Legal aid works! Harm reduction and legal services in Poltava, Ukraine.
Drug users' inability to protect their rights makes them easy targets for extortion and false arrest by law enforcement officials, writes Maxim Demchenko, a lawyer from Poltava. In response, a legal aid project supported by LAHI and OSI's International Harm Reduction Development Program (IHRD) has succeeded in defending drug users against criminal charges and changing the attitudes of some police officers.


Treatment of fungal peritonitis with a combination of intravenous amphotericin B and oral flucytosine, and delayed catheter replacement in continuous ambulatory peritoneal dialysis.
Fungal peritonitis (FP) is associated with significant mortality and high risk of peritoneal failure. The optimum treatment for peritoneal dialysis (PD)-associated FP remains unclear. Since January 2000 we have been treating FP with a combination of intravenous amphotericin B and oral flucytosine, together with deferred catheter replacement. We examined the clinical course and outcome of the FP patients treated with this approach (study group). An outcome comparison was also made to an alternatively treated historic cohort (control group). This was a single-center retrospective study. The clinical course and outcome of 13 consecutive episodes of FP occurring in 13 patients treated between January 2000 and April 2005 with the study approach were examined. The patients were treated with an incremental dose of intravenous amphotericin B to a target dose of 0.75 - 1 mg/kg body weight/day, and oral flucytosine 1 g/day upon a diagnosis of FP at 3.77 +/- 0.93 days from presentation. Replacement of the peritoneal catheter was intended after complete clearing of effluent, after which, antifungal chemotherapy was continued for another 1 - 2 weeks. Their outcome was compared with 14 historic controls that were treated between April 1995 and December 1999. Mean age of the study group was 58.7 +/- 13.2 years; male-to-female ratio was 2:11; 6 (46.1%) were diabetic. All FP were caused by Candida species (C. albicans, 2; C. parapsilosis, 8; C. glabrata, 3). Two (15.4%) patients died before resolution of the peritonitis. The dialysate effluent cleared in 11 patients (84.6%) after 13.2 +/- 3.3 days of treatment, but 2 patients died of acute myocardial infarction before catheter replacement. Nine patients had their catheters replaced at day 26.7 +/- 7.7 of treatment; all 9 returned to PD after a total of 31 +/- 12.2 days of antifungal chemotherapy. Reversible liver dysfunction was common with this regimen. When compared with the 14 cases in the historic control group (Candida species, 13; Trichosporon, 1), who were treated with amphotericin B, fluconazole, or a combination of the two, and the majority (78.6%) of whose catheters were removed before day 10 of presentation, the study group appeared to have a lower technique failure rate (30.8% vs 78.6%, p = 0.013) and similar all-cause mortality (30.7% vs 28.5%, p = NS), FP-related mortality (15.4% vs 28.5%, p = NS), and length of hospitalization (48.5 +/- 30.2 vs 57.0 +/- 37.7 days, p = NS). However, a significantly earlier commencement of antifungal treatment in the study group (3.8 +/- 0.9 vs 5.8 +/- 2.4 days, p = 0.012) could be an important confounder of outcome. Combination of intravenous amphotericin B and oral flucytosine with deferred catheter replacement appears to be associated with a relatively low incidence of PD technique failure, without affecting mortality in patients suffering from FP due to yeasts in this preliminary study. Nonetheless, drug-induced hepatic dysfunction was common; close monitoring during treatment is of paramount importance. The reasons accounting for the observed distinctive outcome remain unclear and further study is required to confirm the results and to investigate for the underlying mechanism.


Bone marrow lesions: a universal bone response to injury?
The ever increasing use of magnetic resonance imaging in clinical practice has led to the recognition of a new entity, bone marrow lesions (BMLs). These lesions are characterized by excessive water signals in the marrow space and have emerged as a central component of many different diseases affecting the musculoskeletal system. BMLs have in particular been associated with a wide variety of inflammatory and non-inflammatory rheumatologic conditions and are not only considered significant sources of pain, but also linked to the worsening of patient prognosis in many disease states. In this review, we summarize the current knowledge on BMLs with an emphasis on the clinical and histological features of this entity in inflammatory and non-inflammatory disease and provide a unifying hypothesis based on the appearance with various imaging technologies. We also try to pair this hypothesis with the apparent beneficial effects of various treatment regimens, mainly within the group of bone antiresorptive drugs (calcitonin, bisphosphonates) on symptoms associated with BMLs.


Limitations of apparent diffusion coefficient-based models in characterizing non-gaussian diffusion.
Diffusion in complex heterogeneous structures, for example, the neural fiber system, is non-gaussian. Recently, several methods have been introduced to address the issue of non-gaussian diffusion in multifiber systems. Some are based on apparent diffusion coefficient (ADC) analysis; and some are based on q-space analysis. Here, using a simple mathematic derivation, ADC-based models are shown to be mathematically self-inconsistent in the presence of non-gaussian diffusion. Monte Carlo simulation on restricted diffusion is applied to demonstrate the poor data fitting that can result from ADC-based models. Specific comparisons are performed between two generalized diffusion tensor imaging methods: one of them is based on ADC analysis, and the other is shown to be consistent with q-space formalism. The issue of imaging asymmetric microstructures is also investigated. Signal phase and spin exchange are necessary to resolve multiple orientations of an asymmetric structure.


Emerging Role of Clinical Genetics in CKD.
Chronic kidney disease (CKD) afflicts 15% of adults in the United States, of whom 25% have a family history. Genetic testing is supportive in identifying and possibly confirming diagnoses of CKD, thereby guiding care. Advances in the clinical genetic evaluation include next-generation sequencing with targeted gene panels, whole exome sequencing, and whole genome sequencing. These platforms provide DNA sequence reads with excellent coverage throughout the genome and have identified novel genetic causes of CKD. New pathologic genetic variants identified in previously unrecognized biological pathways have elucidated disease mechanisms underlying CKD etiologies, potentially establishing prognosis and guiding treatment selection. Molecular diagnoses using genetic sequencing can detect rare, potentially treatable mutations, avoid misdiagnoses, guide selection of optimal therapy, and decrease the risk of unnecessary and potentially harmful interventions. Genetic testing has been widely adopted in pediatric nephrology; however, it is less frequently used to date in adult nephrology. Extension of clinical genetic approaches to adult patients may achieve similar benefits in diagnostic refinement and treatment selection. This review aimed to identify clinical CKD phenotypes that may benefit the most from genetic testing, outline the commonly available platforms, and provide examples of successful deployment of these approaches in CKD.


[Intracerebral subdural hematoma after delivery with peridural catheter anesthesia].
26 days past an obstetric catheter epidural anesthesia a subdural haematoma right fronto-temporal was diagnosed and relieved by operation in a primipara of 19 years of age. Already several days after the delivery the patient was suffering recurrent headaches, at first misinterpreted as post-spinal headaches. Weeks later a cranial computer tomography lead to the right diagnosis. Although the occurrence of a subdural haematoma after catheter epidural anesthesia is extremely rare, untypical headaches following spinal, epidural or caudal procedures, should call your attention towards this complication. Because of the pressing mechanisms during childbearing, delivering mothers run the risk of a subdural haematoma.


Facile synthesis of magnetic one-dimensional polyaniline and its application in magnetic solid phase extraction for fluoroquinolones in honey samples.
In this work, we proposed a simple co-mixing method to fabricate magnetic one-dimensional polyaniline (denoted as 1D-PANIs/MNPs). One-dimensional polyanilines (1D-PANIs) and magnetic nanoparticles (MNPs) were prepared by chemical oxidation and solvothermal methods, respectively. When MNPs and 1D-PANIs (with mass ratio 4:1) were co-mixed and vortexed evenly in a solvent (e.g., ethanol, water, acetonitrile), they could assemble into 1D-PANIs/MNPs spontaneously and thus be magnetically separable. To testify the feasibility of 1D-PANIs/MNPs in sample preparation, it was applied as the sorbent for magnetic solid phase extraction (MSPE) of fluoroquinolones (FQs) in honey samples. Under optimized conditions, a rapid, convenient, and efficient method for the determination of four FQs in honey samples by 1D-PANIs/MNPs-based MSPE coupling with high performance liquid chromatography with fluorescence detection (HPLC-FLD) was established. The limits of detection (LODs) for four FQs ranged from 0.4 to 1.4 ng g(-1). The intra- and interday relative standard deviations (RSDs) were less than 17.6%. The recoveries of FQs for three spiked honey samples ranged from 86.3 to 121.3%, with RSDs of less than 16.3%.


Proteolysis, lipolysis, texture and sensory properties of cheese ripened by Monascus fumeus.
Monascus spp. are fungi that have been applied in food production for centuries and produce a range of bioactive metabolites. The objective of this study was to investigate the characteristics of proteolysis, lipolysis, textural and sensory properties of internal mold-ripened cheese ripened by Monascus fumeus x08. The contents of pH 4.6-soluble nitrogen, 12% trichloroacetic acid-soluble nitrogen and 5% phosphotungstic acid-soluble nitrogen changed significantly during the ripening of the Monascus-ripened cheese. The peptides in the Monascus-ripened cheese were evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and reversed-phase high-performance liquid chromatography. During ripening, many low-molecular-weight peptides (MW < 14400) were found to increase significantly and the ratio of hydrophobic to hydrophilic peptides decreased to 0.81 and 0.34 in the Red-O (outer) and Red-I (interior) parts of the cheese, respectively. The content of total free fatty acids (15 acids, C4:0-C18:3) was significantly increased and the content of unsaturated fatty acids reached 47.89 mg/g fat on day 42 of ripening. The sensory attributes of the Monascus-ripened cheese was assessed using quantitative descriptive analysis. Compared with blue cheese, purchased from a local market, the odor and taste intensity of the Monascus-ripened cheese were significantly lower, while the color intensity and overall receptivity were significantly higher. M. fumeus x08 can be used as a secondary starter to make Monascus-ripened cheese and may be particularly acceptable to consumers in China.


Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-Infected adults treated with rilpivirine or Efavirenz for 96 weeks in the ECHO and THRIVE trials.
Pooled ECHO/THRIVE lipid and body fat data are presented from the ECHO (Efficacy Comparison in Treatment-Naïve, HIV-Infected Subjects of TMC278 and Efavirenz) and THRIVE (TMC278 Against HIV, in a Once-Daily Regimen Versus Efavirenz) trials. We assessed the 96-week effects on lipids, adverse events (AEs), and body fat distribution (dual-energy x-ray absorptiometry) of rilpivirine (RPV) and EFV plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in treatment-naive adults infected with human immunodeficiency virus type 1 (HIV-1). Rilpivirine produced minimal changes in total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Compared with RPV, EFV significantly (P < .001) increased lipid levels. Decreases in the TC/HDL-C ratio were similar with RPV and EFV. Background N[t]RTI affected RPV-induced lipid changes; all levels increased with zidovudine/lamivudine (3TC) and abacavir/3TC (except triglycerides, which were unchanged). With emtricitabine/tenofovir, levels of HDL-C were increased, TC and LDL-C were unchanged, and triglycerides were decreased. With EFV, lipid levels increased in each N[t]RTI subgroup (except triglycerides were unchanged with abacavir/3TC). Fewer (P < .001) RPV-treated patients than EFV-treated patients had TC, LDL-C, and triglyceride levels above National Cholesterol Education Program cutoffs. More RPV- than EFV-treated patients had HDL-C values below these cutoffs (P = .02). Dyslipidemia AEs were less common with RPV than with EFV. Similar proportions of patients had a ≥10% decrease in limb fat (16% with RPV and 17% with EFV). Limb fat was significantly (P < .001) increased to a similar extent (by 12% with RPV and 11% with EFV). At week 96, patients receiving zidovudine/3TC had lost limb fat, and those receiving emtricitabine/tenofovir had gained it. Over the course of 96 weeks, RPV-based therapy was associated with lower increases in lipid parameters and fewer dyslipidemia AEs than EFV-based treatment. Body fat distribution changes were similar between treatments. The N[t]RTI regimen affected lipid and body fat distribution changes.


Management of carotid body paragangliomas and review of a 30-year experience.
Carotid body tumors are rare neoplasms and must be considered in the evaluation of all lateral neck masses; early surgical removal has been recommended. In this study, the medical records of 29 patients with 34 carotid body paragangliomas who were treated at our institution between 1971 and 2001 were retrospectively reviewed. An overview is provided of this lesion, including diagnosis, classification, metastatic potential, possible secretory function, operative techniques, and nonsurgical methods of management. Carotid body tumors may be familial and are more often bilateral in these instances; five patients (17%) had bilateral tumors in this series. The criterion for malignancy is demonstrated by metastatic tumor in lymph nodes or distant organs. Three patients (10%) had malignant tumors, one with hepatic metastases. One patient (3%) in our series exhibited abnormal serotonin production. Vascular reconstruction was necessary in eight cases (28%). No stroke occurred, however, two arterial thromboses (7%), five permanent cranial nerve deficits (17%), and one death (3%) from massive pulmonary embolism were seen. Our experience demonstrates that early operative management is warranted to avoid the possibility of eventual metastasis and progressive local invasion to the point of inoperability.


Benthic nutrient flux in a shallow coastal environment.
Ammonia and nitrate efflux from a fine sand in Carmarthen Bay was studied by incubating undisturbed cores of sediment on board ship. At the end of each incubation, the macrofaunal and bacterial biomass in each core and the organic content of the sediment were determined. Oxygen consumption was measured in another series of cores. The relationship between ammonia flux and biomass was investigated using a lattice of hypotheses approach to multiple linear regression, where all possible submodels of a general model are fitted. Ammonia flux was significantly related to the biomass of polychaetes and molluscs and "other macrofauna" but the inclusion of bacterial biomass did not improve the regressions. The estimated annual efflux of ammonia was 778 mmol N m-2 which is 44% of the estimated annual nitrogen demand of the phytoplankton. However, at the time of maximum primary production in June, only 16% of the phytoplankton requirement for nitrogen was met by benthic ammonia flux. Nitrate efflux was an order of magnitude less than that of ammonia and reached a maximum in the autumn. No significant relationship was found between oxygen consumption and macrofaunal or bacterial biomass at any time of the year.


Gamma irradiation effects on molecular weight and in vitro degradation of poly(D,L-lactide-CO-glycolide) microparticles.
The objective of the reported work was to quantitatively establish gamma-irradiation dose effects on initial molecular weight distributions and in vitro degradation rates of a candidate erodible biopolymeric delivery system. Poly(D,L-lactide-coglycolide) (PLGA) porous microparticles were prepared by a phase-separation technique using a 50:50 copolymer with 30,000 nominal molecular weight. The microparticles were subjected to 0, 1.5, 2.5, 3.5, 4.5, and 5.5 Mrad doses of gamma-irradiation and examined by size exclusion chromatography (SEC) to determine molecular weight distributions. The samples were subsequently incubated in vitro at 37 degrees C in pH 7.4 PBS and removed at timed intervals for gravimetric determinations of mass loss and SEC determinations of molecular weight reduction. Irradiation reduced initial molecular weight distributions as follows (Mn values shown parenthetically for irradiation doses): 0 Mrad (Mn = 25200 Da), 1.5 Mrad (18700 Da), 2.5 Mrad (17800 Da), 3.5 Mrad (13800 Da), 4.5 Mrad (12900 Da), 5.5 Mrad (11300 Da). In vitro degradation showed a lag period prior to zero-order loss of polymer mass. Onset times for mass loss decreased with increasing irradiation dose: 0 Mrad (onset = 3.4 weeks), 1.5 Mrad (2.0 w), 2.5 Mrad (1.5 w), 3.5 Mrad (1.3 w), 4.5 Mrad (1.0 w), 5.5 Mrad (0.8 w). The zero-order mass loss rate was 12%/week, independent of irradiation dose. Onset of erosion corresponded to Mn = 5200 Da, the point where the copolymer becomes appreciably soluble. The data demonstrated a substantial effect of gamma-irradiation on initial molecular weight distribution and onset of mass loss for PLGA, but no effect on rate of mass loss.


Making sense of frailty: An ethnographic study of the experience of older people living with complex health problems.
To explore how older people with complex health problems experience frailty in their daily lives. A better understanding of the personal experience of frailty in the context of fluctuating ill-health has the potential to contribute to the development of personalised approaches to care planning and delivery. An ethnographic study of older people, living at home, receiving support from a community matron service in a large city in the North of England. Up to six care encounters with each of ten older people, and their community matron, were observed at monthly intervals, over a period of time ranging from 4 to 11 months. Semi-structured interviews were conducted with the older participants in their own homes. Fieldwork took place over a 4-year period. Data analysis was undertaken using the constant comparative method. The experience of frailty was understood through the construction of four themes: Fluctuating ill-health and the disruption of daily living; Changes to the management of daily living; Frailty as fear, anxiety and uncertainty; Making sense of changes to health and daily living. Older people work hard to shape and maintain daily routines in the context of complicated and enduring transitions in health and illness. However, they experience episodic moments of frailty, often articulated as uncertainty, where daily living becomes precarious and their resilience is threatened. Developing an understanding of the personal experiences of frail older people in the context of transition has the potential to inform nursing practice in person-centred care . Nurses need to support frail older people to maintain independence and continuity of personhood in the context of daily routines.


Crystallization, microstructure and polymorphic properties of soybean oil organogels in a hybrid structuring system.
Organogels are semi-solid systems where the liquid phase is immobilized for three-dimensional network self-sustained formed by structuring agents capable to hold a larger quantity of liquid oil. The use of these structuring agents or crystallization modifiers, as specific triacylglycerols, emulsifiers and high molecular weight - high melting point lipids, have been recognized as the main alternative for obtaining low saturated fats for food formulation. The aim of this work was to evaluate the crystallization, microstructure and polymorphism properties of hybrid soybean oil (SO) organogels, formulated with 6% (w:w) of structuring agents through a centroid simplex system added singly, in binary or ternary association of candelilla wax (CW), sorbitan monostearate (SMS) and fully hydrogenated palm oil (FHPO). The thermal behavior, crystallization kinetics, physical stability by temperature cyclization, microstructure and polymorphism were evaluated. FHPO and CW increased the stability and ability to form crystalline networks in organogels, while SMS accelerated the crystallization process. The structuring agents increased the initial and final crystallization temperatures, even as the melting temperatures and the enthalpy values of organogels. Time-temperature cyclization (cyclization 1: 5 °C/48 h + 35 °C/24 h + 5 °C/24 h; cyclization 2: 35 °C/48 h + 5 °C/72 h) showed that all the systems resulted in firm and stable organogels, except when SMS or FHPO were used singly. CW promoted formation of denser crystalline networks with higher solids content, quick crystallization onset and higher melting points that indicates adequate thermal resistance; while FHPO increased the solid content although it was effective to obtain organogels only at the cooling temperature (5 °C). The binary interaction of FHPO + CW increased the thermal resistance of organogels; and the interactions among SMS + CW and SMS + CW + FHPO although it was effective to obtain organogels. Regardless of the presence and proportions of structuring agents, organogels were characterized by beta polymorphism.


Effects of ammonium ion removal on growth and MAb production of hybridoma cells.
Production of monoclonal antibody against hepatitis B surface antigen was carried out by perfusion culture coupled with a selective removal system for ammonium ion. The removal system is composed of three sub-systems namely, cell separation by cross-flow ceramic filter, dialysis by hollow fiber module and ion-exchange by zeolite A-3 packed bed column. The ammonium ion concentration in the culture broth was effectively maintained below the inhibitory level, and the viable cell density reached 2.5×10(7) cells ml(-1) which was three times that of conventional perfusion cultures. The monoclonal antibody accumulated to a concentration as high as 26.3×10(5) mIU(-1). This is already almost half of the amount producedin vivo. The numerical investigation of the ammonium ion removal system showed the possibility to improve much more the performance of this perfusion cultivation system.


Peptide Modified Albumin-Paclitaxel Nanoparticles for Improving Chemotherapy and Preventing Metastasis.
Metastasis and recurrence are the main causes of death in cancer patients; however, there are few medicines that can inhibit tumor growth and metastasis at the same time. In this work, a novel nano-drug delivery system (NDDS) based on targeting ligand modified albumin is reported. The hydrophobic drug (paclitaxel) induces albumin self-assembly after treatment of albumin with l-cysteine, forming drug-loaded nanoparticles with a size of 100-200 nm. Importantly, the albumin nanoparticles display enhanced antitumor efficacy against tumor growth/lung metastasis in 4T1 bearing nude mice and prevention of lung metastasis in a B16-F10 model. This study provides a facile method for hydrophobic chemo-drugs loaded albumin nanoparticles preparation and a promising chemotherapy with effective tumor growth inhibition and metastasis prevention.


Decreased plasma levels of lipoprotein(a) in patients with hypertriglyceridemia.
Lipoprotein(a) (Lp(a)) is an atherogenic lipoprotein which is similar in structure to, but metabolically distinct from, LDL. Factors modulating plasma Lp(a) concentrations are poorly understood. To investigate the possible interaction of Lp(a) with triglycerides, we determined the apo(a) phenotype, Lp(a) concentration, and distribution of Lp(a) in a group of patients with triglycerides > 400 mg/dl (n = 60) compared with a control group (n = 128). Lp(a) concentrations were significantly lower in hypertriglyceridemic patients (mean +/- S.E., 13 +/- 4 mg/dl; median, 6 mg/dl; 25/75 percentile, 2-13 mg/dl) as compared with the controls (mean, 22 +/- 2 mg/dl; median, 10 mg/dl; 25/75 percentile, 7-30 mg/dl). Plasma Lp(a) concentrations in the hypertriglyceridemic patients correlated negatively with triglyceride levels (r = -0.69, P = 0.03). The difference in Lp(a) levels between patients and controls was maintained when subjects were stratified by apo(a) phenotype and type of hyperlipidemia. After subdividing the hypertriglyceridemic patients into one group with apo(a) isoforms < or = S2 and one group with apo(a) isoforms > or = S3, we found that the differences in plasma Lp(a) concentrations between patients and controls were more pronounced in the group with the lower molecular weight apo(a) isoforms. These data indicate that hypertriglyceridemia is associated with lower plasma Lp(a) concentrations and suggest that increased levels of triglyceride-rich lipoproteins may influence the metabolism of Lp(a).


Respiratory effects associated with wood fuel use: a cross-sectional biomarker study among adolescents.
The use of wood as heating and cooking fuel can result in elevated levels of indoor air pollution, but to what extent this is related to respiratory diseases and allergies is still inconclusive. Here, we report a cross-sectional study among 744 school adolescents (median age 15 years) using as main outcomes respiratory symptoms and diseases, exhaled nitric oxide, total and aeroallergen-specific IgE in serum, and two epithelial biomarkers in nasal lavage fluid (NALF) or serum, that is, Clara cell protein (CC16) and surfactant-associated protein D (SPD). Information about the wood fuel use and potential confounders was collected via a personal interview of the adolescent and a questionnaire filled out by the parents. Two approaches were used to limit the possible influence of confounders, that is, multivariate analysis using the complete study population or pairwise analysis of matched sub-populations obtained using an automated procedure. Wood fuel use was associated with a decrease of CC16 and an increase of SPD in serum, which resulted in a decreased serum CC16/SPD ratio (median -9%, P = 0.001). No consistent differences were observed for the biomarkers measured in exhaled breath or NALF. Wood fuel use was also associated with increased odds for asthma [odds ratio (OR) 2.2, 95% CI: 1.1-4.4, P = 0.02], hay fever (OR = 2.4, 95% CI: 1.4-4.3, P = 0.002), and sensitization against pollen allergens (OR = 2.1, 95% CI: 1.3-3.4, P = 0.002). The risks of respiratory tract infections, self-reported symptoms, and sensitization against house-dust mite were not increased by wood fuel use. The increased risks of asthma, hay fever and aeroallergen sensitization, and the changes of lung-specific biomarkers consistently pointed towards respiratory effects associated with the use of wood fuel.


Secreted protein acidic and rich in cysteine enhances the chemosensitivity of pancreatic cancer cells to gemcitabine.
It has been previously shown that the simultaneous exposure of colon cancer cells MIP to irinotecan and secreted protein acidic and rich in cysteine (SPARC) enhances anticancer activity. However, whether there is same effect of SPARC in pancreatic cancer remains largely unknown. Therefore in this study, we aimed to investigate the role of SPARC played in the sensitivity of pancreatic cancer to gemcitabine. We first treated MIAPaCa2 and MIAPaCa2/SPARC69 cells with different concentrations of gemcitabine (2, 5, 10, and 20 μM) for 24, 48, and 72 h and selected the appropriated concentration for further study. Then we analyzed cell viability, cell cycle, and apoptosis and the levels of apoptosis-related proteins by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, fluorescence-activated cell sorting and Western blot were used, respectively. In this study, we found that gemcitabine inhibited the proliferation of pancreatic cancer cells in a time- and dose-dependent manner. Overexpression of SPARC increased the inhibiting effect of gemcitabine on pancreatic cancer cells. The colony size of MIAPaCa2/SPARC69 was much smaller than that of MIAPaCa2/V. There was a G0/G1 arrest with significant increase of apoptosis after gemcitabine treatment in MIAPaCa2/SPARC69 cells. Furthermore, our results demonstrated that overexpression of SPARC markedly increased the levels of pro-apoptotic proteins in gemcitabine-treated pancreatic cancer cells. The SPARC can enhance the chemosensitivity of pancreatic cancer cells to gemcitabine via regulating the expression of apoptosis-related proteins. These results have shown that the SPARC/ gemcitabine combination treatment may be a potentially useful therapeutic option for individuals diagnosed with pancreatic cancer.


Nature and place of crime scene management within forensic sciences.
This short paper presents the preliminary results of a recent study aimed at appreciating the relevant parameters required to qualify forensic science as a science through an epistemological analysis. The reader is invited to reflect upon references within a historical and logical framework which assert that forensic science is based upon two fundamental principles (those of Locard and Kirk). The basis of the assertion that forensic science is indeed a science should be appreciated not only on one epistemological criteria (as Popper's falsification raised by the Daubert hearing was), but also on the logical frameworks used by the individuals involved (investigator, expert witness and trier of fact) from the crime scene examination to the final interpretation of the evidence. Hence, it can be argued that the management of the crime scene should be integrated into the scientific way of thinking rather than remain as a technical discipline as recently suggested by Harrison.


Colloidal systems toward 3D cell culture scaffolds.
Three-dimensional porous scaffolds are essential for the development of tissue engineering and regeneration, as biomimetic supports to recreate the microenvironment present in natural tissues. To successfully achieve the growth and development of a specific kind of tissue, porous matrices should be able to influence cell behavior by promoting close cell-cell and cell-matrix interactions. To achieve this goal, the scaffold must fulfil a set of conditions, including ordered interconnected porosity to promote cell diffusion and vascularization, mechanical strength to support the tissue during continuous ingrowth, and biocompatibility to avoid toxicity. Among various building approaches to the construction of porous matrices, selected strategies afford hierarchical scaffolds with such defined properties. The control over porosity, microstructure or morphology, is crucial to the fabrication of high-end, reproducible scaffolds for the target application. In this review, we provide an insight into recent advances toward the colloidal fabrication of hierarchical scaffolds. After identifying the main requirements for scaffolds in biomedical applications, conceptual building processes are introduced. Examples of tissue regeneration applications are provided for different scaffold types, highlighting their versatility and biocompatibility. We finally provide a prospect about the current state of the art and limitations of porous scaffolds, along with challenges that are to be addressed, so these materials consolidate in the fields of tissue engineering and drug delivery.


Hemodynamic effects of increased intra-abdominal pressure in critically ill children.
To evaluate the influence of intra-abdominal pressure on the cardiac index (CI) at different intra-abdominal hypertension grades achieved when performing an abdominal compression maneuver (ACM). Evaluating the effectiveness of the ACM in distending the left internal jugular vein (LIJV). Prospective observational study conducted in the PICU of a quaternary care teaching hospital. Participants underwent the ACM and the IAP was measured with an indwelling urinary catheter. At each IAH grade reached during the ACM, the CI was measured by transthoracic echocardiography and the LIJV cross-sectional area (CSA) was determined by ultrasonography. Twenty-four children were included (median age and weight of 3.5 months and 6.37kg, respectively). The median CI observed at baseline and during IAH grades I, II, III, and IV were 3.65L/min/m2 (IQR 3.12-4.03), 3.38L/min/m2 (IQR 3.04-3.73), 3.16L/min/m2 (IQR 2.70-3.53), 2.89L/min/m2 (IQR 2.38-3.22), and 2.42L/min/m2 (IQR 1.91-2.79), respectively. A 25% increase in the LIJV CSA area was achieved in 14 participants (58%) during the ACM. The ACM significantly increases IAP, causing severe reversible impairment in the cardiovascular system and is effective in distending the LIJV in just over half of the subjects. Even low levels of HIA can result in significant cardiac dysfunction in children. Therefore, health professionals should be aware of the negative hemodynamic repercussions caused by the increased IAP.


Advantages of using development models of the carrion beetles Thanatophilus micans (Fabricius) and T. mutilatus (Castelneau) (Coleoptera: Silphidae) for estimating minimum post mortem intervals, verified with case data.
Some beetles are as useful as blow flies for estimating the minimum post mortem interval (PMImin) or time since death. Examples include Thanatophilus micans (Fabricius) and Thanatophilus mutilatus (Castelneau), two geographically and ecologically overlapping African beetles. Molecular means of identifying these species, descriptions of their natural history, thermal summation models for the development of each species, and a case in which T. micans was recovered are presented. These beetles colonise bodies soon after death, their development spans more time than that of flies, and they may be little affected by maggot-generated heat. From an experimental perspective, they can be reared individually, which allows the identification of sick individuals and has analytical advantages relative to fly larvae that must be reared in groups. Estimating minimum post mortem intervals for both species using the case data strongly suggests that developmental models parameterised for one species should not be used to make forensic estimates for closely related species for which no specific model is available and emphasises the need for correct identifications.


Colonic perforation following ingestion of plastic sheeting.
A case report of fatal faecal peritonitis, in a mentally retarded patient, resulting from perforation of the colon caused by ingested plastic sheeting is presented. Foreign body perforation of the intestines is discussed.


Evaluation of EEG biomarkers of Comprehensive Behavioral Intervention for Tics in children with Tourette syndrome.
Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment of Tourette syndrome (TS). However, the brain mechanisms involved in CBIT are poorly understood. Enhanced frontomesial EEG coherence during a Go/NoGo task has been suggested as a mechanism involved in voluntary tic control. In the current study, we conducted a randomized controlled trial to assess whether EEG coherence during a Go/NoGo task was associated with CBIT outcome. Thirty-two children with TS were randomly assigned to CBIT or to treatment-as-usual (TAU). Treatment outcome was assessed by a blinded evaluator with the Yale Global Tic Severity Scale (YGTSS) and the Clinical Global Impression - Improvement Scale (CGI-I). EEG was recorded during a Go/NoGo task at baseline and endpoint. EEG coherence was computed in the alpha frequency band between a priori selected channel pairs spanning the frontal and motor areas. Tic severity decreased significantly in the CBIT group. However, CBIT did not impact EEG coherence and baseline EEG coherence did not predict treatment outcome. Although CBIT was superior to TAU on blinded clinical outcomes, EEG coherence during the Go/NoGo task was not associated with change in tic severity. The brain processes involved in the inhibition of motor responses do not appear to be involved in CBIT.


Assessing the potential toxic effect of one persistent organic pollutant: non-covalent interaction of dicofol with the enzyme trypsin.
Because of the widespread concern that persistent organic pollutants (POPs) may be adversely affecting the health of humans, reliable assessing their toxic effects is urgently needed. We selectively study the interaction between dicofol (DCF) and trypsin by steady state and time resolved fluorescence quenching measurements and UV-visible absorption spectroscopy under physiological conditions as well as applying molecular docking method to establish the interaction model. The fluorescence results indicate DCF can spontaneously form a complex with trypsin mainly by hydrogen bond with only one binding site, which had been validated in molecular docking. The conformational change of trypsin was proved by UV-visible absorption and synchronous fluorescence spectroscopy indicating a red shift of carbonyl absorption peak. All the results indicated DCF had potential toxic effects on both the structure and activity of the enzyme trypsin and the effects enhanced with the increasing concentration of DCF.


Hemoagglutination and hemagglutination inhibition tests with enterovirus type 70.
Human type "O," guinea pig, and chicken erythrocytes were agglutinated by enterovirus type 70 at 4 degrees C or room temperature. A hemagglutination inhibition test, using human "O" erythrocytes, is described for the serological diagnosis of acute hemorrhagic conjunctivitis caused by enterovirus type 70.


Changes in cellular Ca2+ and Na+ regulation during the progression towards heart failure in the guinea pig.
During compensated hypertrophy in vivo fractional shortening (FS) remains constant until heart failure (HF) develops, when FS decreases from 70% to 39%. Compensated hypertrophy is accompanied by an increase in INa,late and a decrease in Na+ ,K+ -ATPase current. These changes persist as HF develops. SR Ca2+ content increases during compensated hypertrophy then decreases in HF. In healthy cells, increases in SR Ca2+ content and Ca2+ transients can be achieved by the same amount of inhibition of the Na+ ,K+ -ATPase as measured in the diseased cells. SERCA function remains constant during compensated hypertrophy then decreases in HF, when there is also an increase in spark frequency and spark-mediated Ca2+ leak. We suggest an increase in INa,late and a decrease in Na+ ,K+ -ATPase current and function alters the balance of Ca2+ flux mediated by the Na+ /Ca2+ exchange that limits early contractile impairment. We followed changes in cardiac myocyte Ca2+ and Na+ regulation from the formation of compensated hypertrophy (CH) until signs of heart failure (HF) are apparent using a trans-aortic pressure overload (TAC) model. In this model, in vivo fractional shortening (FS) remained constant despite HW:BW ratio increasing by 39% (CH) until HF developed 150 days post-TAC when FS decreased from 70% to 39%. Using live and fixed fluorescence imaging and electrophysiological techniques, we found an increase in INa,late from -0.34 to -0.59 A F-1 and a decrease in Na+ ,K+ -ATPase current from 1.09 A F-1 to 0.54 A F-1 during CH. These changes persisted as HF developed (INa,late increased to -0.82 A F-1 and Na+ ,K+ -ATPase current decreased to 0.51 A F-1 ). Sarcoplasmic reticulum (SR) Ca2+ content increased during CH then decreased in HF (from 32 to 15 μm l-1 ) potentially supporting the maintenance of FS in the whole heart and Ca2+ transients in single myocytes during the former stage. We showed using glycoside blockade in healthy myocytes that increases in SR Ca2+ content and Ca2+ transients can be driven by the same amount of inhibition of the Na+ ,K+ -ATPase as measured in the diseased cells. SERCA function remains constant in CH but decreases (τ for SERCA-mediated Ca2+ removal changed from 6.3 to 3.0 s-1 ) in HF. In HF there was an increase in spark frequency and spark-mediated Ca2+ leak. We suggest an increase in INa,late and a decrease in Na+ ,K+ -ATPase current and function alters the balance of Ca2+ flux mediated by the Na+ /Ca2+ exchange that limits early contractile impairment.


A nursing care-sensitive patient satisfaction measure in older patients.
As a novelty, this article proposes the empirical operationalization of an indicator sensitive to nursing care called patient satisfaction based on functional capacity and quality of life assessments. This was a descriptive cross-sectional study with a sample of 351 individuals aged 65 and older residing in the community. Data acquisition was performed using the structured interview method, employing a core set of 25 codes taken from the International Classification of Functioning, Disability, and Health and the WHOQOL-BREF instrument of the World Health Organization. Confirmatory factor analysis was used to infer the reliability and construct validity of the proposed model, involving three latent factors: functional capacity, quality of life, and patient satisfaction with nursing care received. The proposed model showed good reliability and construct validity, although it failed regarding discriminant validity between latent factors. The greatest statistically significant predictor of the patient satisfaction latent factor was the quality of life latent factor ([Formula: see text]), followed by the functional capacity latent factor ([Formula: see text]). The findings seem to suggest that patient satisfaction is an indicator that may be quantitatively measurable, with functional capacity and quality of life considered very significant predictors of patient satisfaction with the nursing care experience.


Inhibition of inflammatory pain by naloxone and its N methyl quaternary analogue.
Naloxone hydrochloride (Nx) and methylnaloxone methylsulfate (MeNx) antagonized the inflammatory pain, but not oedema, produced by intraplantar carrageenan in rats. The liminar effective dose (3 microgram/kg) was the same for the two drugs after intraplantar or subcutaneous injection. The s.c. dose effects curves were, as a whole, similar for the two drugs. The effect was long lasting and stereospecific. The low "analgesic" s.c. doses of Nx were able to antagonize morphine analgesia, those of MeNx were not. The interpretation is difficult; a peripheral action or better the local production of morphinomimetic metabolite(s) might account for most facts.


From atomic bonding to heterointerfaces: Co2P/WC constructed by lacunary polyoxometalates induced strategy as efficient hydrogen evolution electrocatalysts at all pH values.
Herein, a novel in-situ "atomic binding to heterointerface" strategy is proposed to obtain Co2P/WC@NC/CNTs catalyst with abundant heterointerface between cobalt phosphide and tungsten carbide (Co2P/WC) by the polyoxometalates (POMs)-based metal-organic frameworks (MOFs) precursor. The natural quasi interfaces in K10[Co4(H2O)2(PW9O34)2] molecule crucially guide the abundant Co2P/WC heterointerfaces down to atomic level. Meanwhile, MOFs cages can effectively encapsulate nanosized POMs at molecular level to control the size and dispersion of Co2P/WC nanoparticle, while carbon nanotubes (CNTs) enhance conductivity at nanoscale level. The interfacial electronic modulation between Co2P and WC lowering the energy barrier of the rate determining step, thus Co2P/WC@NC/CNTs showed reasonable hydrogen evolution reaction (HER) activity and stability in all-pH media including sea water. This work provides a "bottom-up" synthetic strategy for confined heterostructures, thus offering the prospect for more efficient interfacial charge modulation.


Comparing novel antibiotics and carbapenems for complicated intra-abdominal infections: a systematic review and meta-analysis of randomized controlled trials.
Carbapenem-sparing antibiotics are needed urgently for patients with complicated intra-abdominal infections (cIAIs). Although several novel antibiotics - novel β-lactam/β-lactamase inhibitor combinations (e.g. ceftolozane-tazobactam and ceftazidime-avibactam) and a novel tetracycline derivative (eravacycline) - have been developed for cIAIs, it remains unclear whether these antibiotics are comparable to carbapenems for the treatment of cIAIs. A comprehensive search of PubMed, Embase, Cochrane Library and ClinicalTrials.gov was conducted until 1 October 2022. Only randomized controlled trials (RCTs) that compared the clinical efficacy and safety of novel antibiotics against carbapenems for patients with cIAIs were included. Among the 11 selected RCTs, no significant differences in clinical cure rate at the test-of-cure visit were observed between the study group and the control group on analysis of the clinically evaluable population [93.6% vs 93.7%, risk ratio (RR) 1.00, 95% confidence interval (CI) 0.98-1.01; P=0.84], microbiologically evaluable population (93.0% vs 94.5%, RR 0.98, 95% CI 0.96-1.00; P=0.10) and modified intention-to-treat population (85.9% vs 87.7%, RR 0.98, 95% CI 0.95-1.01; P=0.13). All findings were consistent across the subgroup analyses and sensitivity tests. Similarly, no significant difference in microbiological eradication was observed between the study group and the control group (87.8% vs 89.7%, RR 0.98, 95% CI 0.96-1.01; P=0.18). The risk of adverse events was similar in both groups. Clinical efficacy, microbiological response and safety of the novel antibiotics, including ceftazidime-avibactam, ceftolozane-tazobactam and eravacycline, are comparable to carbapenems for the treatment of patients with cIAIs. These agents can be potential therapeutic options as carbapenem-sparing antibiotics for cIAIs.


Personal space of war veterans with PTSD - some characteristics and comparison with healthy individuals.
The aim of this study was to determine the size of personal space among war veterans with PTSD, compared to healthy individuals, and to examine its associations with some sociodemographic and clinical characteristics. Participants were 83 male war veterans with chronic PTSD and 85 healthy male employees of the medical institutions. Preferred interpersonal distances were assessed by using a stop-distance technique, where male and female research assistants approached the participants from four directions (front, behind, left, right). The patients filled out The Mississippi Scale for Combat-Related Posttraumatic Stress Disorder (M-PTSD). War veterans with PTSD preferred significantly larger interpersonal distances compared to healthy participants. Larger personal space size was preferred by those who had children, and the largest preferred distances were observed for the approaches from behind. Both samples preferred larger distances when approached by a male person. The findings of this study contribute to increased understanding of the personal space in patients with PTSD, and may be implemented into prevention of aggressive behavior during psychiatric treatment, and into development of more effective therapeutic strategies.


Assessing reliability and validity of the Farsi version of the Toronto Alexithymia Scale in a sample of substance-using patients.
The aim of this study was to estimate reliability and factorial validity of the Farsi version of the Toronto Alexithymia Scale-20 (TAS-20) for 321 substance-abusing patients (187 men and 134 women). All were asked to complete the Farsi version of the Toronto Alexithymia Scale-20, the Emotional Intelligence Scale, and The Mental Health Inventory. Analysis supported the internal consistency, test-retest reliability, concurrent validity, and three-factor structure of the Farsi version of the TAS-20 for substance users. The factors are similar to the three reported previously and were labeled as Difficulty Identifying Feelings, Difficulty Describing Feelings, and Externally oriented Thinking. These results provide evidence for applicability of the TAS-20 and its cross-cultural validity.


BrMYB108 confers resistance to Verticillium wilt by activating ROS generation in Brassica rapa.
Increasing plant resistance to Verticillium wilt (VW), which causes massive losses of Brassica rapa crops, is a challenge worldwide. However, few causal genes for VW resistance have been identified by forward genetic approaches, resulting in limited application in breeding. We combine a genome-wide association study in a natural population and quantitative trait locus mapping in an F2 population and identify that the MYB transcription factor BrMYB108 regulates plant resistance to VW. A 179 bp insertion in the BrMYB108 promoter alters its expression pattern during Verticillium longisporum (VL) infection. High BrMYB108 expression leads to high VL resistance, which is confirmed by disease resistance tests using BrMYB108 overexpression and loss-of-function mutants. Furthermore, we verify that BrMYB108 confers VL resistance by regulating reactive oxygen species (ROS) generation through binding to the promoters of respiratory burst oxidase genes (Rboh). A loss-of-function mutant of AtRbohF in Arabidopsis shows significant susceptibility to VL. Thus, BrMYB108 and its target ROS genes could be used as targets for genetic engineering for VL resistance of B. rapa.


Coordinate up-regulation of the beta-chemokine subfamily in autoimmune sialoadenitis of MRL/lpr mice.
Mononuclear cell (MNC) infiltration of the salivary and lacrimal glands is a major feature in Sjogren's syndrome (SS) and its animal model, murine autoimmune sialoadenitis (MAS). To investigate factors that influence selective infiltration by MNC of submandibular glands in young and adult MRL/lpr mice with MAS, expression of mRNA encoding the beta-chemokines monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and regulated upon activation, normal T-cell expressed and secreted (RANTES) was investigated by in situ hybridization. MCP-1 protein production was also evaluated by immunohistochemistry. Young mice with MAS showed an early up-regulation of mRNA expression for MCP-1, MIP-1beta and RANTES, while MIP-1alpha mRNA expression was not affected. Adult mice with MAS showed a further up-regulation of mRNA expression for MCP-1, MIP-1beta and RANTES, and a remarkably strong up-regulation for MIP-1alpha. Immunohistochemistry revealed that MCP-1 protein production paralleled MCP-1 mRNA expression in both young and adult mice. These observations implicate MCP-1, MIP-1beta and RANTES as potential chemokines in induction of MAS, and MCP-1, MIP-1beta, RANTES and prominently MIP-1alpha in progression and perturbation of MAS.


Is preeclampsia associated with higher frequency of HSP70 gene polymorphisms?
To evaluate the possible association of three different HSP70 gene polymorphisms with preeclampsia. HSPA1A G(190)C, HSPA1B A(1267)G and HSPA1L T(2437)C polymorphisms were analyzed from blood samples of 72 women with preeclampsia and of 70 healthy pregnant women as controls by PCR-RFLP method. HSPA1B (1267)GG and HSPA1L (2437)CC genotypes occurred more frequently in preeclamptic patients compared to healthy controls (p<0.002 [RR: 4.38, 95% CI: 1.56-12.28]) and (p<0.03 [RR: 1.31, 95% CI: 1.03-1.67]), respectively. Significant difference was found in the distribution of HSPA1B A(1267)G genotype between the preeclamptic and control group (p<0.004 [RR: 0.67, 95% CI: 0.51-0.88]). Distribution of HSPA1A G(190)C was similar in the preeclamptic and control group. In controls, genotype distribution of HSPA1A G(190)C and HSPA1L T(2437)C was in Hardy-Weinberg equilibrium, while this criterion was not fulfilled for HSPA1B A(1267)G. We concluded that HSPA1B (1267)GG and HSPA1L (2437)CC genotypes were more frequent among preeclamptic than control patients, suggesting that these genotypes may play a role in the susceptibility for preeclampsia.


Mobility, bioavailability and pH-dependent leaching of cadmium, zinc and lead in a contaminated soil amended with biochar.
The effect of biochar application on the fate of Cd, Zn and Pb was investigated in a contaminated soil amended with three different rates of biochar (1%, 5% and 10%; w/w). In an incubation experiment, the 0.01M CaCl2-extractability of metals after 1h of incubation significantly decreased with increasing rate of biochar application. This effect was mostly attributed to the raise in soil pH. In the presence of 5% and 10% of biochar, the metal extractability continued to decrease over the next 56days, likely due to aging reactions. In a pot experiment, the metal concentration in shoots of ryegrass (Lolium multiflorum Lam.) harvested at 28 and 56days after sowing decreased with increasing rate of biochar application. Using a pH-dependent leaching test, we found that the metal release at a defined pH was not affected by the presence of biochar. However, because the acid neutralizing capacity (ANC) increased with increasing rate of biochar application, the time required to reach a hazardous pH can be predicted to be longer after biochar application. It is concluded that the application of biochar for in situ metal immobilization can be feasible provided soil pH is monitored over time.


Clathrin light chain diversity regulates membrane deformation in vitro and synaptic vesicle formation in vivo.
Clathrin light chain (CLC) subunits in vertebrates are encoded by paralogous genes CLTA and CLTB, and both gene products are alternatively spliced in neurons. To understand how this CLC diversity influences neuronal clathrin function, we characterized the biophysical properties of clathrin comprising individual CLC variants for correlation with neuronal phenotypes of mice lacking either CLC-encoding gene. CLC splice variants differentially influenced clathrin knee conformation within assemblies, and clathrin with neuronal CLC mixtures was more effective in membrane deformation than clathrin with single neuronal isoforms nCLCa or nCLCb. Correspondingly, electrophysiological recordings revealed that neurons from mice lacking nCLCa or nCLCb were both defective in synaptic vesicle replenishment. Mice with only nCLCb had a reduced synaptic vesicle pool and impaired neurotransmission compared to WT mice, while nCLCa-only mice had increased synaptic vesicle numbers, restoring normal neurotransmission. These findings highlight differences between the CLC isoforms and show that isoform mixing influences tissue-specific clathrin activity in neurons, which requires their functional balance.


Synthesis and study of antiviral and anti-radical properties of aminophenol derivatives.
A number of sterically-hindered o-aminophenol derivatives have been synthesized, and their antiviral activity in parallel with reactivity towards commonly encountered free-radical intermediates was investigated. Of the compounds tested, the highest activity in suppressing replication of Herpes simplex type l viruses was displayed by N-acyl and N-aryl derivatives of 4,6-di-tert-butyl-2-aminophenol, which were able to interact with organic free radicals and, at the same time, manifested low reactivity towards reactive oxygen species.


Biodegradation of orthodontic metallic brackets and associated implications for friction.
This study aimed to assess the effect of clinical exposure on the surface morphology, dimensions, and frictional behavior of metallic orthodontic brackets. Ninety-five brackets, of 3 commercial brands, were retrieved from patients who had finished orthodontic treatment. As-received brackets, matched by type and brand, were used for comparisons. Surface morphology and precipitated material were analyzed by optical and scanning electron microscopy and x-ray microanalysis. Bracket dimensions were measured with a measuring microscope. Resistance to sliding on a stainless steel wire was assessed. Retrieved brackets showed surface alterations from corrosion, wear, and plastic deformation, especially in the external slot edges. Film deposition over the alloy surface was observed to a variable extent. The main elements in the film were carbon, oxygen, calcium, and phosphorus. The as-received brackets showed differences (P <0.05) in the slot sizes among brands, and 1 brand showed a 3% increase in the retrieved brackets' slots. The frictional behavior differed among brands. Retrieved brackets of 2 brands showed 10% to 20% increases in resistance to sliding. Metallic brackets undergo significant degradation during orthodontic treatment, possibly with increased friction. At present, it is difficult to predict the impact of these changes on the clinical performance of orthodontic components.


[Aortic arch advancement surgery as treatment for aortic coarctation with hypoplastic aortic arch in children].
Treatment of aortic coarctation with hypoplastic aortic arch is still a surgical challenge. The aortic arch advancement surgery has shown less re-coarctation frequency. To determine the re-coarctation frequency in patients who underwent aortic arch advancement technique for aortic coarctation with hypoplastic aortic arch and analyze the results. Retrospective and observational study of 38 patients who underwent aortic arch advancement in a third level Institution from 2002 to 2010. Twenty four males and 14 females all with aortic arch Z index diameter of < or = -2 were found. The median age was 2.6 months and the median weight was 3.8 kg. Twelve patients (31.5%) did not show post operative complications. Eighteen (47%) had only one complication; one patient (2.6%) had 2 complications and 2 (5.2%) had 3 complications. After a follow up of 3.7 years the frequency of re-coarctation was O%. With the previously mentioned technique the recoarctation frequency on medium and long term basis was 0%. From the anatomical and functional point of view, we believe this technique offers the best possible results.


Concordant CpG island methylation in hyperplastic polyposis.
The CpG island methylator phenotype (CIMP) is a newly described mechanism for carcinogenesis in colorectal carcinomas and adenomas characterized by methylation of multiple CpG islands. The causes of CIMP are unknown. We studied CIMP in hyperplastic polyps (HPs), with emphasis on patients with multiple HPs (5 to 10 HPs), large HPs (one HP >1 cm) or hyperplastic polyposis (>20 HPs). Methylation of p16, MINT1, MINT2, MINT31, and hMLH1 was analyzed by methylation-specific polymerase chain reaction in 102 HPs, 8 serrated adenomas, 19 tubular adenomas, and 9 adenocarcinomas from 17 patients, with multiple/large HPs or hyperplastic polyposis and in 16 sporadic HPs from 14 additional patients. Sporadic HPs were CIMP-negative (not methylated at any locus), but 43% of HPs from multiple/large HPs, or hyperplastic polyposis were CIMP-high (two or more methylated loci, P = 0.00001). Methylation among the four loci was correlated within HPs (odds ratio, 3.41; P = 0.002), and the methylation status of HPs within the same patient was also correlated (odds ratio, 5.92; P = 0.0001). CIMP-high HPs were present primarily in patients with a predominance of HPs in the right colon and/or serrated adenomas (P = 0.0009) and were associated with the absence of K-ras proto-oncogene mutations (odds ratio, 5.08; P = 0.03). Our findings of concordant CpG island methylation of HPs in multiple/large HPs or hyperplastic polyposis supports the concept that some patients have a hypermethylator phenotype characterized by methylation of multiple HPs and other colorectal lesions. The hypermethylator phenotype is related to patient-specific factors, such as carcinogenic exposure or genetic predisposition.


Distortion, Tether, and Entropy Effects on Transannular Diels-Alder Cycloaddition Reactions of 10-18-Membered Rings.
Density functional theory calculations were performed on a set of 13 transannular Diels-Alder (TADA) reactions with 10-18-membered rings. The results were compared with those for bimolecular and intramolecular Diels-Alder reactions in order to investigate the controlling factors of the high TADA reactivities. The effects of tether length, heteroatoms, and alkynyl dienophiles on reactivity were analyzed. We found a correlation between tether length and reactivity, specifically with 12-membered macrocycles undergoing cycloaddition most readily. Furthermore, modifying 12-membered macrocycles by heteroatom substitution and utilizing alkynyl dienophiles enhances the reaction rates up to 10(5)-fold.


Unrelated donor search prognostic score to support early HLA consultation and clinical decisions.
A simple scoring system that can provide a quick search prognosis at the onset of an adult unrelated donor (URD) search could be a useful tool for transplant physicians. We aimed to determine whether patient human leukocyte Ag genotype frequency (GF) could be used as a surrogate measure of whether or not a potential 10/10 and/or 9/10 URD in the Be The Match Registry (BTMR) can be identified for the patient. GF was assigned on a training data set of 2410 patients that searched the BTMR using the reported ethnic group. A proportional odds model was used to correlate GF with defined search productivity categories as follows: 'Good' (>2 10/10), 'Fair' (1-2 10/10 or No 10/10 and >2 9/10) or 'Poor' (No 10/10 and <3 9/10). A second cohort (n=2411) was used to calculate the concordance by the ethnic group in all three categories. In addition, we validated against an independent cohort (n=1344) resolved as having a 10/10 or 9/10 matched URD. Across the ethnic groups, >90% of cases with 'Good' GF prognosis, 20-26% 'Fair' and <10% 'Poor' had a 10/10 URD. Although not a replacement for an actual URD search, GF offers a quick way for transplant physicians to get an indication of the likely search outcome.


Attention to central and peripheral visual space in a movement detection task: an event-related potential and behavioral study. II. Congenitally deaf adults.
We compared the effects of focussed attention upon event-related brain potentials (ERPs) to peripherally and centrally located visual stimuli in congenitally deaf subjects (Ss). The results were compared with those obtained from a group of normal hearing Ss in the same paradigm. ERPs from deaf and hearing Ss displayed similar attention-related changes with attention to the centrally located stimuli. These included enhanced amplitudes of the N1 component (157 ms) over the occipital regions of both hemispheres. By contrast, with attention to peripheral visual stimuli, ERPs from deaf Ss displayed attention-related increases that were several times larger than those from hearing Ss and different in scalp distribution. Whereas for hearing Ss the principal effects of attention to peripheral stimuli occurred over the contralateral parietal region, in deaf Ss the effects were also observed over the occipital regions of both hemispheres. In addition, lateral asymmetries in behavior and the ERPs indicated a greater role for the right hemisphere in this task in hearing Ss, but predominance of the left hemisphere in deaf Ss. These results suggest that auditory deprivation since birth has major effects on the development of the peripheral visual system. The specific pattern of group differences is discussed in relation to other studies of the effects of unimodal deprivation on the development of remaining modalities.


Sphingosine inhibits sphingomyelinase-induced cholesteryl ester formation in cultured fibroblasts.
We have in this study examined the effects of sphingosine, a possible secondary degradation product following sphingomyelin hydrolysis, on cholesterol homeostasis in cultured human fibroblasts treated with sphingomyelinase. The activation of cholesterol esterification, which resulted from the degradation of plasma membrane sphingomyelin (by sphingomyelinase), was observed to be effectively blocked by sphingosine (half-maximal dose 6-7 microM). The inhibitory action of sphingosine could not be reproduced with other amines (e.g., dodecyl amine or imipramine). The onset of inhibition of cholesteryl ester formation by sphingosine was rapid (maximal effect within 15 min). Sphingosine itself had no spontaneous effects on the distribution of cellular cholesterol. At concentrations below 10 microM, sphingosine was not cytotoxic, as determined by cellular trypan blue permeability. The inhibitory action of sphingosine on cholesteryl ester formation apparently did not result from a direct inhibition of acyl-CoA cholesterol acyltransferase (ACAT), since the activity of this enzyme was unaffected by sphingosine (10 microM) in a cell-free homogenate, using [14C]oleoyl-CoA as a co-substrate. Sphingosine was also unable to prevent the formation of activated fatty acids (oleoyl-CoA), since acyl-CoA synthetase activity in a cell-free homogenate was not inhibited by sphingosine (at 5 microM). The cellular cholesteryl ester cycle (i.e., the neutral cholesteryl ester hydrolase) was unaffected by sphingosine (at 5 microM). Down-regulation of PKC activity (24 h exposure of cells to 100 nM (62 ng/ml) phorbol ester) did not affect the sphingomyelinase-induced stimulation of [3H]cholesteryl ester formation. In addition, the sphingosine-induced inhibition of [3H]cholesteryl ester formation was not reversed in the presence of phorbol ester (short-term exposures), suggesting that the effect of sphingosine was not mediated via PKC. In conclusion, we have shown that sphingosine is an inhibitor of cholesteryl ester formation in fibroblasts. The inhibition is only seen with intact cells, which may suggest that a secondary metabolite of sphingosine was responsible for the observed inhibition of cholesteryl ester formation.


Reducing the dose of neuromuscular blocking agents with adjuncts: a systematic review and meta-analysis.
Acute global shortages of neuromuscular blocking agents (NMBA) threaten to impact adversely on perioperative and critical care. The use of pharmacological adjuncts may reduce NMBA dose. However, the magnitude of any putative effects remains unclear. We conducted a systematic review and meta-analysis of RCTs. We searched Medline, Embase, Web of Science, and Cochrane Database (1970-2020) for RCTs comparing use of pharmacological adjuncts for NMBAs. We excluded RCTs not reporting perioperative NMBA dose. The primary outcome was total NMBA dose used to achieve a clinically acceptable depth of neuromuscular block. We assessed the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) criteria. Data are presented as the standardised mean difference (SMD); I2 indicates percentage of variance attributable to heterogeneity. From 3082 records, the full texts of 159 trials were retrieved. Thirty-one perioperative RCTs met the inclusion criteria for meta-analysis (n=1962). No studies were conducted in critically ill patients. Reduction in NMBA dose was associated with use of magnesium (SMD: -1.10 [-1.44 to -0.76], P<0.001; I2=85%; GRADE=moderate), dexmedetomidine (SMD: -0.89 [-1.55 to -0.22]; P=0.009; I2=87%; GRADE=low), and clonidine (SMD: -0.67 [-1.13 to -0.22]; P=0.004; I2=0%; GRADE=low) but not lidocaine (SMD: -0.46 [-1.01 to -0.09]; P=0.10; I2=68%; GRADE=moderate). Meta-analyses for nicardipine, diltiazem, and dexamethasone were not possible owing to the low numbers of studies. We estimated that 30-50 mg kg-1 magnesium preoperatively (8-15 mg kg h-1 intraoperatively) reduces rocuronium dose by 25.5% (inter-quartile range, 14.7-31). Magnesium, dexmedetomidine, and clonidine may confer a clinically relevant sparing effect on the required dose of neuromuscular block ing drugs in the perioperative setting. PROSPERO: CRD42020183969.


A distance-learning programme in pharmacovigilance linked to educational credits is associated with improved reporting of suspected adverse drug reactions via the UK yellow card scheme.
The effect of a distance-learning package linked to educational credits on the rate and quality of spontaneous adverse drug reaction (ADR) reporting by general practitioners (GPs) and pharmacists in Wales was investigated. In April 2000, 477 GPs and 261 pharmacists enrolled in the 12 month programme. The number and quality of yellow card reports improved compared with those of a control region in England (Northern Region). We conclude that an educational initiative in drug safety linked to incentives may be associated with a significant but perhaps short-lived improvement in the rate and quality of ADR reporting.


Low density lipoprotein receptor (LDLR)-targeted lipid nanoparticles for the delivery of sorafenib and Dihydroartemisinin in liver cancers.
Liver cancer is one of the leading causes of cancer mortality worldwide. Inspired by the biological structure and function of low-density lipoprotein (LDL), in this study, an ApopB-100 based targeted lipid nanoparticles was synthesized to improve the therapeutic efficacy in liver cancer treatment. The biological composition of ApopB is similar to LDL which can effectively increase the targeting efficiency of nanoparticles in LDL receptor (LDLR)-overexpressed liver tumors. We have demonstrated that the co-administration of sorafenib (SRF) and Dihydroartemisinin (DHA) could exhibit synergistic anticancer effect in HepG2 liver cancer cells. DHA produced excessive cellular reactive oxygen species (ROS) and induced greater apoptosis of cancer cells. LDL-based SRF/DHA-loaded lipid nanoparticles (LD-SDN) showed remarkable decrease in the cell viability compared to that of either of single drug treated cancer cells. Combination of SRF+DHA resulted in predominant SubG1 proportion of cells. LD-SDN exhibited the highest SubG1 (%) of cells compared to that of any of the individual drugs. Most importantly, robust antitumor response and delayed tumor growth was observed for LD-SDN treated xenograft tumor model. Ki67 proliferation index of LD-SDN (22.1 ± 5.6%) is significantly lesser compared to that of either control (86.2 ± 6.9%) or SRF (75.4 ± 4.89%) or DHA (69.4 ± 6.9%). These data provide strong evidence that LDL-mimetic lipid nanoformulations could be utilized as a biocompatible and tumor targeted platform for the delivery of multiple anticancer drugs in cancer treatment.


Clinical utility of sonography in diagnosing plantar fasciitis.
The purpose of this study was to investigate the efficacy of sonography in the detection of plantar fasciitis (PF) compared with magnetic resonance imaging (MRI) findings in subjects with inferior heel pain. Seventy-seven patients with unilateral (n = 9) and bilateral (n = 68) heel pain were studied. Seventy-seven age- and sex-matched asymptomatic subjects served as a control group. Magnetic resonance imaging was used to establish a diagnosis of PF with sagittal T1-weighted, T2-weighted, and short tau inversion recovery sequences. The sonographic appearances of PF were compared with MRI findings. Plantar fascia and heel pad thickness were also measured on both imaging modalities. Compared with MRI, sonography showed 80% sensitivity and 88.5% specificity in assessing PF. A strong correlation was found between plantar fascia and fat pad thickness measurements done by sonography (P < .001; r = 0.854) and MRI (P < .001; r = 0.798). Compared with the asymptomatic volunteers, patients with PF had significant increases in plantar fascia and heel pad thicknesses, weight, and body mass index (P = .0001). Heel pad thickness was also significantly increased with pain duration (P = .021). Although MRI is the modality of choice in the morphologic assessment of different plantar fascia lesions, sonography can also serve as an effective tool and may substitute MRI in the diagnosis of PF.


iPSCs to the rescue in Alzheimer's research.
A crucial limitation to our understanding of Alzheimer's disease has been the inability to test hypotheses on live, patient-specific neurons. A recent study in Nature by Israel et al. (2012) reports that iPSC-derived neurons from AD patients recapitulate multiple aspects of disease pathology.


Atomic force microscopy: a powerful tool for studying bacterial swarming motility.
Swarming motility is a fascinating phenomenon by which some bacteria use flagella to move over solid surfaces. Understanding the molecular mechanisms underlying swarming motility requires studying the factors that induce and control flagella expression in swarming cells. Traditionally, flagella are observed by optical or electron microscopy, but none of these techniques combine versatility and easiness, with quantitative and high-resolution information. We report an atomic force microscopy (AFM)-based approach for the fast imaging of bacterial phenotypes (cell shape, flagella expression) in swarming motility studies. Cells from the gram-positive bacterium Bacillus thuringiensis sv. israelensis were inoculated on energy-rich media containing increasing agar concentrations. Following swarming assays (2 days), the cell morphology and the amount of flagella were directly observed by AFM imaging in air. Consistent with the macroscopic swarming behavior, cells harvested from the rim of colonies spreading on soft agar were hyperflagellated, elongated and arranged in chains. Increasing the agar concentration led to much lower amounts of flagella and to shorter rod-shaped cells, a finding consistent with the slower swarming motility of the cells. Cells taken from colony centers on soft and hard agar surfaces were generally non-flagellated, rod-shaped, rarely arranged in chains, and exhibited lysis and sporulation. This study shows that AFM imaging can readily discriminate between swarming and non-swarming cells, and quantify their morphological details, thus offering an important tool to study the dynamics of bacterial populations.


Spheroidal filamentous inclusion body cells in von Recklinghausen's disease.
Cells with spheroidal filamentous cytoplasmic bodies, distinctive by both light and electron microscopy, were found in a neoplasm arising from the sciatic nerve of a patient with von Recklinghausen's disease. Tissue fixed with formalin and embedded in paraffin for three years was deparaffinized, reprocessed, and examined with the electron microscope. The morphology of the spheroidal body cells, the close resemblance to erythrophagocytosis, and the possible significance of the changes are discussed.


Electron-capture, capillary column gas chromatographic determination of low-molecular-weight diols in serum.
Research on alcoholism has revealed that concentrations of 1,2-propanediol, d,1-2,3-butanediol and meso-2,3-butanediol may be greater in the serum of chronic alcoholics than in the serum of social drinkers and nondrinkers. In connection with one of these studies, we developed methodology to determine these diols at the micromolar levels in 500 serum samples. The procedure consisted primarily of extraction of the serum with acetonitrile containing internal standard. The extract was then concentrated to dryness and reacted with p-bromophenylboric acid. The reaction mixture was injected into a gas chromatograph fitted with a capillary column and an electron-capture detector. The total coefficients of variation were best for 1,2-propanediol, 6.82 and 10.00%, and worst for d,1-2,3-butanediol, 13.64 and 19.22%. The observed means for the analytes were all within 10% of the spiked level.


Nanomaterials as signal amplification elements in aptamer-based electrochemiluminescent biosensors.
Biosensor technology is experiencing an unprecedented momentum that is driven by rapid advances in material science for utilization in various fields, and is constantly evolving to develop fast, simple and sensitive sensors. Here, we present a comprehensive and concise review on electrochemiluminescent (ECL) nanomaterial-based aptasensors including challenges and applications. ECL aptasensor combines the merits of a biosensor, selectivity of an aptamer, and sensitivity of ECL to construct sensitive and selective sensors. Signal amplification processes through the incorporation of nanomaterials are essential to further enhance the sensitivity of ECL sensing systems. Nanomaterials are commonly utilized in sensor fabrication as (i) electrode modifiers, (ii) nanocarriers, (iii) nanocatalysts, and (iv) luminophores. The review highlights the effects of integrating nanomaterials such as gold nanoparticles, metal nanoparticles, metal oxides, carbon nanomaterials, metal organic frameworks, and quantum dots using various research strategies that address signal amplification to enhance the ECL signal. Furthermore, various concepts have been demonstrated with relevant figures and explanations to serve as a general overview for the design of ECL aptasensors. Lastly, we discuss the underlying problems and possibilities for ECL aptasensor research and development.


Getting teams to talk: development and pilot implementation of a checklist to promote interprofessional communication in the OR.
Pilot studies of complex interventions such as a team checklist are an essential precursor to evaluating how these interventions affect quality and safety of care. We conducted a pilot implementation of a preoperative team communication checklist. The objectives of the study were to assess the feasibility of the checklist (that is, team members' willingness and ability to incorporate it into their work processes); to describe how the checklist tool was used by operating room (OR) teams; and to describe perceived functions of the checklist discussions. A checklist prototype was developed and OR team members were asked to implement it before 18 surgical procedures. A research assistant was present to prompt the participants, if necessary, to initiate each checklist discussion. Trained observers recorded ethnographic field notes and 11 brief feedback interviews were conducted. Observation and interview data were analyzed for trends. The checklist was implemented by the OR team in all 18 study cases. The rate of team participation was 100% (33 vascular surgery team members). The checklist discussions lasted 1-6 minutes (mean 3.5) and most commonly took place in the OR before the patient's arrival. Perceived functions of the checklist discussions included provision of detailed case related information, confirmation of details, articulation of concerns or ambiguities, team building, education, and decision making. Participants consistently valued the checklist discussions. The most significant barrier to undertaking the team checklist was variability in team members' preoperative workflow patterns, which sometimes presented a challenge to bringing the entire team together. The preoperative team checklist shows promise as a feasible and efficient tool that promotes information exchange and team cohesion. Further research is needed to determine the sustainability and generalizability of the checklist intervention, to fully integrate the checklist routine into workflow patterns, and to measure its impact on patient safety.


Scanning-alanine mutagenesis of long loop residues 33-53 in follicle stimulating hormone beta subunit.
Follicle stimulating hormone (FSH) is a gonadotropin and member of the pituitary/placental glycoprotein hormone family which bind to G-protein-coupled receptors. These hormones are heterodimers composed of a common alpha and distinct beta -subunits. Previous experimental evidence suggested that the FSH beta -subunit long loop comprised of amino acids Tyr33 to Phe53 is involved in receptor binding and activation and in subunit interaction. According to recently reported crystal structures of human chorionic gonadotropin (hCG), the homologous long loop of the beta -subunit of hCG associates with the alpha -subunit and is partially exposed to solvent. This report describes the results of scanning alanine mutagenesis used to determine if amino acid side chains in this region of the molecule are required for receptor binding and/or subunit contact. Five mutations were made which spanned this loop and the mutant FSH beta-subunits were co-expressed with alpha-subunit in a Baculovirus-infected insect-cell expression system. Mutation of 48QKTCT52 to 48AAACA52 produced a FSH beta-subunit that failed to form heterodimer, consistent with the crystal structure of hCG which shows these amino acids are buried at the subunit interface. The four remaining mutants produced heterodimer and were assayed for binding to and activation of human FSH receptors. Mutation of 37LVY39 to 37AAA39 caused a 20-fold reduction binding (ID50 of 7.0 nM compared with 0.3 nM for wildtype). Mutation of 34TRDL37 to 34AAAA37 or 44RPKI47 to 44APAA47 caused lesser but measurable effects with ID50 values of 1.1 nM and 1.9 nM, respectively. The (40)KDPA(43) to 40KDPA43 to 40AAPA43 mutation had little effect on receptor binding (ID50 = 0.5 nM).


Glucocorticoid receptors participate in the opiate withdrawal-induced stimulation of rats NTS noradrenergic activity and in the somatic signs of morphine withdrawal.
Recent evidence suggests that glucocorticoid receptor (GR) is a major molecular substrate of addictive properties of drugs of abuse. Hence, we performed a series of experiments to further characterize the role of GR signalling in opiate withdrawal-induced physical signs of dependence, enhanced noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) phosphorylation (activation) as well as GR expression in the nucleus of the solitary tract noradrenergic cell group (NTS-A₂). The role of GR signalling was assessed by i.p. pretreatment of the selective GR antagonist, mifepristone. Rats were implanted with two morphine (or placebo) pellets. Six days later, rats were pretreated with mifepristone or vehicle 30 min before naloxone and physical signs of abstinence, NA turnover, TH activation, GR expression and the hypothalamus-pituitary-adrenocortical axis activity were measured using HPLC, immunoblotting and RIA. Mifepristone alleviated the somatic signs of naloxone-induced opiate withdrawal. Mifepristone attenuated the increase in the NA metabolite, 3-methoxy-4-hydroxyphenylethylen glycol (MHPG), in the PVN, and the enhanced NA turnover observed in morphine-withdrawn rats. Mifepristone antagonized the TH phosphorylation at Ser³¹ and the expression of c-Fos expression induced by morphine withdrawal. Finally, naloxone-precipitated morphine withdrawal induced up-regulation of GR in the NTS. These results suggest that the physical signs of opiate withdrawal, TH activation and stimulation of noradrenergic pathways innervating the PVN are modulated by GR signalling. Overall, the present data suggest that drugs targeting the GR may ameliorate stress and aversive effects associated with opiate withdrawal.


CO2 exchange in the alpine sedge Carex curvula as influenced by canopy structure, light and temperature.
The temperature and light responses of CO2 uptake (Fn) in the sedge Carex curvula were investigated in situ by IRGA technic in the Austrian Central Alps at an altitude of 2,310 m. Fn in Carex leaves reaches a maximum of 15.6 mg CO2 dm-2 h-1 at a leaf temperature of 22.5°C and a quantum flux density larger than 1.0 mmol photons m-2 s-1 (400-700 nm). A model based on a polynomal regression analysis of the Fn responses and informations about the microclimate and the canopy structure was used to simulate F n for individual days and for a whole season. It turned out that the major rate limiting factor is the availability of light in the canopy: The calculated photosynthetic yield for a hypothetical optimum season of clear days with fully illuminated leaves and optimum temperature as well as for a typical season with the actual light and temperature conditions in the canopy, shows that insufficient illumination of the leaves accounts for almost 40% reduction of the possible CO2 uptake while suboptimal temperatures cause only a loss of 8%. Half of the light deficit is caused by mutual shading of the leaves. The minor importance of temperature for the annual CO2 uptake results from the fact that temperature adaptation of F n in this sedge allows optimal utilization of short periods with high light intensity and hence high photosynthetic yield. The weaker the quantum supply the more becomes temperature limiting. This indicates that the length of the growing season is probably less important for the success of this prominent alpine plant than the sum of hours with high radiation.


An open-label, multicentre, randomised phase 2 study of recombinant human granulocyte colony-stimulating factor (filgrastim) as an adjunct to combination chemotherapy in paediatric patients with metastatic neuroblastoma.
Administration of combination chemotherapy to children with metastatic neuroblastoma induces profound myelosuppression resulting in chemotherapy treatment delays and febrile neutropenic episodes. The objective of this randomised multicentre study was to assess the incidence, duration and severity of neutropenia when filgrastim is added to induction chemotherapy administered to patients with metastatic neuroblastoma. In this study, 59 patients with metastatic neuroblastoma were randomised to receive chemotherapy (control group, n = 28) or chemotherapy plus filgrastim (filgrastim group, n = 31). Chemotherapy consisted of four cycles of cyclophosphamide, vincristine and doxorubicin (CADO) alternating at 21-day intervals with cisplatin and etoposide (CDDP-VP16). Filgrastim was administered subcutaneously at a dose of 5 micrograms/kg/day from day 7 for up to 14 days. The incidence of neutropenia (absolute neutrophil count [ANC] < 0.5 x 10(9)/l) in the filgrastim group was not reduced after the first CADO course. However, significant reductions were observed after courses 2, 3 and 4. The duration of neutropenia and of intravenous antibiotic use were significantly reduced in the filgrastim group over the whole study period (9 days versus 26 days, P < 0.001; 12 days versus 20 days, P = 0.04, respectively). However, the duration of hospitalisation and the incidence of febrile neutropenia were not significantly reduced. Compliance to treatment was good and the ability to administer chemotherapy without treatment delays was significantly better in the filgrastim group (P < 0.05). Event-free survival was greater in the filgrastim than in the control group (2.4 years versus 1.3 years; P = 0.072). Filgrastim is a beneficial adjunct to combination induction chemotherapy used in the treatment of metastatic neuroblastoma.


In search of the elusive epidermal stem cell.
Recent studies are beginning to reveal that our basic concepts of epidermal stem cell biology may be based on somewhat tenuous ground. For example, it is often assumed that colony-forming cells represent epidermal stem cells, although this has not proved to be the case in hematopoietic cell lineages. In addition, although most stem cells are not cycling, label-retaining cells are used as a primary measure of epidermal stem cells. Moreover, the locations of stem cell niches in epidermis are still being debated. Finally, while putative stem cell markers abound, the most effective isolation procedure for stem cells has not been determined, and the relative efficiency of various methods of stem cell isolation remains unknown. With a functional assay for epidermal stem cells (analogous to the in-vivo competitive assay used for hematopoiesis), we appear to be in a better position to more clearly define the molecular signature of the true long-term repopulating cell/stem cell of the epidermis. Nonetheless, significant progress has been made in regenerative therapy of the epidermis for ulcer and burn treatment, and for corrective gene therapy for inherited skin diseases.


Sarcopenia and sarcopenic obesity after cholecystectomy: A population-based study.
The present study aimed to investigate the associations of cholecystectomy with low muscle mass, low muscle strength, sarcopenia, and sarcopenic obesity. This population-based study included data from 4,909 participants aged 18 to 80 years. History of cholecystectomy was diagnosed using abdominal ultrasonography. Muscle mass was evaluated using a dual-energy x-ray absorptiometry scan, and muscle strength was evaluated using an electronic hand dynamometer. Sarcopenia was defined as the presence of both low muscle mass and low muscle strength. Sarcopenic obesity was defined as the presence of both sarcopenia and obesity. Multivariable logistic regression models were performed to investigate the associations of cholecystectomy with low muscle mass, low muscle strength, sarcopenia, and sarcopenic obesity. Participants with history of cholecystectomy were more likely than those without to have low muscle mass, low muscle strength, and sarcopenia. Furthermore, compared with cholecystectomy that occurred within 7 years (7 years is the median interval between cholecystectomy and the physical examination), participants with cholecystectomy that occurred more than 7 years ago had higher odds of sarcopenia. Finally, whether obesity was defined by BMI or body fat percentage, cholecystectomy was positively associated with sarcopenic obesity. Cholecystectomy is associated with low muscle mass, low muscle strength, sarcopenia, and sarcopenic obesity.


Effects of trapidil on thromboxane A2-induced aggregation of platelets, ischemic changes in heart and biosynthesis of thromboxane A2.
Trapidil inhibited the aggregation of rat platelets and the contraction of the isolated aortic strip of rabbit mainly caused by thromboxane A2, and the thromboxane A2 biosynthesis in rabbit platelets. The drug also reduced ischemic changes in ECG, the incidence of myocardial infarction, histopathological changes and a decrease in serum high density lipoprotein cholesterol, and inhibited an increase in plasma thromboxane B2 and a decrease in plasma 6-keto-prostaglandin F1 alpha content in the animals with an experimental ischemic heart injury caused by the injection of thromboxane A2 into the coronary artery. These findings suggest that trapidil is a new type of a therapeutic agent for ischemic heart disease which not only dilates the coronary artery but also inhibits the actions and biosynthesis of thromboxane A2 and may promote the biosynthesis of prostaglandin I2.


Dopamine Cytotoxicity on SH-SY5Y Cells: Involvement of α-Synuclein and Relevance in the Neurodegeneration of Sporadic Parkinson's Disease.
The cytotoxicity of dopamine on cultured cells of neural origin has been used as a tool to explore the mechanisms of dopaminergic neurodegeneration in Parkinson's disease. In the current study, we have shown that dopamine induces a dose-dependent (10-40 μM) and time-dependent (up to 96 h) loss of cell viability associated with mitochondrial dysfunction and increased intra-cellular accumulation of α-synuclein in cultured SH-SY5Y cells. Dopamine-induced mitochondrial dysfunction and the loss of cell viability under our experimental conditions could be prevented by cyclosporine, a blocker of mitochondrial permeability transition pore, as well as the antioxidant N-acetylcysteine. Interestingly, the dopamine effects on cell viability and mitochondrial functions were significantly prevented by knocking down α-synuclein expression by specific siRNA. Our results suggest that dopamine cytotoxicity is mediated by α-synuclein acting on the mitochondria and impairing its bioenergetic functions.


Mortality and morbidity in infants with intrauterine growth retardation.
This report is based on an analysis of the experience with all births in several urban and rural areas of the United States. All infants whose birth weight was in the lowest quartile for their week of gestation were designated as small for gestational age regardless of their birth weight or length of gestation; other infants were considered appropriate for gestation age. We interpret the data to indicate that appropriate-for-gestational age and small-for-gestational age infants, all of low birth weight, differ in the nature of their risk for adverse outcome as determined by an assessment at one year of age, although both are at approximately equal risk of adverse outcome overall. In each weight group, the total proportion of infants who either died before one year of age or were handicapped at one year of age was similar for small-for-gestational age and appropriate-for-gestational age infants, but appropriate-for-gestational age infants were at greater risk of neonatal death and small-for-gestational age infants were at greater risk of problems manifested during the first year of life or at one year of age. As the findings are based on data obtained from entire populations (rather than from infants born in particular hospitals), they are likely to be generalizable.


Evaluation of Uosm:Posm ratio as a hydration biomarker in free-living, healthy young women.
Urinary and plasma indices are utilized to assess whole-body water balance in healthy adults, whereas the urine-to-plasma osmolality ratio (Uosm:Posm) rarely is. To explore the efficacy of Uosm:Posm as a hydration biomarker, diet records of 120 college women were analyzed (beverage water+food water=total fluid intake (TFI); 5 days) to identify habitual high-volume (HIGH) and low-volume (LOW) drinkers. The experimental protocol first involved two ad libitum baseline days for HIGH (TFI, 3.21 l per 24 h; n=14) and LOW (TFI, 1.64 l per 24 h; n=14). During a controlled intervention (days 3-6), mineral water was the only beverage; HIGH consumed less than baseline (TFI, 2.00 l per 24 h), and LOW consumed more than baseline (TFI, 3.50 l per 24 h). During ad libitum recovery (day 7), TFI were 3.17 and 1.71 l per 24 h for HIGH and LOW, respectively. Duplicate Uosm (24 h collection) and Posm (morning) samples were analyzed on all days via freezing point depression osmometry. In the evaluation of relative water excess (Uosm:Posm<1.0), 11/13 values occurred for HIGH on days 1, 2 and 7; for LOW, 28/29 occurred on intervention days 3-6. Chi-squared analysis indicated that the treatment and Uosm:Posm were significantly associated (χ(2)1:0.001=23.5, P<0.001). Statistical regression analyses detected a strong, significant relationship between renal free-water clearance (FWC) and Uosm:Posm (r(2)=0.86, P<0.00001); this was not true for FWC and Posm (r(2)=0.00, P=0.40) because Posm values were stable across 7 days. These findings support the use of Uosm:Posm as a hydration biomarker.


Assessment of transcultural psychotherapy to treat resistant major depressive disorder in children and adolescents from migrant families: Protocol for a randomized controlled trial using mixed method and Bayesian approaches.
Cultural variations complicate psychiatric care, especially for migrant children. Transcultural psychotherapy (TCP) is an original psychotherapeutic technique developed to address complex situations of resistant mental disorders in the context of migration. This research will aim to assess the efficacy, the acceptability, and describe the therapeutic processes of TCP for the treatment of depression in first or second generation of migration children and adolescents. Mixed method study using a multicenter, Bayesian randomized clinical trial with blinded evaluation of the primary outcome. Two parallel groups of 40 children or adolescents from 6 to 20 years old and their family will be included. In the experimental group, patients will attend six sessions of transcultural therapy in addition to usual care. The improved Clinical Global Impression scale scores at 6 months will be compared across groups. Qualitative analysis of families and therapists' interviews will allow to specify the therapeutic processes and acceptability of the therapy. The findings will encourage the development and routinization of TCP for second-line use and its adaption as a first-line technique in this population.


Computerized tomography of the spine and its contents.
The authors present their experience with computerized tomography of the spine both with and without contrast material. Our early experience indicated the substantial potential of this new technique. Further experience confirms this earlier impression. Representative cases of computer tomography of the spine and computer-assisted myelography are presented.


Metalloporphyrin catalyzed oxidation of N-hydroxyguanidines: a biomimetic model for the H2O2-dependent activity of nitric oxide synthase.
A chemical model for the H2O2 promoted oxidation by nitric oxide synthase (NOS) has been developed. Biomimetic oxidations were carried out using H2O2 and tetrakis(perfluorophenyl)porphyrinato-iron(III) chloride (FeTPPF20) as a catalyst. Similarly to NOS our model system produces Ndelta-cyanoornithine, citrulline and NO from NOHA and did not oxidize arginine itself. Based on these results we propose a peroxide shunt to be involved in the catalytic cycle of NOS. To the best of our knowledge this is the first chemical system that semiquantitatively mimics NOS activity.


Vagotomy and subsequent development of diabetes - A nested case-control study.
Vagal signaling is involved in gastric emptying and the secretion and effect of a number of hormones regulating gluco-metabolic processes and, thus, crucial for metabolic homeostasis. We hypothesized that vagotomy would increase the risk of developing type 2 diabetes and examined the association between vagotomy and subsequent development of diabetes. A nested case-control study was conducted with information on cases and controls from the Danish National Patient Registry. Cases included individuals with a diabetes diagnosis subsequent (>12months) to the first registration of vagotomy and/or upper gastrointestinal disease in the period 1977-2011. Controls had no subsequent diagnosis of diabetes and were matched by incidence density sampling, age and gender. Logistic regression analyses were conducted. 501,724 diabetes patients and 1,375,567 matched controls were included in the analysis. Vagotomy was performed on 2772 individuals and 148,489 individuals had an upper gastrointestinal diagnosis. In this combined population, 30,902 were diagnosed with diabetes. The mean follow-up was 16years. The unadjusted odds ratio for developing diabetes following vagotomy was 0.64 (95% confidence interval (CI): 0.58-0.71) and did not change in an adjusted analysis (0.64, 95% CI: 0.58-0.70). When restricting the multivariate-adjusted analysis to patients with type 2 diabetes and type 1 diabetes, respectively, the multivariate odds ratios were 0.79 (95% CI: 0.70-0.89) and 0.75 (95% CI 0.53-1.08), respectively. Vagotomy was associated with a significantly decreased risk of developing type 2 diabetes in a population of patients with upper gastrointestinal disease.