Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial.
The present study was a randomized, parallel, double-blind comparison between controlled-release (CR) tramadol and sustained-release (SR) diclofenac in patients with chronic pain due to osteoarthritis of the hips and/or knees. Patients with at least moderate pain intensity, and having received analgesics over the past three months, underwent a two- to seven-day washout of current analgesics before initiation of 200 mg CR tramadol or 75 mg SR diclofenac. During the eight-week study, patients returned to the clinic biweekly. CR tramadol doses were titrated to a maximum of 200 mg, 300 mg or 400 mg per day. SR diclofenac doses were titrated to 75 mg or 100 mg once daily, or 75 mg twice a day based on pain relief and the presence of side effects. For rescue analgesic, patients took acetaminophen as needed, up to 650 mg three times a day. Forty-five patients on CR tramadol and 52 patients on SR diclofenac were evaluable. Significant improvements from prestudy treatment were shown for visual analogue scale pain (P=0.0001), stiffness (P<0.0005) and physical function (P=0.0001) scores for both treatments. There were no significant differences between the two treatments in the Western Ontario and McMaster Universities subscales, overall pain, pain and sleep, or the clinical effectiveness evaluation. Overall incidence of adverse events was similar in both groups, with more opioid-related adverse events with CR tramadol, and two serious adverse events occurring with the use of SR diclofenac. CR tramadol is as effective as SR diclofenac in the treatment of pain due to knee or hip osteoarthritis, with the potential for fewer of the serious side effects that characterize nonsteroidal anti-inflammatory drug administration.


Interleukin-22 Attenuates Acute Pancreatitis-Associated Intestinal Mucosa Injury in Mice via STAT3 Activation.
Interleukin-22 (IL-22) is an important cytokine maintaining homeostasis at barrier surfaces. In this study, the role of IL-22 in acute pancreatitis-associated intestinal injury was further explored. Severe acute pancreatitis (SAP) was induced by administration of L-arginine in Balb/c mice at different time gradients. Histopathological examinations were made in both the pancreas and small intestine. Furthermore, recombinant murine IL-22 (rIL-22) was administrated to L-arginine-induced SAP mice by intraperitoneal injection. The mRNA levels of IL-22R1, Reg-IIIβ, Reg-IIIγ, Bcl-2, and Bcl-xL were detected in the small intestine by real-time polymerase chain reaction, and protein levels of total and phosphorylated STAT3 were assessed via Western blot. Compared with normal control group, 72 hours of L-arginine exposure induced the most characteristic histopathological changes of SAP, evidenced by pathological changes and serum amylase levels. Meanwhile, significant pancreatitis-associated intestinal mucosa injury was also observed. The gene expression levels of antimicrobial proteins Reg-IIIβ, Reg-IIIγ and anti-apoptosis proteins Bcl-2, Bcl-xL were downregulated in small intestine. Furthermore, Larginine- induced SAP was attenuated by rIL-22 treatment. Importantly, pancreatitis-associated intestinal mucosa injury was also ameliorated, reflected by improved pathological changes and significant increase in gene expression levels of Reg-IIIβ, Reg-IIIγ, Bcl-2 and Bcl-xL. Consistently, serum amylase levels and mortality were decreased in mice treated with rIL-22. Mechanistically, the upregulated expressions of these protective genes were achieved by activating STAT3. Exogenous rIL-22 attenuates L-arginine-induced acute pancreatitis and intestinal mucosa injury in mice, via activating STAT3 signaling pathway and enhancing the expression of antimicrobial peptides and antiapoptotic genes.


Myocardial contractile reserve on dobutamine echocardiography predicts late spontaneous improvement in cardiac function in patients with recent onset idiopathic dilated cardiomyopathy.
The purpose of this study was to determine whether identification of contractile reserve with dobutamine would predict recovery of myocardial function during follow-up in patients with recent onset idiopathic dilated cardiomyopathy (IDC). The prognosis of patients presenting with new onset IDC is variable and difficult to predict. Twenty-two patients (17 men, 5 women, 46 +/- 14 years) with recently diagnosed IDC (4 +/- 3 months) underwent dobutamine echocardiography. Left ventricular ejection fraction (LVEF) and LV sphericity before and at peak dobutamine infusion (30 +/- 11 microg/kg/min) were determined. A follow-up echocardiographic assessment was done at 6 +/- 4 months. The LVEF on dobutamine was directly related to baseline LV mass expressed as g/ml (Pearson r = 0.65, p = 0.0003). Baseline variables that were significantly predictive of follow-up LVEF were deceleration time (r = 0.69, p = 0.0006), wall motion score index (WMSI) (r = -0.63, p = 0.002), LV mass (r = 0.56, p = 0.008) and LVEF on dobutamine (r = 0.84, p = 0.0001). When either deceleration time or WMSI or LV mass was entered into a regression equation to predict follow-up LVEF, the LVEF on dobutamine added significantly to predictive power. However, if LVEF on dobutamine was entered first, none of the other three variables added significantly to prediction. Baseline LV sphericity at end diastole (ED) (r = 0.13, p = 0.6) did not correlate with follow-up LV sphericity in ED, whereas LV sphericity in ED on dobutamine (ED [r = 0.70, p = 0.0004]) correlated with LV sphericity in ED on follow up. This study demonstrates that dobutamine-induced improvement in baseline LVEF and LV sphericity identifies patients with IDC who exhibit substantial improvement in LV function and geometry over time.


Drug metabolizing enzyme changes after chronic buthionine sulfoximine exposure modify acetaminophen disposition in rats.
This study examined the effects of prolonged exposure to buthionine sulfoximine (BSO) on 1) the overall elimination pharmacokinetics of acetaminophen; 2) the sulfate and glucuronide conjugation processes primarily responsible for acetaminophen elimination; and 3) in vitro microsomal and cytoplasmic enzyme activities in rats. Rats imbibed drinking water containing 30 mM BSO for 6 days and then received an iv injection of acetaminophen, 150 mg/kg in a propylene glycol vehicle. Exposure to BSO, a specific inhibitor of gamma-glutamylcysteine synthetase, produced marked depletion of glutathione (GSH) and resulted in induction of hepatic UDP-glucuronosyltransferase and GSH-S-transferase enzyme activities, but not cytochrome P-450. BSO pretreatment had no effect on the total or renal clearance of acetaminophen in rats. However, BSO exposure increased the partial clearance of acetaminophen to acetaminophen glucuronide by 47% (1.29 +/- 0.08 vs. 1.90 +/- 0.23 ml/min/kg; p less than 0.01) and significantly (p less than 0.02) increased the percentage of the dose recovered as the glucuronide conjugate from 17.6 +/- 2.5 to 26.5 +/- 0.6 The partial clearance of acetaminophen to acetaminophen sulfate was decreased, although not significantly, from 4.46 +/- 0.62 to 3.39 +/- 0.82 ml/min/kg. BSO treatment increased microsomal UDP-glucuronosyltransferase activity toward three xenobiotic aglycones, p-nitrophenol, 1-naphthol, and morphine by 308, 61, and 66%, respectively (p less than 0.05), but not toward testosterone or estrone. Cytosolic GSH-S-transferase activity toward 1-chloro-2,4-dinitrobenzene was increased 52% by BSO, whereas p-nitrophenol sulfotransferase activity was not altered. Cytochrome P-450 concentration and monooxygenase activity were unchanged by BSO exposure.


Chemokine RANTES promoter dimorphisms and hepatocellular carcinoma occurrence in patients with alcoholic or hepatitis C virus-related cirrhosis.
This study explores the influence of two functional genetic polymorphisms in the regulated on activation in normal T-cell expressed and secreted(RANTES) promoter on the risk of hepatocellular carcinoma (HCC) occurrence in patients with alcoholic or Hepatitis C Virus (HCV)-related cirrhosis. RANTES C-28G and G-403A promoter dimorphisms and RANTES serum levels were assessed in 243 HCV-infected patients and 253 alcoholic patients, included at the time of diagnosis of cirrhosis and prospectively followed-up. During a mean follow-up time of 76 months, 137 (27.6%) patients developed HCC and 170 (34.2%) died or were transplanted. During follow-up, patients with alcoholic cirrhosis and bearing two copies of the RANTES G-403 variant (2G-403 genotype, n = 156/253) had a higher rate of HCC occurrence compared with patients carrying at least one RANTES A-403 allele (26.3% vs. 8.2%, P = 0.0004). The RANTES 2G-403 genotype was a risk factor for HCC occurrence [HR = 3.0 (1.3-5.8); first quartile time to HCC occurrence: 60 vs. 120 months; LogRank = 0.007] and death [HR = 1.4 (1.0-2.0); median time to death: 55 vs. 79 months; LogRank = 0.01] in this subgroup. Carriage of the RANTES 2G-403 genotype was not associated with HCC development or death in patients with HCV-related cirrhosis. The RANTES C-28G dimorphism did not influence the occurrence of death or HCC in either cohort of patients. This study suggests an influence of the chemokine RANTES G-403A dimorphism on the occurrence of HCC in patients with alcoholic cirrhosis. Our findings provide clues for future studies on RANTES gene in relation to HCC susceptibility.


Gene therapy using IL 12 family members in infection, auto immunity, and cancer.
Interleukin-12 (IL-12) is known for several years to have an essential role in inflammatory responses and innate resistance to infection and cancer. This has been largely attributed to its ability to initiate the differentiation of T-helper-1 (Th1) cells producing interferon-gamma. Recently, two new cytokines, IL-23 and IL-27, with homology to IL-12 were discovered and assigned to the IL-12 family of cytokines. Growing evidence supports a role for IL-23 as key mediator of autoimmune disease regulating the new Th17 subset of CD4+ T cells. IL-27 can have pro- and anti-inflammatory effects, which increase Th1 differentiation, suppress Th2 proliferation, or stimulate cytotoxic T cell activity. Several strategies have been pursued to apply the immunological effects of IL-12 family members to the treatment of human disease. Whereas the inhibition of IL-12 and IL-23 signal transduction has shown promising results for the treatment of autoimmune disease, the administration of IL-12 during infection and cancer can increase the host immune reaction. The increasing knowledge about the new IL-12 family members, IL-23 and IL-27, has revealed new therapeutic options for the use of these cytokines. In this review, we discuss therapeutic strategies using IL-12 family members in infection, autoimmunity, and cancer with special focus on gene administration.


Increased left ventricular mass and decreased left ventricular systolic function have independent pathways to ventricular arrhythmogenesis in coronary artery disease.
Following myocardial infarction, individual patients can have wide variations in the extent of left ventricular systolic dysfunction (LVSD) and increased left ventricular (LV) mass. Both affect the risk for sudden cardiac death, but only LV ejection fraction is used for risk prediction. The purpose of this study was to evaluate the independent as well as the additive contributions of increased LV mass and decreased LV ejection fraction to sudden cardiac death in the general population. In the ongoing Oregon Sudden Unexpected Death Study, we studied consecutive SCD cases (n = 191) and coronary artery disease controls (n = 203) from the Portland, Oregon, metropolitan area (population approximately 1,000,000; 2002-2008). Comparisons of echocardiographic LV mass obtained prior and unrelated to sudden cardiac death (SCD) were conducted, and a logistic regression model was used to evaluate the relationship between SCD, severe LVSD, LV mass, and other relevant clinical variables. In a multivariate model, both severe LVSD and left ventricular hypertrophy (LVH) were associated with increased SCD risk (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1-3.2 for severe LVSD; OR 1.8, 95% CI 1.1-2.9 for LVH). In patients with coexisting severe LVSD and LVH, risk of SCD was additive (OR 3.5, 95% CI 1.7-7.2). In the same model, increased age, atrial fibrillation/flutter, elevated creatinine, and diabetes independently increased risk, and use of angiotensin receptor blockers attenuated risk. Reduced LV ejection fraction and increased LV mass had independent and additive effects on risk of sudden death. Despite the significant overlap between the two conditions, these findings point toward the existence of independent mechanistic pathways for ventricular arrhythmias that occur due to LVSD and LVH.


Opinions of key stakeholders regarding the inpatient Individual Care Plan.
In Ireland, regularly reviewed Individual Care Plans (ICPs) for inpatients at all acute psychiatric inpatient units are a requirement of the Mental Health Act 2001. In this study, we comprehensively evaluated and compared opinions of key stakeholders in relation to the ICP as a care delivery tool. We employed a descriptive survey design. Questionnaires were distributed to 123 stakeholders (patients and mental health professionals (MHPs)) to evaluate and compare opinions regarding the impact of the ICP in relation to healthcare delivery and health outcomes, and regarding the structure and frequency of use of the ICP. Ninety-eight stakeholders (80%) completed study questionnaires. Stakeholders (patients (58%) and MHPs (85%)) reported that the ICP assisted in healthcare delivery. However, different attitudes between groups were noted in relation to whether the ICP contributed towards healthcare outcomes, with 64% of patients, but only 41% of MHPs reporting that the ICP positively contributed to mental healthcare outcomes. Some free-text comments described patient dissatisfaction with the role of the ICP for healthcare delivery, and MHP dissatisfaction that the ICP was time-consuming and did not significantly enhance standard patient care. Whilst the implementation of the ICP is generally viewed positively by both patients and MHPs, considerable dissatisfaction by MHPs was also noted with certain aspects of how the ICP was delivered in practice. Practical adjustments to the implementation of ICP in order to build more positive stakeholder experiences appear warranted and worthy of further research.


Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators.
Raloxifene hydrochloride, a selective estrogen receptor modulator, prevents bone loss in postmenopausal women, but whether it reduces fracture risk in these women is not known. To determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures. The Multiple Outcomes of Raloxifene Evaluation (MORE) study, a multicenter, randomized, blinded, placebo-controlled trial. A total of 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and who met World Health Organization criteria for having osteoporosis. The study began in 1994 and had up to 36 months of follow-up for primary efficacy measurements and nonserious adverse events and up to 40 months of follow-up for serious adverse events. Participants were randomized to 60 mg/d or 120 mg/d of raloxifene or to identically appearing placebo pills; in addition, all women received supplemental calcium and cholecalciferol. Incident vertebral fracture was determined radiographically at baseline and at scheduled 24- and 36-month visits. Nonvertebral fracture was ascertained by interview at 6-month-interim visits. Bone mineral density was determined annually by dual-energy x-ray absorptiometry. At 36 months of the evaluable radiographs in 6828 women, 503 (7.4%) had at least 1 new vertebral fracture, including 10.1% of women receiving placebo, 6.6% of those receiving 60 mg/d of raloxifene, and 5.4% of those receiving 120 mg/d of raloxifene. Risk of vertebral fracture was reduced in both study groups receiving raloxifene (for 60-mg/d group: relative risk [RR], 0.7; 95% confidence interval [CI], 0.5-0.8; for 120-mg/d group: RR, 0.5; 95% CI, 0.4-0.7). Frequency of vertebral fracture was reduced both in women who did and did not have prevalent fracture. Risk of nonvertebral fracture for raloxifene vs placebo did not differ significantly (RR, 0.9; 95% CI, 0.8-1.1 for both raloxifene groups combined). Compared with placebo, raloxifene increased bone mineral density in the femoral neck by 2.1 % (60 mg) and 2.4% (120 mg) and in the spine by 2.6% (60 mg) and 2.7% (120 mg) P<0.001 for all comparisons). Women receiving raloxifene had increased risk of venous thromboembolus vs placebo (RR, 3.1; 95% CI, 1.5-6.2). Raloxifene did not cause vaginal bleeding or breast pain and was associated with a lower incidence of breast cancer. In postmenopausal women with osteoporosis, raloxifene increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture.


Usability and Engagement Testing of mHealth Apps in Paediatric Obesity: A Narrative Review of Current Literature.
Mobile health (mHealth) platforms have become increasingly popular for delivering health interventions in recent years and particularly in light of the COVID-19 pandemic. Childhood obesity treatment is an area where mHealth interventions may be useful due to the multidisciplinary nature of interventions and the need for long-term care. Many mHealth apps targeting youth exist but the evidence base underpinning the methods for assessing technical usability, user engagement and user satisfaction of such apps with target end-users or among clinical populations is unclear, including for those aimed at paediatric overweight and obesity management. This review aims to examine the current literature and provide an overview of the scientific methods employed to test usability and engagement with mHealth apps in children and adolescents with obesity. A narrative literature review was undertaken following a systematic search. Four academic databases were searched. Inclusion criteria were studies describing the usability of mHealth interventions for childhood obesity treatment. Following the application of inclusion and exclusion criteria, fifty-nine articles were included for full-text review, and seven studies met the criteria for usability and engagement in a clinical paediatric population with obesity. Six apps were tested for usability and one for engagement in childhood obesity treatment. Sample sizes ranged from 6-1120 participants. The included studies reported several heterogenous measurement instruments, data collection approaches, and outcomes. Recommendations for future research include the standardization and validation of instruments to measure usability and engagement within mHealth studies in this population.


The Photorespiratory Metabolite 2-Phosphoglycolate Regulates Photosynthesis and Starch Accumulation in Arabidopsis.
The Calvin-Benson cycle and its photorespiratory repair shunt are in charge of nearly all biological CO2 fixation on Earth. They interact functionally and via shared carbon flow on several levels including common metabolites, transcriptional regulation, and response to environmental changes. 2-Phosphoglycolate (2PG) is one of the shared metabolites and produced in large amounts by oxidative damage of the CO2 acceptor molecule ribulose 1,5-bisphosphate. It was anticipated early on, although never proven, that 2PG could also be a regulatory metabolite that modulates central carbon metabolism by inhibition of triose-phosphate isomerase. Here, we examined this hypothesis using transgenic Arabidopsis thaliana lines with varying activities of the 2PG-degrading enzyme, 2PG phosphatase, and analyzing the impact of this intervention on operation of the Calvin-Benson cycle and other central pathways, leaf carbohydrate metabolism, photosynthetic gas exchange, and growth. Our results demonstrate that 2PG feeds back on the Calvin-Benson cycle. It also alters the allocation of photosynthates between ribulose 1,5-bisphosphate regeneration and starch synthesis. 2PG mechanistically achieves this by inhibiting the Calvin-Benson cycle enzymes triose-phosphate isomerase and sedoheptulose 1,7-bisphosphate phosphatase. We suggest this may represent one of the control loops that sense the ratio of photorespiratory to photosynthetic carbon flux and in turn adjusts stomatal conductance, photosynthetic CO2 and photorespiratory O2 fixation, and starch synthesis in response to changes in the environment.


Outpatient heroin detoxification with acupuncture and staplepuncture.
Eighteen heroin addicts were treated as outpatients with acupuncture, electrical stimulation and staplepuncture. Results of treatment were compared with results in two similar groups of 18 persons in whom detoxification was carried out using methadone and propoxyphene napsylate. Withdrawal symptoms were relieved for about two hours in most of the patients after a treatment episode of acupuncture and electrical stimulation. Staplepuncture, which is the manipulation by hand of a surgical staple implanted in the concha of the ear, was reported to relieve withdrawal symptoms at least partially in approximately 40 percent of subjects. In only one person of the group treated with acupuncture or staplepuncture was complete detoxification achieved, compared with 13 and 10 persons, respectively, in the methadone and propoxyphene napsylate groups (p<.001). Use of acupuncture and staplepuncture in outpatient clinics may be limited unless techniques can be found that will relieve withdrawal symptoms for a longer period than that observed in this study.


The osteocalcin gene: a model for multiple parameters of skeletal-specific transcriptional control.
Influences of promoter regulatory elements that are responsive to basal and tissue-restricted transactivation factors, steroid hormones, growth factors and other physiologic mediators has provided the basis for understanding regulatory mechanisms contributing to developmental expression of osteocalcin, tissue specificity and biological activity (reviewed in [1-3]). These regulatory elements and cognate transcription factors support postproliferative transcriptional activation and steroid hormone (e.g. vitamin D) enhancement at the onset of extracellular matrix mineralization during osteoblast differentiation. Three parameters of nuclear structure contribute to osteocalcin gene transcriptional control. The linear representation of promoter elements provides competency for physiological responsiveness within the contexts of developmental as well as phenotype-dependent regulation. Chromatin structure and nucleosome organization reduce distances between independent regulatory elements providing a basis for integrating components of transcriptional control. The nuclear matrix supports gene expression by imposing physical constraints on chromatin related to three dimensional genomic organization. In addition, the nuclear matrix facilitates gene localization as well as the concentration and targeting of transcription factors. Several lines of evidence are presented which are consistent with involvement of multiple levels of nuclear architecture in tissue-specific gene expression during differentiation. Growth factor and steroid hormone responsive modifications in chromatin structure, nucleosome organization and the nuclear matrix are considered which influence transcription of the bone tissue-specific osteocalcin gene during progressive expression of the osteoblast phenotype.


Are signs and symptoms associated with persistent corneal abrasions in children?
Corneal abrasions are common eye injuries in children. Most are treated with antibiotic drops or ointment, patching of the affected eye, and follow-up within 24 hours to confirm resolution by fluorescein examination. To determine if signs and symptoms at follow-up were associated with the presence of a persistent corneal abrasion or abnormal visual acuity. Retrospective case series. A children's hospital. Children who were aged 4 years or older with the diagnosis of corneal abrasion between May 1992 and December 1996 and who had a follow-up examination. Seventy-seven patients (57% male) were enrolled (median age, 7 years). The respective sensitivities, specificities, positive predictive values, and negative predictive values of selective signs and symptoms for persistent abrasions were as follows: for pain, 53%, 93%, 80%, and 80%; for photophobia, 57%, 100%, 100%, and 80%; for redness, 100%, 46%, 44%, and 100%; for pain and redness, 40%, 96%, 80%, and 80%; and for at least 1 sign or symptom, 95%, 48%, 47%, and 95%. Twenty-six patients had persistent corneal abrasions at follow-up. Six of these 26 patients were symptom free at follow-up, and 15 patients had only redness as a persistent sign. Five patients had abnormal visual acuity, one of whom was asymptomatic. All 3 patients with complications were symptomatic. Signs and symptoms are inconsistently associated with persistent corneal abrasions. Asymptomatic patients may have persistent corneal abrasions, suggesting the need for selective follow-ups.


Epidural hibernoma as a complication of corticosteroid treatment. Case report.
Centripetal fat deposition is a well-recognized consequence of excessive use of corticosteroids, either endogenous or exogenous. Recently, several patients receiving large doses of corticosteroids have suffered compressive myelopathies due to excessive epidural fat collections, labeled "epidural lipomatosis." Two of these have been children, and a third child is reported here. This child was receiving chronic steroids for juvenile rheumatoid arthritis when he presented with such a myelopathy, which was confirmed by metrizamide computerized tomography myelography as well as by surgical exploration. Histological examination revealed that the epidural tissue was a brown-fat tumor or "hibernoma." An epidural hibernoma has not been described previously. The histological and endocrine features of fat in Cushing's syndrome are discussed, and the literature concerning hibernoma and epidural lipomatosis is reviewed.


The eyes grasp, the hands see: metric category knowledge transfers between vision and touch.
Categorization of seen objects is often determined by the shapes of objects. However, shape is not exclusive to the visual modality: The haptic system also is expert at identifying shapes. Hence, an important question for understanding shape processing is whether humans store separate modality-dependent shape representations, or whether information is integrated into one multisensory representation. To answer this question, we created a metric space of computer-generated novel objects varying in shape. These objects were then printed using a 3-D printer, to generate tangible stimuli. In a categorization experiment, participants first explored the objects visually and haptically. We found that both modalities led to highly similar categorization behavior. Next, participants were trained either visually or haptically on shape categories within the metric space. As expected, visual training increased visual performance, and haptic training increased haptic performance. Importantly, however, we found that visual training also improved haptic performance, and vice versa. Two additional experiments showed that the location of the categorical boundary in the metric space also transferred across modalities, as did heightened discriminability of objects adjacent to the boundary. This observed transfer of metric category knowledge across modalities indicates that visual and haptic forms of shape information are integrated into a shared multisensory representation.


Magnesium absorption using stable isotope tracers in healthy children and children treated for leukemia.
Intestinal magnesium (Mg) absorption was measured in six healthy children (control) and in four children treated for acute lymphoblastic leukemia with the single-isotope fecal recovery technique (SIFRT). The objective of this study was to determine Mg absorption in young children with acute lymphoblastic leukemia using stable isotope tracers. Fractional and absolute absorption levels determined by SIFRT were not significantly different between children with acute lymphoblastic leukemia (fractional absorption: 58.3 +/- 10.6% [mean +/- SEM], absolute absorption: 3.66 +/- 0.71 mg x kg(-1) x d(-1), [0.15 +/- 0.03 mmol x kg(-1) x d(-1)]) and control children (fractional absorption: 61.4 +/- 7.5%, absolute absorption: 5.69 +/- 0.85 mg x kg(-1) x d(-1), [0.23 +/- 0.03 mmol x kg(-1) x d(-1)]). Average Mg absorption in young children (aged 3--8 y) was 60.2 +/- 5.8%. This study describes the first application of the SIFRT to assess Mg absorption in young children and illustrates the feasibility of the SIFRT in this age group to obtain more accurate information on Mg absorption.


Effects of surgery on testosterone secretion in male patients with pituitary adenomas.
The purpose of this study was to assess the effect of surgery on gonadal function in 42 male patients with pituitary adenomas Gonadal functions were evaluated by measuring total serum testosterone concentrations pre- and postoperatively. The subjects of the study were 20 patients with GH secreting adenoma, 7 patients with prolactinoma and 15 patients with nonfunctioning (NF) adenoma. Their ages ranged from 18 to 60 years (mean +/- SEM, 41 +/- 1.9). The serum testosterone concentration was low at less than 300 ng/dl preoperatively in 14 of 20 patients (70%) with GH producing adenoma, 6 of 7 patients (86%) with prolactinoma, and 7 of 15 patients (47%) with NF adenoma. Postoperatively, the total serum testosterone concentration was normalized in 9 of 14 patients (64%) with GH producing adenoma, one of 6 patients (17%) with prolactinoma, and 5 of 7 patients (71%) with NF adenoma. The normalization of serum GH and prolactin concentrations is indispensable for the restoration of gonadal function. It is very important to preserve the normal preoperative gonadotropin secretion by means of gentle surgery.


The synergistic compatibility mechanisms of fuzi against chronic heart failure in animals: A systematic review and meta-analysis.
Background: Fuzi's compatibilities with other medicines are effective treatments for chronic heart failure. Pre-clinical animal experiments have indicated many possible synergistic compatibility mechanisms of it, but the results were not reliable and reproducible enough. Therefore, we performed this systematic review and meta-analysis of pre-clinical animal studies to integrate evidence, conducted both qualitative and quantitative evaluations of the compatibility and summarized potential synergistic mechanisms. Method: An exhaustive search was conducted for potentially relevant studies in nine online databases. The selection criteria were based on the Participants, Interventions, Control, Outcomes, and Study designs strategy. The SYRCLE risk of bias tool for animal trials was used to perform the methodological quality assessment. RevMan V.5.3 and STATA/SE 15.1 were used to perform the meta-analysis following the Cochrane Handbook for Systematic Reviews of Interventions. Result: 24 studies were included in the systematic review and meta-analysis. 12 outcomes were evaluated in the meta-analysis, including BNP, HR, HWI, ALD, LVEDP, LVSP, EF, FS, +dP/dtmax, -dP/dtmax, TNF-α and the activity of Na + -K + -ATPase. Subgroup analyses were performed depending on the modeling methods and duration. Conclusion: The synergistic Fuzi compatibility therapeutic effects against CHF animals were superior to those of Fuzi alone, as shown by improvements in cardiac function, resistance to ventricular remodeling and cardiac damage, regulation of myocardial energy metabolism disorder and RAAS, alleviation of inflammation, the metabolic process in vivo, and inhibition of cardiomyocyte apoptosis. Variations in CHF modeling methods and medication duration brought out possible model-effect and time-effect relationships.


Impact of continuous ambulatory peritoneal dialysis on treatment of renal failure in patients aged over 60.
Thirty eight patients aged over 60 with end stage renal disease were treated by continuous ambulatory peritoneal dialysis for up to three years. Most of these patients, because of their age or coexisting diseases, had been considered to be unsuitable for haemodialysis by the criteria used before the advent of continuous ambulatory peritoneal dialysis in 1980. Actuarial patient survival at one and two years was 72% and 61% respectively, and only two patients were permanently transferred to haemodialysis. Twenty one of the 23 survivors were fully rehabilitated, the remaining two being partially disabled but living at home. Continuous ambulatory peritoneal dialysis permits more liberal selection of patients with end stage renal disease for renal replacement treatment with excellent survival and rehabilitation and without overburdening scarce hospital haemodialysis facilities.


Bone grafts in the management of osteomyelitis.
Chronic osteomyelitis is a condition that requires aggressive surgical treatment in combination with adequate antibiotic therapy. The use of autogenous cancellous bone grafts to fill the defect created by radical sequestrectomy is an effective way of returning function and stability to the involved part and should, therefore, be considered a viable treatment modality by podiatric surgeons who deal with this type of problem.


Constraints on upward migration of hydraulic fracturing fluid and brine.
Recent increases in the use of hydraulic fracturing (HF) to aid extraction of oil and gas from black shales have raised concerns regarding potential environmental effects associated with predictions of upward migration of HF fluid and brine. Some recent studies have suggested that such upward migration can be large and that timescales for migration can be as short as a few years. In this article, we discuss the physical constraints on upward fluid migration from black shales (e.g., the Marcellus, Bakken, and Eagle Ford) to shallow aquifers, taking into account the potential changes to the subsurface brought about by HF. Our review of the literature indicates that HF affects a very limited portion of the entire thickness of the overlying bedrock and therefore, is unable to create direct hydraulic communication between black shales and shallow aquifers via induced fractures. As a result, upward migration of HF fluid and brine is controlled by preexisting hydraulic gradients and bedrock permeability. We show that in cases where there is an upward gradient, permeability is low, upward flow rates are low, and mean travel times are long (often >10⁶ years). Consequently, the recently proposed rapid upward migration of brine and HF fluid, predicted to occur as a result of increased HF activity, does not appear to be physically plausible. Unrealistically high estimates of upward flow are the result of invalid assumptions about HF and the hydrogeology of sedimentary basins.


Study on the treatment of oily wastewater by evaluating the growth process of aggregates in an electrocoagulation reactor.
Electrocoagulation has been widely studied in oily wastewater treatment because of its high demulsification efficiency and no secondary reagent is required. Oil removal largely depends on the properties of the aggregates. This study aimed to explore the growth process of aggregates and oil removal near the anode by electrocoagulation. Four factors, current density, solution temperature, initial pH value, and electrode structure, were investigated. According to the findings, the current density and temperature have the most significant influence on the growth process of aggregates. The oil removal rate depends more on the average particle size than the fractal dimension. The results showed that the current density and solution temperature have the most significant influence on the parameters of the electrocoagulation process. With increasing current density, the aggregate growth rate and average particle size entering the stable period were accelerated, and the oil removal efficiency was promoted. The growth of aggregates was retarded at high temperatures. The change in the scope of the fractal dimension was minor, ranging from 1.65 to 1.84, during the growth process of the aggregates. Foamed aluminium electrodes were beneficial for accelerating aggregate growth instead of aluminium plates, but the energy consumption was obviously increased. The relationship between the mean particle size and mean fractal dimension of aggregates is consistent with the power function. From the point of view of aggregate growth, this study forms the basis for an in-depth understanding of the demulsification mechanism.


Two-photon excited lifetime imaging of autofluorescence in cells during UVA and NIR photostress.
By monitoring coenzyme autofluorescence modifications, as an indicator of cell damage, the cellular response to femtosecond near-infrared (NIR) radiation (two-photon absorption) was compared with exposure to low-power UVA radiation (one-photon absorption). Excitation radiation from a tunable Ti-sapphire laser, focused through high-numerical-aperture microscope optics, provided diffraction-limited microbeams of an adjustable peak power. Laser scanning NIR microscopy was used to detect spatially the intracellular distribution of fluorescent coenzymes by fluorescence intensity imaging as well as fluorescence lifetime imaging (tau-mapping). Upon the onset of UV or NIR exposure, Chinese hamster ovary cells exhibited blue/green autofluorescence with a mean lifetime of 2.2 ns, which was attributed to NAD(P)H in mitochondria. Exposure to 365 nm radiation from a high-pressure mercury lamp (1 mW, 300 J cm-2) resulted in oxidative stress correlated with increased autofluorescence intensity, onset of nuclear fluorescence, and a fluorescence lifetime decrease. The cellular response to femtosecond NIR microbeams depended significantly on peak power. Peak powers above a threshold value of about 0.5 kW (average power: 6 mW). 0.55 kW (7 mW) and 0.8 kW (10 mW) at 730 nm, 760 nm and 800 nm, respectively, resulted in the onset of short-lived luminescence with higher intensity (100 x) than the intracellular NAD(P)H fluorescence. This luminescence, accompanied by destruction of cellular morphology, was localized and occurred in the mitochondrial region. In contrast, beams at a power of less than 0.5 kW allowed nondestructive fluorophore detection with high spatial and temporal resolution without modification of cellular redox state or cell morphology.


Proteomic, cellular, and network analyses reveal new DUSP3 interactions with nucleolar proteins in HeLa cells.
DUSP3 (or Vaccinia virus phosphatase VH1-related; VHR) is a small dual-specificity phosphatase known to dephosphorylate c-Jun N-terminal kinases and extracellular signal-regulated kinases. In human cervical cancer cells, DUSP3 is overexpressed, localizes preferentially to the nucleus, and plays a key role in cellular proliferation and senescence triggering. Other DUSP3 functions are still unknown, as illustrated by recent and unpublished results from our group showing that this enzyme mediates DNA damage response or repair processes. In this study, we sought to identify new interactions between DUSP3 and proteins directly or indirectly involved in or correlated with its biological roles in HeLa cells exposed to gamma or UV radiation. By using GST-DUSP as bait, we pulled down interacting proteins and identified them by LC-MS/MS. Of the 46 proteins obtained, six hits were extensively validated by immune techniques; the proteins Nucleophosmin, HnRNP C1/C2, and Nucleolin were the most promising targets found to directly interact with DUSP3. We then analyzed the DUSP3 interactomes using physical protein-protein interaction networks using our hits as the seed list. The validated hits as well as unvalidated hits fluctuated on the DUSP3 interactomes of HeLa cells, independent of the time post radiation, which confirmed our proteomic and experimental data and clearly showed the proximity of DUSP3 to proteins involved in processes intimately related to DNA repair and senescence, such as Ku70 and Tert, via interactions with nucleolar proteins, which were identified in this study, that regulate DNA/RNA structure and functions.


Directed indices for exploring gene expression data.
Large expression studies with clinical outcome data are becoming available for analysis. An important goal is to identify genes or clusters of genes where expression is related to patient outcome. While clustering methods are useful data exploration tools, they do not directly allow one to relate the expression data to clinical outcome. Alternatively, methods which rank genes based on their univariate significance do not incorporate gene function or relationships to genes that have been previously identified. In addition, after sifting through potentially thousands of genes, summary estimates (e.g. regression coefficients or error rates) algorithms should address the potentially large bias introduced by gene selection. We developed a gene index technique that generalizes methods that rank genes by their univariate associations to patient outcome. Genes are ordered based on simultaneously linking their expression both to patient outcome and to a specific gene of interest. The technique can also be used to suggest profiles of gene expression related to patient outcome. A cross-validation method is shown to be important for reducing bias due to adaptive gene selection. The methods are illustrated on a recently collected gene expression data set based on 160 patients with diffuse large cell lymphoma (DLCL).


Preliminary evaluation of fungicidal and termiticidal activities of filtrates from biomass slurry fuel production.
Biomass slurry fuel (BSF) production has recently been developed as a natural energy for the conversion of solid biomass into fuel. In addition to using fuel, filtrates from BSF production may also serve a chemical source with several organic compounds. There is an increasing interest in the research and application of biomass-based filtrates. In this study, fungicidal and termiticidal properties of filtrates from BSF production using sugi (Cryptomeria japonica) and acacia (Acacia mangium) wood were evaluated in laboratory decay and termite resistance tests. Wood blocks treated with the filtrates showed increased resistance against brown-rot fungus, Fomitopsis palustris. However the filtrates from sugi wood processed at 270 degrees C which contained less phenolic compounds than the other filtrates were effective against white-rot fungus, Trametes versicolor. Phenolic compounds of filtrates seemed to play a role in the decay resistance tests however the filtrates did not increase the durability of the wood blocks against subterranean termites Coptotermes formosanus. Despite high acetic and lactic acid content of the filtrates, vanillin content of the filtrates may have served as an additional food source and promoted termite attack. It can be concluded that filtrates with phenolic compounds from lignin degradation during BSF production can be considered for targeted inhibition of brown-rot.


[Is evidence-based medicine useful for public health?].
Evidence-based medicine is a fashionable topic although the discussions is open regarding whether it has any practical interest for daily medical practice or public health policy. One needs therefore to focus on the way evidence-based medicine can improve matters for physicians, but also on some serious challenges facing health professionals. Upon close examination, it appears that evidence-based medicine provides us with concepts and methods likely to be useful in three directions: improvement of the health care decision-making process, reinforcement of professional accountability dedicated to the promotion of human rights, implementation of fair health policy regulations taking into account the intricate relationships between participants dealing with individual or community oriented interventions. When facing these challenges, evidence-based medicine certainly deserves further attention in the field of community and public health.


Plugs for occlusion of the lacrimal drainage system.
Next to medical therapy, blockage of the lacrimal drainage system is the commonest form of treating dry eye. Rather than applying an artificial tear, the latter helps to preserve any remaining natural tear fluid, which by far has the best wetting and nutrient capacity for the ocular surface. A temporary block is usually induced by implants to tamponade on the level of the lacrimal puncta or canaliculi. A Medline search was performed with the keywords 'lacrimal drainage system, punctum, canaliculus, temporary occlusion, plug, dry eye, keratoconjunctivitis sicca' for the years 1986-2006. Plugs are a suitable treatment in patients with moderate or more severe disease. The characteristics of the devices used and procedures as well as the complications described were analyzed. Criteria such as a lack of Schirmer strip wetting, ocular surface staining and the frequency of artificial tears instillation should be assessed prior to making the decision to occlude the lacrimal drainage. Lacrimal plugs made of silicone or a thermodynamic acrylic polymer, such as hydrogel, appear to be safe and effective, although each patient should be followed on a long-term basis to exclude alterations of the lacrimal system such as chronic inflammatory reactions, extrusion or migration, which may all lead to discomfort. High-frequency ultrasound as a non-invasive, simple diagnostic technique can be used to identify the type or position of plug or inflammatory reaction present. Tamponade of the lacrimal drainage system is a simple procedure that is underused. Preserving natural tears by blocking the lacrimal drainage system can successfully maintain the integrity of the ocular surface and corneal transparency and visual acuity. In patients with moderate or severe dry eye, it is capable of improving quality of life and preventing loss of vision.


Large vancomycin overdose in two premature infants with minimal toxicity.
Two premature infants received 10-fold overdoses of vancomycin with resulting peak plasma concentrations > 300 microg/mL. Discontinuation of vancomycin and watchful waiting were employed, with no specific intervention to accelerate vancomycin clearance. Plasma vancomycin concentration < 40 microg/mL was attained at < 48 hours in one infant and < 72 hours in the other. Although one infant sustained a transient increase in serum creatinine to 1.4 mg/dL, no further evidence of renal, auditory, or other toxicity was detected in either infant acutely or long term. Contemporary preparations of vancomycin appear much less toxic than earlier formulations. Aggressive and invasive interventions to hasten clearance may be unnecessary following overdose in infants with normal or near-normal basal renal function, although careful surveillance for clearance and toxic effects still appear warranted.


Cytochrome P450 1A1 and manganese superoxide dismutase gene polymorphisms in Behçet's disease.
To investigate the association of cytochrome p450 1A1 (CYP1A1) and manganese superoxide dismutase (MnSOD) gene polymorphisms with susceptibility to Behçet's disease (BD) in Taiwan. The polymorphisms of CYP1A1 and MnSOD genes were determined in 51 patients with BD and 91 healthy controls by polymerase chain reaction/restriction fragment length polymorphism methods. The frequencies of CYP1A1 4889G and 4887A were significantly increased in patients with BD. In contrast, there was no significant difference in the frequencies of MnSOD gene polymorphisms between patients with BD and controls. Linkage disequilibrium was found between CYP1A1 4889G and CYP1A1 6235C in controls and patients with BD. However, a similar finding could not be found between CYP1A1 4889G and 4887A. We also found that the association of CYP1A1 4889G with BD was dependent on the presence of CYP1A1 4887A. On the other hand, the association of CYP1A1 4887A with BD was dependent on the presence of CYP1A1 4889G. An additive effect of CYP1A1 4889G and 4887A on the susceptibility to BD could be found. Simultaneous presence of CYP1A1 4889G and 4887A is associated with development of BD in Taiwan.


Electron spin multiplicities of transition-metal aromatic radicals and ions: M[C6(CH3)6] and M(+)[(C6(CH3)6] (M = Ti, V, and Co).
Determination of electron spin multiplicities of transition-metal radicals and ions challenges both experimentalists and theoreticians. In this work, we report preferred electron spin states of M[C(6)(CH(3))(6)] and M(+)(C(6)(CH(3))(6)], where M = Ti, V, and Co. The neutral radicals were formed in a supersonic metal cluster beam source, and their masses were measured with time-of-flight mass spectrometry. Precise ionization energies of the radicals and metal-ligand stretching frequencies of the ions were measured by pulsed field ionization zero electron kinetic energy spectroscopy. C-H stretching frequencies of the methyl group in the radicals were obtained by infrared-ultraviolet two-photon ionization. Electron spin multiplicities of the radicals and ions were investigated by combining the spectroscopic measurements, density functional theory, and Franck-Condon factor calculations. The preferred spin states are quintet, sextet, and quartet for the neutral Ti, V, and Co radicals, respectively; for the corresponding singly charged cations, they are quartet, quintet, and triplet. In these high-spin states, the aromatic ring remains nearly planar. This finding contrasts to the previous study of Sc(hmbz), for which low-spin states are favored, and the aromatic ring is severely bent.


Fam20C Regulates Bone Resorption and Breast Cancer Bone Metastasis through Osteopontin and BMP4.
Fam20C is a kinase that generates the majority of secreted phosphoproteins and regulates biomineralization. However, its potential roles in bone resorption and breast cancer bone metastasis are unknown. Here we show that Fam20C in the myeloid lineage suppresses osteoclastogenesis and bone resorption, during which, osteopontin (OPN) is the most abundant phosphoprotein secreted in a Fam20C-dependent manner. OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C deficiency-induced osteoclast differentiation and bone metastasis. In contrast, Fam20C in breast cancer cells promoted bone metastasis by facilitating the phosphorylation and secretion of BMP4, which in turn enhanced osteoclastogenesis. Mutation of the BMP4 phosphorylation site elevated BMP4 lysosomal degradation and reduced BMP4 secretion. In breast cancer cells, BMP4 depletion or treatment with a BMP4 signaling inhibitor diminished osteoclast differentiation and bone metastasis and abolished Fam20C-mediated regulation of these processes. Collectively, this study discovers distinct roles for Fam20C in myeloid cells and breast cancer cells and highlights OPN and BMP4 as potential therapeutic targets for breast cancer bone metastasis. SIGNIFICANCE: Osteoclastogenesis and bone metastasis are suppressed by myeloid-derived Fam20C, but enhanced by breast cancer-associated Fam20C, uncovering novel Fam20C functions and new therapeutic strategies via targeting Fam20C substrates OPN and BMP4.


Spermatogenetic but not immunological defects in mice lacking the τCstF-64 polyadenylation protein.
Alternative polyadenylation controls expression of genes in many tissues including immune cells and male germ cells. The τCstF-64 polyadenylation protein is expressed in both cell types, and we previously showed that Cstf2t, the gene encoding τCstF-64 was necessary for spermatogenesis and fertilization. Here we examine consequences of τCstF-64 loss in both germ cells and immune cells. Spermatozoa from Cstf2t null mutant (Cstf2t(-/-)) mice of ages ranging from 60 to 108 days postpartum exhibited severe defects in motility and morphology that were correlated with a decrease in numbers of round spermatids. Spermatozoa in these mice also displayed severe morphological defects at every age, especially in the head and midpiece. In the testicular epithelium, we saw normal numbers of cells in earlier stages of spermatogenesis, but reduced numbers of round spermatids in Cstf2t(-/-) mice. Although Leydig cell numbers were normal, we did observe reduced levels of plasma testosterone in the knockout animals, suggesting that reduced androgen might also be contributing to the Cstf2t(-/-) phenotype. Finally, while τCstF-64 was expressed in a variety of immune cell types in wild type mice, we did not find differences in secreted IgG or IgM or changes in immune cell populations in Cstf2t(-/-) mice, suggesting that τCstF-64 function in immune cells is either redundant or vestigial. Together, these data show that τCstF-64 function is primarily to support spermatogenesis, but only incidentally to support immune cell function.


Phytochemical Profile, Antioxidant, Cardioprotective and Nephroprotective Activity of Romanian Chicory Extract.
The present study analyzed the methanol extract and tincture obtained from the spontaneous Romanian Cichorium intybus species, in order to evaluate polyphenols content and some biological properties. Chromatographic and spectrophotometric methods were used for the analysis of polyphenols and the antioxidant capacity was assessed in vitro with DPPH● (2,2-diphenyl-picrylhydrazil) and FRAP (ferric-reducing antioxidant power) tests. The cardio-protective effects of Cichorii herba tincture on myocardial ischemia induced by isoprenaline and nephroprotection on renal failure induced by gentamicin were evaluated on rats. Also, aspartate aminotrasferase (AST), alanine aminotransferase (ALT), creatine kinase-MB (CK-MB) and creatinine clearance (CrCl) were measured. The antioxidant effect was evaluated by determining total oxidative stress (TOS), oxidative stress index (OSI, total antioxidant capacity (TAC), malondyaldehide (MDA), total thiols (SH) and total nitrites and nitrates (NOx). Cichoric acid was the main polyphenolic compound. The extracts had moderate in vitro antioxidant activity but the in vivo antioxidant and anti-inflammatory effects were significant and associated with myocardial and renal dysfunction improvement. The results were attributed to the content of polyphenols in the extracts, for which reason C. intybus may be considered an important raw material for pharmaceuticals formulations recommended in the prevention or treatment of heart or kidney diseases.


The amino acid sequence of a carbohydrate-containing immunoglobulin-light-chain-type amyloid-fibril protein.
The amino acid sequence of an amyloid-fibril protein Es492 of immunoglobulin-lambda-light-chain origin (AL) was elucidated. The amyloid fibrils were obtained from the spleen of a patient who died from systemic amyloidosis. The amino acid sequence was elucidated from structural studies of peptides derived from digestion of the protein with trypsin, thermolysin, chymotrypsin and Staphylococcus aureus V8 proteinase and from cleavage of the protein with CNBr and BNPS-skatole. A heterogeneity in the length of the polypeptide was seen in the C-terminal region. The protein was by sequence homology to other lambda-chains shown to be of the V lambda II subgroup. Although an extensive homology was seen, some amino acid residues in positions 26, 31, 32, 40, 44, 93, 97, 98 and 99 have not previously been reported in these positions of V lambda II proteins. The significance of these residues in the fibril formation is unclear. The protein was found to contain carbohydrate, with glycosylation sites in two of the hypervariable regions.


Elevated serum calcitriol concentrations do not fall in response to hyperphosphatemia in familial tumoral calcinosis.
Five affected members in two branches of a Druze Arab kindred presented with calcified deposits in or about the hips and knees, indicating the diagnosis of tumoral calcinosis. Serum vitamin D metabolite concentrations, immunoreactive parathyroid hormone, and the tubular reabsorption of phosphate were measured in three affected siblings, as well as in their parents and an unaffected sibling. Normocalcemia and hyperphosphatemia with an elevated tubular maximum for phosphate per glomerular filtration rate were found in the affected patients. Levels of serum immunoreactive parathyroid hormone were normal, and the calcitriol value (1,25-dihydroxyvitamin D) was normal or elevated in the three affected patients. A trial of a low-phosphorus diet and oral aluminum hydroxide gel did not lower serum phosphate levels or improve the calcified deposits. These findings suggest that serum calcitriol values do not decline in response to hyperphosphatemia in tumoral calcinosis and that hyperphosphatemia with elevated tubular reabsorption of phosphate is a constant feature of this disorder because the kidney fails to excrete the increased filtered load of phosphate.


[Urinary N-acetyl-beta-D-glucosaminidase and its isoenzymes in smoking and non-smoking workers at copper foundry occupational co-exposed to arsenic cadmium and lead].
The kidneys are the critical organs in the case of a long-term occupational or environmental exposure to heavy metals and tobacco smoke. In diagnostics of renal damage useful are the methods which determine the activity of renal enzymes, quantify in urine (e.g. beta-glucuronidase, N-acetyl-beta-D-glucosaminidase). N-acetyl-beta-D-glucosaminidase (NAG) is one of the most often determined factors of tubular damage, since its activity increases in early stages of renal injury, ahead of appearance of excretory dysfunction. The aim of this research was to assess the influence of occupational exposure of copper-foundry workers to heavy metals (arsenic, cadmium, lead) on total activity of N-acetyl-beta-D-glucosaminidase and its molecular forms in urine. The investigated group was made up of 95 founders (smokers n = 51, non-smokers n = 44) and 43 people in control group (smokers n = 16, non-smokers n = 27). The concentrations of arsenic (As) and cadmium (Cd) were determined in urine, whilst the level of lead (Pb) was determined in whole blood. The activities of NAG and its isoforms were determined in urine. Smoking and non-smoking founders' urine demonstrated 14 times higher concentrations of arsenic levels in comparison with smoking and nonsmoking control group. Cadmium concentrations were 3.5 times higher in urine of smoking founders in comparison with smoking control group and about 3 times higher in case of nonsmoking founders in comparison with non-smoking control group. 7 times increase of lead concentration was observed in the whole blood within the smoking founders group in comparison with the smoking control group. In the blood of non-smoking founders was demonstrated about 10 times increase of lead concentration in comparison with the non-smoking control group. About 3-times increase of total NAG's activity was observed in urine of smoking founders and 4-times increase of non-smoking founders in comparison with smoking and non-smoking control group. The highest activity of NAG-B was observed in urine of smoking founders (11.35 +/- 7.85 U/g creatinine), then non-smoking founders (9.7 +/- 8.75 U/ g creatinine). It was confirmed, that the activity of N-acetyl-beta-D-glucosaminidase is a good factor in the assessment of occupational exposure to heavy metals like arsenic, cadmium and lead.


Effect of thalamotomy on focal hand dystonia in a family with DYT1 mutation.
We report the clinical and molecular features of a family with focal hand dystonia caused by DYT1 mutation. Four members of a family who underwent thalamotomy showed a marked and sustained therapeutic benefit that lasted for up to 12 years without recurrence of dystonia or any significant surgical complication. The hand dystonia caused by DYT1 mutation may be successfully managed by thalamotomy.


Involvement of immune response in the pathogenesis of amyotrophic lateral sclerosis: a therapeutic opportunity?
The immune system has been found to be involved with positive and negative effects in the nervous system of amyotrophic lateral sclerosis (ALS) patients. In general, T cells, B cells, NK cells, mast cells, macrophages, dendritic cells, microglia, antibodies, complement and cytokines participate in limiting damage. Several mechanisms of action, such as production of neurotrophic growth factors and interaction with neurons and glial cells, have been shown to preserve these latter from injury and stimulate growth and repair. The immune system also participates in proliferation of neural progenitor stem cells and their migration to sites of injury and this activity has been documented in various neurologic disorders including traumatic injury, ischemic and hemorrhagic stroke, multiple sclerosis, infection, and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and ALS). Many therapies have been shown to stimulate the protective and regenerative aspects of the immune system in humans, such as intravenous immunoglobulins, and other experimental interventions such as vaccination, minocycline, antibodies and neural stem cells, have shown promise in animal models of ALS. Consequently, several immunosuppressive and immunomodulatory therapies have been tried in ALS, generally with no success, in particular intravenous immunoglobulins. The multiple aspects of the immune response in ALS are beginning to be appreciated, and their potential as pharmacologic targets in neurologic disease is being explored.


Low back pain: a comprehensive approach.
Back pain generally has a good prognosis. Most individuals with low back pain will not be seen by a physician. Symptoms will be resolved spontaneously with time. Patients who are seen with complaints of low back pain need a thorough history and physical examination, with appropriate additional studies as indicated. Conservative therapy will usually prove successful. Current trends in therapy are toward shorter periods of inactivity, with more emphasis on education and rehabilitation, to include active reconditioning in an attempt to decrease the risk of reinjury. For individuals with chronic back pain, referral to a multidisciplinary chronic pain center may be necessary.


Predictors of Placement of Inpatient Palliative Care Consult Orders Among Patients With Breast, Lung, and Colon Cancer in a Safety Net Hospital System.
The provision of palliative and end-of-life care to patients who are underrepresented and underserved provides unique challenges and opportunities. To examine predictors of placement of inpatient palliative care consult orders among patients with breast, lung, and colorectal cancer hospitalized in a safety net hospital in 2010. Simple and multivariable logistic regression of data on selected patients with cancer was performed to identify predictors of placement of inpatient palliative care consult orders. Of 979 patients, 56% had colorectal cancer, 23% had lung cancer, and 21% had breast cancer. Of those patients, 16% received an order for inpatient palliative care consultation during the study period. Patients who had more than 20 prescriptions for opioids ordered (adjusted odds ratio [AOR]: 9.10, 95% confidence interval [CI]: 4.62-17.95), had an order for a radiation oncology consult (AOR: 2.60, 95% CI: 1.50-4.49), or had low albumin (AOR: 2.75, 95% CI: 4.71) were more likely to have an order for an inpatient palliative care consult placed. Race and ethnicity were not statistically significant predictors. In this cohort of patients in a safety net hospital, markers of pain, advanced disease, and poor prognosis were associated with placement of inpatient palliative care consult orders.


Application of Fibrin Associated with Photobiomodulation as a Promising Strategy to Improve Regeneration in Tissue Engineering: A Systematic Review.
Fibrin, derived from proteins involved in blood clotting (fibrinogen and thrombin), is a biopolymer with different applications in the health area since it has hemostasis, biocompatible and three-dimensional physical structure properties, and can be used as scaffolds in tissue regeneration or drug delivery system for cells and/or growth factors. Fibrin alone or together with other biomaterials, has been indicated for use as a biological support to promote the regeneration of stem cells, bone, peripheral nerves, and other injured tissues. In its diversity of forms of application and constitution, there are platelet-rich fibrin (PRF), Leukocyte- and platelet-rich fibrin (L-PRF), fibrin glue or fibrin sealant, and hydrogels. In order to increase fibrin properties, adjuvant therapies can be combined to favor tissue repair, such as photobiomodulation (PBM), by low-level laser therapy (LLLT) or LEDs (Light Emitting Diode). Therefore, this systematic review aimed to evaluate the relationship between PBM and the use of fibrin compounds, referring to the results of previous studies published in PubMed/MEDLINE, Scopus and Web of Science databases. The descriptors "fibrin AND low-level laser therapy" and "fibrin AND photobiomodulation" were used, without restriction on publication time. The bibliographic search found 44 articles in PubMed/MEDLINE, of which 26 were excluded due to duplicity or being outside the eligibility criteria. We also found 40 articles in Web of Science and selected 1 article, 152 articles in Scopus and no article selected, totaling 19 articles for qualitative analysis. The fibrin type most used in combination with PBM was fibrin sealant, mainly heterologous, followed by PRF or L-PRF. In PBM, the gallium-aluminum-arsenide (GaAlAs) laser prevailed, with a wavelength of 830 nm, followed by 810 nm. Among the preclinical studies, the most researched association of fibrin and PBM was the use of fibrin sealants in bone or nerve injuries; in clinical studies, the association of PBM with medication-related treatments osteonecrosis of the jaw (MRONJ). Therefore, there is scientific evidence of the contribution of PBM on fibrin composites, constituting a supporting therapy that acts by stimulating cell activity, angiogenesis, osteoblast activation, axonal growth, anti-inflammatory and anti-edema action, increased collagen synthesis and its maturation, as well as biomolecules.


Molecular detection and characterization of potentially new Babesia and Theileria species/variants in wild felids from Kenya.
Piroplasms frequently infect domestic and wild carnivores. At present, there is limited information on the occurrence and molecular identity of these tick-borne parasites in wild felids in Kenya. In 2009, a pair of captive lions (Panthare leo) was diagnosed with suspected babesiosis and mineral deficiency at an animal orphanage on the outskirts of Nairobi, Kenya. Blood smears indicated presences of haemoparasites in the erythrocytes, however, no further investigations were conducted to identify the infecting agent. The animals recovered completely following diet supplementation and treatment with anti-parasite drug. In this report, we extracted and detected parasite DNA from the two lions and seven other asymptomatic feline samples; two leopards (Panthera pardus) and five cheetahs (Acinonyx jubatus). Reverse line blot with probes specific for Babesia spp. of felines indicated the presence of new Babesia species or genotypes in the lions and leopards, and unknown Theileria sp. in the cheetahs. Phylogenetic analyses using partial sequences of 18S ribosomal RNA (18S rRNA) gene showed that the parasite infecting the lions belong to the Babesia canis complex, and the parasite variant detected in the leopards clusters in a clade bearing other Babesia spp. reported in wild felids from Africa. The cheetah isolates falls in the Theileria sensu stricto group. Our findings indicate the occurrence of potentially new species or genotypes of piroplams in all three feline species.


Giant Effect of Negative Compressibility in a Water-Porous Metal-CO2 System for Sensing Applications.
When compressed, the size of ordinary materials reduces. The opposite effect, when a material or system increases (decreases) its volume upon compression (decompression), is called Negative Compressibility (NC). NC is extremely rare, while being attractive for a wide range of applications. Here we demonstrate, by both experiments and MD simulations, a pronounced effect of volumetric NC in a system consisting of water, porous metal and CO2. This effect is achieved due to a new extrusion-adsorption cycle of water from-into a porous metal driven by a wetting-nonwetting transition due to the increase-decrease of CO2 pressure. The heterogeneous nature of such a system leads to unprecedented NC of up to ∼ 90% in a narrow pressure range, meaning that almost a double volume increase (decrease) upon compression (decompression) is achieved. As long as the wetting-nonwetting transition is achieved, the proposed approach is not limited to water and a specific porous metal. An example of the application of this phenomenon is miniature sensors, particularly for threshold CO2 pressure detection.


Clinical efficacy of an Aloe Vera gel versus a 0.12% chlorhexidine gel in preventing traumatic ulcers in patients with fixed orthodontic appliances: a double-blind randomized clinical trial.
Traumatic oral ulceration (TOU) is one of the most common side effects of orthodontic treatments. The objective of this trial is to compare the clinical efficacy of an 80% Aloe Vera gel, prepared using a master formula, versus a commercial 0.12% Chlorhexidine (CHX) gel for TOU prevention in participants wearing fixed orthodontic appliances. This report represents a single-centre, university-based, double-blinded, randomized controlled trial with 2 parallel arms. Patients aged 12 years or older, in the permanent dentition, and about to start fixed orthodontic treatment in this university setting were randomly allocated to use either Aloe Vera or CHX gel, following the cementation procedure. Pre-treatment and 1 month after the cementation clinical assessment and digital photographic images were taken of the teeth and assessed by 2 clinical assessors for the presence or absence of TOUs. A total of 140 were randomized and completed the trial. The overall prevalence of TOUs was 43.6%. Overall 5.7% of patients treated with Aloe Vera gel showed did not suffer from TOUs, whereas in the CHX arm, a total of 57 (81.4%) were affected by this outcome reaching a significant result (p < 0.001). In terms of relative risk (RRs) and confidence intervals (CIs), Aloe Vera provided better results than CHX with an RR of 0.07 (95%CI 0.03-0.16; p < 0.001), and with a patients' number needed to treat of 1.3 (95%CI 1.16-1.54). There were no adverse effects. These results suggest that Aloe Vera gel administration in patients with fixed orthodontic appliances could be important for effective prevention of TOU.


Drugs that target specificity proteins downregulate epidermal growth factor receptor in bladder cancer cells.
The epidermal growth factor receptor (EGFR) is an important chemotherapeutic target for tyrosine kinase inhibitors and antibodies that block the extracellular domain of EGFR. Betulinic acid (BA) and curcumin inhibited bladder cancer cell growth and downregulated specificity protein (Sp) transcription factors, and this was accompanied by decreased expression of EGFR mRNA and protein levels. EGFR, a putative Sp-regulated gene, was also decreased in cells transfected with a cocktail (iSp) containing small inhibitory RNAs for Sp1, Sp3, and Sp4, and RNA interference with individual Sp knockdown indicated that EGFR expression was primarily regulated by Sp1 and Sp3. BA, curcumin, and iSp also decreased phosphorylation of Akt in these cells, and downregulation of EGFR by BA, curcumin, and iSp was accompanied by induction of LC3 and autophagy, which is consistent with recent studies showing that EGFR suppresses autophagic cell death. The results show that EGFR is an Sp-regulated gene in bladder cancer, and drugs such as BA and curcumin that repress Sp proteins also ablate EGFR expression. Thus, compounds such as curcumin and BA that downregulate Sp transcription factors represent a novel class of anticancer drugs that target EGFR in bladder cancer cells and tumors by inhibiting receptor expression.


Correlating virtual reality and box trainer tasks in the assessment of laparoscopic surgical skills.
The purpose of this study was to examine the correlation in the assessment of laparoscopic surgical skills in medical students with the use of a virtual reality laparoscopic trainer and a low-fidelity video box trainer with comparative tasks. Third-year medical students were asked to perform 3 basic skills set modules on LapSim (Surgical Science, Gothenburg, Sweden): coordination, grasping and lifting, and handling the intestines. Each task was set at the easiest level, and each student was allowed a maximum of 10 attempts to complete each task. Similar-appearing tasks were chosen for comparison with the use of a standard video box trainer: pegboard, cup drop and rope pass, respectively. Laparoscopic skills were evaluated with the use of both trainers during 1 session. Pearson's correlation coefficients were used to compare paired data on each student using statistical software. Forty-seven of 65 medical students were assigned to clinical clerkships on-campus at Temple University School of Medicine participated in the study. All 47 students participated in the video box trainer tasks; 34 students completed both the video box trainer and LapSim skills set. Observations that were obtained on the LapSim virtual reality system and video box trainer simulator demonstrated several correlations. The time to completion for the LapSim coordination task and the pegboard task were correlated (r = 0.507; P = .006), as were the grasping and lifting task completion time on LapSim and the comparative box trainer cup drop task completion time (r = 0.404; P = .022). When accounting for errors, the LapSim coordination task tissue damage score was correlated with the sum of all box trainer errors (r = 0.353; P = .040); the average grasping and lifting tissue damage was correlated with the total number of errors during all box trainer tasks (r = 0.374; P = .035). Overall, in evaluating laparoscopic skills, the LapSim and video box trainer were correlated positively with one another. The scoring of laparoscopic skills by both systems appears to be equivalent for the measurement of time to task completion and number of errors.


Atomic Force Microscopy-Based Nanoscale Infrared Techniques for Catalysis.
Atomic force microscopy (AFM)-based nanoscale infrared (nano-IR) techniques have found extensive application in the fields of chemistry, physics, and materials science, enabling the visualization of nanoscale features that surpass the optical diffraction limit. More recently, tentative investigations have been conducted into the use of these techniques in the field of catalysis, particularly in studying interfacial processes involving molecular monolayer samples. IR nanoimaging and nanospectroscopy offer unique perspectives on catalytic processes. Considering the specific characteristics of catalytic processes, this Perspective highlights the need for and reviews the current status of AFM-based nano-IR techniques for catalysis investigations, which aims to contribute to a deeper understanding of the nanoscale mechanisms underlying the catalytic processes.


Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis.
To provide a systematic and quantitative summary of the association between severe hypoglycaemia and risk of cardiovascular disease in people with type 2 diabetes and to examine the sensitivity of the association to possible uncontrolled confounding by unmeasured comorbid severe illness using a bias analysis. Meta-analysis of observational studies. Medline, Embase, the Cochrane Library, and Web of Science databases were searched to February 2013, without any language restrictions. Two independent reviewers selected cohort studies that evaluated the association of severe hypoglycaemia with cardiovascular events in people with type 2 diabetes; we excluded studies from acute hospital settings. We extracted descriptive and quantitative data. Of 3443 citations screened, six eligible studies with 903, 510 participants were identified. In the conventional random effects meta-analysis, severe hypoglycaemia was strongly associated with a higher risk of cardiovascular disease (relative risk 2.05, 95% confidence interval 1.74 to 2.42; P<0.001). The excess fraction of cardiovascular disease incidence that was attributable to severe hypoglycaemia (the population attributable fraction) was 1.56% (95% confidence interval 1.32% to 1.81%; P<0.001). Although moderate heterogeneity across the studies was suggested (I(2)=73.1%; P=0.002 for heterogeneity), most subgroups showed similar results in stratified analyses. The bias analysis indicated that comorbid severe illness alone may not explain the association between hypoglycaemia and cardiovascular disease; to explain this association, comorbid severe illness would have had to be extremely strongly associated with both severe hypoglycaemia and cardiovascular disease. Our findings suggest that severe hypoglycaemia is associated with a higher risk of cardiovascular disease; they also support the notion that avoiding severe hypoglycaemia may be important to prevent cardiovascular disease in people with type 2 diabetes.


Quest for clarity: investigating concussion-related responsibilities across the New Zealand Rugby Community System.
There is a growing concern around concussions in rugby union, at all levels of the game. These concerns highlight the need to better manage and care for players. However, consistency around concussion-related responsibilities of stakeholders across the community rugby system remains challenging. Taking a systems thinking approach, this pragmatic, qualitative descriptive study explored key stakeholder groups within New Zealand's community rugby system's perceptions of their own and others' concussion-related responsibilities. Participants included players from schools and clubs, coaches, parents, team leads and representatives from four provincial unions. A total of 155 participants (67 females and 88 males) were included in the study. Focus groups and individual interviews were conducted. Thematic content analysis was used to analyse data. Thirty concussion-related responsibilities were identified. These responsibilities were contained within four themes: (1) policies and support (responsibilities which influence policy, infrastructure, human or financial resources); (2) rugby culture and general management (responsibilities impacting players' welfare and safety, attitudes and behaviour, including education, injury reporting and communication); (3) individual capabilities (responsibilities demonstrating knowledge and confidence managing concussion, leadership or role/task shifting) and (4) intervention following a suspected concussion (immediate responsibilities as a consequence of a suspected concussion). The need for role clarity was a prominent finding across themes. Additionally, injury management initiatives should prioritise communication between stakeholders and consider task-shifting opportunities for stakeholders with multiple responsibilities. How concussions will realistically be managed in a real-world sports setting and by whom needs to be clearly defined and accepted by each stakeholder group. A 'framework of responsibilities' may act as a starting point for discussion within different individual community rugby contexts on how these responsibilities translate to their context and how these responsibilities can be approached and assigned among available stakeholders.


Low density lipoprotein as a carrier of cytostatics in cancer chemotherapy: study of stability of drug-carrier complexes in blood.
Several solid tumour and leukemia cell types have a higher low density lipoprotein (LDL) uptake than the corresponding normal cells. We are investigating the possibilities to use LDL as a drug carrier to increase the selectivity of antineoplastic drugs in cancer chemotherapy. We have developed a method to incorporate lipophilic cytotoxic agents without interfering with the in vitro and in vivo properties of LDL. In this study, we examined the stability of some drug-LDL complexes in blood and plasma as this is an important prerequisite to achieve a selective therapy. The in vitro dialysis of N-trifluoroacetyl-adriamycin-14-valerat-LDL (AD-32-LDL) against plasma revealed a slow dissociation of the complex. The same method showed a fast and total leakage of paclitaxel from paclitaxel-LDL into the plasma chamber. The dissociation of paclitaxel was confirmed by an autoradiographic study of the distribution of paclitaxel-LDL in tumour-bearing mice. In patients with leukemia the rapid plasma dissociation of AD-32 from LDL illustrated a much higher in vivo instability of this complex. With this method, cholesteryl-linoleate only could be incorporated into LDL in a stable manner as shown by dialysis and autoradiography results. The incorporation of cytotoxic drug derivatives, containing lipophilic anchors, is now under study in order to obtain LDL complexes with better plasma stability.


Ki-M6 immunostaining in routinely processed sections of reactive and neoplastic human lymphoid tissue.
A monoclonal antibody, termed Ki-M6 (CD68), which shows a restricted reactivity to cells of the monocyte/macrophage system, has been evaluated primarily with the use of cryostat sections. In this study the authors could assess that the Ki-M6 antibody recognizes a fixation-resistant epitope in most human macrophages. The Ki-M6 immunoreactivity with monocyte/macrophage-related cells was established by testing on routinely processed samples of reactive and neoplastic lymphoid tissues; it was compared with the staining for vimentin (V9) and S-100 protein antibodies, with visualization of the stationary elements of lymphoid tissues, with the aim of establishing its value in the study of the nonlymphoid microenvironment. The Ki-M6 antibody reactivity could be achieved with Bouin-fixed, paraffin-embedded tissue sections, without any proteolytic treatment, with the use of the avidin-biotin complex (ABC) method, especially after overnight incubation time at 4 degrees C. Some reduction in antigenic reactivity was observed in B5- or formaldehyde-fixed samples. The antibody reacted with macrophages of all different lymph node compartments; a broad reactivity against cells of macrophage lineage, including multinucleated giant cells, was observed in epithelioid granulomas. Ki-M6-positive cells other than classic macrophages were the so-called "plasmacytoid T-cells" and cells displaying elongated cytoplasms with fibroblastic-like features. Granulocytes, follicular dendritic reticulum cells, and interdigitating reticulum cells did not reveal any reactivity with Ki-M6 antibody. In malignant lesions, neoplastic cells of follicular and diffuse B- and T-cell lymphomas, including large cell non-Hodgkin's lymphomas, and Reed-Sternberg cells of Hodgkin's disease were negative in all cases studied. This study shows that Ki-M6 seems to be another anti-macrophage-specific antibody that reacts, in routinely processed tissue sections, with tissue macrophages but not with accessory cells. Thus, it may be a valuable addition to vimentin and S-100 protein antibodies for investigation of the microenvironmental organization of lymphoid tissues both in normal and neoplastic conditions.


Bioinformatics analyses of immune-related genes and immune infiltration associated with lung ischemia-reperfusion injury.
Ischemia-reperfusion injury (IRI) is a significant complication that can occur following lung transplantation and is known to contribute to poor prognosis. Our research aimed to investigate the potential molecular targets and mechanisms involved in lung IRI (LIRI), in order to improve our understanding of this condition. We downloaded gene expression datasets (GSE127003 and GSE18995) linked to LIRI from the GEO database. Using WGCNA, we identified LIRI-related modules. Functional enrichment analyses were performed on the modules showing significant correlation with LIRI. Core immune-related genes (IRGs) were identified and validated using the GSE18995 dataset. A rat LIRI model was established to validate the expression changes of core IRGs. The LIRI groups were subjected to 60 min of warm ischemia followed by 120 min of reperfusion. Additionally, the xCell algorithm was used to characterize the immune landscape and analyze the relationships between hub IRGs and infiltrating immune cells. A total of 483 genes from the turquoise module were identified through WGCNA, with a predominant enrichment in immune- and inflammation-related pathways. Three IRGs (PTGS2, CCL2, and RELB) were found to be up-regulated after reperfusion in both GSE127003 and GSE18995 datasets, and this was further confirmed using the rat LIRI model. The xCell analysis revealed that immune score, CD8+ naive T cells, eosinophils, neutrophils, NK cells, and Tregs were upregulated after reperfusion. PTGS2, CCL2, and RELB showed positive correlations with CD8+ naive T cells, monocytes, neutrophils, and Tregs. PTGS2, CCL2, and RELB were found to be potential biomarkers for LIRI. Immune and microenvironment scores were higher after reperfusion compared to before reperfusion. PTGS2, CCL2, and RELB appear to play a crucial role in the development of LIRI and may contribute to it by increasing the number of immune cells. Our findings offer new perspectives on potential treatment targets and the pathogenesis of LIRI.


Accumulation of VEGFR2 in zoledronic acid-treated endothelial cells.
Nitrogen-containing bisphosphonates (BIS) are potent inhibitors of bone resorption and are used in the treatment of a number of medical conditions, including multiple myeloma, breast cancer and osteoporosis. Recent experimental evidence demonstrates that BIS also affect endothelial cell functions and angiogenesis; however, the molecular mechanism(s) are unclear. Vascular endothelial growth factor (VEGF) is a potent pro-angiogenic signal for endothelial cells. BIS inhibit VEGF responses in endothelial cells. The VEGF receptor-2 (VEGFR2) is the main signaling receptor for VEGF in endothelial cells. We hypothesized that altered VEGFR2 expression in BIS-treated endothelial cells may account for these attenuated responses to VEGF. The affect of the BIS zoledronic acid (ZOL) was investigated in human umbilical vein endothelial cells using confocal microscopy, Western blotting, real-time PCR and flow cytometry. VEGFR2 accumulated within the ZOL-treated endothelial cells (p=0.0002), though not on the cell surface (p>0.05). ZOL did not induce VEGFR2-specific mRNA (p>0.05). ZOL inhibited endothelial cell chemotaxis towards VEGF (p=0.001). VEGF stimulation significantly reduced the amount of VEGFR2 in the endothelial cells (p=0.01). This response to VEGF was reduced by ZOL (p>0.05). The effects of ZOL on endothelial cell migration, VEGFR2 protein expression and response to VEGF were attenuated by geranylgeranyl pyrophosphate. Two- and one-way ANOVAs with Tukey or Dunnett's multiple comparison adjustments were used. The data suggest that ZOL induces aberrant VEGFR2 accumulation. This is not likely due to the induction of mRNA transcription, but rather to the disruption of the mevalonate pathway.


Atrial natriuretic factor regulates the calcium current in frog isolated cardiac cells.
The effect of external application of synthetic atrial natriuretic factor (ANF) on calcium current (ICa) was studied in single cells isolated from frog ventricle using the whole-cell patch-clamp technique. Rat atriopeptin III (APIII) and 3-28 ANF rat (rANF) had negligible effects on basal ICa at concentrations up to 200 nM. However, when ICa was increased by isoprenaline, both peptides had significant inhibitory effects. rANF (3 nM) decreased isoprenaline-elevated ICa by an average of 33% after 3-5 minutes. APIII was slightly less effective than rANF. The effects of rANF and APIII were dose-dependent in a complex manner: one stimulatory and two different inhibitory effects were observed, one being responsible for an irreversible rundown of ICa. The effects of ANF were not blocked by atropine and desensitization of the cells to isoprenaline did not play a significant role in the response to ANF. When ICa was elevated by intracellular perfusion with cyclic adenosine 3',5'-monophosphate, added to the patch electrode solution or using a perfused pipette, rANF or APIII had less inhibitory effect, and no rundown of ICa was observed. It is proposed that adenylate cyclase may be one of several mechanisms by which ANF regulates ICa.


Raman spectra-based structural classification analysis of quinoidal and derived molecular systems.
This work reports a classification analysis method based on the vibrational Raman spectra of 38 quinones and related structures, spectrally ordering and classifying the compounds. The molecular systems are relevant for chemical and biological processes, with applications in pharmacology, toxicology and medicine. The classification strategy uses a combination of principal component analysis with K-means clustering methods. Both theoretical simulations and experimental data are analysed, thus establishing their spectral characteristics, as related to their chemical structures and properties. The protocol introduced here should be broadly applicable in other molecular and solid state systems.


Secondary tasks impair adaptation to step- and gradual-visual displacements.
Motor adaptation is impaired by the performance of a secondary task which divides cognitive resources. Additionally, we previously reported slowed adaptation when participants were required to switch from one visual displacement adaptation task to another. Here, we examined whether a dividing secondary task had a similar effect on adaptation as switching between opposing visual displacements. The resource-dividing task involved simultaneously adapting to a step-visual displacement whilst vocally shadowing an auditory stimulus. The switching task required participants to adapt to opposing visual displacements in an alternating manner with the left and right hands. We found that both manipulations had a detrimental effect on adaptation rate. We then integrated these tasks and found the combination caused a greater decrease in adaptation rate than either manipulation in isolation. A second set of experiments showed that adaptation to a gradually imposed visual displacement was influenced in a similar manner to step adaptation. In summary, step adaptation slows the learning rate of gradual adaptation to a large degree, whereas gradual adaptation only slightly slows the learning rate of step adaptation. Therefore, although gradual adaptation involves minimal awareness it can still be disrupted with a cognitively demanding secondary task. We propose that awareness and cognitive resource can be regarded as qualitatively different, but that awareness may be a marker of the amount of resource required. For example, large errors are both noticed and require substantial cognitive resource. However, a lack of awareness does not mean an adaptation task will be resistant to interference from a resource-consuming secondary task.


Prospective serial proton MR spectroscopic assessment of response to tamoxifen for recurrent malignant glioma.
Early prediction of imminent failure during chemotherapy for malignant glioma has the potential to guide proactive alterations in treatment before frank tumor progression. We prospectively followed patients with recurrent malignant glioma receiving tamoxifen chemotherapy using proton magnetic resonance spectroscopic imaging ((1)H-MRSI) to identify intratumoral metabolic changes preceding clinical and radiological failure. We performed serial (1)H-MRSI examinations to assess intratumoral metabolite intensities in 16 patients receiving high-dose oral tamoxifen monotherapy for recurrent malignant glioma (WHO grade III or IV) as part of a phase II clinical trial. Patients were followed until treatment failure, death, or trial termination. Patients were officially classified as responders (7 patients) or non-responders (9 patients) 8 weeks into treatment. At 8 weeks, responders and non-responders had different intratumoral intensities across all measured metabolites except choline. Beyond 8 weeks, metabolite intensities remained stable in all responders, but changed again with approaching disease progression. Choline, lipid, choline/NAA, and lactate/NAA were significantly elevated (P < 0.02), while creatine (P < 0.04) was significantly reduced, compared to stabilized levels on average 4 weeks prior to failure. Lactate was significantly elevated (P = 0.036) fully 8 weeks prior to failure. In one patient who was still responding to tamoxifen at the conclusion of the trial, metabolite intensities never deviated from 8-week levels for the duration of follow-up. Characteristic global intratumoral metabolic changes, detectable on serial (1)H-MRSI studies, occur in response to chemotherapy for malignant glioma and may predict imminent treatment failure before actual clinical and radiological disease progression.


Lactobacillus Rhamnosus GG Affects the BDNF System in Brain Samples of Wistar Rats with Pepsin-Trypsin-Digested Gliadin (PTG)-Induced Enteropathy.
Celiac disease (CD) presents as chronic low-grade inflammation of the small intestine often characterized by psychiatric comorbidities. The brain-derived neurotrophic factor (BDNF), which we have shown to be reduced in the serum of CD patients, acts as the bridge between immune activation and the nervous system adaptive response. Since Lactobacillus has been shown to upregulate BDNF, this study aimed to evaluate whether the administration of Lactobacillus rhamnosus GG (L.GG) could positively affect the brain BDNF system in rats mimicking the CD lesions. Data have shown that the administration of pepsin-trypsin digested gliadin (PTG) and L.GG alter the levels of mature BDNF (mBDNF), as evaluated by Western blotting. PTG provoked a reduction of mBDNF compared to controls, and a compensatory increase of its receptor TrkB. L.GG induced a slight positive effect on mBDNF levels under normal conditions, while it was able to rescue the PTG-induced reduced expression of mBDNF. The curative effect of L.GG was finely tuned, accompanied by the reduction of TrkB, probably to avoid the effect of excessive BDNF.


Community-level successes and challenges to implementing adolescent sex education programs.
Best practices for adolescent sex education recommend science-based approaches. However, little is known about the capacity and needs of organizations who implement sex education programs on the local level. The purpose of this research was to describe successes and challenges of community organizations in implementing science-based sex education. Using qualitative methods, we interviewed program directors and educators in 17 state-funded adolescent pregnancy prevention/sex education programs as part of a larger mixed methods evaluation. Semi-structured interviews focused on success and challenges faced in implementing science-based approaches to program design, implementation and evaluation. Interviews were audio-recorded, transcribed and analyzed using a thematic approach. Grantees included a range of programs, from short programs on puberty and HIV for late elementary students, to skills-based curricular sex education programs for high schools, to year-long youth development programs. Key aspects of curricular choice included meeting the needs of the population, and working within time constraints of schools and other community partners. Populations presenting specific challenges included rural youth, youth in juvenile justice facilities, and working with Indiana's growing Latino population. Programs self-developing curricula described challenges related to assessment and evaluation of impact. Programs using commercial curricula described challenges related to curricular selection and adaptation, in particularly shortening curricula, and adapting to different cultural or social groups. A remarkable degree of innovation was observed. The use of qualitative methods permitted the identification of key challenges and successes in a state-sponsored small grants program. Information can be used to enhance program capacity and quality.


Allergic contact dermatitis from povidone-iodine.
A patient developed an erythematous papular, vesicular rash after application of povidone-iodine 10% solution used as a surgical antiseptic. Patch testing revealed positive responses to povidone iodine 10 and 5% in water; 25 controls were negative. Patch testing with iodine, 0.5% in ethanol gave negative results.