Immunohistochemical localization of Ca2+/calmodulin-dependent protein kinase II in rat brain and various tissues.
Polyclonal antibodies against Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) of rat brain were prepared by immunizing rabbits and then purified by antigen-affinity column. The antibodies which recognized both subunits of the enzyme with Mrs 49K and 60K were used for the study on the distribution of CaM kinase II in formalin-fixed, paraffin-embedded tissues. In the brain, a light-microscopic study demonstrated strong immunoreactivity in neuronal somata and dendrites and weak immunoreactivity in nuclei. The densely stained regions included cerebral cortex, hippocampal formation, striatum, substantia nigra, and cerebellar cortex. In substantia nigra, neurites were stained, but not neuronal somata. Electron microscopy revealed that the immunoreactive product was highly concentrated at the postsynaptic densities. In addition to neurons, weak immunoreactivity was also demonstrated in glial cells, such as astrocytes and ependymal cells of ventricles and epithelial cells of choroid plexus. In other tissues, strong immunoreactivity was observed in the islet of pancreas and moderate immunoreactivity in skeletal muscle and kidney tubules. Immunoreactivity was demonstrated in all of the tissues tested. The results suggest that CaM kinase II is widely distributed in the tissues.


How Twitter Is Studied in the Medical Professions: A Classification of Twitter Papers Indexed in PubMed.
Since their inception, Twitter and related microblogging systems have provided a rich source of information for researchers and have attracted interest in their affordances and use. Since 2009 PubMed has included 123 journal articles on medicine and Twitter, but no overview exists as to how the field uses Twitter in research. This paper aims to identify published work relating to Twitter within the fields indexed by PubMed, and then to classify it. This classification will provide a framework in which future researchers will be able to position their work, and to provide an understanding of the current reach of research using Twitter in medical disciplines. Papers on Twitter and related topics were identified and reviewed. The papers were then qualitatively classified based on the paper's title and abstract to determine their focus. The work that was Twitter focused was studied in detail to determine what data, if any, it was based on, and from this a categorization of the data set size used in the studies was developed. Using open coded content analysis additional important categories were also identified, relating to the primary methodology, domain, and aspect. As of 2012, PubMed comprises more than 21 million citations from biomedical literature, and from these a corpus of 134 potentially Twitter related papers were identified, eleven of which were subsequently found not to be relevant. There were no papers prior to 2009 relating to microblogging, a term first used in 2006. Of the remaining 123 papers which mentioned Twitter, thirty were focused on Twitter (the others referring to it tangentially). The early Twitter focused papers introduced the topic and highlighted the potential, not carrying out any form of data analysis. The majority of published papers used analytic techniques to sort through thousands, if not millions, of individual tweets, often depending on automated tools to do so. Our analysis demonstrates that researchers are starting to use knowledge discovery methods and data mining techniques to understand vast quantities of tweets: the study of Twitter is becoming quantitative research. This work is to the best of our knowledge the first overview study of medical related research based on Twitter and related microblogging. We have used 5 dimensions to categorize published medical related research on Twitter. This classification provides a framework within which researchers studying development and use of Twitter within medical related research, and those undertaking comparative studies of research, relating to Twitter in the area of medicine and beyond, can position and ground their work.


Fully automated, deep learning segmentation of oxygen-induced retinopathy images.
Oxygen-induced retinopathy (OIR) is a widely used model to study ischemia-driven neovascularization (NV) in the retina and to serve in proof-of-concept studies in evaluating antiangiogenic drugs for ocular, as well as nonocular, diseases. The primary parameters that are analyzed in this mouse model include the percentage of retina with vaso-obliteration (VO) and NV areas. However, quantification of these two key variables comes with a great challenge due to the requirement of human experts to read the images. Human readers are costly, time-consuming, and subject to bias. Using recent advances in machine learning and computer vision, we trained deep learning neural networks using over a thousand segmentations to fully automate segmentation in OIR images. While determining the percentage area of VO, our algorithm achieved a similar range of correlation coefficients to that of expert inter-human correlation coefficients. In addition, our algorithm achieved a higher range of correlation coefficients compared with inter-expert correlation coefficients for quantification of the percentage area of neovascular tufts. In summary, we have created an open-source, fully automated pipeline for the quantification of key values of OIR images using deep learning neural networks.


Can breast characteristics predict upper torso musculoskeletal pain?
Several studies have associated a large breast size with an increased prevalence and severity of musculoskeletal pain, particularly pain in the upper torso. Despite this evidence, no research has explored whether breast size or related characteristics are risk factors for upper torso musculoskeletal pain. A backward multiple regression analysis was performed to identify whether characteristics of the breasts and upper torso, as well as physical factors known to be associated with musculoskeletal pain, could predict musculoskeletal pain among a cohort of 378 Australian women aged 18 years and over who had a wide range of breast sizes. The model identified that breast volume, age and nipple-to-nipple distance predicted 23% of the variance in upper torso musculoskeletal pain reported by the participants. Women with a larger breast volume, lower age and a greater nipple-to-nipple distance were predicted to report a higher upper torso musculoskeletal pain score.


Minimally invasive surgical coronary artery bypass in women.
Minimally invasive coronary artery bypass grafting (CABG) has emerged as a viable alternative to conventional sternotomy CABG in select patients requiring coronary revascularization. Specific techniques vary, but minimally invasive CABG (i.e., MIDCAB) usually involves revascularization of the left anterior descending (LAD) artery with the left internal mammary artery (LIMA). Minimally invasive CABG can be performed without cardiopulmonary bypass through a small anterior thoracotomy incision with robotic assistance. Use of minimally invasive CABG may offer specific benefits for women requiring revascularization, particularly given that female gender is an independent risk factor for inferior outcomes following CABG. Here we describe how to perform robot-assisted minimally invasive CABG, with a focus on technical modifications aimed at improving outcomes in women.


Case-control study of respiratory dynamic compliance in mechanically ventilated near-term newborns in a pre-hospital setting.
To determine the threshold value between normal or decreased dynamic compliance (Cdyn) in ventilated near-term newborns. A case control study was performed during pediatric transport. Controls were newborns without pulmonary disease (group 1; n = 30) and cases were newborns with respiratory distress syndrome, the paradigm of decreased Cdyn (group 2; n = 30). All consecutive newborns of more than 34 weeks' gestation and less than 5 days of life, intubated and ventilated with Babylog 8,000 plus (Dräger, Lübeck, Germany) were included from February 2008 to June 2010. Newborns were assigned to groups 1, 2, or 3 (other patients with disease where the compliance is not easily predictable) by two physicians, using predefined criteria. Cdyn was as measured by the ventilator in spontaneous mandatory ventilation mode with less than 15% leaks. One hundred and twelve newborns were included in the study. In the multivariate analysis, the groups of diseases and height were statistically associated with Cdyn (p < 0.001). The receiver operating characteristic curve of Cdyn corrected for height constructed with group 1 and 2 newborns yielded a cutoff value of 2.02 mL/mbar/m with a sensitivity of 100% (95% confidence interval [100-100%]) and a specificity of 96% (95% confidence interval [90-100%]) to differentiate between group 1 and 2 newborns. Ventilator-measured dynamic compliance can differentiate normal and decreased compliance in near-term newborns of more than 34 weeks' gestation in the clinical setting.


The role of urinary cytology when diagnostic workup is suspicious for upper tract urothelial carcinoma but tumour biopsy is nonconfirmatory.
We sought to determine the value of obtaining preoperative urinary cytology when diagnostic workup of an upper tract mass is suspicious for upper tract urothelial carcinoma (UTUC), but biopsy fails to confirm the diagnosis. Using billing code data, 239 patients were identified as having undergone radical nephroureterectomy (RNU) by 16 urologists from September 29, 1998 to July 31, 2015. Of this group, 19 adult patients had a presumed preoperative diagnosis of UTUC in a native kidney, at least three months of followup, no history of concurrent radical cystectomy with RNU, and negative/non-diagnostic tissue biopsy. These patients were divided into three groups: Group A had no urinary cytology taken (n=6); Group B had upper and/or lower tract cytology performed with neither positive nor atypical (n=7); Group C had upper and/or lower tract cytology performed with at least one positive or atypical (n=6). Demographic information and diagnostic workup was similar between the groups, although Group A had more patients with a history of prior radical cystectomy for bladder cancer (p=0.02). One patient in Group B had benign tissue on final pathology. All patients in Groups A and C had malignancy on final pathology and overall, the three groups had similar rates of malignancy. When a composite of clinical findings suggest UTUC, performing urinary cytology may not be necessary. A negative result in this setting should not be used to rule out UTUC, as this is often discordant with final pathology. A positive cytology result may help solidify the diagnosis when other findings are less clear.


Central neuron initiation of periodic gill movements.
In Aplysia periodic spontaneous gill movements are controlled by activity endogenous to the abdominal ganglion. These movements were still observed when only the ctenidio-genital nerve was left intact between the ganglion and the gill. One kind of spontaneous gill movement (one per 5 minutes at 15 degrees C) was correlated with the expression of activity of interneuron II; others were not. With reference to this kind of spontaneous gill movement, four types of central neurons in the ganglion send processes to the gill via the nerve. Two cell types (ii, iii) are inhibited and the other two (i, iv) are excited. Two types (i, ii) elicited gill movement-one type activating large gill areas elicited spontaneous gill movements, and the other activating specific gill regions did not participate in the spontaneous gill movements. The value of this preparation in studying the role of central neurons eliciting specific patterned movements and the temporal organization of their activity is shown.


Chronic interstitial lung disease due to Epstein-Barr virus infection in two infants.
This case study reports on two infants, 5 and 6 months of age, respectively, with chronic interstitial lung disease who presented with failure to thrive, tachypnoea, rales and mild hypoxaemia. Epstein-Barr virus (EBV) was detected by in situ hybridization in lung biopsy specimens and by EBV-deoxyribonucleic acid-polymerase chain reaction (PCR) in bronchoalveolar lavage (BAL) fluid in one patient and by in situ hybridization and PCR analysis in BAL fluid in the second patient. There was serological evidence of immunoglobulin G antibodies to EBV capsid antigen by indirect immunofluorescence in both patients. After 7 months of respiratory symptoms one patient was successfully treated with a 10 day course of intravenous ganciclovir followed by oral acyclovir for 20 days. The other patient became symptom free after 3.5 months of respiratory symptoms, without any specific antiviral medication. During a follow-up of 2 and 1.5 yrs, respectively, both infants remained symptom free and showed normal physical development.


Scalp psoriasis: an overview of the disease and available therapies.
The scalp is one of the regions of the body most commonly affected by psoriatic lesions. While the head represents only 10 percent of the body's surface area, the consequences of scalp psoriasis are disproportionate to the area, as it can be seriously debilitating and presents social and emotional distress to the affected individual. Scalp lesions are often well-demarcated and may have thick gray or white scale; patients with scalp psoriasis frequently complain of pruritus and shedding of scale. Current treatment modalities--including phototherapy, topical corticosteroids, topical vitamin D analogues and conventional systemic therapies--have produced unsatisfactory results for patients with moderate-to-severe scalp psoriasis due to difficulties in administration to the disease site, poor compliance, toxicity and inadequate long-term efficacy. The emergence of biologic therapies as an effective modality for the treatment of plaque psoriasis may provide another option for patients suffering from plaque psoriasis of the scalp.


Total knee arthroplasty after high tibial osteotomy. A comparison study in patients who had bilateral total knee replacement.
The outcome of total knee replacement after high tibial osteotomy remains uncertain. We hypothesized that the results of total knee replacement with or without a previous high tibial osteotomy are similar. The results of a consecutive series of thirty-nine bilateral total knee arthroplasties performed with cement at an average of 8.7 years after unilateral high tibial osteotomy were reviewed. There were twenty-seven men and twelve women. Preoperatively, the knee scores according to the system of the Knee Society were similar for all of the knees; however, valgus alignment and patella infera were more common in the knees with a previous high tibial osteotomy. Bilateral total knee replacement was staged in seven patients and was simultaneous in thirty-two patients. The results of the total knee arthroplasties were retrospectively reviewed with respect to the knee and function scores according to the system of the Knee Society, the radiographic findings, and the complications. Intraoperatively, no notable differences were identified in the number of medial, lateral, or lateral patellar releases required. However, less lateral tibial bone was resected in the group with a previous high tibial osteotomy (average, 3.3 millimeters) than in the group without a high tibial osteotomy (average, 7.5 millimeters). The average duration of follow-up was 7.5 years (range, three to sixteen years) in the group with a previous high tibial osteotomy and 6.8 years (range, two to ten years) in the group without a high tibial osteotomy. At the time of the final follow-up, the knee and function scores were similar for the two groups (89.0 and 81.0 points, respectively, for the group with a previous high tibial osteotomy, and 89.6 and 83.9 points, respectively, for the group without a high tibial osteotomy). Although more knees were free of pain in the group without a previous high tibial osteotomy (thirty-six) than in the group with a previous osteotomy (thirty-three), this difference was not found to be significant with the numbers available (p = 0.4810). Knee alignment and stability, femoral and tibial component alignment, and range of motion also were similar in both groups postoperatively. One allpolyethylene tibial component was revised in the high tibial osteotomy group. Two knees in each group required manipulation. There were no deep infections. While patients with a previous high tibial osteotomy may have important differences preoperatively, including valgus alignment, patella infera, and decreased bone stock in the proximal part of the tibia, the present study suggests that the clinical and radiographic results of primary total knee arthroplasty in knees with and without a previous high tibial osteotomy are not substantially different. In our relatively small group of patients, the previous high tibial osteotomy had no adverse effect on the outcome of the subsequent total knee replacement.


Airway scope for tracheal intubation in the lateral position.
Tracheal intubation in the lateral position is difficult because the laryngeal view is compromised during direct laryngoscopy. The Airway Scope facilitates intubation even when laryngeal views are poor with direct laryngoscopy, as they often are in the lateral position. We thus compared the efficacy of the Airway Scope in supine patients with those in the left- and right-lateral positions. Anesthetized adults were randomly assigned to supine, left-lateral, or right-lateral position (n = 43 for each group). Laryngeal views were obtained in the designated position with a Macintosh laryngoscope, and patients' tracheas were subsequently intubated with the Airway Scope. Specifically, we tested the hypothesis that the time required for intubation in the left- and right-lateral positions is not increased by >10 seconds compared with tracheal intubation in the supine position. Overall intubation success was 100% in the 2 lateral positions, and 98% in the supine position. Intubation times were similar in the left-lateral (24 [5] seconds, mean [SD]), right-lateral (24 [6] seconds), and supine (22 [7] seconds) positions. The numbers of required intubation attempts were similar in the 2 lateral positions and in the supine and left-lateral positions. However, more intubation attempts were required in the supine position than in the right-lateral position (P = 0.004). The incidences of airway complications were similar in each position; no hypoxia, dental injury, or esophageal intubation was observed. Modified Cormack-Lehane and the percentage of glottic opening scores obtained with the Macintosh laryngoscope did not differ between the 2 lateral positions, but the modified Cormack-Lehane and percentage of glottic opening scores were superior in the supine position (all P < 0.001) compared with either of the lateral positions. Despite worse laryngoscopic views in either lateral position than when patients were supine, intubation with the Airway Scope offered high success rates. Furthermore, intubation time using the Airway Scope in either lateral position was not longer by >10 seconds than in the supine position. The Airway Scope thus seems to be a useful tool when tracheal intubation is required in a laterally positioned patient.


Intraguild predation behaviour of ladybirds in semi-field experiments explains invasion success of Harmonia axyridis.
Harmonia axyridis has been introduced as a biological control agent in Europe and the USA. Since its introduction, it has established and spread, and it is now regarded as an invasive alien species. It has been suggested that intraguild predation is especially important for the invasion success of H. axyridis. The aim of this study was to compare the intraguild predation behaviour of three ladybird species (Coccinella septempunctata, Adalia bipunctata, and H. axyridis). Predation behaviour was investigated in semi-field experiments on small lime trees (Tilia platyphyllos). Two fourth-instar larvae placed on a tree rarely made contact during 3-hour observations. When placed together on a single leaf in 23%-43% of the observations at least one contact was made. Of those contacts 0%-27% resulted in an attack. Harmonia axyridis attacked mostly heterospecifics, while A. bipunctata and C. septempunctata attacked heterospecifics as often as conspecifics. In comparison with A. bipunctata and C. septempunctata, H. axyridis was the most successful intraguild predator as it won 86% and 44% of heterospecific battles against A. bipunctata and C. septempunctata respectively, whilst A. bipunctata won none of the heterospecific battles and C. septempunctata won only the heterospecific battles against A. bipunctata. Coccinella septempunctata dropped from a leaf earlier and more often than the other two species but was in some cases able to return to the tree, especially under cloudy conditions. The frequency with which a species dropped did not depend on the species the larva was paired with. The results of these semi-field experiments confirm that H. axyridis is a strong intraguild predator as a consequence of its aggressiveness and good defence against predation from heterospecific species. The fact that H. axyridis is such a strong intraguild predator helps to explain its successful establishment as invasive alien species in Europe and the USA.


Predictors of metabolic risk in childhood obesity.
Most of the complications of juvenile obesity are due to metabolic disturbances induced by an excessive accumulation of fat which leads to chronic diseases like type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Finding effective ways of identifying obese paediatric patients who are at increased risk of developing cardiovascular and metabolic complications has been recognised to be a promising strategy to improve prevention of complications of early obesity. Moreover, correctly identifying obese children who are already affected by metabolic co-morbidities should be a clinical priority. According to the state of the art summarised in this review, traditional metabolic variables included in the definitions of metabolic syndrome (MS), pre-diabetes, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steato-hepatitis and, in obese girls, the presence of polycystic ovary syndrome are the best available longitudinal predictors of CVD and T2DM among obese children and adolescents. In clinical practice, traditional metabolic variables included in the definitions of MS should be assessed in all obese children and adolescents; fasting metabolic variables have been proposed to identify obese patients likely to be affected by impaired glucose tolerance or T2DM, and ultrasound has proved to be a valid surrogate for biopsy in the diagnosis of NAFLD. Further large longitudinal and cross-sectional studies are needed to improve our chances of identifying obese youth at the highest metabolic risk.


[WHO Framework Convention on Tobacco Control (FCTC) Article 8: protection from exposure to tobacco smoke].
It is necessary to implement 100% smoke-free environments in all indoor workplaces and indoor public places in order to protect people from exposure to second-hand tobacco smoke (SHS). Forty-four countries have already implemented comprehensive smoke-free legislations according to the Framework Convention on Tobacco Control (FCTC) Guidelines on protection from exposure to tobacco smoke. The Occupational Safety and Health Law (OSHL) was partially revised to strengthen the countermeasures against SHS in Japan in 2014. However, the revision was only minimal. Firstly, it is necessary to make efforts to implement countermeasures against SHS (their implementations are not obligatory, as required in Article 8). Secondly, the revised OSHL allowed the implementation of designated smoking rooms inside workplaces (Article 8 requires 100% smoke-free environments). Thirdly, revised OSHL does not effectively cover the small-scale entertainment industry so that workers in restaurants and pubs will not be protected from occupational SHS. We explain the importance of implementation of 100% smoke-free environments by law, using the data on leakage of smoke from designated smoking rooms, and occupational exposure to SHS among service industry workers. The decrease in the incidence of smoking-related diseases in people where a comprehensive smoke-free law is implemented is also introduced. These data and information should be widely disseminated to policy makers, media, owners of service industries, and Japanese people.


Survey nonresponse is associated with increased mortality in patients with rheumatoid arthritis and in a community population.
To determine whether nonresponse to a mailed health survey predicts mortality in patients with rheumatoid arthritis (RA) and in a community sample in Finland. A 5-page health questionnaire was administered in 2000. Two years later the vital status of the subjects was ascertained from the Population Registry. A total of 1095 (73%) patients with RA and 1530 (77%) community control subjects returned a completed questionnaire. Over the 2-year period, the number of deaths was 57 (5.2%) in RA responders and 37 (9.3%) in RA nonresponders (p = 0.004). The corresponding figures in community controls were 34 (2.2%) and 23 (4.9%) (p = 0.002). In a Cox regression model adjusted for age and sex, RA patient and community control nonresponders were respectively 1.65 (95% CI 1.07 to 2.55) and 2.89 (95% CI 1.69 to 4.94) times more likely to die over the 2 years compared to the responders. Nonresponders to a mailed health survey were more likely to die over 2 years compared to responders. The possible nonresponse bias should be kept in mind in the interpretation of the results of studies that are based on mail questionnaires only.


High-dose cisplatin concurrent to conventionally delivered radiotherapy is associated with unacceptable toxicity in unresectable, non-metastatic stage IV head and neck squamous cell carcinoma.
Unresectable head and neck squamous cell carcinoma (HNSCC), non-metastatic, comprises a heterogeneous group of patients (pts), formed of stage III and IV pts. Since the available literature had not distinguished among these two groups, we prospectively addressed whether the recommended regimen involving cisplatin 100 mg/m2 concurrent to conventionally delivered radiotherapy (RT) is feasible in stage IV pts, based on the efficacy and safety of this regimen. A total of 30 pts were enrolled onto this study. Chemoradiation (CRT) consisted of RT 70 Gy, delivered in 35 daily fractions of 2 Gy, in 7 weeks, concurrent to cisplatin 100 mg/m2 on days 1, 22 and 43. Supportive treatment was provided as needed. Twenty-eight pts had tumors staged as T4 and 20 had N2 or N3 cervical involvement. The most common primary sites were the oral cavity and the oropharynx (23 pts). We observed six complete responses and 12 partial responses, with an overall response rate of 60%. A high rate of treatment-related toxicities was observed, with three deaths during CRT, and 26 pts suffering from one or more grade 3/4 toxicities, mainly dysphagia, mucositis, dermatitis, vomiting, infection or anemia. A prolonged treatment time was observed (63 days), as a result of unplanned treatment breaks. The lack of requirement of red blood cell transfusion was favorably related to the response to the treatment (93% vs. 50%, P=0.033). For the whole population, with a median follow-up of 20.8 months, the median progression-free survival (PFS) was 8.0 months, and the median overall survival (OS) was 17.3 months. Longer median PFS and OS were seen in responding pts (12.8 vs. 4.1 months, P=0.0001; and not reached (NR) vs. 10.4 months, P=0.0037, respectively), as well as in those pts not requiring red blood cell transfusion (12.8 vs. 3.9 months, P=0.0162; and NR vs. 10.4 months, P=0.0176, respectively). In conclusion, this concurrent CRT regimen is hardly delivered in stage IV, unresectable, locally advanced HNSCC pts, due to treatment-related toxicities and longer RT duration. As a subset of pts may benefit from this regimen, adequate patient selection and aggressive supportive measures are essential.


Predictors of Initiation of Medication for Opioid Use Disorder and Retention in Treatment Among U.S. Pregnant Women, 2013-2017.
To describe trends and factors associated with medication administration for opioid use disorder (OUD) and retention in treatment among pregnant women with OUD. This is a retrospective, nationwide, cross-sectional analysis of treatment episodes for primary OUD among pregnant women from 2013 to 2017. The primary outcome was initiation of methadone, buprenorphine, or naltrexone. Secondary outcomes were retention in treatment defined as length of treatment episode lasting six months or greater, and completion of treatment. Descriptive statistics and logistic regression were applied to describe trends in, and identify factors associated with the outcomes. There were 42,239 treatment episodes for primary OUD among pregnant women who reported using heroin (65.0%, 27,459), synthetic opioid (33.2%, 14,034), or nonprescribed methadone (1.8%, 746) between 2013 and 2017. Medications for OUD were administered in 47.4% (20,013) of episodes. Retention in treatment occurred in 16.6% of episodes without medications for OUD, and 37.8% of episodes with medications for OUD (P=.01). The rate of medication administration for OUD increased from 41.0% in 2013 to 52.0% in 2017; however, retention rates declined from 39.0% to 33.0% among treatment episodes with medication for OUD. History of at least one prior treatment episode was associated with both administration of medications for OUD and retention in treatment. In spite of current guidelines, most treatment episodes for OUD during pregnancy did not involve administration of medications for OUD. Although administration of medications for OUD has improved over time, retention in treatment is lagging. These findings highlight gaps in the U.S. addiction care system.


Short stature and growth hormone use in pediatric hemodialysis patients.
End-stage renal disease (ESRD) causes growth retardation in children, and poor growth has been linked to worse outcomes. Recombinant human growth hormone (rhGH) can increase growth velocity and final adult height in pediatric ESRD patients. We aimed to identify clinical predictors of short stature (height standard deviation score (Ht SDS) <-1.88) and rhGH use in short stature pediatric hemodialysis patients. In 2002, the Centers for Medicare & Medicaid Services (CMS) Clinical Performances Measures (CPM) ESRD Project collected demographic, clinical and laboratory data as well as rhGH use on all in-center hemodialysis patients in the US aged <18 years. The odds ratios (OR) of short stature and rhGH use for individual predictors were determined by multivariate logistic regression modeling. Six-hundred and fifty-one (92%) of 710 eligible patients were included for analysis. Of these, 266 (41%) had Ht SDS <-1.88. After adjustment, short stature was predicted by congenital/urologic causes of ESRD ((OR 5.4; 95% confidence interval [CI], 2.1-13.8; p <0.001) in patients aged 10-14 years; (OR 2.8; 95% CI, 1.5-5.4; p <0.01) in patients aged 15-18 years) and increasing years on dialysis ((OR 1.2; 95% CI, 1.1-1.4; p <0.01) in patients aged 10-14 years; (OR 1.2; 95% CI, 1.1-1.4; p <0.001) in patients aged 15-18 years). Of 266 short stature patients, 214 (80.5%) had data on rhGH use. Of these, 80 (37%) had been prescribed rhGH. After adjustment, use of rhGH in short-stature patients was predicted by white race (OR 2.1; 95% CI, 1.1-4.0; p <0.05), increasing years on dialysis (OR 1.13; 95% CI, 1.05-1.22; p <0.01) and patients with BMI <16.6 kg/m(2) (OR 3.1; 95% CI, 1.2-8.4; p <0.05). Increasing age and level of intact parathyroid hormone were not associated with rhGH use among short stature patients. A significant proportion of pediatric hemodialysis patients have short stature. The majority of short-stature patients are not receiving rhGH. Patients with short stature who are white, have longer durations on dialysis and have lower BMI are more likely to receive rhGH.


Agave REVEILLE1 regulates the onset and release of seasonal dormancy in Populus.
Deciduous woody plants like poplar (Populus spp.) have seasonal bud dormancy. It has been challenging to simultaneously delay the onset of bud dormancy in the fall and advance bud break in the spring, as bud dormancy, and bud break were thought to be controlled by different genetic factors. Here, we demonstrate that heterologous expression of the REVEILLE1 gene (named AaRVE1) from Agave (Agave americana) not only delays the onset of bud dormancy but also accelerates bud break in poplar in field trials. AaRVE1 heterologous expression increases poplar biomass yield by 166% in the greenhouse. Furthermore, we reveal that heterologous expression of AaRVE1 increases cytokinin contents, represses multiple dormancy-related genes, and up-regulates bud break-related genes, and that AaRVE1 functions as a transcriptional repressor and regulates the activity of the DORMANCY-ASSOCIATED PROTEIN 1 (DRM1) promoter. Our findings demonstrate that AaRVE1 appears to function as a regulator of bud dormancy and bud break, which has important implications for extending the growing season of deciduous trees in frost-free temperate and subtropical regions to increase crop yield.


[Levels of clinical adaptation among schizophrenic patients with a paroxysmal course].
The term "adaptation" is considered as a process of biological and social adjustment of a schizophrenic to the conditions of his life and activity altered as a result of his disease. During follow up study of 266 patients with paroxysmal schizophrenia, the authors made attempts to give a clinical assessment of adaptation. Levels of clinical adaptation and criteria of their identification are described. The authors show a possibility of using the specified levels for studying clinico-social correlations of adaptation and developing its typology.


Skin whitening effect of linoleic acid is enhanced by liposomal formulations.
Linoleic acid (LA) is known to have a whitening effect on hyperpigmented skin, and is encapsulated in liposomes for topical application because of its low solubility in aqueous solution, although the effect of liposomalization of LA on the whitening activity has not been evaluated. In the present study, we evaluated the effect of liposomalization on the whitening activity of LA by using LA in ethanol, hydrogel containing LA, and hydrogel containing liposomal LA towards the UV-stimulated hyperpigmented dorsal skin of brownish guinea pigs. The whitening effect was far greater for hydrogel containing liposomal LA (0.1% w/w as a final concentration of LA) than for free LA in ethanol or hydrogel containing LA. Next, the whitening effect of LA was examined with UV-stimulated hyperpigmented human upper arm skin by using a hydrogel containing liposomal LA (0.1% LA) and non-liposomal LA (3.0, 10.0% LA). Liposomal LA (0.1%) showed a whitening effect comparable to 10.0% non-liposomal LA and was far more effective than 3.0% non-liposomal LA. These results indicate that liposomal formulations are favorable for the transdermal application of LA.


Victimisation of individuals with serious mental illness living in sheltered housing: differential impact of risk factors related to clinical and demographic characteristics.
Sheltered housing is associated with quality-of-life improvements for individuals with serious mental illness (SMI). However, there are equivocal findings around safety outcomes related to this type of living condition. We aimed to investigate raw differences in prevalence and incidence of crime victimisation in sheltered housing compared with living alone or with family; and to identify groups at high risk for victimisation, using demographic and clinical factors. We do so by reporting estimated victimisation incidents for each risk group. A large, community-based, cross-sectional survey of 956 people with SMI completed the Dutch Crime and Victimisation Survey. Data was collected on victimisation prevalence and number of incidents in the past year. Victimisation prevalence was highest among residents in sheltered housing (50.8%) compared with persons living alone (43%) or with family (37.8%). We found that sheltered housing was associated with increased raw victimisation incidence (incidence rate ratio: 2.80, 95% CI 2.36-3.34 compared with living with family; 1.87, 95% CI 1.59-2.20 compared with living alone). Incidence was especially high for some high-risk groups, including men, people with comorbid post-traumatic stress disorder and those with high levels of education. However, women reported less victimisation in sheltered housing than living alone or with family, if they also reported drug or alcohol use. The high prevalence and incidence of victimisation among residents in sheltered housing highlights the need for more awareness and surveillance of victimisation in this population group, to better facilitate a recovery-enabling environment for residents with SMI.


Linkage of familial euthyroid goiter to the multinodular goiter-1 locus and exclusion of the candidate genes thyroglobulin, thyroperoxidase, and Na+/I- symporter.
Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also indicate a genetic predisposition for euthyroid simple goiter. In hypothyroid goiters several molecular defects in the thyroglobulin (TG), thyroperoxidase (TPO), and Na+/I- symporter (NIS) genes have been identified. The TSH receptor with its central role for thyroid function and growth is also a strong candidate gene. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthyroid goiter. Sequence analysis of the complementary DNA (cDNA) of the TPO and TSH receptor genes revealed several previously reported polymorphisms. As it is not possible to exclude a functional relevance for all polymorphisms, we opted for linkage analysis with microsatellite markers to investigate whether the candidate genes are involved in the pathogenesis of euthyroid goiter. The markers for the genes TG, TPO, and NIS gave two-point and multipoint logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of linkage was found, we conclude that these candidate genes can be excluded as a major cause of the euthyroid goiters in this family. In contrast, we have found evidence for linkage of familial euthyroid goiter to the recently identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxic goiter.


Effect of age on biochemical recurrence after radical prostatectomy.
The aim of the study was to evaluate the relationship between patient's age and biochemical recurrence (BCR) after radical retropubic prostatectomy (RRP). Data from RRP applied to 305 patients with clinically localized prostate cancer were included in the study. Patients were divided into the three age groups, < 60 years, 60-70 years, and > 70 years. The groups were compared regarding adverse pathological findings on RRP specimen, BCR, and biochemical recurrence-free survival (bRFS) rates. The rates of positive surgical margin, seminal vesicle invasion, lymph node involvement, RRP specimens' Gleason score, and BCR were not significantly different among the three age groups. bRFS rates were not different either. Nonorgan-confined disease and extracapsular extension (ECE) rates were significantly higher in the group of 60-70 years group than in the other two age groups. Factors associated with BCR in multivariate Cox regression analysis were ECE, seminal vesicle invasion, positive surgical margin, and RRP specimens' Gleason score of ≥ 4+3. Patient age and preoperative prostate specific antigen levels were not identified to be associated with BCR. Post-RRP nonorgan-confined disease and ECE are more frequently seen in patients of 60-70 years of age group than in other age groups. However, patient age is not an independent prognostic factor associated with bRFS.


Oral lactose tolerance test in foals: technique and normal values.
Oral lactose tolerance tests were evaluated in 25 healthy foals (principals) assigned to 4 groups of approximately 1 week, 4 weeks, 8 weeks, and 12 weeks of age. Lactose monohydrate (1 g/kg of body weight [in a 20% water solution]) was administered via nasogastric tube after a 4-hour fast. Plasma glucose concentrations were monitored before dosing (0 minutes) and sequentially for 300 minutes. Six control foals were given a volume of water equivalent to the volume of lactose monohydrate administered to principal foals. After oral lactose loading, mean plasma glucose concentrations of all principal foals increased from 99.76 mg/dl at 0 minutes to 176.80 mg/dl by 90 minutes. Peak increases in plasma glucose concentrations were attained by 8% of the foals (2 foals) at 30 minutes, 76% (19 foals) at 60 minutes, and 16% (4 foals) at 90 minutes. The mean plasma glucose concentration increase of principal foals, regardless of age or time of peaking, was 77.04 mg/dl. There was no significant (P greater than 0.05) difference in fasting plasma glucose concentrations (0 minutes) among the 4 groups of principal foals or between principal and control foals; however, there was a significant (P less than 0.05) difference in peak glucose concentrations between 1-week-old and 12-week-old principal foals, with the older foals having the higher concentrations. Mean plasma glucose concentrations of control foals decreased from 79.67 mg/dl at 0 minutes to 55.17 mg/dl by 180 minutes. The mean peak decrease in plasma glucose concentrations of control foals, regardless of time of peaking, was 24.50 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)


HARMONIES: A Hybrid Approach for Microbiome Networks Inference via Exploiting Sparsity.
The human microbiome is a collection of microorganisms. They form complex communities and collectively affect host health. Recently, the advances in next-generation sequencing technology enable the high-throughput profiling of the human microbiome. This calls for a statistical model to construct microbial networks from the microbiome sequencing count data. As microbiome count data are high-dimensional and suffer from uneven sampling depth, over-dispersion, and zero-inflation, these characteristics can bias the network estimation and require specialized analytical tools. Here we propose a general framework, HARMONIES, Hybrid Approach foR MicrobiOme Network Inferences via Exploiting Sparsity, to infer a sparse microbiome network. HARMONIES first utilizes a zero-inflated negative binomial (ZINB) distribution to model the skewness and excess zeros in the microbiome data, as well as incorporates a stochastic process prior for sample-wise normalization. This approach infers a sparse and stable network by imposing non-trivial regularizations based on the Gaussian graphical model. In comprehensive simulation studies, HARMONIES outperformed four other commonly used methods. When using published microbiome data from a colorectal cancer study, it discovered a novel community with disease-enriched bacteria. In summary, HARMONIES is a novel and useful statistical framework for microbiome network inference, and it is available at https://github.com/shuangj00/HARMONIES.


Impact of four fiber-rich supplements on nutrient digestibility, colostrum production, and farrowing performance in sows.
This study aimed to investigate the impact of dietary fiber (DF) sources on sow and litter performance, and apparent total tract digestibility (ATTD) of gross energy (GE) and nutrients. A total of 48 sows were stratified for body weight at mating and randomly assigned to one of four DF sources (mixed fiber [MF], palm kernel expellers [PKE], sugar beet pulp [SBP], or soy hulls [SH]) and fed the diet from mating until farrowing. Within DF treatments, sows were supplemented with one of two extra energy sources (glycerol or sugar dissolved in water), whereas a third group (control) received water from day 108 of gestation until farrowing. The number of total born, live-born, and stillborn pigs; birth time and birth weight of the pigs; farrowing duration; and farrowing assistance (FA) were recorded. Live-born pigs were weighed again at 12 and 24 h after birth to record weight gain, which was used to estimate intake and yield of colostrum. Blood samples were collected once daily from day -3 relative to farrowing until day 1 after farrowing in sows and once from selected pigs right after birth. Fecal samples were collected on day 114 of gestation and colostrum at 0, 12, 24, and 36 h after onset of farrowing. Intake of soluble and insoluble nonstarch polysaccharides (NSP) was greater for SBP (P < 0.001) and PKE (P < 0.001) supplemented sows, respectively, when compared with other groups. Farrowing duration and stillbirth rate were not affected by DF sources, but PKE and SH supplemented sows had greater FA than SBP and MF supplemented sows (P < 0.001). Extra energy supplement did not improve the farrowing performance. Concentration (P = 0.02) and output (P = 0.04) of dry matter in colostrum, and ATTD of GE (P < 0.001) and crude protein (CP; P < 0.001) were lower for PKE supplemented sows than in sows from the remaining groups. Intake of insoluble NSP correlated negatively with ATTD of GE (P < 0.001) and CP (P < 0.001). Concentrations of glucose (P < 0.001), lactate (P < 0.001), CO2 (P < 0.001), and HCO3 (P < 0.001) in sows blood were increased with time progress relative to farrowing. Newborn pigs from PKE supplemented sows had greater concentration of lactate (P = 0.02) and lower blood pH (P = 0.02) than the remaining treatments. In conclusion, PKE supplement reduced ATTD of GE and CP, and concentration and output of dry matter in colostrum but increased FA. Results of this experiment indicated that the use of PKE as a fiber source for late gestating sows should be avoided.


Peripheral stimulation for treatment of trigeminal postherpetic neuralgia and trigeminal posttraumatic neuropathic pain: a pilot study.
Trigeminal neuropathic pain (TNP) after facial trauma or herpes zoster infection is often refractory to treatment. Peripheral nerve stimulation has been used to treat occipital neuralgia; however, efficacy in controlling facial TNP or postherpetic neuralgia is unknown. A retrospective case series of patients who underwent subcutaneous placement of stimulating electrodes for treatment of V(1) or V(2) TNP secondary to herpetic infection or facial trauma is presented. Ten patients received implanted subcutaneous pulse generators and quadripolar electrodes for peripheral stimulation of the trigeminal nerve supraorbital or infraorbital branches. Long-term treatment results were determined by retrospective review of medical records (1998-2003) and by independent observers interviewing patients using a standard questionnaire. Surgical complication rate, preoperative symptom duration, degree of pain relief, preoperative and postoperative work status, postoperative changes in medication usage, and overall degree of therapy satisfaction were assessed. Mean follow-up was 26.6 +/- 4.7 months. Peripheral nerve stimulation provided at least 50% pain relief in 70% of patients with TNP or postherpetic neuralgia. Medication use declined in 70% of patients, and 80% indicated that they were mostly or completely satisfied with treatment overall. There were no treatment failures (<50% pain relief and a lack of decrease in medication use) in the posttraumatic group, and two failures (50%) occurred in the postherpetic group. The complication rate requiring reoperation was 30%. Peripheral nerve stimulation of the supraorbital or infraorbital branches of the trigeminal nerve is an effective method for relief of TNP after facial trauma or herpetic infection. A prospective trial using this novel approach to treat these disorders is thus warranted.


Simulations of jets driven by black hole rotation.
The origin of jets emitted from black holes is not well understood; however, there are two possible energy sources: the accretion disk or the rotating black hole. Magnetohydrodynamic simulations show a well-defined jet that extracts energy from a black hole. If plasma near the black hole is threaded by large-scale magnetic flux, it will rotate with respect to asymptotic infinity, creating large magnetic stresses. These stresses are released as a relativistic jet at the expense of black hole rotational energy. The physics of the jet initiation in the simulations is described by the theory of black hole gravitohydromagnetics.


β-Adrenergic stimulation and rapid pacing mutually promote heterogeneous electrical failure and ventricular fibrillation in the globally ischemic heart.
Global ischemia, catecholamine surge, and rapid heart rhythm (RHR) due to ventricular tachycardia or ventricular fibrillation (VF) are the three major factors of sudden cardiac arrest (SCA). Loss of excitability culminating in global electrical failure (asystole) is the major adverse outcome of SCA with increasing prevalence worldwide. The roles of catecholamines and RHR in the electrical failure during SCA remain unclear. We hypothesized that both β-adrenergic stimulation (βAS) and RHR accelerate electrical failure in the globally ischemic heart. We performed optical mapping of the action potential (OAP) in the right ventricular (RV) and left (LV) ventricular epicardium of isolated rabbit hearts subjected to 30-min global ischemia. Hearts were paced at a cycle length of either 300 or 200 ms, and either in the presence or in the absence of β-agonist isoproterenol (30 nM). 2,3-Butanedione monoxime (20 mM) was used to reduce motion artifact. We found that RHR and βAS synergistically accelerated the decline of the OAP upstroke velocity and the progressive expansion of inexcitable regions. Under all conditions, inexcitability developed faster in the LV than in the RV. At the same time, both RHR and βAS shortened the time to VF (TVF) during ischemia. Moreover, the time at which 10% of the mapped LV area became inexcitable strongly correlated with TVF (R(2) = 0 .72, P < 0.0001). We conclude that both βAS and RHR are major factors of electrical depression and failure in the globally ischemic heart and may contribute to adverse outcomes of SCA such as asystole and recurrent/persistent VF.


Effects of Serial Skin Testing with Purified Protein Derivative on the Level and Quality of Antibodies to Complex and Defined Antigens in Mycobacterium bovis-Infected Cattle.
Several serological tests designed to detect antibodies to immunodominant Mycobacterium bovis antigens have recently emerged as ancillary tests for the detection of bovine tuberculosis in cattle, particularly when used after the injection of purified protein derivative (PPD) for skin testing, which significantly boosts M. bovis-specific antibody responses. The present findings demonstrate the onset and duration of boosted antibody responses after the injection of M. bovis PPD for the caudal fold test (CFT) and Mycobacterium avium and M. bovis PPDs for the comparative cervical test (CCT), administered in series in cattle experimentally infected with M. bovis. While skin tests boosted the responses to certain antigens (i.e., MPB83 and MPB70), they did not affect the responses to other antigens (e.g., ESAT-6, CFP10, MPB59, and MPB64). Administration of the CCT 105 days after the CFT resulted in an even greater secondary boost in antibody responses to MPB83 and MPB70 and to a proteinase K-digested whole-cell sonicate (WCS-PK) of M. bovis. Both IgM and IgG contributed to the initial boost in the MPB83/MPB70-specific antibody response after the CFT. The secondary boost after the CCT was primarily due to increased IgG levels. Also, the avidity of antibodies to MPB83 and MPB70 increased after the CCT in M. bovis-infected cattle. The avidity of antibodies to the WCS-PK antigens increased in the interval between the CFT and the CCT but did not increase further after the CCT. Together, these findings demonstrate that the administration of PPDs for skin tests results in additive enhancement (i.e., when the CFT and CCT are performed in series), both qualitative and quantitative, of MPB83/MPB70-specific antibody responses.


The Association of Hypoglycemia Assessed by Continuous Glucose Monitoring With Cardiovascular Outcomes and Mortality in Patients With Type 2 Diabetes.
Objective: Hypoglycemia has been shown to promote inflammation, a common pathogenic process, in many chronic health conditions including diabetes and cardiovascular disease. The aim of this study was to investigate the association of hypoglycemia, assessed by continuous glucose monitoring (CGM) with major adverse cardiovascular event (MACE) outcomes and all-cause mortality. Methods: A retrospective cohort study was conducted with 1,520 patients with type 2 diabetes mellitus (T2DM). The severity of hypoglycemia event was assessed by CGM system. Results: Three hundred and forty-seven participants experienced hypoglycemia events (323 with mild hypoglycemia and 24 with severe hypoglycemia). A fraction of 72.62% hypoglycemia was asymptomatic. During a median follow-up of 31 months, 380 participants reached the primary outcome of MACE (61 cardiovascular death, 50 non-fatal myocardial infarction [MI], 116 non-fatal stroke, 153 unstable angina requiring hospitalization), 80 participants died before the end of the study. In multivariate Cox regression models, hypoglycemia was associated with cardiovascular death (HR 2.642[95CI% 1.398-4.994]), non-fatal stroke (HR 1.813 [95CI% 1.110-2.960]) and all-cause mortality (HR 1.960 [95 CI% 1.124- 3.418]) after the full adjustment. Hypoglycemia was not associated with non-fatal MI and unstable angina. The HR of severe hypoglycemia was higher than mild hypoglycemia for cardiovascular death. Patients with symptomatic and asymptomatic hypoglycemia had similar MACE outcomes and all-cause mortality. Conclusions: CGM is effective to detect asymptomatic and nocturnal hypoglycemia. Hypoglycemia is associated with an increased risk of non-fatal stroke, cardiovascular related death, and total mortality. The cardiovascular mortality is dose-dependent on the severity of hypoglycemia.


Improved protection of rhesus macaques against intrarectal simian immunodeficiency virus SIV(mac251) challenge by a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen.
In this study we investigated the ability of a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen to induce protective immunity in rhesus macaques against pathogenic simian immunodeficiency virus(mac251). Immunization of macaques by two sequential administrations of the same recombinants by the same route resulted in boosting and persistence of SIV-specific cellular immune responses for 42 weeks past the initial immunization. Anti-SIV gp120 immunoglobulin G (IgG) and IgA antibodies were induced in secretory fluids, and all macaques exhibited serum neutralizing antibody activity. After intrarectal SIV(mac251) challenge, all of the macaques became infected. However, relative protection, as assessed by statistically significant lower SIV viral loads in plasma at both acute infection and set point, was observed in 8 out of 12 immunized non-Mamu-A(*)01 animals. Elevated mean cellular immune responses to Gag and Env, neutralizing antibody activity, and IgG and IgA binding antibody levels were observed in the eight protected macaques. Statistically significant correlations with protective outcome were observed for cellular immune responses to SIV Env and Gag and for SIV gp120-specific IgG antibodies in nasal and vaginal fluids. Two macaques that exhibited the greatest and most persistent viremia control also exhibited strong CD8(+) T-cell antiviral activity. The results suggest that a spectrum of immune responses may be necessary for adequate control of viral replication and disease progression and highlight a potential role for nonneutralizing antibodies at mucosal sites.


Central obesity and not age increases skeletal muscle lipids, without influencing lean body mass and strength.
To measure skeletal muscle lipid infiltration, its association with insulin resistance (IR) lean mass and function, in Chilean men differing in age and body composition. Our hypothesis was that muscle lipid accumulation would be higher among older and heavier individuals and this would deteriorate insulin sensitivity (IS) and decrease muscle mass and function, both features of the ageing process. Healthy men (38 < 55 and 18 > 65 years), underwent anthropometric measurements, body composition assessment through radiologic densitometry, Nuclear Magnetic Resonance spectroscopy at the tibialis anterioris muscle to measure intra (IMCL) and extramyocellular lipids (EMCL), quadriceps and handgrip strength, 12 minute walking distance and serum biochemistry (haemoglobin, lipoproteins, creatinine, ultrasensitive C Reactive Protein, fasting and post glucose insulin and glucose concentrations, to assess IS). Physical activity was estimated by actigraphy. 23 men were eutrophic, 26 were overweight and 7 were obese and mostly sedentary, independent of age. Both IMCL and EMCL were higher in overweight/ obese men. Abdominal fat was negatively associated with IS and positively correlated with muscle lipid accretion (both IMCL and EMCL), but not with age. As expected, older individuals had lower muscle mass and strength, but not more adipose tissue nor intramyocellular lipids, yet were more glucose intolerant. central obesity was associated with IMCL and EMCL infiltration and IR. This type of lipid accretion was not related with ageing nor age-related sarcopenia. Older individuals were more glucose intolerant, which was explained by a decrease of insulin secretion more than adiposity-related IR.


Successful medical treatment of pulmonary petriellidiosis.
We have reported a case with culture and serologic evidence of pulmonary infection with Petriellidium boydii treated with intravenous miconazole, resulting in dramatic symptomatic improvement, stabilization of x-ray changes, and clearing of Petriellidium on sputum culture. Although no biopsy was done to establish absolute diagnosis of invasive disease, and thus the results of this case cannot be taken as an absolute criterion for therapy, this may represent the first medical cure of pulmonary infection with this agent.


Loss of axons in the cat optic nerve following fetal unilateral enucleation: an electron microscopic analysis.
Between the 48th day of gestation (E-48) and maturity, the number of axons in the cat optic nerve is reduced by approximately 50%. On the basis of an electron microscopic assay, the axon population of the E-48 nerve was estimated to be 328,000. In contrast, estimates from two normal adults were 159,000 and 158,000. In utero unilateral enucleation (at E-45 and E-46) attenuated the severity of this loss since the optic nerves of the experimental animals contained 200,000 and 198,000 fibers. These results indicate that prenatal binocular competition is involved in the elimination of ganglion cell axons during the normal development of the cat's visual system. The increased number of axons in the optic nerve of the prenatally enucleated animals could be due to reduced ganglion cell death or a failure to retract supernumerary axon collaterals. It is suggested that the former explanation is more consistent with what is currently known about the development of retinofugal projections.


GFAP (Glial Fibrillary Acidic Protein)-Positive Progenitor Cells Contribute to the Development of Vascular Smooth Muscle Cells and Endothelial Cells-Brief Report.
While GFAP (glial fibrillary acidic protein) is commonly used as a classical marker for astrocytes in the central nervous system, GFAP-expressing progenitor cells give rise to other cell types during development. The goal of this study was to investigate whether GFAP-expressing progenitor cells contribute to the development of vascular cells in major arteries. Approach and Results: To label GFAP-expressing progenitor cells and their progeny, we crossed GFAP promoter-driven Cre recombinase mice (GFAP-Cre) with transgenic mice expressing the Cre-dependent mTmG dual fluorescent reporter gene. Using this genetic fate-mapping approach, here we demonstrate that GFAP-positive progenitor cells contribute to the development of vascular smooth muscle cells in both neural crest- and non-neural crest-derived vascular beds. In addition, GFAP-positive progenitor cells contribute to a subset of endothelial cells in some vasculature. Furthermore, fate-mapping analyses at multiple time points of mouse development demonstrate a time-dependent increase in the contribution of GFAP-positive progenitors to vascular smooth muscle cells, which mostly occurs in the postnatal period. Our study demonstrates that vascular smooth muscle cells and endothelial cells within the same vascular segment are developmentally heterogeneous, where varying proportions of vascular smooth muscle cells and endothelial cells are contributed by GFAP-positive progenitor cells.


Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses.
Chronic excessive alcohol consumption may lead to dependence, and to alcohol withdrawal syndrome (AWS) in case of abrupt drinking cessation. Gamma-hydroxybutyric acid (GHB) can prevent and suppress withdrawal symptoms, and improve the medium-term abstinence rate. A clear balance between effectiveness and harmfulness has not been yet established. To evaluate the efficacy and safety of GHB for treatment of AWS and prevention of relapse We searched Cochrane Drugs and Alcohol Group' Register of Trials (October 2008), PubMed, EMBASE, CINAHL (January 2005 - October 2008), EconLIT (1969 to February 2008), reference list of retrieved articles Randomized controlled trials (RCTs) and Controlled Prospective Studies (CPS) evaluating the efficacy and the safety of GHB vs placebo or other pharmacological treatments. Three authors independently extracted data and assessed the methodological quality of studies. Thirteen RCTs were included. Eleven studies were conducted in Italy.For withdrawal syndrome, comparing GHB 50mg with placebo, results from 1 study, 23 participants favour GHB for withdrawal symptoms: WMD -12.1 (95% CI, -15.9 to -8.29) and side effects were more frequent in the placebo group: RR 16.2 (95% CI, 1.04 to 254.9).In the comparison with Chlormetiazole, for GHB 50mg, results from 1 study, 21 participants favour GHB for withdrawal symptoms: MD -3.40 (95% CI -5.09 to -1.71), for GHB 100mg, results from 1 study, 98 participants favour anticonvulsants for side effects: RR 1.84 (95% CI 1.19 to 2.85).At mid-term, comparing GHB with placebo, results favour GHB for abstinence rate (RR 5.35; 1.28-22.4), controlled drinking (RR 2.13; 1.07-5.54), relapses (RR 0.36; 0.21-0.63), and number of daily drinks (WMD -4.60; -6.18 to -3.02). GHB performed better than NTX and Disulfiram on abstinence (RR 2.59; 1.35-4.98, RR 1.66; 0.99-2.80 respectively). The association of GHB and NTX was better than NTX on abstinence (RR 12.2; 1.79-83.9), as well was the association of NTX, GHB and Escitalopram versus Escitalopram alone (RR 4.58; 1.28-16.5). For Alcohol Craving Scale results favour GHB versus placebo (WMD -1.90; -2.45 to 1.35) and Disulfiram (WMD -1.40; -1.86 to-0.94). GHB 50mg is effective compared to placebo in the treatment of AWS, and in preventing relapses in previously detoxified alcoholics at 3 months follow-up, but the results of this review do not provide sufficient evidence in favour of GHB compared to benzodiazepines and Chlormethiazole for AWS prevention. GHB is better than NTX and Disulfiram in maintaining abstinence and it has a better effect on craving than placebo and Disulfiram. Side effects of GHB are not statistically different from those with BZD, NTX or Disulfiram. However, concern has been raised regarding the risk of developing addiction, misuse or abuse, especially in polydrug abusers.


A new composite flap: rectus abdominis muscle flap harvested with pubic bone segment--anatomic considerations.
The aim of this study was to incorporate a segment of pubic bone to rectus abdominis muscle (RAM). Eight RAM flaps from four fresh cadavers were used. During surgical dissection, utmost care was paid to enclose the areolar tissue between the main deep inferior epigastric (DIE) vessels and the pubic bone. A bone segment, 1.5 x 5 cm in dimension with an intact periosteum, was included with the RAM. Surgical dissections revealed two major vascular branches. The first branch arising from the DIE artery (DIEA) at a distance of 5.2 +/- 1.4 cm from the origin gave rise to two consistent subbranches. The second major branch originated from the DIEA at a distance of 8.4 +/- 1.8 cm from the origin. The first branch gave off two subbranches. The second subbranch coursed anteromedially and nourished the periosteum of the pubic bone. Microangiography showed a similar branching pattern of the vessels that create two significant networks. The X-rays confirmed a rich vascular network around the periosteum of the pubic bone. This wealthy nourishment of the pubic periosteum comes mainly from the perpendicular descending branches. In conclusion, a vascularized part of pubic bone can be incorporated to the RAM flap by preserving the delicate vascular network between the DIE vessels and the pubic periosteum.


Similarity of junctions between plasma membranes and endoplasmic reticulum in muscle and neurons.
The structure of membranes at junctions between the plasma membrane and underlying cisterns of endoplasmic reticulum in amphioxus muscle and mouse cerebellar neurons was studied using the freeze-fracture technique. In amphioxus muscle, subsurface cisterns of sarcoplasmic reticulum form junctions with the surface membrane at the level of the sarcomere I bands. On the protoplasmic leaflet of the sarcolemma overlying these junctions were aggregates of large particles. On the protoplasmic leaflet of the membranes of cerebellar basket, stellate and Purkinie cells there were similar aggregates of large particles. In both tissues, the corresponding external membrane halves had arrays of pits apparently complementary to the aggregates of large particles. Cross fractures through junctions showed that the particle aggregates in neuronal and muscle membranes were consistently located over intracellular cisterns closely applied to the plasma membrane. Thus, a similar plasma membrane specialization is found at subsurface cisterns in mammalian neurons and amphioxus muscle. This similarity supports the hypothesis that subsurface cisterns in neurons, like those in muscle, couple some intracellular activity to the electrical activity of the plasma membrane.


[Study on the repeated batch fermentation of lipase by immobilized Rhizopus].
Repeated batch fermentation with Rhizopus arrhizus immobilized by polyurethane was optimized in details including the time to replace, the volume of the replaced medium and the optimal composition of the medium to replace. Immobilized cells showed stability for repeated use. Immobilized cells could be used for 9 batches, lasting 140h in flask and 6 batches in 5L fermenter when the substitute culture medium consisted of (%): soybean flour 3.0, earthnut oil 0.5 and the liquid was replaced by 40% . The time for fermentation was reduced largely and the lipase productivity was 3 - 6 times as high as that in batch fermentation.


Monitoring protein-protein interactions using split synthetic renilla luciferase protein-fragment-assisted complementation.
In this study we developed an inducible synthetic renilla luciferase protein-fragment-assisted complementation-based bioluminescence assay to quantitatively measure real time protein-protein interactions in mammalian cells. We identified suitable sites to generate fragments of N and C portions of the protein that yield significant recovered activity through complementation. We validate complementation-based activation of split synthetic renilla luciferase protein driven by the interaction of two strongly interacting proteins, MyoD and Id, in five different cell lines utilizing transient transfection studies. The expression level of the system was also modulated by tumor necrosis factor alpha through NFkappaB-promoter/enhancer elements used to drive expression of the N portion of synthetic renilla luciferase reporter gene. This new system should help in studying protein-protein interactions and when used with other split reporters (e.g., split firefly luciferase) should help to monitor different components of an intracellular network.


Embolism of a Piece of Iron after Penetrating Neck Injury: From Right Internal Jugular Vein to Left Lower Lobe of the Lung.
This case report of a 40-year-old male patient describes the embolization of a piece of iron trapped in the jugular vein following an industrial injury. The 40-year-old male patient was admitted to the emergency service for bleeding from the neck. In contrast to the first X-ray image, no foreign body was observed at the injury site or aspiration of fluid during emergency surgery. Following x-ray radiography, an opacity was observed in the left lower lobe of the lung, consistent with a foreign body. Echocardiography demonstrated no pathological manifestation in the atria, ventricles, or major pulmonary artery. There was no need to intervene because the patient was asymptomatic and had no noticeable symptoms of hemoptysis. The outpatient clinic's radiological and clinical control examinations were normal at the end of six months. The movement of the foreign body to the lung within one or two hours may have resulted from our manipulation or may have occurred spontaneously. As a result, any foreign bodies that have invaded the vascular system should be removed as soon as possible.


Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial.
The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing cardiovascular morbidity and mortality. We assessed the effects of these drug combinations on progression of chronic kidney disease. ACCOMPLISH was a double-blind, randomised trial undertaken in five countries (USA, Sweden, Norway, Denmark, and Finland). 11 506 patients with hypertension who were at high risk for cardiovascular events were randomly assigned via a central, telephone-based interactive voice response system in a 1:1 ratio to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or benazepril (20 mg) plus hydrochlorothiazide (12.5 mg; n=5762), orally once daily. Drug doses were force-titrated for patients to attain recommended blood pressure goals. Progression of chronic kidney disease, a prespecified endpoint, was defined as doubling of serum creatinine concentration or end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1.73 m(2) or need for dialysis). Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00170950. The trial was terminated early (mean follow-up 2.9 years [SD 0.4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All randomised patients were included in the ITT analysis. There were 113 (2.0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR 0.52, 0.41-0.65, p<0.0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33.7%; benazepril plus hydrochlorothiazide, 85 of 532, 16.0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group. Initial antihypertensive treatment with benazepril plus amlodipine should be considered in preference to benazepril plus hydrochlorothiazide since it slows progression of nephropathy to a greater extent. Novartis.


Typing of Helicobacter pylori with monoclonal antibodies against Lewis antigens in lipopolysaccharide.
Recently, it has been shown that the lipopolysaccharide (LPS) O antigen of Helicobacter pylori contains Lewis x (Lex), Lewis y (Ley), or both Lex and Ley antigens. We applied a serotyping method for H. pylori by an enzyme-linked immunosorbent assay with monoclonal antibodies (MAbs) specific for these antigens and the related fucosylated H type 1 (H1) antigen. The selected MAbs recognized the Lex and/or Ley structures in the LPS of H. pylori. The agreement between the results of biochemical compositional analysis and the serological data validated our serotyping system. A total of 152 strains from different geographic origins (The Netherlands, Canada, Poland, Italy, and People's Republic of China) were examined for typeability based on the presence of Lewis antigens. One hundred twenty-nine (84.9%) strains were typeable, and 12 different serotyping patterns were observed; 80.9% of the strains contained Lex and/or Le(y) antigens, and 18.4% reacted with the MAb against the related H1 antigen either alone or in combination with the Lex and/or Ley antigen. Our results show that the Lex and Ley antigens are frequently encountered in the LPS of H. pylori strains from various geographic origins. This typing method is an easy-to-perform technique, which can be used for strain differentiation in epidemiological studies of H. pylori infections.


Oral lichen planus: controversies surrounding malignant transformation.
Studies of the malignant potential of oral lichen planus (OLP) have been hampered by inconsistencies in the diagnostic criteria used for OLP, the criteria adopted to identify a true case of malignant transformation in OLP, the risk factors for malignant transformation and the optimum management of patients to ensure the early diagnosis of transformation. Consensus remains elusive, and leading workers in this field have recently published conflicting reports on the malignant potential of OLP and on the important question of the advisability of excluding patients with epithelial dysplasia or a tobacco habit from studies on this issue. The present review outlines these debates and proposes a possible a molecular basis for the malignant transformation in this disease.


Creep and thermal rounding close to the elastic depinning threshold.
We study the slow stochastic dynamics near the depinning threshold of an elastic interface in a random medium by solving a particularly suited model of hopping interacting particles that belongs to the quenched-Edwards-Wilkinson depinning universality class. The model allows us to compare the cases of uniformly activated and Arrhenius activated hops. In the former case, the velocity accurately follows a standard scaling law of the force and noise intensity with the analog of the thermal rounding exponent satisfying a modified "hyperscaling" relation. For the Arrhenius activation, we find, both numerically and analytically, that the standard scaling form fails for any value of the thermal rounding exponent. We propose an alternative scaling incorporating logarithmic corrections that appropriately fits the numerical results. We argue that this anomalous scaling is related to the strong correlation between activated hops that, alternated with deterministic depinning-like avalanches, occur below the depinning threshold. We rationalize the spatiotemporal patterns by making an analogy of the present model in the near-threshold creep regime with some well-known models with extremal dynamics, particularly the Bak-Sneppen model.


Mortality rates after incident non-traumatic fractures in older men and women.
Non-traumatic fractures at typical osteoporotic sites are associated with increased mortality across all age groups, particularly in men. Furthermore, in certain age subgroups of women and men, this rate remained elevated beyond 5 years for fractures of the hip, vertebrae, humerus, and other sites. Increased mortality rates have been documented following non-traumatic hip, vertebral, and shoulder fractures. However, data are lacking as to the duration of excess mortality and whether there is increased mortality following fractures at other sites. We determined mortality up to 15 years following incident fractures at typical osteoporotic sites. Using healthcare databases for the Province of Manitoba, Canada, we identified individuals 50 years and older with an incident non-traumatic fracture between 1986 and 2007. Each fracture case was matched to three fracture-free controls. Generalized linear models were used to test for trends in mortality and to estimate the relative risk for cases after adjusting for co-morbidity and living arrangements. During the study period, we identified 21,067 incident fractures in men followed by 10,724 (50.1%) deaths and 49,197 incident fractures in women followed by 22,018 deaths (44.8%). Seventy-six percent of the fractures were at sites other than the hip and vertebrae. After adjustment for age, number of co-morbidities, and level of dependence in living arrangements, the risk of death in cases, relative to controls, was increased in both sexes for hip, vertebral, humerus, wrist (in men only), and other fracture sites. Post-fracture mortality was higher in men than women. Relative mortality was the highest in the younger age groups across the spectrum of fracture sites. Fractures at typical osteoporotic sites are associated with increased mortality across all age groups, particularly in men. Better understanding of factors associated with increased post-fracture mortality should inform the development of management strategies.


Laboratory and field assessment of some kairomone blends for host-seeking Aedes aegypti.
Using laboratory Y-tube olfactometers, the attractiveness of lactic acid and 2 kairomone blends from the United States Department of Agriculture (USDA) and BioGents GmbH (BG) was assessed for attractiveness to Aedes aegypti. Four geographically disparate populations were assessed: North Queensland Australia (NQA), Florida USA, Minas Gerais Brazil (MGB), and Singapore. In descending order, populations were attracted to USDA, BG blends, and lactic acid. MGB was poorly attracted to lactic acid alone. The blends were less attractive than human odor. Proprietary blends were modified, and their attractiveness was assessed to find the optimum attractive mixture for NQA. Adding acetone to BG, and ammonia and caproic acid to USDA, improved attractiveness in the laboratory. Field attractiveness was assessed by coupling the blends with a newly developed BG-Sentinel Ae. aegypti trap. Trials were carried out using the BG blend, BG blend plus acetone, USDA blend, USDA blend plus ammonia and caproic acid, and a control trap with no kairomones. The traps were highly effective, with mean 24-h collections up to 11.15 Ae. aegypti per trap, and this species made up 91.7% of collections. However, the effectiveness of the unbaited control trap indicated that the BG-Sentinel has visual attractive properties for Ae. aegypti and that the kairomone lures added little to trap performance in NQA.


Barriers and enablers of kangaroo mother care implementation from a health systems perspective: a systematic review.
Kangaroo Mother Care (KMC) is an evidence-based intervention that reduces neonatal morbidity and mortality. However, adoption among health systems has varied. Understanding the interaction between health system functions-leadership, financing, healthcare workers (HCWs), technologies, information and research, and service delivery-and KMC is essential to understanding KMC adoption. We present a systematic review of the barriers and enablers of KMC implementation from the perspective of health systems, with a focus on HCWs and health facilities. Using the search terms 'kangaroo mother care', 'skin to skin (STS) care' and 'kangaroo care', we searched Embase, Scopus, Web of Science, Pubmed, and World Health Organization Regional Databases. Reports and hand searched references from publications were also included. Screening and data abstraction were conducted by two independent reviewers using standardized forms. A conceptual model to assess KMC adoption themes was developed using NVivo software. Our search strategy yielded 2875 studies. We included 86 studies with qualitative data on KMC implementation from the perspective of HCWs and/or facilities. Six themes emerged on barriers and enablers to KMC adoption: buy-in and bonding; social support; time; medical concerns; training; and cultural norms. Analysis of interactions between HCWs and facilities yielded further barriers and enablers in the areas of training, communication, and support. HCWs and health facilities serve as two important adopters of Kangaroo Mother Care within a health system. The complex components of KMC lead to multifaceted barriers and enablers to integration, which inform facility, regional, and country-level recommendations for increasing adoption. Further research of methods to promote context-specific adoption of KMC at the health systems level is needed.


Noninterventional, Naturalistic, Retrospective Study to Describe Prescription Patterns of Long-Acting Injectable Antipsychotics and the Impact of Introducing a New Atypical Antipsychotic in the Spanish Province of Tarragona Catchment Area.
We studied the patterns and predictors of long-acting injectable (LAI) antipsychotic (AP) use in the treatment of schizophrenia and the effect of introducing a new LAI (paliperidone palmitate [paliperidone-LAI]) in the Spanish province of Tarragona. This noninterventional, naturalistic, retrospective study included electronic medical record data from a large population-based database of 1,646 patients who were diagnosed with schizophrenia according to ICD-10 criteria and treated between January 2011 and December 2013. During the study period, 42.0% of patients were treated with an LAI AP. The most frequently prescribed initial LAI was risperidone (52.0% of patients). A total of 23% of patients initially treated with an oral AP were switched to an LAI AP, a change that was associated with younger age (P = .001), undifferentiated schizophrenia (P = .015), substance abuse (P < .001), and neuropsychiatric comedication with the following agents: anticonvulsants (P = .004), anticholinergics (P < .001), and hypnotics/sedatives (P = .03). The change from an oral AP to paliperidone-LAI was predicted by younger age (P < .001). Overall, 27.5% of patients switched to another LAI AP, and paliperidone-LAI was the preferred option in 64.7% of cases. The most frequent change involved patients taking risperidone-LAI, many of whom transitioned to paliperidone-LAI (85.0% of cases), particularly patients with a disease duration > 5 years (P = .019). There was a progressive increase in the use of LAI formulations in our catchment area. These agents were preferentially prescribed to patients with chronic disease and a history of substance abuse, as well as patients receiving neuropsychiatric comedication. One-month LAI formulations were commonly used in young patients.


Preferential expression of PAPPA in human preadipocytes from omental fat.
Fat distribution differs between individuals, and those with visceral fat predominance develop metabolic profiles that increase the risk of adverse cardiovascular events. This is due, in part, to the proinflammatory state associated with visceral obesity as well as depot-specific adipogenesis. The IGF system is important in adipose tissue development and metabolic function. Pregnancy-associated plasma protein A (PAPPA) is a novel zinc metalloproteinase that regulates local IGF availability. The first aim of this study was to characterize PAPPA mRNA and protein expression in primary cultures of human preadipocytes isolated from omental, mesenteric, and subcutaneous depots. PAPPA expression was significantly increased in omental preadipocytes compared with mesenteric and subcutaneous preadipocytes. The second aim of this study was to investigate the factors regulating PAPPA expression, focusing on proinflammatory cytokines and resveratrol that have been shown to have negative and positive effects, respectively, on metabolism and diet-induced obesity. Treatment of cultured primary human preadipocytes with tumor necrosis factor α and interleukin 1β led to significant increases in PAPPA expression. Activated pathways mediating cytokine-induced PAPPA expression include the nuclear factor κB pathway and the MAPK family, particularly c-Jun NH2-terminal kinase and p38 MAPK. Resveratrol, a polyphenolic compound with beneficial cardiometabolic effects, significantly downregulated PAPPA expression under basal and stimulated conditions. Effects of resveratrol on PAPPA appeared to be mediated through pathways independent of silent mating type information regulation 2 homolog 1 (SIRT1) and AMP kinase activation. Depot-specific PAPPA expression in human preadipocytes may contribute to a depot-specific function.


The impact of life events on patients with rheumatoid arthritis: a psychological myth?
A large number of studies from the field of "psychorheumatology" have investigated the relationship between critical life events and disease parameters with varying results. In the present study 48 patients with rheumatoid arthritis (RA) (mean age 57.8; range 32-78 years) were questioned about life events within the past two years using an "inventory for assessing life change events"-ILE (1). In contrast to previous studies, this inventory not only assesses the number of life events, but also captures the extent of subjectively experienced stress caused by these events. Since psychosocial factors such as social support and coping strategies influence subjectively experienced stress, these factors were taken into consideration for the definition of "life event". Furthermore, a series of objective medical parameters as well as the patient's and the physician's subjective impression of disease activity were assessed. The results show that patients with RA in the earlier stages of the disease cannot be differentiated from severely affected patients in later stages on the basis of life event parameters. In addition, no differences in the life event data could be observed between patients with and those without subjectively experienced episodes of illness in the two years immediately preceding the study. Our results suggest that the course of RA is influenced neither by the number of life events nor by the extent of stress caused by these life events. Therefore, the role of life events should not be overemphasized, at least as far as the disease parameters in RA is concerned.


Peculiar immunobiology of bone marrow allografts. II. Rejection of parental grafts by resistant F 1 hybrid mice.
F(1) hybrid mice are capable of rejecting inbred parental strain bone marrow grafts after a single lethal exposure to X-rays. The incompatibility is genetically controlled by the Hybrid-histocompatibility-1 (Hh-1) locus in or near the D end of the Histocompatibility-2 (H-2) region. The onset of parental graft rejection begins 9-12 hr after transplantation and is completed by 24 hr. Maturation of hybrid resistance does not occur until the 22nd day of life. In adults, the resistance to parental marrow grafts can be temporarily abrogated or weakened by administration of cyclophosphamide or dead cultures of Corynebacterium parvum, acute supralethal exposures to radiation, or by split-dose irradiation with 6-37-day intervals. Parental marrow grafts elicit a transplantation reaction in irradiated F(1) mice which is indistinguishable from that elicited in irradiated allogeneic (H-2-incompatible) hosts. Because of this immunogenetic similarity, the following question is raised: are the same or different alloantigens responsible for rejection of parental and allogeneic marrow grafts? In the first case, Hh-1 alleles would be recessive determinants of tissue-specific transplantation antigens, whereas in the second case they would be the determinants of parental- and tissue-specific antigens subject to genetic suppression in Hh-1 heterozygotes. Although the available evidence is not conclusive in excluding one of the two possibilities, it favors the concept that allograft reactivity to hemopoietic cells is elicited by recessive tissue-specific antigens.


Tolerance and overcompensation to infection by Phytophthora infestans in the wild perennial climber Solanum dulcamara.
Studies of infection by Phytophthora infestans-the causal agent of potato late blight-in wild species can provide novel insights into plant defense responses, and indicate how wild plants might be influenced by recurrent epidemics in agricultural fields. In the present study, our aim was to investigate if different clones of Solanum dulcamara (a relative of potato) collected in the wild differ in resistance and tolerance to infection by a common European isolate of P. infestans. We performed infection experiments with six S. dulcamara genotypes (clones) both in the laboratory and in the field and measured the degree of infection and plant performance traits. In the laboratory, the six evaluated genotypes varied from resistant to susceptible, as measured by degree of infection 20 days post infection. Two of the four genotypes susceptible to infection showed a quadratic (concave downward) relationship between the degree of infection and shoot length, with maximum shoot length at intermediate values of infection. This result suggests overcompensation, that is, an increase in growth in infected individuals. The number of leaves decreased with increasing degree of infection, but at different rates in the four susceptible genotypes, indicating genetic variation for tolerance. In the field, the inoculated genotypes did not show any disease symptoms, but plant biomass at the end of the growing season was higher for inoculated plants than for controls, in-line with the overcompensation detected in the laboratory. We conclude that in S. dulcamara there are indications of genetic variation for both resistance and tolerance to P. infestans infection. Moreover, some genotypes displayed overcompensation. Learning about plant tolerance and overcompensation to infection by pathogens can help broaden our understanding of plant defense in natural populations and help develop more sustainable plant protection strategies for economically important crop diseases.


Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy.
We examined the cytotoxicity of the immunosuppressant agent rapamycin and its analogue CCI-779 in human brain tumor cell lines in vitro and in vivo as single agents and in combination with standard chemotherapeutic drugs. In the rapamycin-sensitive PNET/MB cell line DAOY, rapamycin exhibited additive cytotoxicity with cisplatin and with camptothecin. In vivo, CCI-779 delayed DAOY xenograft growth by 160% after 1 week and 240% after 2 weeks of systemic treatment, compared with controls. Single high-dose treatment induced 37% regression of tumor solume. Growth inhibition of DAOY xenografts was 1.3 times greater after simultaneous treatment with CCI-779 and cisplatin than after cisplatin alone. Interestingly, CCI-779 also produced growth inhibition of xenografts derived from U251 malignant glioma cells, a human cell line resistant to rapamycin in vitro. These studies suggest that the rapamycin analogue CCI-779 is an important new agent to investigate in the treatment of human brain tumors, particularly PNET/MB.


Consequences of hormone-induced desensitization of adenylate cyclase in intact cells.
A hypothesis on the role of the hormone-induced desensitization of adenylate cyclase is proposed. It is suggested that the desensitization process could provide the cell with a highly efficient cyclic AMP system for transmitting hormone stimulus without requiring a large energy consumption. Theoretical considerations show that in fact the desensitization phenomenon allows the cyclic AMP system to present a good compromise between the efficiency and economy requirements of the cells.


Solution structure of microtubule-associated protein light chain 3 and identification of its functional subdomains.
Microtubule-associated protein (MAP) light chain 3 (LC3) is a human homologue of yeast Apg8/Aut7/Cvt5 (Atg8), which is essential for autophagy. MAP-LC3 is cleaved by a cysteine protease to produce LC3-I, which is located in cytosolic fraction. LC3-I, in turn, is converted to LC3-II through the actions of E1- and E2-like enzymes. LC3-II is covalently attached to phosphatidylethanolamine on its C terminus, and it binds tightly to autophagosome membranes. We determined the solution structure of LC3-I and found that it is divided into N- and C-terminal subdomains. Additional analysis using a photochemically induced dynamic nuclear polarization technique also showed that the N-terminal subdomain of LC3-I makes contact with the surface of the C-terminal subdomain and that LC3-I adopts a single compact conformation in solution. Moreover, the addition of dodecylphosphocholine into the LC3-I solution induced chemical shift perturbations primarily in the C-terminal subdomain, which implies that the two subdomains have different sensitivities to dodecylphosphocholine micelles. On the other hand, deletion of the N-terminal subdomain abolished binding of tubulin and microtubules. Thus, we showed that two subdomains of the LC3-I structure have distinct functions, suggesting that MAP-LC3 can act as an adaptor protein between microtubules and autophagosomes.


Energy system contribution during 200- to 1500-m running in highly trained athletes.
The purpose of the present study was to profile the aerobic and anaerobic energy system contribution during high-speed treadmill exercise that simulated 200-, 400-, 800-, and 1500-m track running events. Twenty highly trained athletes (Australian National Standard) participated in the study, specializing in either the 200-m (N = 3), 400-m (N = 6), 800-m (N = 5), or 1500-m (N = 6) event (mean VO2 peak [mL x kg(-1)-min(-1)] +/- SD = 56+/-2, 59+/-1, 67+/-1, and 72+/-2, respectively). The relative aerobic and anaerobic energy system contribution was calculated using the accumulated oxygen deficit (AOD) method. The relative contribution of the aerobic energy system to the 200-, 400-, 800-, and 1500-m events was 29+/-4, 43+/-1, 66+/-2, and 84+/-1%+/-SD, respectively. The size of the AOD increased with event duration during the 200-, 400-, and 800-m events (30.4+/-2.3, 41.3+/-1.0, and 48.1+/-4.5 mL x kg(-1), respectively), but no further increase was seen in the 1500-m event (47.1+/-3.8 mL x kg(-1)). The crossover to predominantly aerobic energy system supply occurred between 15 and 30 s for the 400-, 800-, and 1500-m events. These results suggest that the relative contribution of the aerobic energy system during track running events is considerable and greater than traditionally thought.


Hazards of 'deleading' homes of children with lead poisoning.
"Deleading" the homes of children with lead poisoning is a necessary step to terminate the child's exposure to lead. Lead poisoning as a result of lead exposure during the process of deleading has occurred in deleading workers but has not been well documented among children whose homes are deleaded. We treated four children with classes I through III lead poisoning (range of blood lead [Pb-B] level, 1.6 to 2.75 mumol/L [33 to 57 micrograms/dL]) who had significant elevation of their Pb-B levels (range, peak 4.34 to 6.27 mumol/L [90 to 130 micrograms/dL]) following deleading of their homes. The methods used for deleading included scraping, sanding, and burning of the paint. Symptoms included irritability (n = 3) and vomiting (n = 1). The elevation of the Pb-B levels was detected early, allowing prompt chelation therapy. Because exacerbation of lead poisoning may occur in children following deleading of their homes, safer approaches of deleading should be determined.