Phosphatidylcholine structure determines cholesterol solubility and lipid polymorphism.
In the present work, we demonstrate that phosphatidylcholine with (16:1)9 acyl chains undergoes polymorphic rearrangements in mixtures with 0.6-0.8 mol fraction cholesterol. Studies were performed using differential scanning calorimetry, X-ray diffraction, cryo-electron microscopy, 31P NMR static powder patterns and 13C MAS/NMR. Mixtures of phosphatidylcholine with (16:1)9 acyl chains and 0.6 mol fraction cholesterol, after being heated to 100 degrees C, can form an ordered array with periodicity 14 nm which may be indicative of a cubic phase. Our results indicate that the formation of highly curved bilayer structures, such as those required for membrane fusion, can occur in mixtures of cholesterol with certain phosphatidylcholines that do not form non-lamellar structures in the absence of cholesterol. We also determine the polymorphic behavior of mixtures of symmetric phosphatidylcholines with cholesterol. Species of phosphatidylcholine with (20:1)11, (22:1)13 or (24:1)15 acyl chains in mixtures with 0.6-0.8 mol fraction cholesterol undergo a transition to the hexagonal phase at temperatures 70-80 degrees C. This is not the case for phosphatidylcholine with (18:1)6 acyl chains which remains in the lamellar phase up to 100 degrees C when mixed with as much as 0.8 mol fraction cholesterol. Thus, the polymorphic behavior of mixtures of phosphatidylcholine and cholesterol is not uncommon and is dependent on the intrinsic curvature of the phospholipid. Crystals of cholesterol can be detected in mixtures of all of these phosphatidylcholines at sufficiently high cholesterol mole fraction. What is unusual about the formation of these crystals in several cases is that cholesterol crystals are present in the monohydrate form in preference to the anhydrous form. Furthermore, after heating to 100 degrees C and recooling, the cholesterol crystals are again observed to be in the monohydrate form, although pure cholesterol crystals require many hours to rehydrate after being heated to 100 degrees C. Both the nature of the acyl chain as well as the mole fraction cholesterol determine whether cholesterol crystals in mixtures with the phospholipids will be in the monohydrate or in the anhydrous form.


Minimally Invasive, Spring-Assisted Correction of Sagittal Suture Synostosis: Technique, Outcome, and Complications in 83 Cases.
This series describes the results of minimally invasive strip craniotomy with additional spring distraction. Included are the first 83 consecutive patients who underwent this procedure (January 1, 2010, to January 1, 2014). Outcome parameters were collected prospectively and included surgical parameters and complications, the occurrence of papilledema, skull growth, cephalic index, and photographic scores. Duration of surgery was 63 minutes, 19 percent required blood transfusion, and complications were minor. Postoperative papilledema occurred in two patients (2.4 percent). Head growth increased after insertion of the springs and declined afterward to 0.7 SD, comparable to earlier cohorts in the authors' center. The cephalic index increased from 67 before surgery to 74 after surgery and showed a small decrease during the 4-year follow-up. Photographic scores confirmed the initial improvement and showed a trend to further improvement during follow-up. In this cohort, spring-assisted, minimally invasive strip craniotomy was safe and effective. Results were similar to those from other techniques but with smaller incisions, shorter interventions, reduced blood loss, and a lower incidence of postoperative papilledema. Therapeutic, IV.


Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells.
Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.


Trans-cervical double balloon catheter with and without extra-amniotic saline infusion for cervical ripening: a prospective quasi-randomized trial.
To compare the efficacy and safety of the trans-cervical double balloon catheter with and without extra-amniotic saline infusion (EASI) for cervical ripening. This is a secondary analysis of a prospective randomized study conducted between November 2007 and January 2011 evaluating different ripening methods. Women presenting for labor induction were assigned to receive the double balloon catheter with (study group) or without EASI (control group). Outcomes included time from device insertion to delivery, cesarean section rates, and adverse events. One hundred and sixty women completed the study. Cesarean section rate (8.3% in study group, versus 20% in controls p = 0.07) and ripening success were comparable between the groups. Catheter insertion to delivery interval was significantly shorter and spontaneous catheter expulsion rate was significantly higher in the study group (14:19 hours versus 20:45 hours, p < 0.001, and 68.5% versus 51%, p = 0.04, respectively). Hospitalization length was significantly shorter in the study arm. There were no differences in other outcomes evaluated. A multivariable analysis found the EASI to be an independent predictor of a shorter insertion to delivery interval. The addition of EASI to the double balloon catheter for cervical ripening results in a shorter labor induction process without compromising its safety.


Secretion of matrix metalloproteinase 3 by expanded articular chondrocytes as a predictor of ectopic cartilage formation capacity in vivo.
Monolayer expansion of human articular chondrocytes (HACs) is known to result in progressive dedifferentiation of the chondrocytes and loss of their stable cartilage formation capacity in vivo. For an optimal outcome of chondrocyte-based repair strategies, HACs capable of ectopic cartilage formation may be required. This study was undertaken to identify secreted candidate molecules, in supernatants of cultured HACs, that could serve as predictors of the ectopic cartilage formation capacity of cells. Standardized medium supernatants (n = 5 knee cartilage samples) of freshly isolated HACs (PD0) and of HACs expanded for 2 or 6 population doublings (PD2 and PD6, respectively) were screened by a multiplexed immunoassay for 15 distinct interleukins, 8 matrix metalloproteinases (MMPs), and 11 miscellaneous soluble factors. Cartilage differentiation markers such as cartilage oligomeric matrix protein and YKL-40 were determined by enzyme-linked immunosorbent assay. HACs from each culture were subcutaneously transplanted into SCID mice, and the capacity of the chondrocytes to form stable cartilage was examined histologically 4 weeks later. Whereas freshly isolated (PD0) HACs generated stable ectopic cartilage that was positive for type II collagen, none of the cell transplants at PD6 formed cartilaginous matrix. Loss of the ectopic cartilage formation capacity between PD0 and PD6 correlated with a drop in the secretion of MMP-3 to <10% of initial levels, whereas changes in the other investigated molecules were not predictive. Chondrocytes with MMP-3 levels of >or=20% of initial levels synthesized cartilaginous matrix, whereas those with low MMP-3 levels (<10% of initial levels) at PD2 failed to regenerate ectopic cartilage. Loss of the capacity for stable ectopic cartilage formation in the course of HAC dedifferentiation can be predicted by determining the relative levels of MMP-3, demonstrating that standardized culture supernatants can be used for quality control of chondrocytes dedicated for cell therapeutic approaches.


Altered frontostriatal white matter microstructure is associated with familial alcoholism and future binge drinking in adolescence.
Adolescence is a time of significant neurobiological development, including changes in white matter microstructure. Familial alcoholism and adolescent binge-drinking have both been associated with altered white matter microstructure; however, the temporal nature of these effects, and their interaction, is unclear. Using diffusion-weighted imaging and voxel-wise multilevel modeling, the effects of familial alcoholism and future binge-drinking on white matter microstructural development were assessed in 45 adolescents, who went on to binge-drink (but were alcohol-naive at baseline), and 68 adolescents, who remained largely alcohol-naive, all with varying degrees of familial alcoholism. Both future binge-drinking and familial alcoholism were associated with altered frontostriatal white matter microstructure early in adolescence, prior to alcohol use. While several binge-drinking-related effects persisted throughout adolescence (in the posterior limb of the internal capsule, superior corona radiata, and cerebellar peduncles), the association between familial alcoholism and altered white matter microstructure dissipated across adolescence in all regions. There were no white matter regions identified where future binge-drinking or familial alcoholism were significantly associated with emergent or exacerbated alterations in white matter microstructure. Altogether, these findings suggest that alterations in frontostiatal white matter microstructure, some of which are associated with familial alcoholism, may be used to predict which adolescents are more likely to go on and engage in alcohol use. Meanwhile, a reduction in family history-related associations with altered white matter microstructure by late-adolescence is encouraging for future prevention work targeted at at-risk youth.


Temporary clamping of drain combined with tranexamic acid reduce blood loss after total knee arthroplasty: a prospective randomized controlled trial.
Total knee arthroplasty (TKA) is associated with a significant blood loss. Several methods have been reported to reduce postoperative blood loss and avoid homologous blood transfusions. In this study, we investigated the efficacy of temporary clamping of the drain either or not in combination with tranexamic acid administration for controlling blood loss after TKA. The prospective, randomized, and double-blinded study was conducted in our institute. Total of 240 patients, who diagnosed primary osteoarthritis and scheduled to undergo a primary TKA,,were randomized into one of the four groups: Group A or control group, the drain was not clamped and the patient received a placebo; Group B, the drain was not clamped and the patient received tranexamic acid; Group C, the drain was clamped and the patient received a placebo; and Group D, the drain was clamped and the patient received tranexamic acid. The volume of drained blood at 48 hours postoperatively, the decreasing of hemoglobin (Hb) level at 12 hours postoperatively and the number of patients requiring blood transfusion were recorded and compared. The mean postoperative volumes of drained blood and the amount of blood transfusion in the three study groups (group B, C and D) were significantly lower than those in the control group (p < 0.05), which group D had the lowest values. Furthermore, group B and D could maintain the Hb level better than group A and C (p < 0.001). In terms of blood transfusions rate, although the patients in group D required transfusion less than group A and C (p < 0.05), there was no significant difference between group D and B. The relative risks for transfusion requirement were 4.4 for group A, 1.4 for group B and 3.0 for group C when compared to group D. The clamping of drain combined with tranexamic acid administration could reduce postoperative blood loss and blood transfusion after TKA, significantly greater than using tranexamic acid or drain clamping alone. ClinicalTrials.gov NCT01449552.


Osteofibrous Dysplasia of the Tibia in Children: Outcome Without Resection.
The proposed association between osteofibrous dysplasia and adamantinoma has led some to advocate resection of the entire lesion, which can require major subsequent reconstruction. However, this link remains unproven and there is some support in more recent literature for a less aggressive approach. This study aims to describe our experience managing pediatric tibial osteofibrous dysplasia with such an approach and to report functional outcomes in children treated thus. A total of 28 cases of osteofibrous dysplasia in 25 patients were managed at a referral center for pediatric bone tumors with observation in the first instance, then limited surgical intervention if required to address pain and deformity. Surgery aimed to restore stability and alignment without excising the lesion. Clinical records provided basic clinical outcome measures involving walking, recreation, orthoses and school/work participation and patients provided a Musculoskeletal Tumour Society score (MSTS) where contactable. Mean age at presentation was 6.0 years and mean follow-up was 8.3 years. Only 8 patients required surgery. According to basic outcome measures, 13 patients were symptom-free. About 15 patients (17 cases) provided a MSTS and the mean score was 24 of 30. No transformation to adamantinoma was observed. Those who presented at a younger age and with bilateral disease more often required surgery and remained symptomatic. A less aggressive approach to pediatric tibial osteofibrous dysplasia achieves good functional outcomes and patient satisfaction in most cases. Surgery is required in the minority of cases. Transformation to adamantinoma was not observed in this series. We recommend patient education, clinical observation and reactive intervention if required, rather than proactive resection and reconstruction. Level IV-case series.


[NO-DEPENDENT MECHANISM OF THE CARDIOPROTECTIVE ACTION OF PHENIBUT ON STRESS-INDUCED VIOLATION OF CONTRACTILE FUNCTION OF THE HEART].
A stressor action for 24 h reduces both ino- and chronotropic reserves of animal heart as evidenced by a decrease in rate growth increments of contraction and relaxation of the myocardium, left ventricular pressure (LVP), heart rate, and the maximum intensity of functioning (MIF) as compared to intact animals during testing for adrenoreactivity and maximum isometric load caused by clamping of the ascending part of the aortic arch. Blockade of NO-synthase leads to a high percentage of animal death during the stressor action, anesthesia, opening of the chest, and functional tests and causes marked reduction in the growth rates of contraction (+dP/dt max) and relaxation (-dP/dt max) speed, LVP, heart rate, and MIF--on the average about 2 times (p < 0.05) under load testing conditions as compared to a control group of stressed animals. Phenibut limits stress-induced violations of the myocardium contractility, as indicated by a higher growth of performance in stress tests--on the average about 1.8 times (p < 0.05) in comparison to the control group of animals. The cardioprotective effect of phenibut is less pronounced when it is introduced on the background of the blockade of NO-ergic system. Under these conditions, there are cases of animal death, predominantly during the stressor action. The results obtained suggest that, for ensuring cardioprotective action of phenibut under conditions of stress-induced myocardial damage, it is necessary to provide for participation of nitric oxide system.


Plasma lipid and lipoprotein response of humans to beef fat, coconut oil and safflower oil.
This study's purpose was to evaluate the fasting human plasma lipid and lipoprotein responses to dietary beef fat (BF) by comparison with coconut oil (CO) and safflower oil (SO), fats customarily classified as saturated and polyunsaturated. Nineteen free-living normolipidemic men aged 25.6 +/- 3.5 yr consumed centrally-prepared lunches and dinners of common foods having 35% fat calories, 60% of which was the test fat. The test fats were isocalorically substituted, and each fed for five weeks in random sequences with intervening five weeks of habitual diets. Plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) concentrations among individuals follows the same relative rank regardless of diet. Triglycerides (TG) concentrations among individuals also maintain their relative rank regardless of diet but in a different order from that of the cholesterols. Plasma TC, HDL-C, and LDL-C responses to BF were significantly lower and TG higher than to CO. As compared to SO, BF produced equivalent levels of TG, HDL-C, and LDL-C and marginally higher TC. Thus, the customary consideration of BF as "saturated" and grouping it with CO appears unwarranted.


Cross-cultural experiences of maternal depression: associations and contributing factors for Vietnamese, Turkish and Filipino immigrant women in Victoria, Australia.
To investigate in an Australian study of immigrant women conducted 6-9 months following childbirth (a) the associations of a range of demographic, obstetric, health and social context variables with maternal depression, and (b) women's views of contributing factors in their experiences of depression. Three hundred and eighteen Vietnamese, Turkish and Filipino women participated in personal interviews conducted by three bicultural interviewers in the language of the women's choice. Utilising three approaches to the assessment of maternal depression, the consistency of associations on the different measures is examined. Women's views of contributing factors are compared with previous research with largely English-speaking Australian-born women. Analysis of the associations of maternal depression revealed considerable consistency in associations among the three approaches to assessing depression. Significant associations with depression on at least two of the measures were seen for: mothers under 25 years, shorter residence in Australia, speaking little or no English, migrating for marriage, having no relatives in Melbourne, or no friends to confide in, physical health problems, or a baby with feeding problems. There were no consistent associations found with family income or maternal education, method of delivery and a range of other birth events, or women's views about maternity care. The issues most commonly identified by women in this study as contributing to depression are similar to those found previously for Australian-born women: isolation (in this study, including being homesick)--29%; lack of support and marital issues--25%; physical ill-health and exhaustion--23%; family problems--19%, and baby-related issues--17%. There were some differences in the importance of these among the three country-of-birth groups, but all except family issues were in the top four contributing factors mentioned by women in all groups. These findings support the evidence for quite marked cross-cultural similarity in the associations of maternal depression and in women's views about their experiences.


Numb contributes to renal fibrosis by promoting tubular epithelial cell cycle arrest at G2/M.
Numb is a multifunctional protein involved in diverse cellular processes. However, the function of Numb in kidney remains unclear. Here, we reported that Numb is expressed in renal tubules and glomeruli in normal adult kidney. Numb expression was upregulated in fibrotic kidneys induced by unilateral ureteral obstruction (UUO) in mice as well as in human fibrotic kidney tissues. Numb overexpression in cultured proximal tubular cells increased the G2/M cell population and upregulated the expression of TGF-β1 and CTGF. Whereas, proximal tubule Numb knockout (PEPCK-Numb-KO) mice showed reduced G2/M arrest, decreased expression of TGF-β1 and CTGF, and attenuated fibrotic lesions due to either UUO or unilateral ischemia reperfusion nephropathy. Inhibiting p53 activity by pifithrin-` dramatically mitigated Numb-induced G2/M arrest, indicating that Numb potentiates G2/M arrest via stabilizing p53 protein. Together, these data suggest that Numb is a potential target for anti-fibrosis therapy.


Effect of viscoelasticity on adhesion of bioinspired micropatterned epoxy surfaces.
The effect of viscoelasticity on adhesion was investigated for micropatterned epoxy surfaces and compared to nonpatterned surfaces. A two-component epoxy system was used to produce epoxy compositions with different viscoelastic properties. Pillar arrays with flat punch tip geometries were fabricated with a two-step soft lithography process. Adhesion properties were measured with a home-built adhesion tester using a spherical sapphire probe as a counter-surface. Compared to flat controls, micropatterned epoxy samples with low viscoelasticity (i.e., low damping factors) showed at least a 20-fold reduction in pull-off force per actual contact area for both low (E' = 2.3 MPa) and high (E' = 2.3 GPa) storage moduli. This antiadhesive behavior may result from poor contact formation and indicates that the adhesion performance of commonly used elastomers for dry adhesives (e.g., polydimethylsiloxane) is governed by the interfacial viscoelasticity. Adhesion significantly increased with increasing viscoelasticity. Micropatterned samples with high viscoelasticity showed a 4-fold reduction in adhesion for aspect ratio (AR) 1.1 patterns but a 2-fold enhancement in adhesion for AR 2.2 patterns. These results indicate that viscoelasticity can enhance the effect of surface patterning on adhesion and should be considered as a significant parameter in the design of artificial patterned adhesives.


Telehealth for rural diverse populations: telebehavioral and cultural competencies, clinical outcomes and administrative approaches.
Rural health care settings are challenged to provide timely and evidence-based care, particularly for culturally diverse patients with behavioral health disorders. Telepsychiatry and telebehavioral health improve access to care and leverage scarce resources. This scoping review from January 2000 - July 2019 was conducted to see if the literature had data for two related the research questions, "What are the components of culturally competent, telepsychiatric clinical care, and what approaches have clinicians and systems taken to implement and evaluate it?" The review focused on key words in four concept areas: (I) competencies; (II) telehealth in the form of telepsychiatry, telebehavioral or telemental health; (III) culture; and (IV) health. It was done in accordance with the six-stage scoping review process in PubMed/Medline and other databases. The screeners reviewed the full-text articles for final inclusion based on inclusion (mesh of the key words) and exclusion (e.g., need for only, skills abstractly discussed) criteria. From a total of 1,118 papers, the authors found 44 eligible for full text review and found 7 papers directly relevant to the concepts. Few studies specifically discuss skills and competencies of both telehealth and cultural factors. Many organizations are attending to cultural competencies and approaches to care, but there are no specific competencies that integrate telepsychiatry or telebehavioral health with culture. Existing telepsychiatric (i.e., video, social media, mobile health) and one set telebehavioral health competencies included cultural component, including use of interpreters and language matters. Administrative adjustments are suggested to promote culturally competent care by telehealth via clinical, educational, quality improvement, program/system evaluation, and other (e.g., finance and reimbursement) interventions. More structured research is needed on development, implementation and evaluation of combined competencies in rural settings.


Relationship of Race With Functional and Clinical Outcomes With the REHAB-HF Multidomain Physical Rehabilitation Intervention for Older Patients With Acute Heart Failure.
Background The REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) randomized trial demonstrated that a 3-month transitional, tailored, progressive, multidomain physical rehabilitation intervention improves physical function, frailty, depression, and health-related quality of life among older adults with acute decompensated heart failure. Whether there is differential intervention efficacy by race is unknown. Methods and Results In this prespecified analysis, differential intervention effects by race were explored at 3 months for physical function (Short Physical Performance Battery [primary outcome], 6-Minute Walk Distance), cognition, depression, frailty, health-related quality of life (Kansas City Cardiomyopathy Questionnaire, EuroQoL 5-Dimension-5-Level Questionnaire) and at 6 months for hospitalizations and death. Significance level for interactions was P≤0.1. Participants (N=337, 97% of trial population) self-identified in near equal proportions as either Black (48%) or White (52%). The Short Physical Performance Battery intervention effect size was large, with values of 1.3 (95% CI, 0.4-2.1; P=0.003]) and 1.6 (95% CI, 0.8-2.4; P<0.001) in Black and White participants, respectively, and without significant interaction by race (P=0.56). Beneficial effects were also demonstrated in 6-Minute Walk Distance, gait speed, and health-related quality of life scores without significant interactions by race. There was an association between intervention and reduced all-cause rehospitalizations in White participants (rate ratio, 0.73 [95% CI, 0.55-0.98]; P=0.034) that appears attenuated in Black participants (rate ratio, 1.06 [95% CI, 0.81-1.41]; P=0.66; interaction P=0.067). Conclusions The intervention produced similarly large improvements in physical function and health-related quality of life in both older Black and White patients with acute decompensated heart failure. A future study powered to determine how the intervention impacts clinical events is required. REGISTRATION URL: https://www.clinicaltrials.gov. Identifier: NCT02196038.


Anionic and cationic Hofmeister effects on hydrophobic and hydrophilic surfaces.
Using a two-step modeling approach, we address the full spectrum of direct, reversed, and altered ionic sequences as the charge of the ion, the charge of the surface, and the surface polarity are varied. From solvent-explicit molecular dynamics simulations, we extract single-ion surface interaction potentials for halide and alkali ions at hydrophilic and hydrophobic surfaces. These are used within Poisson-Boltzmann theory to calculate ion density and electrostatic potential distributions at mixed polar/unpolar surfaces for varying surface charge. The resulting interfacial tension increments agree quantitatively with experimental data and capture the Hofmeister series, especially the anomaly of lithium, which is difficult to obtain using continuum theory. Phase diagrams that feature different Hofmeister series as a function of surface charge, salt concentration, and surface polarity are constructed from the long-range force between two surfaces interacting across electrolyte solutions. Large anions such as iodide have a high hydrophobic surface affinity and increase the effective charge magnitude on negatively charged unpolar surfaces. Large cations such as cesium also have a large hydrophobic surface affinity and thereby compensate an external negative charge surface charge most efficiently, which explains the well-known asymmetry between cations and anions. On the hydrophilic surface, the size-dependence of the ion surface affinity is reversed, explaining the Hofmeister series reversal when comparing hydrophobic with hydrophilic surfaces.


Interventions to prevent sexually transmitted infections, including HIV infection.
The Centers for Disease Control and Prevention (CDC) Sexually Transmitted Disease (STD) Treatment Guidelines were last updated in 2006. To update the "Clinical Guide to Prevention Services" section of the 2010 CDC STD Treatment Guidelines, we reviewed the recent science with reference to interventions designed to prevent acquisition of STDs, including human immunodeficiency virus (HIV) infection. Major interval developments include (1) licensure and uptake of immunization against genital human papillomavirus, (2) validation of male circumcision as a potent prevention tool against acquisition of HIV and some other sexually transmitted infections (STIs), (3) failure of a promising HIV vaccine candidate to afford protection against HIV acquisition, (4) encouragement about the use of antiretroviral agents as preexposure prophylaxis to reduce risk of HIV and herpes simplex virus acquisition, (5) enhanced emphasis on expedited partner management and rescreening for persons infected with Chlamydia trachomatis and Neisseria gonorrhoeae, (6) recognition that behavioral interventions will be needed to address a new trend of sexually transmitted hepatitis C among men who have sex with men, and (7) the availability of a modified female condom. A range of preventive interventions is needed to reduce the risks of acquiring STI, including HIV infection, among sexually active people, and a flexible approach targeted to specific populations should integrate combinations of biomedical, behavioral, and structural interventions. These would ideally involve an array of prevention contexts, including (1) communications and practices among sexual partners, (2) transactions between individual clients and their healthcare providers, and (3) comprehensive population-level strategies for prioritizing prevention research, ensuring accurate outcome assessment, and formulating health policy.


Nonautonomous apoptosis is triggered by local cell cycle progression during epithelial replacement in Drosophila.
Tissue remodeling involves collective cell movement, and cell proliferation and apoptosis are observed in both development and disease. Apoptosis and proliferation are considered to be closely correlated, but little is known about their coordinated regulation in physiological tissue remodeling in vivo. The replacement of larval abdominal epidermis with adult epithelium in Drosophila pupae is a simple model of tissue remodeling. During this process, larval epidermal cells (LECs) undergo apoptosis and are replaced by histoblasts, which are adult precursor cells. By analyzing caspase activation at the single-cell level in living pupae, we found that caspase activation in LECs is induced at the LEC/histoblast boundary, which expands as the LECs die. Manipulating histoblast proliferation at the LEC/histoblast boundary, either genetically or by UV illumination, indicated that local interactions with proliferating histoblasts triggered caspase activation in the boundary LECs. Finally, by monitoring the spatiotemporal dynamics of the S/G₂/M phase in histoblasts in vivo, we found that the transition from S/G₂ phases is necessary to induce nonautonomous LEC apoptosis at the LEC/histoblast boundary. The replacement boundary, formed as caspase activation is regulated locally by cell-cell communication, may drive the dynamic orchestration of cell replacement during tissue remodeling.


[Patient participation for safer health care – interviews with physicians and nurses].
Patient participation for safer health care - interviews with physicians and nurses Patient participation to achieve safer care is an area of growing policy, research and health care management and practice interest. Patients are uniquely placed to observe their treatment, care and physical environment throughout their journey in the health care system. However, very few studies have investigated health care providers' attitudes and beliefs concerning patient participation for improved patient safety. This study explored factors that acted as facilitators and/or barriers to patient participation for safer care, as perceived by physicians and nurses in Swedish health care. Interviews were conducted with 13 physicians and 11 nurses, using a purposeful sampling strategy to achieve a heterogeneous sample of providers. We identified nine categories of factors, many of which functioned as barriers to patient participation to achieve safer care.


Histopathological profile of benign colorectal diseases in Al- Madinah region of Saudi Arabia.
Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Colon cancer risk in IBD increases with longer duration and greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. This study aimed to characterize the histopathological pattern of benign colorectal diseases among Saudi patients and to highlight age and gender variations of lesions as base line data for future studies to investigate the link between benign / IBD and colorectal cancers in the local population. The materials consisted of 684 biopsies, reported as benign (excluding malignancies and polyps) at the Department of Pathology, King Fahad Hospital, Madinah, Saudi Arabia from January 2006 to December 2013. Data collected and entered in MS-Excel and were analyzed using SPSS-20. Of 684 colorectal tissues reviewed, 408 specimens (59.6%) were from male patients and 276 specimens (40.4%) were from females giving a male: female ratio of 1.5:1. Age of the patients ranged from 4 to 75 years with a mean of 39.6 years. The most frequent histologic diagnosis was a chronic non specific proctocolitis followed by ulcerative colitis, accounting respectively for 52.6% and 31.7% of all cases. These were followed by Crohn's disease 22 (3.2%), ischemic bowel disease 20 (2.9%), diverticular disease 14 (2%), eosinophilic colitis 12 (1.7%) and solitary rectal ulcer 12 (1.7%). A minority of 21 patients (3.1%) were cases of acute nonspecific proctocolitis, schistosomiasis, tuberculosis, volvulus and pseudomembranous colitis. These data show that although chronic non specific proctocolitis and ulcerative colitis were the dominant diagnoses, Crohn's disease, ischemic bowel disease and diverticular disease also existed to a lesser extent and should be considered in the differential diagnosis of benign colorectal diseases. This study provides a base line data for future studies which would be taken up to investigate the link between benign / IBD and colorectal cancers in the local population.


Differential expression of GRO-alpha and IL-8 mRNA in psoriasis: a model for neutrophil migration and accumulation in vivo.
Dense focal accumulation of neutrophils in the upper epidermis is a hallmark of psoriasis. Because the signals for neutrophil diapedesis and migration in vivo are not fully understood, psoriatic lesions with pronounced migration of neutrophils may serve as an important model for studying neutrophil chemotaxis. In this study, we present evidence for differential expression of the neutrophil chemotactic cytokines growth-related oncogene alpha, interleukin-8, and ENA-78 (epithelial cell derived and neutrophil-activating properties, 78 amino acids) in psoriatic lesions. In situ hybridization and immunohistochemistry of serial sections were employed to identify and microanatomically localize the cells producing these chemokines. High levels of focal interleukin-8 message were found to be expressed in the upper epidermis by keratinocytes and, most importantly, neutrophils themselves. Growth-related oncogene alpha transcripts were detected in clusters of keratinocytes of the upper epidermis at the same sites where interleukin-8 mRNA was abundant. In contrast to interleukin-8, growth-related oncogene alpha was also detected in the papillary dermis produced by vessel-associated cells. Sites of interleukin-8 and growth-related oncogene alpha mRNA expression were associated with infiltration of neutrophils. Interestingly, mRNA expression of the highly homologous chemokine ENA-78 was quiescent. In conclusion, our data indicate that growth-related oncogene alpha is an important chemoattractant for neutrophil diapedesis in vivo, whereas further migration of neutrophils and formation of micropustules appears to be influenced by the cooperative action of both growth-related oncogene alpha and interleukin-8.


Increased expression of renal aquaporin water channels in spontaneously hypertensive rats.
The present study was aimed to determine whether there exists an altered regulation of aquaporin (AQP) water channels in hypertension. Male spontaneously hypertensive rats (SHR) aged 10-12 weeks were used. Age-matched Wistar-Kyoto (WKY) rats served as control. The abundance of AQP1-4 proteins in the kidney was determined by Western blot analysis. The protein expression and activity of adenylyl cyclase were also determined. The medullary expression of AQP2 and AQP3 proteins was increased in SHR compared with that in WKY rats. The expression of AQP1 protein was also significantly increased in the inner medulla, while that of AQP4 was not. Immunohistochemistry of AQP2 revealed that principal cells of the collecting duct have strong immunoreactivity, the degree of which was augmented with prominent apical labeling in SHR. The plasma level of arginine vasopressin (AVP) was higher in SHR; the adenylyl cyclase activity stimulated by AVP was augmented, along with increased expression of type VI adenylyl cyclase. The urine was more concentrated with its volume decreased in SHR. The expression of AQP1-3 channels is increased in the kidney, in association with enhanced activity of the AVP/cAMP pathway, in SHR.


Efficacy and tolerability of levetiracetam versus phenytoin after supratentorial neurosurgery.
Antiepileptic drugs are routinely given after craniotomy. Though phenytoin (PHT) is still the most commonly used agent, levetiracetam (LEV) is increasingly administered for this purpose. This retrospective study compared the use of LEV and PHT as monotherapy prophylaxis following supratentorial neurosurgery. Patients receiving LEV monotherapy after supratentorial craniotomy were reviewed and compared to a control group of patients receiving PHT monotherapy. One of 105 patients taking LEV and 9/210 patients taking PHT had seizures within 7 days of surgery (p = 0.17). Adverse drug reactions requiring change in therapy during hospitalization occurred in 1/105 patients taking LEV and 38/210 patients taking PHT (p < 0.001). Among patients followed for at least 12 months, 11/42 (26%) treated with LEV vs 42/117 (36%) treated with PHT developed epilepsy (p = 0.34); 64% remained on LEV, while 26% remained on PHT (p = 0.03). Both levetiracetam (LEV) and phenytoin (PHT) were associated with a low risk of early postoperative seizures and a moderate risk of later epilepsy. LEV was associated with significantly fewer early adverse reactions than PHT and with a higher retention rate in patients who were followed for at least 1 year and developed epilepsy.


Catecholamines, calcium and cardiomyopathy.
The cardiomyopathic Syrian hamster has a genetically transmitted form of dilated cardiomyopathy and is an important paradigm of myocardial disease, particularly for studies addressing the earliest stages of myocardial dysfunction. This model exhibits an increase in cardiac sympathetic tone in the presence of an altered expression of sarcolemmal calcium channels or of alpha 1 receptors, and a defective handling of calcium by both cardiomyocytes and vascular smooth muscle cells. Increased expression of the oncogene c-myc is evident in cardiomyocytes before any overt evidence of heart disease. Alterations in a nuclear phosphoprotein, which appears to be important in the regulation of gene expression, have also been identified. The disease becomes phenotypically manifest by the development of microvascular spasm, reperfusion injury and myocyte loss. Myocyte loss, in turn, burdens the remaining cells with an increasing load, increasing sympathetic stimulation, myocyte hypertrophy and further cell loss--a continuing vicious spiral that culminates in the development of myocardial failure. All of the features of hamster cardiomyopathy may be prevented by the administration of verapamil or prazosin to juvenile hamsters before the phenotypic onset of their heart disease. This understanding has led to the study of new imaging agents that promise the detection of such forms of cardiomyopathy in their earliest stages and a means by which the effects of therapy can be assessed. If such mechanisms are applicable to human cardiomyopathy, early treatment of patients with adrenergic antagonists or calcium antagonists should be beneficial.


Collecting Data During the COVID-19 Pandemic: Lessons From an In-Person Survey of People Who Use Opioids.
In response to the COVID-19 pandemic, much in-person data collection has been suspended or become tele-remote. However, tele-remote methods often exclude marginalized groups, including people who use drugs, many of whom lack the technology to participate. To inform future surveillance and research during the pandemic and other public health disasters, we report methods and lessons learned from an in-person survey of people who use opioids conducted by the New York City Department of Health and Mental Hygiene (DOHMH) during the COVID-19 pandemic. This public health surveillance was a component of the Centers for Disease Control and Prevention Overdose Data to Action initiative and aimed to inform overdose prevention efforts. Survey domains inquired about participants' drug use patterns, risk behaviors, overdose history, and service use. From June 16 through September 9, 2020, DOHMH staff members conducted 329 surveys with participants from 4 syringe service programs (n = 148, 44.9%) and via street intercept (n = 81, 55.1%). To survey participants safely and effectively, it was important to build rapport upfront so that requests to maintain distance were not perceived as stigmatizing. DOHMH staff members offered all participants, regardless of survey eligibility, Narcan and hygiene products, including face masks and soap. Surveys administered outdoors during the COVID-19 pandemic should be limited to 30 minutes. Although conducting in-person surveys poses unique challenges, this method should be considered so marginalized populations are included in data collection and public health responses.


Clear cell carcinoma of the endometrium: an analysis of 21 cases.
Twenty-one cases of clear cell carcinoma of the endometrium are analysed in an effort to characterize the histologic features and biologic behavior of this type of neoplasm in the uterus and thereby to shed further light on the histogenesis of clear cell carcinoma in the female genital tract. The clinical profile of the patients closely paralleled that of women with the usual types of carcinoma of the endometrium. Fifteen (71%) were stage I, five were stage II, and one was stage IV at diagnosis. An assessment of the clinical stage and depth of myometrial invasion are useful in predicting the prognosis. The actuarial survival for all stages is 55.3% at 5 years, which is somewhat lower than that of adenocarcinoma of the endometrium in general. Operation alone or combined with radiation therapy is the treatment of choice for stage 1 clear cell carcinoma of the endometrium. The most cogent evidence for a müllerian rather than a mesonephric origin for clear cell carcinoma in the female genital tract is its presence in the endometrium, a Müllerian derivative. More specific points that support this concept are the findings of clear cell carcinoma confined to an otherwise benign endometrial polyp in two instances, the initimate admixture of clear cell and typical adenocarcinoma in three other instances, and the absence of mesonephric remnants in any of the 21 cases.


Verapamil vs quinine in recumbent nocturnal leg cramps in the elderly.
In an open-labeled trial with eight elderly patients (aged 62 to 87 years) suffering from nocturnal leg cramps refractory to treatment with quinine sulfate, we ruled out other active disease processes and substituted verapamil hydrochloride therapy (120 mg at bedtime). Response to treatment was assessed by biweekly observations by the primary care physician and nightly by the research registered nurse for the entire duration of the trial, lasting eight weeks. Observations made and clinical conditions reported were indicative of improvement and disappearance of cramping when therapy was changed from quinine to verapamil. This noteworthy improvement in patients with recumbent nocturnal leg cramps is an important finding and merits further investigation.


The effect of coffee, tea, and caffeine consumption on serum uric acid and the risk of hyperuricemia in Korean Multi-Rural Communities Cohort.
Caffeine, a commonly consumed food constituent, is known to exert beneficial physiological effects in humans. There is a lack of comprehensive population data for the effects of caffeine intake on urate metabolism. Therefore, the aim of this study was to determine whether coffee, tea, and caffeine intake influences serum uric acid and the risk of hyperuricemia in the Korean Multi-Rural Communities Cohort. We enrolled 9,400 participants in this study. An assessment of various dietary intake amounts of substances such as coffee and tea was performed using a food frequency questionnaire. The content of caffeine was calculated from coffee (74 mg/cup) and tea (15 mg/cup) intake information from the past year. Multivariate logistic regression models, multiple linear regression models, and analysis of covariance were applied to identify any association of dietary intake with serum uric acid levels or the risk of hyperuricemia. No trends for coffee, tea, or caffeine intake were found according to each quintile with serum uric acid in males, although there were weak, marginally significant trends between the content of coffee and caffeine intake and serum uric acid level in females (p = 0.07 for both). Tea intake in males and caffeine intake in females were significantly different between non-hyperuricemia and hyperuricemia (p = 0.04 and p = 0.04, respectively). In addition, a significant association of serum uric acid level with tea intake in males (β = 0.0006, p = 0.02) and with tea intake and caffeine intake in females (β = 0.0003, p = 0.04 and β = 0.0006, p = 0.02, respectively) was observed. There was no effect of coffee, tea, or caffeine intake on the risk of hyperuricemia in either males or females. This study suggests that caffeine consumption might have an effect on serum uric acid in females. However, coffee, tea, and caffeine intake amounts were not associated with the risk of hyperuricemia.


Cadaveric elbow allografts. A six-year experience.
Transplantation of total elbow allografts has been employed as a salvage procedure in an attempt to provide patients with a useful, painless range of motion of the elbow. Patients who are candidates for this procedure include those with disabling elbow joint symptoms who refuse an arthrodesis or are not candidates for conventional total elbow replacement because of excessive bone loss or young age. Allografts must be subjected to rigid internal fixation. Rush rod fixation used early in this series was associated with a high incidence of nonunion. In this series, ten patients followed for one to six years were provided with a functional elbow. However, long-term results are still unknown. Although not recommended for routine use, this operation is viewed as a salvage procedure. The use of allografts in elbow reconstruction does not preclude subsequent reconstruction with another allograft or fusion. In patients with deficient bone stock, the allografts reestablish bone mass to permit an arthrodesis or reconstructive arthroplasty.


Spectator motives and points of attachment: an investigation on professional basketball.
Spectator attendance to professional basketball in Turkey is significantly less than desired. Keeping in mind how important spectators are for team sports, understanding factors that affect game attendance will offer essential clues in terms of increasing spectator attendance. The main purpose of this study was to determine the relationships between basketball spectators' motives and points of attachment. With consideration to this purpose, the present study has tested the validity and reliability of the Motivation Scale for Sport Consumption and the Points of Attachment Index for Turkish basketball spectators. 197 basketball spectators participated in the study. Confirmatory factor analysis results demonstrated that the original models of the measurement tools employed for the study showed an acceptable degree of fit with the data. The internal consistency coefficients of the scales were found to be between 0.59 and 0.80 for the Motivation Scale for Sport Consumption and between 0.53 and 0.88 for the Points of Attachment Index. The canonical correlation analysis only returned a single significant function. The motives aesthetics and escape stood out in terms of the significant function, while the sport type (basketball in this study) stood out in the sense of attachment. Relationships identified between basketball spectators' motives and points of attachment could help sports managers and marketing experts to develop strategies focusing on increasing spectator attendance to their teams' games.


Determining benchmarks for evaluation and management coding in an academic division of general surgery.
Academic divisions of general surgery are facing ever-increasing financial pressures. Cost-cutting is a common approach to maintaining profitability, but strategies to increase revenue should not be ignored. One specific avenue for enhanced revenue generation in general surgery is that of coding for evaluation and management (E&M). Although this is the financial life-blood for many of the consultative services in departments of medicine, E&M coding is an often neglected and misunderstood component of surgical care. The financial records for the Division of General Surgery were reviewed for the period of January 2001 to June 2003. Specifically, charges and receipts for inpatient procedures and hospital visits (CPT codes 99231, 99232, and 99233) were determined. The analysis was limited to surgeons with a primary clinical focus based at the University hospital rather than the neighboring community or Veteran's Affairs hospitals. In addition, ICD-9 and All Patient Refined Diagnosis Related Groups (APR-DRG) data were analyzed to determine the surgeon-specific number of inpatients and inpatient-days with more than one ICD-9 code or secondary ICD-9 codes, or both, or an APR-DRG severity of illness score of 2, 3, or 4. These categories were defined to determine the number of inpatient-days for which E&M coding could be billed for management of secondary medical diagnoses. Analysis demonstrates that actual E&M charges were 40% to 47% of predicted minimums for E&M charges for the period under study. In theory, this result translates into an annual gain in receipts of 400,000 dollars to 600,000 dollars. We conclude that the ICD-9 and APR-DRG models may serve as benchmarks to determine the limits for E&M revenue stream, and E&M coding may represent an underutilized source of revenue among academic departments of surgery.


Can school-based distribution be used to maintain coverage of long-lasting insecticide treated bed nets: evidence from a large scale programme in southern Tanzania?
Many sub-Saharan African countries have achieved substantial gains in insecticide treated bednet coverage since 2005. The Tanzania National Malaria Control Programme identified school-based net distribution as one potential 'keep-up' strategy for the purpose of maintaining long-lasting insecticidal net (LLIN) coverage after a nationwide mass campaign in 2011. The School Net Programme (SNP) was implemented in three regions of southern Tanzania and distributed one LLIN to each enrolled child attending schools in primary grades (standards) 1, 3, 5 and 7, and secondary grades (forms) 2 and 4 in 2013 and again with slightly modified eligibility criteria in 2014 and 2015. Household surveys in the programme area as well as in a control area were conducted after each of the SNP distributions to measure ownership and use of long-lasting insecticide treated nets. Ownership of at least one LLIN after the first distribution was 76.1% (95% CI 70.8-80.7) in the intervention area and 78.6% (95% CI 74.4-82.3) in the control area. After the second distribution, ownership of at least one LLIN had dropped significantly in the control area to 65.4% (95% CI 59.5-71.0) in 2015 (P < 0.001), while coverage in the intervention area was maintained at 79.3% (95% CI 75.4 × 82.6). Ownership of at least one LLIN in intervention area remained stable following the second round of net distribution. During the same period LLIN ownership, especially of enough nets to ensure all household member access, fell significantly in the control area. These results demonstrate that the SNP may be sufficient to maintain stable LLIN coverage following a mass distribution of LLINs.


Phosphorus supplementation of cattle.
Severe lameness in a large proportion of an Angus cattle herd was attributed to phosphorus deficiency. The diagnosis was supported by a rapid response to phosphorus supplementation of the diet. A brief review of the development and diagnosis of phosphorus deficiency is presented. Practical considerations severely limit the choice of a phosphorus supplement. Directions for the use of the supernatant of high-phosphorus fertiliser and water mixtures, as feed or stock water additive and the production of a phosphorus lick are described. Other phosphorus supplements are discussed with particular reference to the fluorine hazard.


Time lapse imaging techniques for comparison of mineralization dynamics in primary murine osteoblasts and the late osteoblast/early osteocyte-like cell line MLO-A5.
Mineralization of bone matrix and osteocyte differentiation occur simultaneously and appear interrelated both spatially and temporally. Although these are dynamic events, their study has been limited to using static imaging approaches, either alone or in combination with chemical and biochemical analysis and/or genetic manipulation. Here we describe the application of live cell imaging techniques to study mineralization dynamics in primary osteoblast cultures compared to a late osteoblast/early osteocyte-like cell line, MLO-A5. Mineral deposition was monitored using alizarin red as a vital stain for calcium. To monitor differentiation into an osteocyte-like phenotype, the calvarial cells were isolated from transgenic mice expressing green fluorescent protein (GFP) driven by an 8-kb dentin matrix protein-1 (Dmp1) promoter that gives osteocyte-selective expression. Time lapse imaging showed that there was a lag phase of 15-20 h after beta-glycerophosphate addition, followed by mineral deposition that was rapid in primary osteoblast cultures but more gradual in MLO-A5 cultures. In primary osteoblast cultures, mineral was deposited exclusively in association with clusters of cells expressing Dmp1-GFP, suggesting that they were already differentiating into osteocyte-like cells. In MLO-A5 cells, the first indication of mineralization was the appearance of punctate areas of alizarin red fluorescence of 4-7 mum in diameter, followed by mineral deposition throughout the culture in association with collagen fibrils. A high amount of cell motility was observed within mineralizing nodules and in mineralizing MLO-A5 cultures. These studies provide a novel approach for analyzing mineralization kinetics that will enable us to dissect in a time-specific manner the essential players in the mineralization process.


Benzene exposure and non-Hodgkin lymphoma: a systematic review and meta-analysis of human studies.
Non-Hodgkin lymphoma comprises a heterogeneous group of cancers with unresolved aetiology, although risk factors include environmental exposures to toxic chemicals. Although the ubiquitous pollutant benzene is an established leukemogen, its potential to cause non-Hodgkin lymphoma has been widely debated. We aimed to examine the potential link between benzene exposure and risk of non-Hodgkin lymphoma in humans by evaluating a wide array of cohort and case-control studies using electronic systematic review. We did a comprehensive systematic review and meta-analysis of all qualified human epidemiological studies that assessed the relationship between benzene exposure and non-Hodgkin lymphoma. We queried the PubMed and Embase databases for relevant articles published before June 5, 2019, and applied the SysRev platform for study selection. All peer-reviewed human cohort and case-control studies that reported non-Hodgkin lymphoma risk estimates specifically for benzene exposure were eligible for inclusion. Studies that calculated relative risks (RRs) for industries or job types without identifying those specifically exposed to benzene, that combined non-Hodgkin lymphoma with other cancer types, or that reported many different solvent exposures together were excluded. From each study, two investigators independently extracted information on the study design, location, years, sample size, participation rates, age, sex, sources of cases and controls, diagnosis, histological verification, exposure assessment, results, adjustment, and statistical analysis, and subsequently assessed study quality. We calculated the meta-analysis relative risk (meta-RR) and CIs using the fixed effect and random effect models, as well as assessing publication bias. Our search yielded 2481 articles. After screening and removal of duplicates, 20 case-control studies and eight cohort studies were included in our meta-analysis, which included a total of 9587 patients with non-Hodgkin lymphoma. We reported an increased meta-relative risk (meta-RR) of 33% in highly exposed groups, when data were available (meta-RR 1·33 [95% CI 1·13-1·57], n=28). The meta-RR rose to 1·51 (1·22-1·87, n=18) in the studies that provided results specifically for highly exposed individuals. In particular, we reported a doubling of this risk for diffuse large B-cell lymphoma, a major non-Hodgkin lymphoma subtype (1·67 [1·01-2·77]). We also detected increased risks for follicular lymphoma (1·47 [0·95-2·27]) and hairy cell leukaemia (1·77 [0·99-3·16]), though they were not statistically significant. Funnel plot, Egger's test (p=0·77) and Begg's test (p=0·98) did not show evidence of publication bias. We evaluated the major aspects of causal inference and found evidence to support all the Hill considerations for assigning causation. Our findings suggest a causal link between benzene exposure and non-Hodgkin lymphoma, especially for diffuse large B-cell lymphoma. National Institute of Environmental Health Sciences.


Early diagnosis, early treatment and the new diagnostic criteria of diabetes mellitus.
The main purpose of treating diabetes is to prevent chronic complications. Strict glycemic control is known to suppress the occurrence and progression of these complications. The test for plasma glucose is essential to identify diabetic patients, as mild hyperglycemia without symptoms can be a risk factor for complications. The new classification and diagnostic criteria for diabetes were proposed by the American Diabetes Association (ADA), WHO and Japan Diabetes Society (JDS) between 1997 and 1999. Diabetes is classified into four etiological categories; type 1, type 2, diabetes due to other specific mechanisms or conditions, and gestational diabetes. Another classification system according to the degree of metabolic abnormality has also been adopted. For diagnosis of diabetes, the JDS Committee classified the glycemic state into three categories based on fasting plasma glucose (FPG) and 2-h plasma glucose in the 75 g oral glucose tolerance test (2hPG); normal type (FPG <110 and 2hPG <140 mg/dl), diabetic type (FPG > or =126 and/or 2hPG > or =200 mg/dl), and borderline type (neither normal nor diabetic type). The borderline type corresponds to the sum of impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT) based on ADA and WHO. Using the JDS criteria, diabetes is diagnosed when hyperglycemia of 'diabetic type' is confirmed on two or more occasions. ADA recommends the use of FPG alone for the diagnosis of diabetes, but findings from both Japan and Europe indicate that many diabetic subjects would be classified as non-diabetic solely on the FPG test. JDS recommends the use of the glucose tolerance test when the elevation of FPG is mild. Keeping glycemia near-normal by periodic monitoring of glycemic parameters and by appropriate treatment would prevent or reduce the diabetic complications in patients to a minimum.


Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?
Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment of the mitochondrial oxidative phosphorylation (OXPHOS). The unique features of mitochondrial genetics and the pivotal role of mitochondria in cell biology explain the phenotypical heterogeneity of primary mitochondrial diseases and the resulting diagnostic challenges that follow. Some peculiar features ("red flags") may indicate a primary mitochondrial disease, helping the physician to orient in this diagnostic maze. In this narrative review, we aimed to outline the features of the most common mitochondrial red flags offering a general overview on the topic that could help physicians to untangle mitochondrial medicine complexity.


Suture or graft? Changing trends in melanoma wound closure.
The method of wound repair following excision of primary cutaneous malignant melanoma has been assessed in a consecutive series of 256 melanomas of the trunk and limbs between 1972 and 1986. Excision margins of 1, 2 and 3-5 cm were used according to clinical assessment of tumour thickness. Primary closure was the preferred method of wound repair and split skin grafting when it could not be achieved. 30% of wounds were closed primarily between 1972-81, rising to 54% between 1982-86. This change has been partly due to an increase in the number of thin lesions, but also due to improved surgical technique. Simple interrupted suture was used between 1972-81. In 1982 a multilayer subcutaneous and subcuticular prolene suture was introduced as an improved method of direct closure, and led to a reversal in the ratio of grafting to primary closure. This technique is particularly beneficial for wounds with excision margins of 2 and 3 cm. Complication rates have been lower for primary suture (4%) than split skin graft (12%).


Free covalent aggregates of therapeutic insulin in blood of insulin-dependent diabetics.
Immunoreactive insulin (IRI) in the circulation of diabetics using insulin includes a 12,000-Mr covalent aggregate of insulin. In this study, both free and bound IRI were measured in nine type I diabetics who were treated sequentially for 3 wk with constant doses of conventional beef-pork, biosynthetic human, and beef-pork insulins (phases 1, 2, and 3, respectively). The aggregate accounted for 19 +/- 5.7, 38 +/- 7.7, and 26 +/- 7% of bound IRI, and 19 +/- 8.3, 35 +/- 7.3, and 31 +/- 5.0% of free IRI during phases 1, 2, and 3, respectively. Taken as concentrations (microU/ml), the absolute amounts of aggregate in the bound fraction were significantly (P less than .001) greater than those that were free, whereas the ratios of aggregate to monomer within each pool were similar (P greater than .1). The relative and absolute amounts of the insulin aggregate during each of the three treatment phases (compared by analysis of variance) were indistinguishable (P greater than 0.5). However, the aggregate was overestimated by a factor of approximately 2 when measurements were made on the basis of an insulin-monomer standard. We conclude that both the bound and free fractions of IRI contain insulin aggregate. Overreactivity of the aggregate in the radioimmunoassay contributes to the so-called hyperinsulinism of type I diabetes. As with insulin monomer, most of the 12,000-Mr aggregate is bound to antibodies. Because some of the aggregate is free, its biologic consequences must be assessed.


Mental disorders among Maori attending their general practitioner.
This paper identifies rates of common mental disorders among Maori and non-Maori consulting a general practitioner (GP), and explores the association between ethnicity and social and material deprivation. Survey of GPs and their patients. Participants were randomly selected GPs (n = 70), and their patients (n = 3414, of whom a subset of 786 form the basis of this paper). The main comparison is between self-identified ethnicity, mental disorder assessed by the Composite International Diagnostic Interview, and social and material deprivation measured by NZDep2001 (an area based measure), and an individualized index of deprivation. Rates of mental disorder among Maori general practice attenders were higher than among non-Maori. Overall, Maori women attenders were twice as likely as non-Maori women attenders to have a diagnosable mental disorder. The rates of anxiety, depressive and substance use disorders were all higher for Maori than for others attending GPs. Treatment for psychological problems was offered by the GP at similar rates to both Maori and non-Maori. Although there were differences between Maori and non-Maori in terms of social and material deprivation, higher rates of mental disorder among Maori attending GPs compared to non-Maori cannot be accounted for by these differences alone. These findings support the view that whilst social and material deprivation may play a role in the high rates of mental disorders among Maori general practice attenders, there are additional ethnicity-specific factors involved. Interventions to address Maori mental health (whether by reducing risk factors for mental disorder, by promoting disclosure, early recognition and intervention, or by ensuring access to acceptable and effective treatments) may need to explicitly take those factors into account.


Establishment of Drosophila imaginal precursor cells is controlled by the Arrowhead gene.
Metamorphosis in Drosophila melanogaster requires synchronization of numerous developmental events that occur in isolated imaginal precursor tissues. The imaginal primordia are established during embryonic stages and are quiescent for much of larval life. The Arrowhead gene is necessary for establishment of proper numbers of cells within a subset of imaginal precursor tissues. Loss-of-function mutations in Arrowhead reduce the number of abdominal histoblasts and salivary gland imaginal ring cells before the proliferative stages of their development. The number of abdominal histoblasts in mutant animals is approximately half that of wild-type, as might result from failure of a single early division of these cells. A neomorphic Arrowhead allele results in the specific loss of the retinal precursors by the early third instar, before they have begun to differentiate. Since Arrowhead mutations affect only subsets of imaginal tissue, there must be distinctions in the developmental regulation of different imaginal precursors. Arrowhead may be part of a regulatory pathway responsible for establishing the proper number of abdominal histoblasts and salivary gland imaginal ring cells. The neomorphic Arrowhead allele, which may cause misexpression of the Arrowhead gene in the eye-antenna imaginal disc, interferes with the establishment or proliferation of retinal precursor cells.


Estrogen signaling pathway and hormonal therapy.
Hormonal therapy, such as estrogen-targeting therapy, has undergone remarkable development in recent several years, using drugs such as LH-RH agonists, new SERMs and third-generation aromatase inhibitors. Several ongoing large-scale international clinical trials for hormonal therapy are establishing the standard protocol for treatments with these drugs. On the other hand, there have been attempts to predict the individual efficacy of hormonal therapy using classical molecular biomarkers such as ER and PgR. However, approximately one-third of ERalpha-positive patients do not respond to endocrine therapy, while some ERalpha-negative patients are responsive. These discrepancies may be due to the different estrogen-related intracellular signaling pathways in breast cancer cells. Furthermore, the ineffectiveness of hormonal therapy in some individuals (due to, for example, aromatase inhibitor resistance) may be caused by these mechanisms. In this paper, we discuss the molecular mechanisms of these different responses to hormonal therapies and their implications for the estrogen signaling pathway in breast cancer cells. Furthermore, we touch upon basic studies into predicting the efficacy of hormonal therapy and new strategies in this field.


Flash Sterilization and Component Reimplantation Is a Viable Option for Articulating Antibiotic Spacers in Periprosthetic Knee Infections.
The articulating antibiotic spacer is a treatment utilized for two-stage revision of an infected total knee arthroplasty. The original femoral component is retained and reused in one described variation of this technique. The purpose of this study is to determine the safety and efficacy of flash sterilization of the femoral component for reimplantation in an articulating antibiotic spacer for the treatment of chronic periprosthetic joint infection. A total of 10 patients were identified prospectively with a culture positive infected total knee arthroplasty. The patients underwent explantation, debridement, and placement of an articulating antibiotic spacer consisting of the explanted and sterilized femoral component and a new polyethylene tibial insert. The explanted tibial components were cleaned and flash-sterilized with the femoral components, but the components were then aseptically packaged and sent to our microbiology laboratory for sonication and culture of the sonicate for 14 days. Ten of 10 cleaned tibial components were negative for bacterial growth of the infecting organism after final testing and analysis. At 18-month follow-up, 9 of 10 of patients remained clear of infection. Among the 10 patients, 7 were pleased with their articulating spacer construct and had no intention of electively pursuing reimplantation. Also, 3 of 10 of patients were successfully reimplanted at a mean of 6.5 months after explantation. Autoclave sterilization and reimplantation of components may be a safe and potentially resource-sparing method of articulating spacer placement in two-stage treatment of PJI. Patient follow-up demonstrated clinical eradication of infection in 90% of cases with good patient tolerance of the antibiotic spacer.


Does BLOODCARE Powder Prevent Postoperative Chylous Ascites After Lymphadenectomy for Gynecological Malignancies?
The aim of this study was to evaluate the effect of an intraoperative hemostatic cellulose agent (BLOODCARE powder [Life Line, Brno, Czech Republic]) on reducing the incidence of postoperative chylous ascites (PCA) after complete pelvic and para-aortic lymphadenectomy (PPALN) in patients with gynecological cancers treated with laparotomy. This case control study reviewed 150 patients with gynecological cancer who underwent PPALN. In the study group (n = 75), BLOODCARE powder was applied below the left renal vein and bilateral obturator fossa. In the control group (n = 75), no sealant agent was used after the procedure, such as fibrin glue or a hemostatic cellulose agent. The demographic and surgical characteristics of the patients in both groups were similar. Chylous ascites occurred in 9 cases (6%). The incidence of PCA was lower in the study group (1 [1.3%] vs 8 [10.7%]; P = 0.03). Logistic regression analysis indicated that using BLOODCARE powder during the surgery independently protected against the development of PCA. Using BLOODCARE powder during retroperitoneal surgery may prevent PCA. This simple, effective agent should be used after PPALN for gynecological cancers.


Impact of delivery room resuscitation on outcomes up to 18 months in very low birth weight infants.
To examine the relationships between intensity of delivery room resuscitation and short- and long-term outcomes of very low birth weight infants enrolled in the Caffeine for Apnea of Prematurity (CAP) Trial. The CAP Trial enrolled 2006 infants with birthweights between 500 and 1250 g who were eligible for caffeine therapy. All levels of delivery room resuscitation were recorded in study participants. We divided infants in 4 groups of increasing intensity of resuscitation: minimal, n = 343; bag-mask ventilation, n = 372; endotracheal intubation, n = 1205; and cardiopulmonary resuscitation (chest compressions/epinephrine), n = 86. We used multivariable logistic regression models to compare outcomes across the 4 groups. The observed rates of death or disability, death, cerebral palsy, cognitive deficit, and hearing loss at 18 months increased with higher levels of resuscitation. Risk of bronchopulmonary dysplasia, severe retinopathy of prematurity, and brain injury also increased with higher levels of resuscitation. Adjustment for prognostic variables reduced the differences between the groups for most outcomes. Only the adjusted rates of bronchopulmonary dysplasia and severe retinopathy remained significantly higher after more intense resuscitation. In CAP Trial participants, the risk of death or neurodevelopmental disability at 18 months did not increase substantially with increasing intensity of delivery room resuscitation.


Agricultural runoff fuels large phytoplankton blooms in vulnerable areas of the ocean.
Biological productivity in most of the world's oceans is controlled by the supply of nutrients to surface waters. The relative balance between supply and removal of nutrients--including nitrogen, iron and phosphorus--determines which nutrient limits phytoplankton growth. Although nitrogen limits productivity in much of the ocean, large portions of the tropics and subtropics are defined by extreme nitrogen depletion. In these regions, microbial denitrification removes biologically available forms of nitrogen from the water column, producing substantial deficits relative to other nutrients. Here we demonstrate that nitrogen-deficient areas of the tropical and subtropical oceans are acutely vulnerable to nitrogen pollution. Despite naturally high nutrient concentrations and productivity, nitrogen-rich agricultural runoff fuels large (54-577 km2) phytoplankton blooms in the Gulf of California. Runoff exerts a strong and consistent influence on biological processes, in 80% of cases stimulating blooms within days of fertilization and irrigation of agricultural fields. We project that by the year 2050, 27-59% of all nitrogen fertilizer will be applied in developing regions located upstream of nitrogen-deficient marine ecosystems. Our findings highlight the present and future vulnerability of these ecosystems to agricultural runoff.


Marked depletion of plasma 1,5-anhydroglucitol, a major polyol, in streptozocin-induced diabetes in rats and the effect of insulin treatment.
Plasma levels of 1,5-anhydroglucitol (1,5AG), a major polyol resembling glucose in structure, fell rapidly and dramatically in streptozocin (STZ)-treated rats. 1,5AG fell immediately after STZ injection, reaching a plasma level 6 h after administration of the drug that was one-third that in the plasma of control rats. Reduction of 1,5AG was independent of the profile of blood glucose induced by STZ. After intravenous injection of [14C]-1,5AG, its plasma half-life was determined to be between 120 and 180 min. After a phase of acute decrease, the reduction of 1,5AG became gradual, stopping within 6 days after treatment. However, in some cases, the drop in 1,5AG was partially reversible by insulin treatment. The extent to which 1,5AG fell did not strictly correspond to the dose of STZ. The particular organ(s) consuming or accumulating 1,5AG was not identified. However, aside from the large amount of 1,5AG in plasma and the small amount of 1,5AG in the urine, the liver appears to be a significant organ for metabolism of 1,5AG.


Preparation of a multiple antigen glycopeptide (MAG) carrying the Tn antigen. A possible approach to a synthetic carbohydrate vaccine.
The glycosidic tumor-associated Tn antigen was conjugated to a lysine backbone containing a helper T-cell epitope in order to activate immune responses specific for some types of carcinomas. As opposed to traditional protein conjugates, this multiple antigen glycopeptide (MAG) offers the advantages of the lack of immunogenicity of the polylysine core and of accurate chemical definition. The MAG construction was assembled by conventional solid-phase peptide synthesis. The analysis of its antigenicity demonstrated that the Tn antigen on the MAG is recognized by Tn-specific monoclonal antibodies.


C4d deposition in cardiac allografts correlates with alloantibody.
The presence of C4d along the peritubular capillaries in kidney allografts correlates with the presence of anti-donor serum alloantibodies. We applied C4d staining to cardiac allograft and non-allograft biopsies to determine if C4d staining in heart allografts correlates with anti-donor serum alloantibodies. We stained for C4d all available frozen tissue biopsies from cardiac transplant recipients between 1997 and 2002, including autopsies. Two hundred twenty-one tissue samples from 124 patients were analyzed. Included in both groups were a variety of International Society for Heart and Lung Transplantation (ISHLT) grades of rejection plus post-implant cardiac ischemic injury (PIMI), and biopsies from patients who had received OKT3. Patients were matched by age, gender and interval after transplantation. Forty-four additional controls were included from patients biopsied for non-transplant-related cardiac disease. C4d staining of the myocardial capillaries correlated well with the presence of anti-donor alloantibodies. Twenty-one of 25 biopsies from patients with anti-donor alloantibodies showed C4d staining (84%), whereas only 7 of 60 without anti-donor alloantibodies stained for C4d. C4d staining did not correlate with ischemia or OKT3 therapy. Only 4 of 44 non-transplant biopsies stained for C4d (9%). An example of the clinical utility of C4d staining in patient care is presented. C4d staining of the capillaries in cardiac allografts correlates well with anti-donor serum alloantibodies, is a useful assay to verify alloantibody deposition, and can be used to establish one of the criteria for antibody-mediated cardiac rejections.


N-Glycosylation of laminin-332 regulates its biological functions. A novel function of the bisecting GlcNAc.
Laminin-332 (Lm332) is a large heterotrimeric glycoprotein that has been identified as a scattering factor, a regulator of cancer invasion as well as a prominent basement membrane component of the skin. Past studies have identified the functional domains of Lm332 and revealed the relationships between its activities and the processing of its subunits. However, there is little information available concerning the effects of N-glycosylation on Lm332 activities. In some cancer cells, an increase of beta1,6-GlcNAc catalyzed by N-acetylglucosaminyltransferase V (GnT-V) is related to the promotion of cancer cell motility. By contrast, bisecting GlcNAc catalyzed by N-acetylglucosaminyltransferase III (GnT-III) suppresses the further processing with branching enzymes, such as GnT-V, and the elongation of N-glycans. To examine the effects of those N-glycosylations to Lm332 on its activities, we purified Lm332s from the conditioned media of GnT-III- and GnT-V-overexpressing MKN45 cells. Lectin blotting and mass spectrometry analyses revealed that N-glycans containing the bisecting GlcNAc and beta1,6-GlcNAc structures were strongly expressed on Lm332 purified from GnT-III-overexpressing (GnT-III-Lm332) and GnT-V-overexpressing (GnT-V-Lm332) cells, respectively. Interestingly, the cell adhesion activity of GnT-III-Lm332 was apparently decreased compared with those of control Lm332 and GnT-V-Lm332. In addition, the introduction of bisecting GlcNAc to Lm332 resulted in a decrease in its cell scattering and migration activities. The weakened activities were most likely derived from the impaired alpha3beta1 integrin clustering and resultant focal adhesion formation. Taken together, our results clearly demonstrate for the first time that N-glycosylation may regulate the biological function of Lm332. This finding could introduce a new therapeutic strategy for cancer.


Infrared receptors in the facial pits of the Australian python Morelia spilotes.
There is a series of pits in the scales of the rostrum and posterior portion of the lower lips in some pythons and boas. In the Australian python Morelia spilotes, these pits are innervated by the maxillary and mandibular branches of the trigeminal nerve. Structural and neurophysiological evidence indicate that in the pits there are receptors that function as detectors of radiant heat flux.


Cytoplasmic residues influence the voltage-dependence of the gating of human K+ channels.
Shaker type potassium channels are strongly voltage dependent and potassium selective. Kv1.4 channels from a variety of sources exhibit a much shallower voltage-dependence of activation than other members of the family. We have made a chimeric construct consisting of the N-terminal chain of hKv1.1 spliced onto the transmembrane portion of hKv1.4 (IN/4). When expressed in Xenopus oocytes, the chimeric channel exhibits a voltage dependence that is similar to hKv1.1 although the voltage sensing and transduction machinery presumably reside in the transmembrane portion of the channel. Loss of the N-terminal ball and chain from hKv1.4 is not responsible for this as a truncation construct, starting close to the splice junction, has the same voltage-dependence as full length hKv1.4. We suggest that residues from the N-terminal chain of hKv1.1 interact with the machinery that transduces movement of the voltage sensor into channel opening. If so, this chimeric construct could provide a handle to the identification of elements of this transduction machinery.


beta-Hydroxybutyrate fuels synaptic function during development. Histological and physiological evidence in rat hippocampal slices.
To determine whether ketone bodies sustain neuronal function as energy substrates, we examined the effects of beta-hydroxybutyrate (betaHB) on synaptic transmission and morphological integrity during glucose deprivation in rat hippocampal slices. After the depression of excitatory postsynaptic potentials (EPSPs) by 60 min of glucose deprivation, administration of 0.5-10 mM D-betaHB restored EPSPs in slices from postnatal day (PND) 15 rats but not in slices from PND 30 or 120 rats. At PND 15, adding D-betaHB to the media allowed robust long-term potentiation of EPSPs triggered by high frequency stimulation, and prevented the EPSP-spike facilitation that suggests hyperexcitability of neurons. Even after PND 15,D-betaHB blocked morphological changes produced by either glucose deprivation or glycolytic inhibition. These results indicate that D-betaHB is not only able to substitute for glucose as an energy substrate but is also able to preserve neuronal integrity and stability, particularly during early development.


Initiation of protein synthesis in animal mitochondria. Purification and characterization of translational initiation factor 2.
Bovine liver mitochondrial translational initiation factor 2 (IF-2mt) has been purified to near homogeneity. The scheme developed results in a 24,000-fold purification of the factor with about 26% recovery of activity. SDS-polyacrylamide gel electrophoresis indicates that IF-2mt has a subunit molecular mass of 85 kDa. IF-2mt promotes the binding of formyl(f)Met-tRNA to mitochondrial ribosomes but is inactive with the nonformylated derivative. IF-2mt is active on chloroplast 30 S ribosomal subunits, but IF-2chl has no activity in promoting fMet-tRNA binding to animal mitochondrial ribosomes. IF-2mt is sensitive to elevated temperatures and is inactivated by treatment with N-ethylmaleimide. It is partially protected from heat and N-ethylmaleimide inactivation by the presence of either GTP or GDP suggesting that guanine nucleotides may bind to this factor directly. The binding of fMet-tRNA to mitochondrial ribosomes requires the presence of GTP and is inhibited by GDP. DeoxyGTP is very effective in replacing GTP in promoting fMet-tRNA binding to ribosomes and some activity is also observed with ITP. No activity is observed with ATP, CTP, or UTP. Nonhydrolyzable analogs of GTP can promote formation of both 28 S and 55 S initiation complexes indicating that GTP hydrolysis is not required for subunit joining in the animal mitochondrial system.


Strength properties of concrete incorporating coal bottom ash and granulated blast furnace slag.
Coal bottom ash (CBA) and fly ash (FA) are by-products of thermal power plants. Granulated blast-furnace slag (GBFS) is developed during iron production in iron and steel plants. This research was conducted to evaluate the compressive strength property and some durability characteristics of concrete incorporating FA, CBA, and GBFS. FA is used as an effective partial cement replacement; CBA and GBFS are used as partial replacement for fine aggregate without grinding. Water absorption capacity, unit weight and compressive strengths in 7, 28, and 90-day ages were assessed experimentally. For these experiments, concrete specimens were produced in the laboratory in appropriate shapes. The samples are divided into two main categories: M1, which incorporated CBA and GBFS; and M2, which incorporated FA, CBA, and GBFS. Remarkable decreases are observed in compressive strength and water absorption capacity of the concrete; bulk density of the concrete is also decreased. It can be concluded that if the content of CBA and GBFS is limited to a reasonable amount, the small decreases in strength can be accepted for low strength concrete works.


Experimental quantification of the free-carrier effect in silicon waveguides at extended wavelengths.
We examine the electro-optic effect at wavelengths ranging from 1.31 to 2.02 μm for: (1) an Electronic Variable Optical Attenuator (EVOA); and (2) a Micro-Ring Resonator (MRR). For the EVOA, simulations were performed to ascertain the relationship between free-carrier concentration and optical attenuation, and are in agreement with our observation of an increase in attenuation with increasing wavelength. MRRs were fabricated for use around wavelengths of 2 μm to explore the sensitivity of operation to bus-to-ring coupling gap and p-n junction offset. Trends observed in the experiment are replicated by simulation, calibrated using the observations of the EVOA operation. The previously proposed efficiency increase of operation around 2 μm compared to more traditional wavelengths is demonstrated. Future development of devices for these wavelengths, supported by amplification using Thulium Doped Fiber Amplifier (TDFA) technology, is a promising route to aid in the alleviation of increasing demands on communication networks.


Methodological challenges and potential solutions for economic evaluations of palliative and end-of-life care: A systematic review.
Given the increasing demand for palliative and end-of-life care, along with the introduction of costly new treatments, there is a pressing need for robust evidence on value. However, comprehensive guidance is missing on methods for conducting economic evaluations in this field. To identify and summarise existing information on methodological challenges and potential solutions/recommendations for economic evaluations of palliative and end-of-life care. We conducted a systematic review of publications on methodological considerations for economic evaluations of adult palliative and end-of-life care as per our PROSPERO protocol CRD42020148160. Following initial searches, we conducted a two-stage screening process and quality appraisal. Information was thematically synthesised, coded, categorised into common themes and aligned with the items specified in the Consolidated Health Economic Evaluation Reporting Standards statement. The databases Medline, Embase, HTADatabase, NHSEED and grey literature were searched between 1 January 1999 and 5 June 2023. Out of the initial 6502 studies, 81 were deemed eligible. Identified challenges could be grouped into nine themes: ambiguous and inaccurate patient identification, restricted generalisability due to poor geographic transferability of evidence, narrow costing perspective applied, difficulties defining comparators, consequences of applied time horizon, ambiguity in the selection of outcomes, challenged outcome measurement, non-standardised measurement and valuation of costs as well as challenges regarding a reliable preference-based outcome valuation. Our review offers a comprehensive context-specific overview of methodological considerations for economic evaluations of palliative and end-of-life care. It also identifies the main knowledge gaps to help prioritise future methodological research specifically for this field.


Identifying the causes of road crashes in Europe.
This research applies a recently developed model of accident causation, developed to investigate industrial accidents, to a specially gathered sample of 997 crashes investigated in-depth in 6 countries. Based on the work of Hollnagel the model considers a collision to be a consequence of a breakdown in the interaction between road users, vehicles and the organisation of the traffic environment. 54% of road users experienced interpretation errors while 44% made observation errors and 37% planning errors. In contrast to other studies only 11% of drivers were identified as distracted and 8% inattentive. There was remarkably little variation in these errors between the main road user types. The application of the model to future in-depth crash studies offers the opportunity to identify new measures to improve safety and to mitigate the social impact of collisions. Examples given include the potential value of co-driver advisory technologies to reduce observation errors and predictive technologies to avoid conflicting interactions between road users.


[Repercussion of different types of colostomy on the nutrition condition and type of stools].
Colectomies are considered, in general, not causing of serious problems of morbidity and mortality. It does not seem logical that the total or partial loss of the colon, whose anatomy and function are highly differentiated recognized, should be tolerated without clinically detectable impact, even for simple procedures such as those used in this study. We have reviewed 31 patients undergoing colectomy in our center, an average of 67.26 months before the present study. They are divided into 3 groups: 14 patients undergoing resection of ileocecal junction (RUIC), 7 to total colectomy (CT) and 10 to distal colectomy (CD). We have studied the frequency and consistency of depositions in all patients, as well as body growth (weight, height and nutritional index) and body composition (triceps skinfold, brachial perimeter and body fat percentage). Most patients undergoing RUIC or CT perform 3 or more depositions daily. No patient with CT presents depositions of normal consistency and they do so only 50% of the RUIC (p <0.05 versus CD). In patients with CD anthropometric values are normal. In patients undergoing CT, a decrease in corporal growth is detected (p <0.05) and in the group RUIC, a minor component of total body fat (p <0.05). Children subjected to RUIC or CT present anatomical and functional inadequacies that make depositions more frequent and smaller consistency than those after CD, which are normal. The abolition of the sphincter and valvular mechanism in RUIC and the decrease in the absorption area after CT can be held accountable for this. So are the decline in body mass in patients with CT and the increased involvement of its fatty component in RUIC. The apparent contradiction between these two forms of nutritional alterations detected by auxologic anthropometry might be explained by bacterial contamination of the distal ileum, and ileal secondary illness after the abolition of ileocecal antireflux mechanism, in the presence of faecal flora with colon. We believe that patients undergoing RUIC and CT presented detectable alterations by simple clinical referrals procedures, which can be applied, possibly throughout the pediatric age, to optimize their attention.


Differential requirements for ras and the retinoblastoma tumor suppressor protein in the androgen dependence of prostatic adenocarcinoma cells.
Prostate cells are dependent on androgen for proliferation, but during tumor progression prostate cancer cells achieve independence from the androgen requirement. We report that androgen withdrawal fails to inhibit cell cycle progression or influence the expression of cyclin-dependent kinase (CDK)/cyclins in androgen-independent prostate cancer cells, indicating that these cells signal for cell cycle progression in the absence of androgen. However, phosphorylation of the retinoblastoma tumor suppressor protein (RB) is still required for G1-S progression in androgen-independent cells, since the expression of constitutively active RB (PSM-RB) or p16ink4a caused cell cycle arrest and mimicked the effects of androgen withdrawal on downstream targets in androgen-dependent LNCaP cells. Since Ras is known to mediate mitogenic signaling to RB, we hypothesized that active V12Ras would induce androgen-independent cell cycle progression in LNCaP cells. Although V12Ras was able to stimulate ERK phosphorylation and induce cyclin D1 expression in the absence of androgen, it was not sufficient to promote androgen-independent cell cycle progression. Similarly, ectopic expression of CDK4/cyclin D1, which stimulated RB phosphorylation in the presence of androgen, was incapable of inactivating RB or driving cell cycle progression in the absence of androgen. We show that androgen regulates both CDK4/cyclin D1 and CDK2 complexes to inactivate RB and initiate cell cycle progression. Together, these data show that androgen independence is achieved via deregulation of the androgen to RB signal, and that this signal can only be partially initiated by the Ras pathway in androgen-dependent cells.


The protective effect of autophagy on ischemia/reperfusion-induced hearing loss: implications for sudden hearing loss.
The present study aimed to determine the effects of ischemia/reperfusion (IR) injury for the carotid system on hearing, particularly, the role of autophagy in this process. Sixty-three Sprague-Dawley rats were divided randomly into three groups: sham surgery animals (S), temporary carotid artery occlusion (ischemia) for 30 min (I30), and temporary carotid artery occlusion for 60 min (I60). Auditory brainstem response measurements were performed on mice. After 72 h of reperfusion, the microcirculation was measured in mice after ischemia injury. Immunofluorescence was used to examine the expression of caspase-3 and light chain 3B in the cochlear sections. Temporary carotid artery occlusion lasting for 30 (I30) or 60 min (I60) caused significant hearing loss in the ischemia phase. Following a recovery during the postreperfusion phase, the temporal threshold shift occurred in the I30 group, whereas a permanent threshold shift occurred in the I60 group. Moreover, both microcirculation and autophagy affected hearing 24 h after reperfusion, whereas at 72 h, autophagy works as an intrinsic cellular process that protects against death from the IR effect. These results suggest that the sooner the reperfusion, the better the hearing recovery. In conclusion, autophagy promotes cell survival in the cochlea; however, excessive IR damage counteracts the beneficial potential of autophagy protection and leads to a permanent threshold shift.


Characterization of a T7-like lytic bacteriophage (phiSG-JL2) of Salmonella enterica serovar gallinarum biovar gallinarum.
PhiSG-JL2 is a newly discovered lytic bacteriophage infecting Salmonella enterica serovar Gallinarum biovar Gallinarum but is nonlytic to a rough vaccine strain of serovar Gallinarum biovar Gallinarum (SG-9R), S. enterica serovar Enteritidis, S. enterica serovar Typhimurium, and S. enterica serovar Gallinarum biovar Pullorum. The phiSG-JL2 genome is 38,815 bp in length (GC content, 50.9%; 230-bp-long direct terminal repeats), and 55 putative genes may be transcribed from the same strand. Functions were assigned to 30 genes based on high amino acid similarity to known proteins. Most of the expected proteins except tail fiber (31.9%) and the overall organization of the genomes were similar to those of yersiniophage phiYeO3-12. phiSG-JL2 could be classified as a new T7-like virus and represents the first serovar Gallinarum biovar Gallinarum phage genome to be sequenced. On the basis of intraspecific ratios of nonsynonymous to synonymous nucleotide changes (Pi[a]/Pi[s]), gene 2 encoding the host RNA polymerase inhibitor displayed Darwinian positive selection. Pretreatment of chickens with phiSG-JL2 before intratracheal challenge with wild-type serovar Gallinarum biovar Gallinarum protected most birds from fowl typhoid. Therefore, phiSG-JL2 may be useful for the differentiation of serovar Gallinarum biovar Gallinarum from other Salmonella serotypes, prophylactic application in fowl typhoid control, and understanding of the vertical evolution of T7-like viruses.