall survival rates for fetal bradyarrhythmia with CHD were 66% and 48%, respectively. Pacemaker implantation was needed in 17 cases (89%). Beta-sympathomimetics were administered in utero in 13 cases and were effective in 6, but were not associated with prognosis. All cases of corrected TGA or ventricular rate ≥70 beats/min survived. A ventricular rate <55 beats/min had significant effects on fetal myocardial dysfunction (P=0.02) and fetal hydrops (P=0.04), resulting in high mortality. The prognosis of fetal bradyarrhythmia with CHD is still poor. The type of CHD, fetal myocardial dysfunction, and fetal hydrops were associated with a poor prognosis, depending on the ventricular rate.


Differential in vitro effects of chemotherapeutic agents on primary cultures of human ovarian carcinoma.
The treatment of ovarian cancer principally relies on the use of platinum and taxane chemotherapeutic agents. Short-term clinical results have been encouraging, but long-term responses remain limited. In this report, an in vitro assay system that utilizes cells grown from human tumor explants has been used to quantitatively evaluate responses to relevant concentrations of alternative chemotherapeutic agents. The results suggest that there are significant differences in the responses of explant-derived cultured cells to the different agents tested. In an evaluation of 276 primary ovarian cancer specimens, five nonstandard drugs were tested in 51 cases. Of these 51 cases, cyclophosphamide had the highest rate of response at 67%, followed by doxorubicin at 61%, gemcitabine at 49%, etoposide at 48%, and topotecan at 14%. Venn diagrams, representing the in vitro responses to the platins and taxanes, as well as the responses to the nonstandard drugs, illustrate that there clearly are distinct differences among patients in a given population. These data underscore the potential importance of evaluating each patient's response to a number of different drugs to optimize the therapeutic decision-making process.


Proliferating trichilemmal cysts of the scalp on CT.
Proliferating trichilemmal cysts, also known as pilar tumors, are slow-growing lobulated masses most commonly found on the scalp of elderly women. We present the case of a 69-year-old woman with a 25-year history of multiple enlarging scalp masses. The patient was evaluated for surgical consultation after the dominant mass presented with malignant degeneration. A CT of the head revealed multiple large, subcutaneous, cystic masses with calcifications.


GP37 expression in normal and diseased human epidermis: a marker for keratinocyte differentiation.
An antiserum prepared against a glycoprotein (GP37) extracted from the upper epidermal layers, was used to stain frozen sections of human oral mucosa, normal and abnormal skin by an indirect immunofluorescence technique. On normal human epidermis, this antiserum mainly reacted with the cytoplasm of granular cells, whereas on buccal mucosa the recognized antigen was observed as scattered dots limited to the upper epithelial layers. In epidermal diseases, alterations in the staining pattern were observed. In psoriasis, the labelling was markedly diminished; in contrast, in lichen planus it was intense and present on the 3-6 uppermost cellular layers. Basal cell epitheliomas were almost negative, except around horn cysts. In Bowen's disease dyskeratotic cells were strongly labelled. In squamous cell carcinomas a clear-cut staining was observed in squamous nests. On cultures, GP37 expression could be induced by growing epidermal cells in vitamin A-depleted medium. The biological significance of the observed staining patterns remains to be precised. Nevertheless, GP37 represents a sensitive marker of epidermal differentiation and may be useful in skin pathology and in in vitro studies.


Using the Redundant Convolutional Encoder-Decoder to Denoise QRS Complexes in ECG Signals Recorded with an Armband Wearable Device.
Long-term electrocardiogram (ECG) recordings while performing normal daily routines are often corrupted with motion artifacts, which in turn, can result in the incorrect calculation of heart rates. Heart rates are important clinical information, as they can be used for analysis of heart-rate variability and detection of cardiac arrhythmias. In this study, we present an algorithm for denoising ECG signals acquired with a wearable armband device. The armband was worn on the upper left arm by one male participant, and we simultaneously recorded three ECG channels for 24 h. We extracted 10-s sequences from armband recordings corrupted with added noise and motion artifacts. Denoising was performed using the redundant convolutional encoder-decoder (R-CED), a fully convolutional network. We measured the performance by detecting R-peaks in clean, noisy, and denoised sequences and by calculating signal quality indices: signal-to-noise ratio (SNR), ratio of power, and cross-correlation with respect to the clean sequences. The percent of correctly detected R-peaks in denoised sequences was higher than in sequences corrupted with either added noise (70-100% vs. 34-97%) or motion artifacts (91.86% vs. 61.16%). There was notable improvement in SNR values after denoising for signals with noise added (7-19 dB), and when sequences were corrupted with motion artifacts (0.39 dB). The ratio of power for noisy sequences was significantly lower when compared to both clean and denoised sequences. Similarly, cross-correlation between noisy and clean sequences was significantly lower than between denoised and clean sequences. Moreover, we tested our denoising algorithm on 60-s sequences extracted from recordings from the Massachusetts Institute of Technology-Beth Israel Hospital (MIT-BIH) arrhythmia database and obtained improvement in SNR values of 7.08 ± 0.25 dB (mean ± standard deviation (sd)). These results from a diverse set of data suggest that the proposed denoising algorithm improves the quality of the signal and can potentially be applied to most ECG measurement devices.


Analysis of cervical smears in a Muslim population.
Screening for cancer of the cervix remains a neglected health care issue in Pakistan. To provide baseline data for future efforts to improve screening, we conducted a retrospective analysis of cervical smears taken in the obstetrics and gynaecological clinics of the Aga Khan University Hospital, Karachi, Pakistan. We collected data on cervical smear cytology for cervical smears taken from January 1, 1990 to December 31, 1996. We assessed risk factors for dysplasia, including age, age at first marriage, and number of pregnancies. The overall prevalence of abnormal smears in our study was 0.5%. Of 20,995 cervical smears, 12,451 (59.3%) smears showed non-specific inflammation, 7302 (34.8%) were reported as normal, 809 (3.85%) showed monillial infection, 148 (0.71%) showed atypia, 105 (0.5%) had dysplastic cytology, and 52 (0.25%) samples were inadequate. The highest incidence of dysplastic smears was seen in the age group 35 to 44 years. Of 105 patients with dysplasia, 12 were pregnant, and all were asymptomatic, while in 93 non-pregnant women, 33 were symptomatic. The low prevalence of abnormal smears, compared with data from Western populations, could be due to the inherent bias of health awareness in the women who attended our hospital. The results of this study may serve as a baseline for future comparisons. A larger community-based study may establish the exact prevalence of malignant and premalignant lesions so as to plan for future screening.


Long-term Functional and Oncologic Outcomes of Partial Adrenalectomy for Pheochromocytoma.
To evaluate the recurrence and functional outcomes in a primarily hereditary cohort of patients undergoing partial adrenalectomy for pheochromocytoma. A retrospective review from a prospectively managed database of patients undergoing partial adrenalectomy from 1995 to 2018 at the National Cancer Institute was performed. Local recurrence was defined as imaging evidence of a recurrent or de novo lesion on the operative side. Steroid dependency was defined as requiring daily steroid replacement at time of last follow-up. One hundred and twenty-four partial adrenalectomies, removing 162 tumors, were performed in 107 patients. Most patients had a known hereditary predisposition to develop bilateral, multifocal, and recurrent pheochromocytoma. Median tumor size was 2 cm (interquartile range (IQR) 1.5-2.8). Median follow-up was 60 months (IQR 13-131). Local recurrence occurred in 17 patients (15.8%) and were managed with active surveillance or surgery. A single patient (1/106, 0.9%) developed metastatic spread of pheochromocytoma approximately 14 years after his first of 2 partial adrenalectomies and remains alive under active surveillance. Median time to recurrence was 71 months (IQR 26-127) with 10 patients (9.3%) requiring daily steroid replacement at time of last follow-up. Partial adrenalectomy offers excellent oncologic and functional outcomes, sparing most patients from lifelong steroid replacement therapy. Recurrences can be easily managed with repeat surgery or active surveillance via functional work-up and imaging. Partial adrenalectomy remains the recommended surgical management for patients pre-disposed to development of bilateral, multifocal and recurrent pheochromocytoma.


Null mutation of c-fos causes exacerbation of methamphetamine-induced neurotoxicity.
Methamphetamine neurotoxicity has been demonstrated in rodents and nonhuman primates. These neurotoxic effects may be associated with mechanisms involved in oxidative stress and the activation of immediate early genes (IEG). It is not clear, however, whether these IEG responses are involved in a methamphetamine-induced toxic cascade or in protective mechanisms against the deleterious effects of the drug. As a first step toward clarifying this issue further, the present study was thus undertaken to assess the toxic effects of methamphetamine in heterozygous and homozygous c-fos knock-out as well as wild-type mice. Administration of methamphetamine caused significant reduction in [(125)I]RTI-121-labeled dopamine uptake sites, dopamine transporter protein, and tyrosine hydroxylase-like immunohistochemistry in the striata of wild-type mice. These decreases were significantly exacerbated in heterozygous and homozygous c-fos knock-out mice, with the homozygous showing greater loss of striatal dopaminergic markers. Moreover, in comparison with wild-type animals, both genotypes of c-fos knock-out mice showed more DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled nondopaminergic cells in their cortices and striata. In contrast, wild-type mice treated with methamphetamine demonstrated a greater number of glial fibrillary acidic protein-positive cells than did c-fos knock-out mice. These data suggest that c-fos induction in response to toxic doses of methamphetamine might be involved in protective mechanisms against this drug-induced neurotoxicity.


Developing and implementing innovative public safety programs for healthcare.
Opportunities in hospital security for improving performance and enhancing recognition through a highly professional public safety team exist in a number of areas. In this article, the author reviews 33 innovative programs introduced in a seven-year period for a leading health system.


The increasing prevalence of obesity in New Zealand: is it related to recent trends in smoking and physical activity?
To describe recent trends in body mass in Auckland, and to determine whether associated changes in cigarette smoking and physical activity could explain these trends. Risk factors for coronary heart disease were measured in three age-stratified random samples of Europeans aged 35-64 years using a standard protocol in 1982, 1986-8 and 1993-4. Body mass index (BMI) was calculated as weight in kg/(height in m2), with overweight or obese being defined as BMI>25. Results. The age-standardised mean BMI increased from 26.6 (25.4-25.8) to 26.4 (26.2-26.7) in men and from 24.6 (24.2-24.9) to 25.1 (24.8-25.5) in women between 1982 and 1993-4. The prevalence of overweight and obese people increased from 52.8% (48.1-57.7) to 64.2% (58.1-70.3) in men and from 36.5% (31.5-41.5) to 44.9% (39.7-50.1) in women. Self reported cigarette smoking declined between 1982 and 1993-94 with an associated increase in the prevalence of ex-smokers. The change in smoking status accounted for only 7% and 10% of the observed increase in BMI in men and women respectively. Most of the observed change in BMI was due to a general increase in BMI in all smoking categories in both sexes. The prevalence o leisure time physical activity increased in both sexes between 1986-88 and 1993-94 while work physical activity decreased. The change in physical activity should have decreased mean BMI by approximately 4% in men and 14% in women. As with smoking there was a trend towards increasing mean BMI irrespective of the activity undertaken. Recent trends in smoking cessation explain only a small percentage of the increase in body mass while the trends in physical activity would have predicted a small decrease in the prevalence of obesity, contrary to the observed trends. By exclusion, an increase in total energy intake, is the most likely explanation for the observed trends.


Sudden death due to subarachnoid haemorrhage in an infant with autosomal dominant polycystic kidney disease.
Intracranial aneurysm rupture is the most serious and potentially lethal extra-renal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Almost all cases of ruptured intracranial aneurysm occur in adult patients with a median age of rupture of 40 years. We report the occurrence of sudden death in a newborn infant born to a mother with typical ADPKD in the first week of life. Post-mortem examination revealed the cause of death to be subarachnoid haemorrhage with focal glomerular and tubular cysts detected in the kidney. This is the earliest reported case of intracranial aneurysm rupture in ADPKD and should raise awareness of this rare but lethal complication in younger patients.


Run-in periods in randomized trials: implications for the application of results in clinical practice.
Prerandomization run-in periods are being used to select or exclude patients in an increasing number of clinical trials, but the implications of run-in periods for interpreting the results of clinical trials and applying these results in clinical practice have not been systematically examined. We analyzed illustrative examples of reports of clinical trials in which run-in periods were used to exclude noncompliant subjects, placebo responders, or subjects who could not tolerate or did not respond to active drug. The Physicians' Health Study exemplifies the use of a prerandomization run-in period to exclude subjects who are nonadherent, while recent trials of tacrine for Alzheimer disease and carvedilol for congestive heart failure typify the use of run-in periods to exclude patients who do not tolerate or do not respond to the study drug. The reported results of these studies are valid. However, because the reported results apply to subgroups of patients who cannot be defined readily based on demographic or clinical characteristics, the applicability of the results in clinical practice is diluted. Compared with results that would have been observed without the run-in period, the reported results overestimate the benefits and underestimate the risks of treatment, underestimate the number needed to treat, and yield a smaller P value. The Cardiac Arrhythmia Suppression Trial exemplifies the use of an active-drug run-in period that enhances clinical applicability by selecting a group of study subjects who closely resembled patients undergoing active clinical management for this problem. Run-in periods can dilute or enhance the clinical applicability of the results of a clinical trial, depending on the patient group to whom the results will be applied. Reports of clinical trials using run-in periods should indicate how this aspect of their design affects the application of the results to clinical practice.


Egg Consumption Increases Vitamin E Absorption from Co-Consumed Raw Mixed Vegetables in Healthy Young Men.
Most people living in the United States underconsume vitamin E, and dietary approaches to increase the absorption of vitamin E may help individuals to meet their body's needs. We assessed the effect of adding cooked whole egg to a raw mixed-vegetable salad on α-tocopherol and γ-tocopherol absorption. With the use of a randomized-crossover design, 16 healthy young men [mean ± SD age: 24 ± 4 y; mean ± SD body mass index (in kg/m2): 24 ± 2] consumed the same salad (all served with 3 g canola oil) with no egg [control (CON)], with 75 g cooked egg [low egg (LE)], or with 150 g cooked egg [high egg (HE)]; a 1-wk dietary washout period was included between trials. For the first 7 d of each trial, participants consumed a low-vitamin E diet to reduce plasma vitamin E concentrations. Blood was collected hourly for 10 h and the triacylglycerol-rich lipoprotein fractions (TRLs) were isolated. α-Tocopherol and γ-tocopherol concentrations in TRLs were analyzed and composite areas under the curve (AUCs) were calculated. The α-tocopherol 0- to 10-h AUCs (AUCs0-10 h) in TRLs was higher (P < 0.05) for the HE trial (least-squares mean ± SE: 981 ± 162 nmol/L ⋅ 10 h) than for the LE (311 ± 162 nmol/L ⋅ 10 h) and CON (117 ± 162 nmol/L ⋅10 h) trials, which did not differ from one another. The γ-tocopherol AUCs0-10 h in TRLs was also higher (P < 0.05) for the HE trial (402 ± 54 nmol/L ⋅ 10 h) than for the CON trial (72 ± 54 nmol/L ⋅ 10 h). The consumption of cooked whole eggs is an effective way to increase the absorption of α-tocopherol and γ-tocopherol from a co-consumed meal that naturally contains vitamin E, such as a raw mixed-vegetable salad, in healthy young men. This trial was registered at clinicaltrials.gov as NCT01951313.


Molecular Identification of Enteroviruses from Cattle and Goat Feces and Environment in Thailand.
The identification and characterization of viruses of the genus Enterovirus in healthy and infected livestock, including cattle and goats, have been increasing. Enterovirus E (EV-E) and Enterovirus F (EV-F) are commonly found in cattle, whereas Enterovirus G (EV-G) is found in goats. In this study, molecular and phylogenetic analyses were performed to determine the prevalence of EVs in cattle and goat feces from Kanchanaburi Province, Thailand. The presence of EVs in water samples and the feces of other animals collected from the areas surrounding cattle and goat farms was also investigated. By use of 5'-untranslated region (5' UTR) real-time reverse transcription-PCR (RT-PCR), EVs were detected in 39.5% of cattle samples, 47% of goat samples, 35.3% of water samples, and one pool of chicken feces. Phylogenetic analysis revealed the presence of EV-E and EV-F in cattle, EV-E and EV-G in goats, and EV-F in water samples and chicken feces. Analysis of enteroviral VP1 sequences from cattle revealed that the EV-E genotypes circulating in the study region were EV-E1, with a possible new genotype that is closely related to EV-E2. Analysis of enteroviral VP1 sequences from goats suggested the circulation of EV-G5 and a possible new genotype that is closely related to EV-G20. Sequence analyses also suggested that although the VP1 sequences from goats were closely related to those of EV-G, which were considered porcine enterovirus sequences, their 5' UTRs form a separated cluster with sequences of sheep and goat origin, suggesting a new classification of the ovine/caprine-specific enterovirus group.IMPORTANCE Possible new EV-E and EV-G genotypes were identified for EVs detected in this study. The EV-E viruses were also successfully isolated from MDBK cells. The goat EV sequence analysis suggested the presence of an ovine/caprine-specific EV group that is different from EV-G of porcine origin. The significance of our research is that it identifies and characterizes possible novel EVs, thereby indicating that enteroviruses in animals are continually evolving. The facts that enteroviruses can persist in the environment, contaminate it for long periods, and be transmitted between animals raise serious concerns regarding this group of viruses as emerging livestock pathogens.


Anti hyperlipidemic and hepatoprotective effects of native date fruit variety "Aseel" (Phoenix dactylifera).
Diet rich in saturated fats and sugars have been associated with obesity, insulin resistance, hyperlipidemia and fatty liver disease. Especially high serum lipid levels are directly connected to the progression of cardiovascular disorders, which are the leading cause of death all over the world. Date palm fruit (Phoenix dactylifera) is known for numerous health benefits however little information is available about in vivo clinical and preclinical benefits, hence antihyperlipidemic and hepatoprotective potential of native date variety Aseel has been assessed in hyperlipidemia induced albino rats. Forty adult male albino rats were divided into five groups with 8 animals in each group. One group was kept as normal control while remaining four groups were fed high fat high sugar diet for 8 weeks; from this one group was reserved as disease control while two groups as treated which received 300 and 600mg/kg of date fruit suspension. The fourth group served as positive control and received standard drug atorvastatin in the dose of 2.1mg/kg. After 14 days serum lipid profile, hepatic profile and fasting blood sugar were determined for all groups. Fasting blood sugar, cholesterol, triglycerides, LDL and VLDL along with cholesterol- HDL and LDL-HDL ratio were significantly decreased at 300 mg/kg without any increase in liver enzymes as observed in positive control group. Animals received 600 mg/kg also revealed significant decline in fasting blood sugar, triglyceride, VLDL and alkaline phosphatase. Hence present results demonstrate ameliorative role of date fruit in hyperlipidemia and fatty liver however more studies are required to gain insight into the possible mechanism of action and confirmation of these effects on human subjects.


Variance in biomass-allocation fractions is explained by distribution in European trees.
Intraspecific variability in ecological traits confers the ability of a species to adapt to an ever-changing environment. Fractions of biomass allocation in plants (BAFs) represent both ecological traits and direct expressions of investment strategies and so have important implications on plant fitness, particularly under current global change. We combined data on BAFs of trees in > 10 000 forest plots with their distributions in Europe. We aimed to test whether plant species with wider distributions have more or less variable intraspecific variance of the BAFs foliage-woody biomass and shoot-root ratios than species with limited distribution. Irrespective of corrections for tree age and phylogenetic relatedness, the standard deviation in BAFs was up to three times higher in species with the most extensive distributions than in those with the least extensive distribution due to a higher genetic diversity. Variance in BAFs also increased with latitude. We show that a combination of 36% tree genetic diversity and 64% environmental variability explains variance in BAFs and implies that changes in genetic diversity occur quickly. Genetic diversity should thus play a key role in regulating species responses to future climate change. Loss of habitat, even if transient, could induce a loss of genetic diversity and hinder species survival.


Dust exposure and respiratory symptoms among cement factory workers in the United Arab Emirates.
This study was conducted in a cement factory in the United Arab Emirates to assess cement dust exposure and its relationship to respiratory symptoms among workers. A total of 149 exposed and 78 unexposed workers participated in this cross-sectional study. Information on demographic and respiratory symptoms was collected by questionnaire. Personal total dust levels were determined by the gravimetric method. Concentration of the total dust ranged between 4.20 mg/m(3) in the crushers and 15.20 mg/m(3) in the packaging areas, and exceeded the exposure limit in the packaging and raw mill areas. The prevalence of respiratory symptoms was higher among the exposed workers, but the difference from that of unexposed workers was statistically significant only for cough (19.5%; OR=4.5; 95%CI=1.5-13.2), and phlegm (14.8%; OR=13.3; 95%CI=1.8-100.9). Cough and phlegm were found to be related to exposure to dust, cumulative dust and smoking habit, while chronic bronchitis was related to smoking habit. The few factory workers (19.5%) who used masks all the time had a lower prevalence rate of respiratory symptoms than those not using them. High dust level was the only variable that influenced the workers to use the mask all the time. It is recommended that control measures be adopted to reduce the dust and workers should be encouraged to use respiratory protection devices during their working time.


Hyperactivity in the medial olivocochlear efferent system is a common feature of tinnitus and hyperacusis in humans.
Tinnitus and hyperacusis are common, burdensome sources of morbidity with a high rate of co-occurrence. Knudson et al. (J Neurophysiol 112: 3197-3208, 2014) demonstrated that efferent suppression of cochlear activity by the medial olivocochlear system is enhanced in individuals with tinnitus and/or hyperacusis. Their findings stress that atypical activity in the efferent auditory pathway may represent a shared substrate, as well as a potential therapeutic target, in tinnitus and hyperacusis.


Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance.
Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001-2014). We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance. This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations.


Core column prediction for protein multiple sequence alignments.
In a computed protein multiple sequence alignment, the coreness of a column is the fraction of its substitutions that are in so-called core columns of the gold-standard reference alignment of its proteins. In benchmark suites of protein reference alignments, the core columns of the reference alignment are those that can be confidently labeled as correct, usually due to all residues in the column being sufficiently close in the spatial superposition of the known three-dimensional structures of the proteins. Typically the accuracy of a protein multiple sequence alignment that has been computed for a benchmark is only measured with respect to the core columns of the reference alignment. When computing an alignment in practice, however, a reference alignment is not known, so the coreness of its columns can only be predicted. We develop for the first time a predictor of column coreness for protein multiple sequence alignments. This allows us to predict which columns of a computed alignment are core, and hence better estimate the alignment's accuracy. Our approach to predicting coreness is similar to nearest-neighbor classification from machine learning, except we transform nearest-neighbor distances into a coreness prediction via a regression function, and we learn an appropriate distance function through a new optimization formulation that solves a large-scale linear programming problem. We apply our coreness predictor to parameter advising, the task of choosing parameter values for an aligner's scoring function to obtain a more accurate alignment of a specific set of sequences. We show that for this task, our predictor strongly outperforms other column-confidence estimators from the literature, and affords a substantial boost in alignment accuracy.


Highly sensitive antibody-free μLC-MS/MS quantification of rhTRAIL in serum.
We describe an antibody-free approach to quantify rhTRAIL(WT) (wild-type) and its closely related death receptor 4 selective variant rhTRAIL(4C7) in human and murine serum by multiplex LC-MS/MS on a microfluidics interface. Enrichment of rhTRAIL was performed by strong cation-exchange (SCX) followed by immobilized metal affinity (IMAC) solid-phase extraction. This was followed by trypsin digestion and using methionine-containing signature peptides after fully oxidizing the methionine residue with 0.25% (w/w) hydrogen peroxide. Absolute quantification was reaching down to 0.5 ng/ml for rhTRAIL(WT) (8.5 pM) and 2 ng/ml for rhTRAIL(4C7) (34 pM) in 100 μl human serum. To support preclinical studies in mice, the analysis was optimized further, for a sample volume of 20 μl murine serum.


Spiritual thoughts, coping and 'sense of coherence' in brain tumour patients and their spouses.
When a person is diagnosed with a life-threatening disease, existential questions are easily triggered. The aims of this study were to explore to what extent brain tumour patients and their next of kin were able to cope, understand and create meaning in their situation, to explore whether spirituality could be supportive and to analyse whether these concepts are related to Antonovsky's concept of sense of coherence. Using a purposive sampling technique, 20 patients and 16 of their next of kin took part in tape-recorded interviews. A content and context analysis was performed using a hermeneutic approach. We found that comprehensibility was to a large extent constructed by the patient's own thoughts and theories, despite an insecure situation. Manageability was achieved by active information-seeking strategies, by social support and by coping, including positive reinterpretation of the situation. Meaningfulness was central for quality of life and was created by close relations and faith, as well as by work. A crucial factor was whether the person had a 'fighting spirit' that motivated him or her to go on. As only three patients were believers, trust in God had generally been replaced by a belief and confidence in oneself, in science, in positive thinking and by closeness to nature. Sense of coherence as a concept can explain how exposed persons handle their situation. In its construction, sence of coherence integrates essential parts of the stress/coping model (comprehensibility, manageability) and of spirituality (meaning).


Physicochemical properties and in vitro starch digestibility of potato starch/protein blends.
This study aimed to investigate effects of starch-protein interactions on physicochemical properties and in vitro starch digestibility of composite potato starch/protein blends (0, 5, 10, or 15% protein) during processing (cooking, cooling and reheating). The effect on recrystallization and short-range ordering in starch was studied by light microscopy, differential scanning calorimetry and Fourier transform infrared spectroscopy. The results show that protein in the blend proportionally restricted starch granule swelling during cooking and facilitated amylopectin recrystallization during cold-storage. The facilitating effect of protein diminished with increasing blend ratio. Resistant starch content in the processed blends was positively correlated to intensity ratio of 1053/1035cm(-1) in FTIR spectra arising from slow retrogradation of amylopectin (r(2)>0.88, P≤0.05), whose formation was favored by the presence of protein in the blends and further enhanced by cooling of cooked blends. As a conclusion, starch-protein interaction reduced starch digestibility of the processed blends.


Disparities in genetics assessment for women with ovarian cancer: Can we do better?
We sought to characterize referral patterns for genetic counseling for women with ovarian cancer and hypothesized that differences in referral and testing rates are shaped by socioeconomic factors. Patients were identified by pathology reports from August 2012 to January 2016 containing the words "serous" or "ovarian." Patient information was obtained via electronic medical record. Primary outcomes were placement of a genetics referral and completion of counseling. A secondary outcome was completion of genetic testing. We identified 246 women with a diagnosis of ovarian cancer. Ten were previously counseled and excluded. 53% of patients were referred for counseling with mean time from diagnosis to counseling of 4.6months. Age and family history were not associated with referral, however rates differed by race with 61% of Caucasian and 40%, 38% and 33% of Asian, Latina and Black women, respectively, referred (p=0.035). Overall, 36% of patients diagnosed underwent counseling, and 33% were tested. English language (p<0.0001), high-grade serous histology (p=<0.0001) and private or Medicare insurance (p<0.0001) were significantly associated with referral. We have not yet reached the Society of Gynecologic Oncology recommendation for referral to genetics. Women of color and those with public insurance have lower referral rates. This disparity in care impacts cancer treatment options and prevents appropriate screening for other hereditary malignancies. To provide comprehensive oncology care, including genetic assessment, we recommend focusing on these barriers including improving outreach and interpreter services.


807 C/T Polymorphism of the glycoprotein Ia gene and pharmacogenetic modulation of platelet response to dual antiplatelet treatment.
Glycoprotein (GP) Ia/IIa is a major platelet-collagen receptor playing a key role in thrombosis following collagen exposure. The 807 C/T polymorphism of the GP Ia gene (ITGA2) has been associated with platelet GP Ia/IIa receptor expression, having T-allele carriers, increased receptor density and thrombotic risk. The aim of the study was to assess the role of the 807 C/T polymorphism on modulating platelet function in patients undergoing coronary stenting receiving a 300 mg clopidogrel loading dose. Platelet aggregation was assessed in 44 patients by light transmittance aggregometry following adenosine diphosphate and collagen stimuli at baseline, and 10 min, 4 h and 24 h after clopidogrel front loading. The T allele was found in 73% of patients. Clopidogrel reduced adenosine diphosphate-induced platelet aggregation (P < 0.01), which was similar in carriers and non-carriers of the T allele throughout the study (P = 0.73). Clopidogrel reduced collagen-induced platelet aggregation only in non-carriers of the T allele (P = 0.03), which resulted in an increase in T allele carriers during the overall study (P = 0.04). In conclusion, the T allele of the GP Ia gene modulates platelet aggregation and clopidogrel antiplatelet effects, suggesting an enhanced reactivity to fibrillar collagens (exposed during coronary stenting) in T allele carriers and might contribute to an increased thrombotic risk in these patients.


Autoantibodies, histocompatibility antigens and testosterone in males with alcoholic liver cirrhosis.
Titres and immunoglobulin classes of autoantibodies were examined in 69 male patients with alcoholic liver cirrhosis and the findings were related to particular human leucocyte antigens and serum concentration of testosterone. Both anti-nuclear antibodies (ANA) and smooth muscle antibodies (SMA) were significantly more prevalent in patients with cirrhosis than in sex- and age-matched controls. Antimitochondrial antibodies and liver cell membrane antibody were found in 4% of the patients, and in none of the controls, but this difference was not significant. Patients with HLA-B8 and/or HLA-B12 had higher titres of ANA (n.s.) and SMA (P less than 0.05) than patients without these HLA antigens. Serum concentrations of testosterone were significantly lower in ANA-positive patients than in those negative (P less than 0.05), and a similar tendency was found in SMA-positive patients. With increasing titres of ANA the concentration of testosterone fell. Serum concentration of testosterone correlated inversely (P less than 0.05) with plasma immunoglobulin G and A. It is concluded that both genetic and hormonal factors may influence the humoral immune response in these patients.


Progress in high resolution scanning ion microscopy and secondary ion mass spectrometry imaging microanalysis.
The performance of a new high resolution scanning ion microprobe (SIM) is elucidated with regard to imaging capabilities using the ion-induced secondary electron (ISE) or secondary ion (ISI) signals, and the mass-resolved signal from a secondary ion mass spectrometry (SIMS) system. The new instrument focuses a beam extracted from a liquid metal ion source (LMIS) to a range of spot sizes reaching the 20 nm level. The probe current (1.6 pA) available at this level of lateral resolution, which approaches the theoretical resolution limits of the SIMS method, is still adequate to obtain detailed isotopic maps for surfaces rich in the elements of low ionization potential (positive ISI), or high electron affinity (negative ISI). In addition to examples of high resolution ISE and ISI images of objects displaying sufficiently small topographic detail, mass spectra and isotopic maps are shown, testing both the lateral and depth resolution attained. The latter results belong with a program of interdisciplinary research applications of the new microprobe, which include studies of e.g., the monolayer lateral distribution of intercalant in SbCl5 intercalated graphite and of silicate minerals and iron distribution in sections of chondrules and their rims (components of chondrites, a class of stony meteorites). In the biomedical field, the new microprobe finds application in e.g., the study of human renal calculi and bone. Most promising is the use of stable isotope tracers (e.g., Ca44) to unravel the dynamics of bone mineralization, as thus far shown with the in-vitro culture of the skull bone of neonatal mice.


Guidelines for allergic rhinitis need to be used in primary care.
Clinical Practice Guidelines for allergic rhinitis have been developed over the past 15 years and have been found to improve the care for patients with allergic rhinitis. The ARIA (allergic rhinitis and its impact on asthma) guideline was the first of these evidenced-based guidelines, developed with primary care physicians. Subsequent guidelines include those by the IPCRG, BSACI, the AAAAI/ACAAI Practice Parameters for the diagnosis and management of rhinitis, and the ARIA 2008 Update. These guidelines were based on various evidencebased models, but the first to use GRADE methodology (Grading of Recommendations Assessment, Development and Evaluation) is the ARIA 2009 Revision. Since primary care physicians treat the majority of patients with allergic rhinitis it is essential that they are involved in the development and implementation of guidelines for allergic rhinitis. Prior to their implementation, guidelines should be evaluated for their accuracy and user friendliness - specifically for primary care physicians - but such validation is rarely performed. This is of great importance, in particular as regards evaluating the applicability of evidence from high quality randomised controlled trials (RCTs) which are often based on highly selected patients not representing the population of patients seen in day-to-day practice.


Myocardial injury in patients with hemodynamic derangements during and/or after liver transplantation.
Myocardial injury, defined as an elevation of cardiac troponin (cTn) resulting from ischemia, is associated with substantial mortality in surgical patients, and its incidence, risk factors, and impact on patients undergoing liver transplantation (LT) are poorly understood. In this study, adult patients who experienced perioperative hemodynamic derangements and had cTn measurements within 30 days after LT between 2006 and 2013 were studied. Of 502 patients, 203 (40.4%) met the diagnostic criteria (cTn I ≥0.1 ng/mL) of myocardial injury. The majority of myocardial injury occurred within the first three postoperative days and presented without clinical signs or symptoms of myocardial infarction. Thirty-day mortality in patients with myocardial injury was 11.4%, significantly higher compared with that in patients without myocardial injury (3.4%, P<.01). Cox analysis indicated the peak cTn was significantly associated with 30-day mortality. Multivariable logistic analysis identified three independent risk factors: requirement of ventilation before transplant (odds ratios (OR) 1.6, P=.006), RBC≥15 units (OR 1.7, P=.006), and the presence of PRS (OR 2.0, P=.028). We concluded that post-LT myocardial injury in this high-risk population was common and associated with mortality. Our findings may be used in pretransplant stratification. Further studies to investigate this postoperative cardiac complication in all LT patients are warranted.


Human colorectal CD24+ cancer stem cells are susceptible to epithelial-mesenchymal transition.
Conventional cancer chemotherapy preferentially destroys non-stem cancer cells within a tumor, and a subpopulation of cancer stem cells (CSCs) is more resistant and survives, leading to relapses and metastasis. Howeve, recent studies suggest that CD24 and susceptibility to epithelial-mesenchymal transition (EMT) can serve as markers of CSCs. We report that CD24(+) cells are susceptible to induction of EMT, a phenotype important for cancer metastasis. We studied the responsiveness of CSC markers to TGF-β , an effective EMT inducer. The data on CD24 demonstrated that CD24(+) cells are susceptible to EMT, a phenotype important for cancer metastasis in two colorectal cancer cell lines, the CaR-1 and CCK81. CD24(+) cells expressed Notch 1 in response to exposure to TGF-β in culture and showed higher tumorigenic activity compared to controls. This evidence shows that CD24(+) cells are susceptible to EMT induction and to cancer progression and is indicative of the candidacy of CD24 as a therapeutic target in CSC.


A Systematic Approach for the Prevention and Reduction of Hypoglycemia in Hospitalized Patients.
Hypoglycemia and severe hypoglycemia (SH) in the inpatient setting are associated with poor outcomes. This review is designed to highlight approaches to predict and prevent inpatient hypoglycemia that has been successfully implemented focusing on developing overlapping policies and procedures that allow safe glycemic management to occur at all levels of the institution. Standardizing point-of-care (POC) testing, nursing protocols, meal delivery, and formulary restriction are useful tools to prevent hypoglycemia. Informatics and real-time alert processes are highly effective tools to reduce hypoglycemia but require a significant investment in time and infrastructure as well as clear policies on how alerts are acted upon. Computerized dosing support technology and continuous glucose monitoring (CGM) technology are an emerging area of investigation showing promising results. Inpatient hypoglycemia is often predictable and preventable and requires institutional support to deliver targeted and safe diabetes care. This requires each institution to do periodic reassessment of policies and technologies. Future research needs to focus on the cost/benefits of interventions including studies of automated dosing algorithms as well as CGM in higher-risk patient populations.


Polymorphisms in the TLR3 gene are associated with risk for type 1 diabetes mellitus.
Viral pathogens seem to play a role in triggering the autoimmune destruction that leads to the development of type 1 diabetes mellitus (T1DM). Toll-like receptor 3 (TLR3) has been shown to recognize double-stranded RNA, a molecular signature of most viruses. It is expressed at high levels in pancreatic β-cells and immune cells, suggesting a role for it in the pathogenesis of T1DM. Therefore, the aim of this study was to investigate whether TLR3 polymorphisms are associated with T1DM. Frequencies of the TLR3 rs11721827, rs13126816, rs5743313, rs7668666, and rs3775291 polymorphisms were analyzed in 449 T1DM patients and in 507 nondiabetic subjects. Haplotypes constructed from the combination of these polymorphisms were inferred using a Bayesian statistical method. The rs3775291 and rs13126816 polymorphisms were associated with T1DM, and the strongest association was observed for the additive model (odds ratio (OR)=2.3, 95% CI 1.3-4.2 and OR=2.1, 95% CI 1.3-3.1 respectively). In the same way, the frequency of T1DM was higher as more risk alleles of the five polymorphisms were present (P-trend=0.001). Moreover, in T1DM patients, the minor alleles of the rs5743313 and rs117221827 polymorphisms were associated with an early age at diagnosis and worse glycemic control. The TLR3 rs3775291 and rs13126816 polymorphisms are associated with risk for T1DM, while the rs5743313 and rs11721827 polymorphisms are associated with age at T1DM diagnosis and poor glycemic control. The number of risk alleles of the five TLR3 polymorphisms in the haplotypes seems to influence the risk for T1DM, suggesting that these polymorphisms might interact in the susceptibility for the disease.


Biomarkers in acute lung injury.
Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) result in high permeability pulmonary edema causing hypoxic respiratory failure with high morbidity and mortality. As the population ages, the incidence of ALI is expected to rise. Over the last decade, several studies have identified biomarkers in plasma and bronchoalveolar lavage fluid providing important insights into the mechanisms involved in the pathophysiology of ALI. Several biomarkers have been validated in subjects from the large, multicenter ARDS clinical trials network. Despite these studies, no single or group of biomarkers has made it into routine clinical practice. New high throughput "omics" techniques promise improved understanding of the biologic processes in the pathogenesis in ALI and possibly new biomarkers that predict disease and outcomes. In this article, we review the current knowledge on biomarkers in ALI.


Experiences of people with intellectual disability and dementia: A systematic review.
Dementia disproportionately affects people with intellectual disability. Most qualitative studies explore their experiences by utilising proxy-reports. A smaller number of studies illustrate the possibility of exploring perspectives directly from people with intellectual disability and dementia. This systematic review synthesised findings from existing studies (n = 8) that involve people with intellectual disability and dementia as participants to understand their experiences of dementia. Searches were conducted using CINAHL, PsychInfo and Social Services Abstracts. Findings include descriptions of changes in individual functioning, a narrowing of social worlds and of how people made sense of the changes despite often having no knowledge of their dementia diagnosis. Additionally, discussion focuses on how people's experiences are shaped by their environments. The review recognises the complexities of speaking to people with intellectual disability about dementia, challenges views that people with intellectual and dementia cannot be involved in research and makes recommendations to support inclusion in future studies.


Total knee arthroplasty in hemophilic arthropathy.
Arthropathy of the knee frequently develops in patients with hemophilia, who may require a total knee arthroplasty at a young age. Hemophilic patients, who require regular intravenous replacement of coagulation factor, have a higher prevalence of human immunodeficiency virus (HIV) infection, which can compromise the outcome of the arthroplasty. The purpose of this study was to evaluate prosthetic survival following total knee arthroplasty and identify factors associated with failures of the arthroplasties in hemophilic patients. The results of fifty-three total knee arthroplasties performed in thirty-eight patients (twenty-nine of whom were seropositive for HIV) to treat hemophilic arthropathy between 1976 and 1998 were retrospectively reviewed. Inpatient and outpatient medical records were studied to determine the HIV status, CD4 lymphocyte count, type of prosthesis, duration of prosthetic survival, cause of failure, and cause of death. If an arthroplasty failed, the outcome of the treatment of the failed arthroplasty was also determined. The rate of survival of the prostheses was 90% after five years. Eleven total knee arthroplasties failed. The most common cause of failure was infection (seven knees), which developed at an average of sixty months (range, three to 138 months) after the arthroplasty. There was no significant difference in the CD4 lymphocyte counts between the patients in whom infection developed and those in whom it did not. The HIV status also did not appear to be related to the development of infection. Thirteen patients died, and the most common cause of death was complications associated with acquired immunodeficiency syndrome (AIDS). Total knee arthroplasty performed to treat hemophilic arthropathy has a high risk of failure as a result of infection. Most infections developed late and were frequently caused by Staphylococcus epidermidis, suggesting that a likely cause of failure due to infection was hematogenous spread during administration of coagulation factor. It may be difficult to salvage a prosthesis complicated by infection. However, the life expectancy of hemophilic patients is lower than that of the general population of patients treated with total knee arthroplasty, and the improvement in the quality of life after total knee arthroplasty for hemophilic arthropathy may outweigh the risk of failure.


Children's motivation in elementary physical education: an expectancy-value model of achievement choice.
This study examined children's motivation in elementary physical education within an expectancy-value model developed by Eccles and her colleagues. Four hundred fourteen students in second and fourth grades completed questionnaires assessing their expectancy-related beliefs, subjective task values, and intention for future participation in physical education. Results indicated that expectancy-related beliefs and subjective task values were clearly distinguishable from one another across physical education and throwing. The two constructs were related to each other positively. Children's intention for future participation in physical education was positively associated with their subjective task values and/or expectancy-related beliefs. Younger children had higher motivation for learning in physical education than older children. Gender differences emerged and the findings provided empirical evidence supporting the validity of the expectancy-value model in elementary physical education.


Progesterone retards postpartum involution of the rabbit myometrium.
Postpartum involution of the uterus was significantly reduced in rabbits by immediate and repeated injections of progesterone. Progesterone had no effect if the injections commenced 24 hours after delivery. The decrease in concentration of progesterone that accompanies birth results in release of proteolytic and other degradative enzymes from subcellular particles; these enzymes cause the involution, and, once the enzymes are released into the cellular milieu, progesterone has no effect.


When field experiments yield unexpected results: lessons learned from measuring selection in White Sands lizards.
Determining the adaptive significance of phenotypic traits is key for understanding evolution and diversification in natural populations. However, evolutionary biologists have an incomplete understanding of how specific traits affect fitness in most populations. The White Sands system provides an opportunity to study the adaptive significance of traits in an experimental context. Blanched color evolved recently in three species of lizards inhabiting the gypsum dunes of White Sands and is likely an adaptation to avoid predation. To determine whether there is a relationship between color and susceptibility to predation in White Sands lizards, we conducted enclosure experiments, quantifying survivorship of Holbrookia maculate exhibiting substrate-matched and substrate-mismatched phenotypes. Lizards in our study experienced strong predation. Color did not have a significant effect on survival, but we found several unexpected relationships including variation in predation over small spatial and temporal scales. In addition, we detected a marginally significant interaction between sex and color, suggesting selection for substrate matching may be stronger for males than females. We use our results as a case study to examine six major challenges frequently encountered in field-based studies of natural selection, and suggest that insight into the complexities of selection often results when experiments turn out differently than expected.


Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage.
Current genome-editing technologies introduce double-stranded (ds) DNA breaks at a target locus as the first step to gene correction. Although most genetic diseases arise from point mutations, current approaches to point mutation correction are inefficient and typically induce an abundance of random insertions and deletions (indels) at the target locus resulting from the cellular response to dsDNA breaks. Here we report the development of 'base editing', a new approach to genome editing that enables the direct, irreversible conversion of one target DNA base into another in a programmable manner, without requiring dsDNA backbone cleavage or a donor template. We engineered fusions of CRISPR/Cas9 and a cytidine deaminase enzyme that retain the ability to be programmed with a guide RNA, do not induce dsDNA breaks, and mediate the direct conversion of cytidine to uridine, thereby effecting a C→T (or G→A) substitution. The resulting 'base editors' convert cytidines within a window of approximately five nucleotides, and can efficiently correct a variety of point mutations relevant to human disease. In four transformed human and murine cell lines, second- and third-generation base editors that fuse uracil glycosylase inhibitor, and that use a Cas9 nickase targeting the non-edited strand, manipulate the cellular DNA repair response to favour desired base-editing outcomes, resulting in permanent correction of ~15-75% of total cellular DNA with minimal (typically ≤1%) indel formation. Base editing expands the scope and efficiency of genome editing of point mutations.


Differential effect of p75 neurotrophin receptor on expression of pro-apoptotic proteins c-jun, p38 and caspase-3 in dorsal root ganglion cells after axotomy in experimental diabetes.
We have hypothesized that p75 neurotrophin receptor (p75(NTR))-mediated activation of the pro-apoptotic proteins c-jun, p38 and caspase-3 underlies the neuronal cell loss in dorsal root ganglia (DRG) neurons after axotomy in normal mice, and that this activation is exaggerated in experimental diabetes. To test this hypothesized relationship, we compared the expression of pro-apoptotic proteins in fifth lumbar DRG (L5DRG) neurons of wildtype Balb/c (p75+/+) mice and p75(NTR) knockout (p75-/-) mice, assigned to either non-diabetic control groups or to diabetic (1 month) groups, all with a unilateral sciatic nerve crush produced 10 days before tissue preparation. The absolute number of L5DRG neurons expressing immunoreactivities (IR) for phosphorylated c-jun (P-c-jun-IR), phosphorylated p-38 (P-p38-IR) and cleaved caspase-3 (caspase-3-IR) were estimated in semi-thick sections using the optical fractionator. Nerve crush increased the numbers of P-c-jun-IR and caspase-3-IR neurons in all four groups. On the crush side, diabetes did not exaggerate the increase of P-c-jun-IR or caspase-3-IR neurons in p75+/+ mice, whereas in p75-/- mice diabetes reduced the increase of P-c-jun-IR neurons. Also, in p75-/- mice there was fewer caspase-3-IR cells on the intact and crushed side in comparison with p75+/+ mice independent of the presence of diabetes. This study demonstrates that (1) diabetes of 1 month's duration does not potentiate the expression of three pro-apoptotic markers p38, caspase-3 and P-c-jun neither in intact neurons nor after nerve crush, and that (2) p75(NTR) is required for activation of the pro-apoptosis signal caspase-3 after nerve crush in both diabetic and non-diabetic mice.


Global HIV control: is the glass half empty or half full?
The massive scale-up of HIV treatment and prevention over the past two decades has resulted in important reductions in new infections and mortality globally. Reduction in HIV incidence, however, has been unequal, with worsening epidemics in regions where the reach and scale of HIV control programmes have been insufficient, especially in eastern Europe, central Asia, the Middle East, north Africa, and Latin America where HIV epidemics are concentrated among key populations, including people who inject drugs, men who have sex with men, transgender people, and some minority racial and ethnic groups. The global state of the HIV pandemic highlights disparities in HIV control efforts and provides a roadmap for what should be done, including investment to better implement the effective HIV prevention and treatment tools that are available, but whose adoption and scale-up are not yet sufficient to get us close to an AIDS-free generation. To achieve the full potential of global HIV control, we call for urgent, evidence-informed implementation at scale of our existing and novel HIV prevention and treatment strategies in ways that are better, faster, more efficient, and cost-effective, especially in key populations and regions where the HIV pandemic continues to expand.


Kinetoplastid glucose transporters.
Protozoa of the order kinetoplastida have colonized many habitats, and several species are important parasites of humans. Adaptation to different environments requires an associated adaptation at a cell's interface with its environment, i.e. the plasma membrane. Sugar transport by the kinetoplastida as a phylogenetically related group of organisms offers an exceptional model in which to study the ways by which the carrier proteins involved in this process may evolve to meet differing environmental challenges. Seven genes encoding proteins involved in glucose transport have been cloned from several kinetoplastid species. The transporters all belong to the glucose transporter superfamily exemplified by the mammalian erythrocyte transporter GLUT1. Some species, such as the African trypanosome Trypanosoma brucei, which undergo a life cycle where the parasites are exposed to very different glucose concentrations in the mammalian bloodstream and tsetse-fly midgut, have evolved two different transporters to deal with this fluctuation. Other species, such as the South American trypanosome Trypanosoma cruzi, multiply predominantly in conditions of relative glucose deprivation (intracellularly in the mammalian host, or within the reduviid bug midgut) and have a single, relatively high-affinity type, transporter. All of the kinetoplastid transporters can also transport d-fructose, and are relatively insensitive to the classical inhibitors of GLUT1 transport cytochalasin B and phloretin.


Effect of live music therapy for patients undergoing magnetic resonance imaging.
The purpose of the current study was to identify the effects of live music therapy interventions compared with preferred recorded music for patients undergoing MRI scans. To date, there has not been a published study involving the use of live music therapy during MRI scans. The current study investigated the differences between teenage through adult patients receiving live music therapy intervention during outpatient MRI scans versus the standard protocol of care listening to recorded music (N = 88). Subjects ranged in age from 15 to 93 years old. Results indicated subjects who received the live music therapy protocol reported significantly better perception of the MRI procedure (p < 0.05). Additionally, subjects receiving the live music therapy protocol had fewer scans repeated due to movement. Of the repeated images, 26% occurred in the live music group and 73% occurred in the recorded music group. Subjects receiving live music therapy also requested less breaks from the scan. Two percent of the live music subjects requested a break and 17.6% of the control patients requested breaks. When comparing the same type of scan between groups, subjects receiving the live music protocol required less time to complete the scans. For lumbar scans without contrast (N = 14, n = 7, n = 7), live music subjects spent an average of 4.63 less min per scan for a total of 32 less min for 7 subjects. For brain scans (N = 8, n = 4, n = 4), live music subjects spent an average of 5.8 less min per scan for a total of 23 less min for 4 subjects. Results of the current study supports the use of live music therapy intervention for teenage and adult patients undergoing MRI scans to reduce patient anxiety and improve patient perception of the scan experience. Additionally, live music therapy has the potential to shorten the length of time required for patients to complete MRI scans due to decreased patient movements and fewer breaks requested during the scans. The cost savings impact of reduced procedure time can positively impact the facility productivity by allowing more scans to be scheduled daily.


Odorant Sensory Input Modulates DNA Secondary Structure Formation and Heterogeneous Ribonucleoprotein Recruitment on the Tyrosine Hydroxylase and Glutamic Acid Decarboxylase 1 Promoters in the Olfactory Bulb.
Adaptation of neural circuits to changes in sensory input can modify several cellular processes within neurons, including neurotransmitter biosynthesis levels. For a subset of olfactory bulb interneurons, activity-dependent changes in GABA are reflected by corresponding changes in Glutamate decarboxylase 1 (Gad1) expression levels. Mechanisms regulating Gad1 promoter activity are poorly understood, but here we show that a conserved G:C-rich region in the mouse Gad1 proximal promoter region both recruits heterogeneous nuclear ribonucleoproteins (hnRNPs) that facilitate transcription and forms single-stranded DNA secondary structures associated with transcriptional repression. This promoter architecture and function is shared with Tyrosine hydroxylase (Th), which is also modulated by odorant-dependent activity in the olfactory bulb. This study shows that the balance between DNA secondary structure formation and hnRNP binding on the mouse Th and Gad1 promoters in the olfactory bulb is responsive to changes in odorant-dependent sensory input. These findings reveal that Th and Gad1 share a novel transcription regulatory mechanism that facilitates sensory input-dependent regulation of dopamine and GABA expression.SIGNIFICANCE STATEMENT Adaptation of neural circuits to changes in sensory input can modify several cellular processes within neurons, including neurotransmitter biosynthesis levels. This study shows that transcription of genes encoding rate-limiting enzymes for GABA and dopamine biosynthesis (Gad1 and Th, respectively) in the mammalian olfactory bulb is regulated by G:C-rich regions that both recruit heterogeneous nuclear ribonucleoproteins (hnRNPs) to facilitate transcription and form single-stranded DNA secondary structures associated with repression. hnRNP binding and formation of DNA secondary structure on the Th and Gad1 promoters are mutually exclusive, and odorant sensory input levels regulate the balance between these regulatory features. These findings reveal that Th and Gad1 share a transcription regulatory mechanism that facilitates odorant-dependent regulation of dopamine and GABA expression levels.


The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome.
Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21-specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR ≤ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS- without CHD (FDR ≤ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yet-unidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture.


Associations of Abdominal Skeletal Muscle Mass, Fat Mass, and Mortality among Men and Women with Stage I-III Colorectal Cancer.
The associations of abdominal skeletal muscle mass index (SMI), visceral and subcutaneous adipose tissue (VAT and SAT, respectively), and mortality among patients with stage I-III colorectal cancer may differ for men and women, but only few studies stratified their data into men and women. We investigated associations of abdominal SMI, VAT, and SAT with overall mortality among men and among women with stage I-III colorectal cancer. SMI, VAT, and SAT were assessed from abdominal CT images for 1,998 patients with stage I-III colorectal cancer diagnosed between 2006 and 2015. Restricted cubic splines (RCS) were used to investigate associations of SMI, VAT, and SAT with overall mortality. Average age of the participants was 67.9 ± 10.6 years and 58% were men. During a median follow-up of 4.3 years, 546 (27%) patients died. Among men, the association of SMI and mortality was statistically significant in a nonlinear way in the RCS analyses, with lower SMI levels associated with higher mortality. SMI was not associated with mortality among women. SAT was associated with mortality in a nonlinear way for men and for women, with lower SAT levels being associated with higher mortality. VAT was not significantly associated with mortality in men or women. Associations of abdominal skeletal muscle mass with mortality among patients with colorectal cancer were not the same for men and for women. This study stresses the importance for more attention on sex-related differences in body composition and cancer outcomes.


Comparison of galactose-1-phosphate uridyl transferase in fetal and adult tissues.
Galactose-1-phosphate uridyl transferase, the enzyme deficient in galactosemia, is demonstrated to be present in erythrocytes from fetuses of 12--30 weeks gestation. The specific activity and starch gel electrophoretic pattern of this enzyme in fetal erythrocytes is virtually identical to that found in erythrocytes postnatally. This enzyme was also studied in cultured fibroblasts from skin and amniotic cells and found to have similar specific activity and identical electrophoretic mobility in tissues from both sources. There does not appear to be a fetal isozyme for galactose-1-phosphate uridyl transferase in either erythrocytes or cultured fibroblasts. Thus, with fetal erythrocytes obtained by fetoscopy, it is likely that prenatal diagnosis of galactosemia can be rapidly and reliably accomplished.


Is frozen section analysis of pelvic lymph nodes accurate in locally advanced cervical cancer patients administered preoperative chemoradiation?
No thorough investigation of the diagnostic performance of frozen section analysis in predicting the final status of lymph nodes after exposure to concomitant chemoradiation (CT/RT) has been performed until now. The aim of the study was to analyze the accuracy of pelvic lymph node frozen section examination in a large, consecutive series of locally advanced cervical cancer (LACC) patients undergoing preoperative CT/RT. A total of 123 consecutive LACC patients underwent preoperative CT/RT followed by radical hysterectomy according to Piver classification, with bilateral systematic pelvic lymphadenectomy. If pelvic nodes were intraoperatively defined as positive for tumor metastasis, para-aortic lymphadenectomy up to inferior mesenteric artery was carried out. The diagnostic performance of frozen section examination of pelvic lymph nodes was assessed by calculating the negative predictive value (NPV), the positive predictive value (PPV), specificity, sensitivity, and overall accuracy. A total of 1647 and 4345 pelvic lymph nodes were analyzed by frozen section examination and at final diagnosis, respectively. Lymph node metastases were found in 11 cases (8.9%) at frozen section examination, and in 14 cases (11.4%) at definitive histological diagnosis. We found 7 incorrect diagnoses at frozen section examination, represented by 5 false negative and 2 false positive cases. Specificity, sensitivity, overall accuracy, NPV, and PPV were 98.2%, 64.3%, 94.3%, 95.5% and 81.8%, respectively. Preoperative chemoradiation does not impair the role of frozen section analysis in predicting the pelvic lymph node involvement in LACC patients.


Gluconate zinc in acrodermatitis enteropathica.
Two children with characteristic findings of acrodermatitis enteropathica were found to have low serum zinc levels prior to therapy. Treatment with zinc gluconate in low dosages resulted in an increase in serum zinc levels and clinical improvement. All family members studied had low serum zinc levels. In addition, we noted a change of hair color to red and excessive drooling just prior to exacerbations in these two patients. The hair color returned to normal with remission.