Intergenerational Transmission of Female Genital Cutting: Community and Marriage Dynamics.
This study examined how characteristics of households and communities are linked with the intergenerational transmission of gender inequality and particularly female genital cutting (FGC). Human capital perspectives suggest that socioeconomic inequality predicts FGC continuation. This study contributes to discussions of institutional change by examining the association of decisions to forego FGC with household decision-making patterns and community gender norms. Multilevel logistic regression was deployed to analyze a pooled sample (N = 12,144) of six Demographic and Health Surveys from Burkina Faso, Egypt, Guinea, Kenya, Mali and Nigeria. A series of models examined how decision-making styles, both at the household and community levels (2,524 DHS cluster aggregations), and community levels of FGC, correspond with the risk of having a daughter cut. Results show that daughters are less likely to be cut when parents make key household decisions jointly. Autonomous decision-making by women at the community level was associated with lower odds of daughters being cut. However, at the community level, the impacts of women's household decision-making were attenuated when FGC was more prevalent. The findings suggest that women's decision-making status is an important factor in FGC abandonment although that association is less robust when FGC is highly institutionalized. This study provides new insights into how women, families, and communities can disrupt the intergenerational transmission of behaviors associated with institutionalized gender inequality.


Association between sleep bruxism and anxiety symptoms in adults: A systematic review.
The purpose of this systematic review was to evaluate the association between sleep bruxism (SB) and anxiety symptoms in adults. A systematic review was performed and studies assessing SB by means of questionnaires, clinical examination and/or polysomnography (PSG), and validated questionnaires to assess anxiety, were included. Search strategies were developed for seven main electronic databases. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Analytical Cross-Sectional Studies, and confidence in cumulative evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation criteria. Eight cross-sectional studies were included, of which five were judged with low and three with moderate risk of bias. No association with SB was observed in three studies that investigated generic levels of anxiety, while other two papers that evaluated generic anxiety levels through the State-Trait Anxiety Inventory (STAI) found a positive association with probable and definite SB in both STAI-1 and STAI-2 subscales. Only one study evaluated dental anxiety in particular and an association with probable SB was observed regarding very anxious or extremely anxious scores. Two studies assessed specific symptoms of anxiety using the panic-agoraphobic spectra evaluation (PAS-SR) questionnaire. Significantly higher PAS-SR total scores were observed in both studies with regard to SB. No study with definitive assessment of SB was identified. Current literature is controversial regarding an association between SB and generic symptoms of anxiety in adults. It seems that some specific symptoms of the anxiety disorders spectrum might be associated with probable SB.


Sample processing method for the determination of perchlorate in milk.
In recent years, many different water sources and foods have been reported to contain perchlorate. Studies indicate that significant levels of perchlorate are present in both human and dairy milk. The determination of perchlorate in milk is particularly important due to its potential health impact on infants and children. As for many other biological samples, sample preparation is more time consuming than the analysis itself. The concurrent presence of large amounts of fats, proteins, carbohydrates, etc., demands some initial cleanup; otherwise the separation column lifetime and the limit of detection are both greatly compromised. Reported milk processing methods require the addition of chemicals such as ethanol, acetic acid or acetonitrile. Reagent addition is undesirable in trace analysis. We report here an essentially reagent-free sample preparation method for the determination of perchlorate in milk. Milk samples are spiked with isotopically labeled perchlorate and centrifuged to remove lipids. The resulting liquid is placed in a disposable centrifugal ultrafilter device with a molecular weight cutoff of 10 kDa, and centrifuged. Approximately 5-10 ml of clear liquid, ready for analysis, is obtained from a 20 ml milk sample. Both bovine and human milk samples have been successfully processed and analyzed by ion chromatography-mass spectrometry (IC-MS). Standard addition experiments show good recoveries. The repeatability of the analytical result for the same sample in multiple sample cleanup runs ranged from 3 to 6% R.S.D. This processing technique has also been successfully applied for the determination of iodide and thiocyanate in milk.


Comparative effects of HMG-CoA reductase inhibitors on apo B production in the casein-fed rabbit: atorvastatin versus lovastatin.
Rabbits fed a diet enriched in casein develop an endogenous hypercholesterolemia (EH) due both to an increased low density lipoprotein (LDL) synthetic rate and decreased LDL receptor activity. Pre-established EH in this model was used to assess the ability and mechanism by which atorvastatin lowers total plasma cholesterol (TPC) compared to the reference agent lovastatin. Rabbits were fed a casein diet for 6 weeks, obtaining average TPC levels above 200 mg/dl. To ensure equivalent mean cholesterol concentrations, animals were randomized into treatment groups based on the 6-week TPC levels, and fed the casein diet alone or in combination with either atorvastatin or lovastatin for an additional 6 weeks. Under these conditions, new steady-state cholesterol values were established. Lipoprotein concentrations and distributions were determined at this point. Compared to pretreatment values, TPC were similar in untreated animals. Atorvastatin, however, significantly reduced TPC by 38%, 45%, and 54% at the 1, 3, and 10 mg/kg doses, respectively. Statistically significant lowering of TPC (35%) by lovastatin was only achieved at the 10 mg/kg dose. To determine the mechanism by which atorvastatin lowered TPC in the EH rabbits, kinetic studies using human [125I]-LDL were performed in a subset of animals maintained on the casein diet alone (n = 5), or those treated with 3 mg/kg of atorvastatin (n = 5) or lovastatin (n = 7). In this set of studies, atorvastatin significantly lowered TPC compared to control and lovastatin-treated rabbits by 57% and 46%, respectively. Lovastatin treatment resulted in a 20% decrease in TPC as compared to untreated controls.(ABSTRACT TRUNCATED AT 250 WORDS)


Control of pelvic cancer with hyperthermic isolation-perfusion.
Eight patients with refractory pelvic cancer were treated with a technique of hyperthermic pelvic isolation-perfusion (rectosigmoid colon 7, bladder 1). The procedure was successful in achieving regional hyperthermia in all patients. All five patients experiencing severe pelvic pain prior to surgery had resolution of pain, although in one patient this relief was transient. Five patients had additional intraabdominal procedures at the time of laparotomy to control unsuspected foci of recurrent cancer. There were no operative deaths. Five complications occurred in four patients although only one was considered life threatening (fracture of aorta at the time of cross-clamping). Sloughing of necrotic tumor occurred between 1 and 2 weeks postperfusion and at times was dramatic. The efficacy of this technique is impressive and it is suggested that it be utilized earlier in the course of disease in patients with uncontrolled pelvic cancer.


The metabolic vascular syndrome - guide to an individualized treatment.
In ancient Greek medicine the concept of a distinct syndrome (going together) was used to label 'a group of signs and symptoms' that occur together and 'characterize a particular abnormality and condition'. The (dys)metabolic syndrome is a common cluster of five pre-morbid metabolic-vascular risk factors or diseases associated with increased cardiovascular morbidity, fatty liver disease and risk of cancer. The risk for major complications such as cardiovascular diseases, NASH and some cancers develops along a continuum of risk factors into clinical diseases. Therefore we still include hyperglycemia, visceral obesity, dyslipidemia and hypertension as diagnostic traits in the definition according to the term 'deadly quartet'. From the beginning elevated blood pressure and hyperglycemia were core traits of the metabolic syndrome associated with endothelial dysfunction and increased risk of cardiovascular disease. Thus metabolic and vascular abnormalities are in extricable linked. Therefore it seems reasonable to extend the term to metabolic-vascular syndrome (MVS) to signal the clinical relevance and related risk of multimorbidity. This has important implications for integrated diagnostics and therapeutic approach. According to the definition of a syndrome the rapid global rise in the prevalence of all traits and comorbidities of the MVS is mainly caused by rapid changes in life-style and sociocultural transition resp. with over- and malnutrition, low physical activity and social stress as a common soil.


Reduced creatine kinase activity in transgenic amyotrophic lateral sclerosis mice.
Creatine (Cr), the substrate of the creatine kinase (CK) isoenzymes, was shown to be neuroprotective in several models of neurodegeneration, including amyotrophic lateral sclerosis (ALS). In order to investigate the mechanism of this beneficial effect, we determined CK activities and mitochondrial respiration rates in tissues from G93A transgenic mice, which overexpress a mutant form of human superoxide dismutase associated with familial ALS (FALS). While respiration rates of mitochondria from G93A transgenic or wild-type control mice isolated from spinal cord showed no difference, a significant and dramatic loss of CK activity could be detected in these tissues. In homogenates from spinal cord of G93A transgenic mice, CK activity decreased to 49% and in mitochondrial fractions to 67% compared to CK activities in wild-type control mice. Feeding the G93A transgenic mice with 2% Cr, the same tissues showed no statistically significant increase of CK activity compared to regular fed G93A transgenic mice. Experiments with isolated mitochondria, however, showed that Cr and adenosine triphosphate (ATP) protected mitochondrial CK activity against peroxynitrite-induced inactivation, which may play a role in tissue damage in neurodegeneration. Our data provide evidence for oxidative damage to the CK system in ALS, which may contribute to impaired energy metabolism and neurodegeneration.


Cardiac valve papillary fibroelastoma: surgical excision for revealed or potential embolization.
We have reviewed the case histories of 4 patients who underwent operations between September 1994 and November 1997 at Broussais Hospital for cardiac valvular papillary fibroelastoma. Diagnosis was strongly suggested by echocardiography. Tumor locations were mitral (1), tricuspid (1), and aortic (2). Indications for operation were previous stroke for the mitral tumor, prophylaxis for the tricuspid tumor, syncopal episodes for the first aortic tumor, and transient ischemic attack and mesenteric ischemia for the second aortic tumor. Surgical excision with a conservative, valve-sparing approach was performed in all cases. For the first aortic tumor, aortic valve reconstruction was achieved with part of a cryopreserved aortic homograft cusp. Intraoperative transesophageal echocardiography showed no evidence of valvular regurgitation after excision in all cases. All patients had uneventful postoperative recoveries. No evidence of regurgitation or recurrence was seen on echocardiography at follow-up. Despite their histologically benign aspect, cardiac papillary fibroelastomas should be excised because of potential embolic complications. A conservative, valve-sparing approach is recommended, however, because of the absence of recurrence after total excision.


Cross-scale interactions affect tree growth and intrinsic water use efficiency and highlight the importance of spatial context in managing forests under global change.
1. We investigated the potential of cross-scale interactions to affect the outcome of density reduction in a large-scale silvicultural experiment to better understand options for managing forests under climate change. 2. We measured tree growth and intrinsic water-use efficiency (iWUE) based on stable carbon isotopes δ13C) to investigate impacts of density reduction across a range of progressively finer spatial scales: site, stand, hillslope position, and neighborhood. In particular, we focused on the influence of treatments beyond the boundaries of treated stands to include impacts on downslope and neighboring stands across sites varying in soil moisture. 3. Trees at the wet site responded with increased growth when compared with trees at the dry site. Additionally, trees in treated stands at the dry site responded with increased iWUE while trees at the wet site showed no difference in iWUE compared to untreated stands. 4. We hypothesized that water is not the primary limiting factor for growth at our sites, but that density reduction released other resources, such as growing space or nutrients to drive the growth response. At progressively finer spatial scales we found that tree responses were not driven by hillslope location (i.e., downslope of treatment) but to changes in local neighborhood tree density. 5. Synthesis. This study demonstrated that water can be viewed as an agent to investigate cross-scale interactions as it links processes operating at coarse to finer spatial scales and vice versa. Consequently, management prescriptions such as density reductions to increase resistance and resilience of trees to climate change, specifically to drought, need to consider cross-scale interactions as specific magnitude and mechanisms of growth responses can only be predicted when multiple scales are taken into account.


Calcifications are potential surrogates for prostate localization in image-guided radiotherapy.
To investigate the feasibility of using calcifications as surrogates for the prostate position during cone-beam computed tomography (CBCT) image-guided radiotherapy. The twice-weekly CBCT images taken during the treatment course of 4 patients were retrospectively studied for the stability of the calcifications. The geometric center of three fiducial markers was used as the reference. The planning CT images of 131 prostate patients recently treated with external beam radiotherapy at our center were reviewed to estimate the calcification occurrence rate. Analysis was conducted using the Varian Eclipse treatment planning system. Two patients were treated using prostate calcifications as the landmark in on-line registration. Both the Varian standard and the low-dose CBCT modes were used for imaging. The calcifications were found to be stable during the treatment course. At the 95% confidence interval, the difference between the distance from an identified calcification to the fiducial markers on CBCT and the distance on the planning CT scans was 0.2 +/- 2.0 mm, 0.8 +/- 2.2 mm, and 0.4 +/- 2.4 mm in the left-right, anteroposterior, and superoinferior direction, respectively. Of the 131 patients, 46 (35%) had well-defined calcifications either inside the prostate or near the borders. Our experience in treating the first 2 patients demonstrated that the calcifications are easily distinguished on low-dose scans and that calcification registration can be precisely performed. The results of our study have shown that calcifications can be reliable markers of prostate position and allow for precise image guidance with a low-imaging dose. With this approach, potentially about one-third of prostate patients could benefit from precise image guidance without the invasive use of markers.


Plasma and skeletal muscle free amino acids in type I, insulin-treated diabetic subjects.
Insulin-dependent diabetes mellitus (IDDM) induces plasma amino acid (AA) abnormalities, including low alanine and high branched-chain (BCAA). While insulin treatment restores plasma AA pattern, proline, methionine, valine, isoleucine, and total BCAA remain elevated in skeletal muscle intracellular water. This suggests that the restoration of plasma AA concentrations is not a satisfactory index of recovered AA metabolism in IDDM.


Non-metastatic hepatic dysfunction associated with renal carcinoma.
A retrospective computer analysis of 102 patients treated for renal tubular carcinoma revealed 7 patients who presented with non-metastatic hepatic dysfunction. Of these 7 patients 5 also had the triad of fever, weight loss and fatigue. Only 1 patient survived more than 10 years after nephrectomy. A review of the literature on non-metastatic hepatic dysfunction revealed a significant interval between onset of symptoms and detection of the underlying renal malignancy, as well as a poor over-all survival rate if the syndrome persisted after nephrectomy.


Aerobic endurance capacity affects spatial memory and SIRT1 is a potent modulator of 8-oxoguanine repair.
Regular exercise promotes brain function via a wide range of adaptive responses, including the increased expression of antioxidant and oxidative DNA damage-repairing systems. Accumulation of oxidized DNA base lesions and strand breaks is etiologically linked to for example aging processes and age-associated diseases. Here we tested whether exercise training has an impact on brain function, extent of neurogenesis, and expression of 8-oxoguanine DNA glycosylase-1 (Ogg1) and SIRT1 (silent mating-type information regulation 2 homolog). To do so, we utilized strains of rats with low- and high-running capacity (LCR and HCR) and examined learning and memory, DNA synthesis, expression, and post-translational modification of Ogg1 hippocampal cells. Our results showed that rats with higher aerobic/running capacity had better spatial memory, and expressed less Ogg1, when compared to LCR rats. Furthermore, exercise increased SIRT1 expression and decreased acetylated Ogg1 (AcOgg1) levels, a post-translational modification important for efficient repair of 8-oxo-7,8-dihydroguanine (8-oxoG). Our data on cell cultures revealed that nicotinamide, a SIRT1-specific inhibitor, caused the greatest increase in the acetylation of Ogg1, a finding further supported by our other observations that silencing SIRT1 also markedly increased the levels of AcOgg1. These findings imply that high-running capacity is associated with increased hippocampal function, and SIRT1 level/activity and inversely correlates with AcOgg1 levels and thereby the repair of genomic 8-oxoG.


Simultaneous visualization of multiple radionuclides in vivo.
The insufficient energy and spatial resolutions of radionuclide imaging with conventional scintillation detectors restrict the visualization of multiple radionuclides and of microstructures in tissue. Here we report the development and performance of an imaging system equipped with a cadmium telluride diode detector that achieves an energy resolution of 1.7% at 140 keV and a spatial resolution of 250 μm. The combination of high-resolution spectra fitted to an X-ray analysis model of the emission lines of the radionuclides in a chosen energy band allowed us to accurately determine individual radiation activities from three radionuclides to simultaneously visualize thyroid tissue (via intravenously administered iodine-125), mandibular lymph nodes (via the intramuscular injection of indium-111) and parotid lymph nodes (via a subcutaneous injection of technetium-99m) in mice. Multi-radionuclide imaging may find advantageous applications in biomedical imaging.


Inhibition of Mitochondrial Voltage-Dependent Anion Channels Increases Radiosensitivity of K562 Leukemic Cells.
We studied the effect of inhibition of mitochondrial voltage-dependent anion channels with DIDS on radiosensitivity and mitochondrial status of K562 leukemic cells. The number of apoptotic and necrotic cells, mitochondrial transmembrane potential, and mitochondrial mass were evaluated after irradiation of cells in doses of 4 and 12 Gy in the presence and absence of the inhibitor. Inhibition of mitochondrial voltage-dependent anion channels increased radiosensitivity of K562 cells by 50-70% and decreased both mitochondrial transmembrane potential and mitochondrial mass. Inhibitors of voltage-dependent anion channels are promising agents capable of improving the effectiveness of cancer radiotherapy.


Colorectal cancer in the young.
Colorectal cancer (CRC) is generally thought of as a disease of older persons; however a significant proportion of patients <40 years present with this disease. Many investigators have published single-institution series on CRC in the young, yet the data vary markedly. We performed a structured review of the current literature aiming to (1) characterize CRC in the young population and (2) determine how CRC in this population should be further addressed regarding detection and treatment. A Medline literature search was completed. Articles were chosen to include those studies that examined patients <40 years old. A total of 55 articles were chosen from the search and review of the bibliographies. We found that CRC in the young population appears to be more aggressive, to present with later stage, and to have poorer pathologic findings. However, if detected early, young patients with Dukes' stage A or B lesions have better overall 5-year survival rates. These findings emphasize the need for health care providers to have a heightened awareness when caring for this young population, particularly because excellent modalities exist to diagnose and treat colorectal cancer.


(51)V solid-state NMR investigations and DFT studies of model compounds for vanadium haloperoxidases.
Three cis-dioxovanadium(V) complexes with similar N-salicylidenehydrazide ligands modeling hydrogen bonding interactions of vanadate relevant for vanadium haloperoxidases are studied by (51)V solid-state NMR spectroscopy. Their parameters describing the quadrupolar and chemical shift anisotropy interactions (quadrupolar coupling constant C(Q), asymmetry of the quadrupolar tensor eta(Q), isotropic chemical shift delta(iso), chemical shift anisotropy delta(sigma), asymmetry of the chemical shift tensor eta(sigma) and the Euler angles alpha, beta and gamma) are determined both experimentally and theoretically using DFT methods. A comparative study of different methods to determine the NMR parameters by numerical simulation of the spectra is presented. Detailed theoretical investigations on the DFT level using various basis sets and structural models show that by useful choice of the methodology, the calculated parameters agree to the experimental ones in a very good manner.


Dual potent ALK and ROS1 inhibitors combating drug-resistant mutants: Synthesis and biological evaluation of aminopyridine-containing diarylaminopyrimidine derivatives.
To identify ALK and ROS1 dual inhibitors conferring resistance to ALK secondary mutations, especially 'gatekeeper' L1196 M and the most predominant ceritinib-resistant G1202R mutations, a series of novel 2,4-diarylaminopyrimidine analogues were designed and synthesized by incorporating 2-alkoxy-6-alicyclic aminopyridinyl motifs. The biological evaluations on cellular and enzymatic assays led to identification of compound F-1, which turned out to be effective against ALKWT, ROS1WT, ALKL1196M and ALKG1202R kinases with IC50 of 2.1 nM, 2.3 nM, 1.3 nM and 3.9 nM, respectively, superior to crizotinib and ceritinib. Moreover, F-1 exhibited significant cytotoxicity on ALK-addicted Karpas299, H2228, and Ba/F3 cell expressing G1202R mutant, as well as ROS1-positive HCC78 cell with IC50 values ranging from 10 nM to 43 nM. Notably, F-1 was capable of suppressing phospho-ALK and its relative downstream signaling pathways, and eventually, inducing cell apoptosis in a dose-dependent manner in Karpas-299 cell. Together, F-1 is validated as a promising ALK/ROS1 dual inhibitor great potential for G1202R ALK mutation cancers.


Advanced human iPSC-based preclinical model for Parkinson's disease with optogenetic alpha-synuclein aggregation.
Human induced pluripotent stem cells (hiPSCs) offer advantages for disease modeling and drug discovery. However, recreating innate cellular pathologies, particularly in late-onset neurodegenerative diseases with accumulated protein aggregates including Parkinson's disease (PD), has been challenging. To overcome this barrier, we developed an optogenetics-assisted α-synuclein (α-syn) aggregation induction system (OASIS) that rapidly induces α-syn aggregates and toxicity in PD hiPSC-midbrain dopaminergic neurons and midbrain organoids. Our OASIS-based primary compound screening with SH-SY5Y cells identified 5 candidates that were secondarily validated with OASIS PD hiPSC-midbrain dopaminergic neurons and midbrain organoids, leading us to finally select BAG956. Furthermore, BAG956 significantly reverses characteristic PD phenotypes in α-syn preformed fibril models in vitro and in vivo by promoting autophagic clearance of pathological α-syn aggregates. Following the FDA Modernization Act 2.0's emphasis on alternative non-animal testing methods, our OASIS can serve as an animal-free preclinical test model (newly termed "nonclinical test") for the synucleinopathy drug development.


Anti-aquaporin-4 autoantibodies in systemic lupus erythematosus persist for years and induce astrocytic cytotoxicity but not CNS disease.
Anti-aquaporin-4 autoantibodies are specific for the neuromyelitis optica spectrum disorders (NMOSD) and they have also been described in patients with systemic lupus erythematosus (SLE) with neurological signs consistent with NMOSD. Our objective was to test for the presence and pathogenicity of anti-AQP4 antibodies in SLE patients without neurological disease. Sera from 89 non-CNS-SLE patients were screened for anti-AQP4 autoantibodies. Two of the 89 patients were positive. Archived samples dating back 11 years were also positive. A brain and spinal cord MRI did not reveal any NMOSD-compatible lesions. An in vitro cytotoxicity assay showed that either sera or purified IgG from these patients induced a complement-mediated damage in cultured astrocytes comparable to antibodies obtained from typical NMO patients. We conclude that AQP4-antibodies can be present in SLE patients and persist for many years, without concurrent clinical or radiological NMOSD signs. It is unclear why the anti-AQP4 antibodies did not induce CNS disease.


Laparoscopic colectomy for recurrent and complicated diverticulitis: a prospective study of 396 patients.
It was the aim of this prospective study to evaluate the outcome of laparoscopic surgery for diverticular disease. All patients who underwent elective laparoscopic colectomy for diverticular disease within a 10-year period were prospectively entered into a PC database registry. Indications for laparoscopic surgery were acute complicated diverticulitis (Hinchey stages I and IIa), chronically recurrent diverticulitis, sigmoid stenosis or outlet obstruction caused by chronic diverticulitis. Surgical procedures (sigmoid and anterior resection, left colectomy and resection rectopexy) included intracorporeal dissection and colorectal anastomosis. Parameters studied included age, gender, stage of disease, procedure, duration of surgery, intraoperative technical variables, transfusion requirements, conversion rate, total complication rate including major (requiring re-operation), minor (conservative treatment) and late-onset (post-discharge) complication rates, stay on ICU, hospitalisation, mortality, and recurrence. For objective evaluation, only laparoscopically completed procedures were analysed. Comparative outcome analysis was performed with respect to stage of disease and experience. A total of 396 patients underwent laparoscopic colectomy. Conversion rate was 6.8% ( n=27), so that laparoscopic completion rate was 93.2% ( n=369). Most common reasons for conversion were directly related to the inflammatory process, abscess or fistulas. The most common procedure was sigmoid resection ( n=279), followed by anterior resection ( n=36) and left colectomy ( n=29). Total complication rate was 18.4% ( n=68). Major complication rate was 7.6% ( n=28), whereas the most common complication requiring re-operation was haemorrhage in 3.3% ( n=12). Anastomotic leakage occurred in 1.6% ( n=6). Minor complications were noted in 10.7% ( n=40), late-onset complications occurred in 2.7% ( n=10). Mortality was 0.5% ( n=2). Mean duration of surgery was 193 (range 75-400) min, return to normal diet was completed after 6.8 (range 3-19) days. Mean hospital stay was 11.8 (range 4-71) days. No recurrence of diverticulitis occurred. Laparoscopic surgery for diverticular disease is safe, feasible and effective. Therefore, laparoscopic colectomy has replaced open resection as standard surgery for recurrent and complicated diverticulitis at our institution.


The C-terminal domains of melanocortin-2 receptor (MC2R) accessory proteins (MRAP1) influence their localization and ACTH-induced cAMP production.
ACTH binding to the human melanocortin-2 receptor (MC2R) requires the presence of the MC2R accessory protein1 isoforms, MRAPα or MRAPβ. This study evaluated the role of the isoform-specific C-terminal domains of MRAP with regard to their cellular localization, topology, interaction with MRAP2 and cAMP production. When stably expressed in HEK293/FRT cells or in B16-G4F mouse melanoma cells (an MSH receptor-deficient cell clone), MRAPα and MRAPdCT (truncated MRAP1, N-terminal only) localized mainly around the nuclear envelope and within dense intracellular endosomes, while MRAPβ exhibited a strong localization at the plasma membrane, and partially with rapid recycling endosomes. MRAPβ and MRAPdCT both exhibited dual-topology (N(cyto)/C(exo) and N(exo)/C(cyto)) at the plasma membrane whereas MRAPα exhibited only N(cyto)/C(exo) topology at the plasma membrane while adopting dual-topology in intracellular compartments. Both MRAPα and MRAP2 colocalized in intracellular compartments, as opposed to weak colocalization between MRAPβ and MRAP2. MRAP2 and MC2R enhanced the expression of MRAP1 isoforms and vice versa. Moreover, in both HEK293/FRT and B16-G4F cells, ACTH failed to activate MC2R unless MRAP1 was present. MRAP1 expression enhanced MC2R cell-surface expression as well as concentration-dependent cAMP accumulation. In the presence of human or zebrafish MC2R, MRAPβ induced the highest cAMP accumulation while MRAPdCT induced the lowest. Together, the present findings indicate that the C-terminal domains of MRAP dictate their intracellular localization in addition to regulating ACTH-induced cAMP production. These preferential localizations suggest that MRAPα is involved in MC2R targeting to the plasma membrane, while MRAPβ may enhance ACTH-MC2R coupling to cAMP production.


Do Intramedullary Screws Provide Adequate Fixation for Humeral and Ulnar Components in Total Elbow Arthroplasty? A Cadaveric Analysis.
The objective of this study was to determine the structural properties of the cadaver bone-screw interface for cementless intramedullary screw fixation in the context of total elbow arthroplasty. The intramedullary canals of seven humerus and seven ulna specimens from fresh-frozen cadavers were drilled using custom drill bits until the inner cortex was reached and then hand tapped for the corresponding thread size. Titanium screws were advanced into the tapped holes until securely seated. The bones were potted and then mounted on a uniaxial material testing machine. A tensile load was applied, and end-of-test elongation, failure load, energy absorbed, and stiffness were determined. End-of-test load and elongation were defined as the elongation and load experienced by the structure at 3,000 N or failure. Each specimen was inspected for evidence of pullout, loosening, or visible fractures. The end-of-test load and elongation for the humerus specimens were 2721 ± 738 N and 3.0 ± 0.9 mm, respectively. The ulna specimens reached 92% of the humerus specimens' end-of-test load at 2,514 ± 678 N and 120% of their end-of-test elongation (3.6 ± 0.6 mm). The stiffness of the humerus specimens was 1,077 ± 336 N/mm, which was 1.3 times greater than the stiffness of the ulna specimens (790 ± 211 N/mm). Lastly, the energy absorbed by the humerus samples was 3.6 ± 1.6 J, which was 92% of the energy absorbed by the ulna samples at 3.9 ± 1.1 J. One humerus and three ulnas failed before the end-of-test load of 3,000 N. Two failures were caused by screw pullout and two by bone fracture. Our findings demonstrate that intramedullary screw fixation is successful in withstanding forces that are greater than required for osseointegration. Uncemented fixation may be beneficial in elbow arthroplasty.


Evaluating the technical efficiency of neonatal health service among primary hospitals of northwest Ethiopia: Using two-stage data envelopment analysis and Tobit regression model.
Most cases of neonatal mortality are preventable but a substantial number of cases get complicated and become irreversible not only due to scarcity but also due to inefficient utilization of available resources in the health service. However, limited evidence shows the efficiency level of health facilities in Ethiopia. Therefore, this study aimed to assess the technical efficiency of neonatal health service and its associated factors among primary hospitals in three zones of Northwest Ethiopia. A facility-based cross-sectional study was conducted among fifteen randomly selected primary hospitals from March 17 to April 17, 2021. Input data on non-salary recurrent costs, salary costs, and the number of beds, and output data on neonatal admissions, outpatient visits, and referrals for the 2019/20 fiscal year were collected using a document review. In the first stage of analysis, input-oriented data envelopment analysis with a variable return-to-scale assumption was employed to estimate the efficiency scores using DEAP 2.1. A Tobit regression model was fitted in the second stage to identify the associated factors with technical efficiency. Variables with a p-value <0.05 were declared as statistically associated factors. In this study, 80% of the primary hospitals were pure technical efficient whereas 46.67% of the facilities were scale efficient with all of the scale inefficient hospitals operating below their scale. The mean pure technical and scale efficiency score of primary hospitals was 0.948±0.113 and 0.887±0.143, respectively. Total catchment population, incentive packages for the clinical staff, and the educational status of the manager were positively associated with the technical efficiency of hospitals. On the other hand, technical efficiency was negatively associated with the presence of a health facility that provides neonatal health services near the hospital and the distance of the manager's residence. Though most of the primary hospitals in Northwest Ethiopia were technical efficient, more than half of them were working below their scale of operation. Our results also indicated that introducing the performance-based provision of incentive packages for clinical staff and employing master's and above-educated health professionals as a manager might improve the efficient utilization of resources in primary hospitals.


Diagnostic value of the preoperative platelet/lymphocyte ratio and red cell distribution volume in patients with renal masses.
Inflammatory markers indicate immune system responses. We retrospectively explored whether the platelet/lymphocyte ratio (PLR), neutrophil/lymphocyte ratio (NLR), and red blood cell distribution width (RDW) were predictive of malignant disease. Between 2019 and 2023, 148 patients diagnosed with malignant and benign renal tumors via imaging or biopsy were included. Of these tumors, 117 were malignant and 31 were benign. Blood samples were taken for calculation of the NLR, PLR, and RDW prior to renal biopsy or operation. The NLR, PLR, and RDW did not differ significantly between patients with malignant and benign renal masses (all p > 0.05). The PLR significantly increased with the T stage of malignant masses (p = 0.011). According to the T stage, the RDW cutoff was 45.7, the sensitivity was 40 %, and the specificity 82.4 %; the respective values for PLR were 134.9, 70 %, and 70.5 % (p = 0.026 and p = 0.003, respectively). The NLR, PLR, and RDW were not predictive in this study because we only included early- stage patients lacking lymph node involvement and the follow-up was short. In patients with renal cell carcinomas, the RDW and PLR increase with the tumor burden and predict poor prognosis (Tab. 5, Fig. 1, Ref. 23). Text in PDF www.elis.sk Keywords: neutrophil/lymphocyte ratio, platelet/ lymphocyte ratio, renal mass.


Private expenditures on brand name prescription drugs after generic entry.
Generic drugs offer a less expensive and therapeutically equivalent alternative to brand name drugs. Nevertheless, many Canadian private drug plans continue to pay for brand name drugs even after generics become available. The objective of this study was to quantify the excess spending resulting from this practice. We used the IMS Brogan PharmaStat database to study private-plan drug spending in Ontario from 2000 to 2009. We focused on three widely used drug classes: proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs), and angiotensin-converting enzyme (ACE) inhibitors. For each specific molecule, we determined the difference between what private plans spent on the brand name version and what would have been spent if an available generic version of the same molecule had been purchased instead. We found that prescriptions paid for by private drug plans were often filled with brand name drugs after generics became available. This led to excess private spending of more than Can$107.8 million for these three drug classes over our study period: Can$54.4 million for PPIs, Can$32.4 million for SSRIs and Can$21.0 million for ACE inhibitors. Brand name drugs continue to be reimbursed by Canadian private drug plans at higher prices even after less expensive generic alternatives are available. By mandating generic substitution, substantial cost savings on benefit plans could be achieved.


Synthesis and biological evaluation of 2-phenylthiazole-4-carboxamide derivatives as anticancer agents.
A series of substituted 2-phenylthiazole-4-carboxamide derivatives were synthesized as potential cytotoxic agents and evaluated against three human cancer cell lines including T47D (Breast cancer), Caco-2 (Colorectal cancer) and HT-29 (Colon cancer). The SAR of the arylacetamido pendent connected to the para-position of 2-phenylthiazole were explored. It was found that substitution at the 4-position by a methoxy group led to improvement of activity against Caco-2 cells while 2-methoxy substituent could maintain the high activity against HT-29 and T47D cell lines. Also, 3-fluoro analog showed good cytotoxic activity profile against all cell lines with IC(50) values less than 10 μg/mL.


Incidence and risk factors of bradycardia in pediatric patients undergoing intranasal dexmedetomidine sedation.
Dexmedetomidine is widely used for non-invasive pediatric procedural sedation. However, the hemodynamic effects of intravenous dexmedetomidine are a concern. There has been a growing interest in the application of intranasal dexmedetomidine as a sedative in children. To investigate the incidence of bradycardia in children undergoing intranasal dexmedetomidine sedation and to identify the associated risk factors. Data pertaining to pediatric patients who underwent intranasal dexmedetomidine sedation for non-invasive investigations at the Kunming Children's Hospital between October 2017 and August 2018 were retrospectively analyzed. Out of 9984 children who qualified for inclusion, 228 children (2.3%) developed bradycardia. The incidence of bradycardia in the group that received additional dose of dexmedetomidine was higher than that in the group that did not receive additional dose (9.2% vs 16.7%; P = .003). The incidence of bradycardia in males was higher than that in females (2.6% vs 1.8%; P = .007). On multivariate logistic regression, only male gender showed an independent association with the occurrence of bradycardia (odds ratio 1.48; 95% confidence interval 1.11-1.97; P = .008). The overall incidence of bradycardia in children after sole use of intranasal dexmedetomidine sedation was 2.3%. Male children showed a 1.48-fold higher risk of bradycardia. However, the blood pressure of the children who developed bradycardia was within the normal range. Simple wake-up can effectively manage bradycardia induced by intranasal dexmedetomidine sedation.


Magnetotactic bacteria and magnetofossils: ecology, evolution and environmental implications.
Magnetotactic bacteria (MTB) are a group of phylogenetically diverse and morphologically varied microorganisms with a magnetoresponsive capability called magnetotaxis or microbial magnetoreception. MTB are a distinctive constituent of the microbiome of aquatic ecosystems because they use Earth's magnetic field to align themselves in a north or south facing direction and efficiently navigate to their favored microenvironments. They have been identified worldwide from diverse aquatic and waterlogged microbiomes, including freshwater, saline, brackish and marine ecosystems, and some extreme environments. MTB play important roles in the biogeochemical cycling of iron, sulphur, phosphorus, carbon and nitrogen in nature and have been recognized from in vitro cultures to sequester heavy metals like selenium, cadmium, and tellurium, which makes them prospective candidate organisms for aquatic pollution bioremediation. The role of MTB in environmental systems is not limited to their lifespan; after death, fossil magnetosomal magnetic nanoparticles (known as magnetofossils) are a promising proxy for recording paleoenvironmental change and geomagnetic field history. Here, we summarize the ecology, evolution, and environmental function of MTB and the paleoenvironmental implications of magnetofossils in light of recent discoveries.


Resource use, energetic profitability, and behavioral decisions in migrant rufous hummingbirds.
Migrant Rufous Hummingbirds (Selasphorus rufus) defend nectar resources at stopover sites while replenishing fat reserves needed for migratory flights. During late summer in the Sandia Mountains, central New Mexico, they defend the wasp- and bee-pollinated Scrophularia montana from other hummingbirds. Both hummingbirds and hymenopterans exploit Scrophularia nectar during the early part of its flowering period. As summer colony growth increases the densities of the eusocial hymenopterans by 100-150%, their exploitation of Scrophularia nectar lowers its mean standing crop in flowers by 200-300%. Sometime during the summer, Rufous Hummingbirds abandon and do not further use this resource for the remaining 3-4 weeks of its flowering period. The abandonment always occurs when the mean standing crop of nectar is approximately 0.2-0.3 μL/ flower. This paper describes a model of Rufous Hummingbird energetics, that shows abandonment occurred 1-3 days after they passed the threshold at which the resource could have provided their minimum daily energy requirements. I suggest that constraints imposed by a highly competitive social environment severely reduced the options available to the hummingbirds, and caused them to continue to defend a resource that could no longer meet their energetic requirements.


ZnS quantum dots surface-loaded with zinc(II) ions as a viable fluorescent probe for glutathione.
The fluorescence of ZnS quantum dots in colloidal water solution changes very slightly on addition of glutathione (GSH) but is strongly enhanced in the presence of Zn(II) even in concentrations as low as 10 μM. The resulting Zn(II)-enhanced fluorescence is found to be quenched by GSH. In contrast to GSH, cysteine does not cause an effect. Response surface methodology was applied to optimize the experimental parameters. The best data can be obtained at 305/427 nm as excitation/emission wavelengths. These findings were used to design an indirect method for the fluorometric determination of GSH that has a 0.9 μM detection limit and a response that is linear in the 2.0-104.0 μM GSH concentration range. The relative standard deviation at a level of 65 μM of GSH (for n = 5) is 1.9%. Graphical abstract Schematic presentation of the detection strategy for glutathione and the influence of the mediator (Zn2+). Direct pathway shows that the glutathione cannot cause a change in the blue fluorescence of ZnS QDs. The presence of Zn2+ causes the enhancement of the fluorescence intensity, and this generates the indirect pathway to glutathione detection.


Autophagy in cancer: The cornerstone during glutamine deprivation.
Over the past two decades, researchers have revealed the crucial functions of glutamine in supporting the hyperproliferation state of cancer cells. Glutamine acts on maintaining high energy production, supporting redox status and amino acid homeostasis. Therefore, cancer cells exhibit excessive uptake of the extracellular glutamine, synthesize it in some cases, and recycle intracellular and extracellular proteins to provide an additional source of glutamine to satisfy the increasing glutamine demand. On the other hand, autophagy's role is still debated regarding tumor initiation and progression. However, most cancer cells urgently need autophagy to overcome the existential threats during glutamine restriction stress. Downstream to various stress pathways induced during such a condition, autophagy is considered an indispensable cytoprotective tool to maintain cell integrity and survival. However, the overactivation of the autophagy process is related to lethal consequences. This review summarized glutamine pathways to control autophagy and highlighted autophagy's primary activation pathways, and discussed the roles during glutamine deprivation.


Trichinellosis: a possible link between human infection and the traditional earth-oven or 'mumu' method of cooking in Morehead District, Western Province, Papua New Guinea.
To investigate if the traditional method of cooking pig meat in an earth-oven or mumu, as practiced by people in Morehead District, Western Province, Papua New Guinea (PNG), could be a source of infection with Trichinella papuae and of the disease trichinellosis. As the locality lacks suitable river stones normally used in a mumu in PNG, people use various substitute materials, such as pieces of termite mounds, balls of dried clay and small rough stones. Samples of these were tested and compared with conventional mumu stones in their capacity to retain heat. None of the substitute materials tested was as efficient in retaining heat as the conventional mumu stones. Cooking pig meat in a mumu in Morehead District has the potential to be a source of infection with T. papuae. Loss of heat in a Morehead mumu is accelerated probably as the mumu is prepared on the surface of the ground and not in a shallow pit or depression as is the custom elsewhere in the country.


Integral hair lipid in human hair follicle.
Integral hair lipid (IHL) is bound to the keratinized cell surface to make an environmentally resistant lipid envelope. It is mainly positioned on the hair cuticle and inner root sheath. IHL in the hair follicle may regard as hair barrier to be similar to the epidermal lipid layer functioning as skin barrier. Major constituents of IHL are fatty acid, phytosphingosine, ceramide in decreasing order. Minor constituents of IHL are cholesterol, cholesterol sulfate and cholesterol oleate. Cuticle or cortical cell surface in hair are abundant in fatty acids unlike the keratinized area of epidermis or sebaceous gland, and about 30-40% of such fatty acids are composed of 18-methyl-eicosanoic acid which is known to be bound to proteins by ester or thioester bond. Various factors including moisture, solvent, oxidative damage during bleaching or permanent waving affect IHL. Photochemical changes also can occur in IHL as well as in hair protein and hair pigment. Lipid metabolism is thought to play an essential role in lipid envelope of hair, but also involvement in hair development and function.


It's in the Milk: Feeding the Microbiome to Promote Infant Growth.
Malnutrition is a global health burden affecting the development of millions of children worldwide, but the effects of current treatment strategies are modest. Charbonneau et al. (2016) identify sialylated oligosaccharides in breast milk as microbiota-dependent growth-promoting metabolites, paving the way for a new rational treatment of severe infant stunting.


Comparison of two selective media developed to isolate Pseudomonas cepacia from patients with cystic fibrosis.
Two media selective for Pseudomonas cepacia have been described recently: OF-polymyxinbacitracin-lactose agar (OFPBL) and P. cepacia agar (PCA). We compared these by culturing sputum from 27 patients with cystic fibrosis. Sputum from each patient was studied using streak-plate (SP) and quantitative (Q) culture methods. Five strains of P. cepacia were isolated from four patients (15%). P. cepacia was not found on routine media by SP or Q methods in three of the four patients. All five isolates grew on both OFPBL and PCA and all were recovered by SP and Q culture methods. Colony counts of P. cepacia obtained by Q cultures were similar on both selective media. Each of the selective media allowed the growth of other organisms; nineteen of 27 specimens cultured on OFPBL yielded non-P. cepacia spp. and six of 27 specimens cultured on PCA yielded non-P. cepacia spp. species (p less than 0.005). Pseudomonas aeruginosa was isolated from 26 of 27 patients on routine media (96%). This organism was recovered from four specimens cultured on OFPBL but from none on PCA (p less than 0.05). OFPBL and PCA are both selective for P. cepacia and enhance the ability to recover this organism from patients with cystic fibrosis using either SP or Q cultures of sputum; however, PCA is significantly more inhibitory for non-P. cepacia spp. than OFPBL.


[Current possibilities of bloodless quantitative evaluation of the pumping function reserve of the heart based on the study of oxygen consumption during the treadmill test].
Estimations of minute circulation volume (MCV) and the recovery coefficient (RC) as a parameter of oxygen debt were compared during the treadmill test in 83 cardiologic patients and 32 normal subjects in order to assess their pumping activity. At every stage of exercise, MCV was calculated on the basis of oxygen uptake, using Hossak's formula. MCV values were similar in the patients and normal subjects at similar stages of the treadmill test, and in patients belonging to different severity classes. RC variation was, on the contrary, different and depended on the magnitude of hemodynamic disorders: as pumping insufficiency developed, there was an abrupt drop in RC. A method is proposed for the quantitative assessment of pumping functional reserve on the basis of the ratio of oxygen uptake (at the stage where RC change occurred) to the maximum achievable by a normal subject of the same age, sex and body weight.


Cytotoxicity of anti-c-erbB-2 immunoliposomes containing doxorubicin on human cancer cells.
We have examined the selective cytotoxicity of immunoliposomes containing doxorubicin (chemoimmunoliposomes, CILs) targeting the c-erbB-2 gene product (gp185) or gp125. Anti-gp185 and anti-gp125 CILs were prepared by conjugation of doxorubicin-containing liposomes with monoclonal antibodies SER4 (IgG) and HBJ127 (IgG) respectively. Both CILs bound to human SKBr-3 breast cancer cells and MKN-7 human gastric cancer cells, which express both antigens in high density. The IC50 of anti-gp185 CILs on protein synthesis by SKBr-3 cells was respectively 2- and 25-fold lower than that of anti-gp125 CILs and unmodified liposomes. Furthermore, anti-gp185 CILs significantly inhibited neither the phytohaemagglutin response of normal lymphocytes nor protein synthesis of gp185-negative T24 bladder cancer. Quantitative analysis of cell-associated doxorubicin revealed that, compared with anti-gp125 CILs, anti-gp185 CILs required, respectively 4.5 and 4.3 times less doxorubicin association in SKBR-3 and MKN-7 cells, for 50% cytotoxicity. In addition, flow cytometric analysis showed that both SKBr-3 and MKN-7 internalised more anti-gp185 CILs and processed them more efficiently than anti-gp125 CILs. These results suggest that anti-gp185 CILs act selectively against gp185-expressing cancer cells and that gp185 is a more sensitive antigen for CIL cytotoxicity associated with endocytosis activity.


survcomp: an R/Bioconductor package for performance assessment and comparison of survival models.
The survcomp package provides functions to assess and statistically compare the performance of survival/risk prediction models. It implements state-of-the-art statistics to (i) measure the performance of risk prediction models; (ii) combine these statistical estimates from multiple datasets using a meta-analytical framework; and (iii) statistically compare the performance of competitive models.


Neuroanatomical correlates of impaired recognition of emotion in dementia.
Neurodegenerative diseases frequently affect brain regions important for emotional processing, offering a valuable opportunity to study the effects of brain injury on emotion. The current study examined the neuroanatomical correlates of impaired recognition of emotions in patients with neurodegenerative disease. Performance on recognition of facial expressions, as measured by the Florida Affect Battery, was correlated with regional changes in gray matter tissue content in 50 patients with neurodegenerative disease using voxel-based morphometry. Recognition accuracy in the group was poor for negative emotions (fear, anger and sadness) and good for happiness, consistent with previous studies. For negative emotions, a region in the right lateral inferior temporal gyrus (Brodman's area (BA) 20) extending into the right middle temporal gyrus (BA 21) was correlated with accuracy. This effect appeared to be strongest for sadness, which was also independently correlated with atrophy in the superior temporal gyrus. These data suggest that regions in the right lateral and inferolateral temporal lobe are important for visual processing of negative emotions from faces and that functioning of this right temporal network is most critical for recognition of sad faces.


How mood tunes prediction: a neurophenomenological account of mood and its disturbance in major depression.
In this article, we propose a neurophenomenological account of what moods are, and how they work. We draw upon phenomenology to show how mood attunes a person to a space of significant possibilities. Mood structures a person's lived experience by fixing the kinds of significance the world can have for them in a given situation. We employ Karl Friston's free-energy principle to show how this phenomenological concept of mood can be smoothly integrated with cognitive neuroscience. We will argue that mood is a consequence of acting in the world with the aim of minimizing expected free energy-a measure of uncertainty about the future consequences of actions. Moods summarize how the organism is faring overall in its predictive engagements, tuning the organism's expectations about how it is likely to fare in the future. Agents that act to minimize expected free energy will have a feeling of how well or badly they are doing at maintaining grip on the multiple possibilities that matter to them. They will have what we will call a 'feeling of grip' that structures the possibilities they are ready to engage with over long time-scales, just as moods do.


Effect of a single growth hormone (rbST) treatment at breeding on conception rates and pregnancy retention in dairy and beef cattle.
Initiation of long-term treatment with rbST (Posilac, Monsanto, St. Louis, MO) coincident with first insemination increased pregnancy rates in dairy cattle, but neither the efficacy of using only the initial injection, nor its effects on retention of pregnancy are known. Lactating dairy cows, dairy heifers, and lactating beef cows were assigned at random to treatment (rbST) or control. Dairy cows, dairy heifers, and beef cows received 500 mg rbST (n = 48, 35, 137 inseminations, respectively) at artificial insemination or were left untreated (n = 62, 33, 130 inseminations, respectively). Pregnancy was diagnosed by ultrasonography at 28-36 days. Treatment with rbST at insemination improved conception rates in dairy cows (60.4% versus 40.3%; P < 0.05), but not in dairy heifers or beef cows. Conception rates did not differ in dairy cows at < or =100 days in milk (DIM), but were improved in cows treated with rbST after 100 DIM (64.3% versus 25.8%; P < 0.05). Retention of pregnancy to approximately 60 days and sizes of CL, diameter of follicles > or =5 mm, and crown-rump lengths of embryos were not affected by treatment. The second objective was to examine the effects of rbST at insemination on birth weight and post-natal calf growth in beef cows. However, birth and weaning weights of beef calves were not affected by treatment. In conclusion, a single treatment with rbST at insemination increased conception rates in dairy cows, specifically in those >100 DIM.


[Linear psoriasis (linear psoriatic epidermal nevus) in a patient with HIV infection].
The Authors report a 24 year-old female who presented a linear localized epidermal nevus, from birth. Few months after a diagnosis of HIV infection (ARC WR 4) they observed the flaring-up of psoriasis both on the typical cutaneous sites, and on nevus, which looked like linear psoriasis.


The role of NK cell activity in the pathogenesis of poly I:C accelerated and spontaneous diabetes in the diabetes prone BB rat.
The development of insulin dependent diabetes mellitus (IDDM) and diabetes in the diabetes prone (DP) BB rat animal model of IDDM is thought to be due to an autoimmune process. Natural killer (NK) cells have been implicated but not proven to play a pathogenetic role in BB rats due to the increased NK cell number and activity found in these animals. We have recently reported that poly I:C, an inducer of cytokines and a potent enhancer of NK cell function, accelerates the development of diabetes in DP BB rats and induces diabetes in diabetes resistant (DR) BB rats. Since we have further demonstrated that poly I:C administration to BB rats increases NK cell number and levels of inducers of NK cell activity, interferon-alpha and IL-6 which is described therein, we tested the hypothesis that NK cell activity plays an important role in poly I:C accelerated disease. The role of NK cells in poly I:C accelerated diabetes and spontaneous diabetes was examined by determining whether selective depletion of NK cells using a rat NK cell specific antibody (anti-NKR-P1 antibody) alters the development of diabetes. The treatment of BB rats with anti-NKR-P1 antibody resulted in a significantly lower mean NK cell activity of splenic mononuclear cells than that found in control animals. However, the development of diabetes and degree of insulitis was not significantly different between treatment groups. BB rats administered anti-NKR-P1 antibody with poly I:C had a lower mean splenocyte NK cell activity and lower mean NK cell number within the peripheral blood and inflamed islets than rats administered poly I:C alone. However, anti-NKR-P1 antibody administration did not alter the accelerated development of diabetes or the degree of insulitis in poly I:C treated animals. These data document that NK cells do not play a major role in the pathogenesis of poly I:C accelerated diabetes or spontaneous diabetes in the DP BB rat.


Verbalization, Categorization, and Evaluation of Fundamental Surgical Skills: An Expert Consensus in Open Head and Neck Surgery.
This study aimed to verbalize fundamental surgical skills required for open head and neck surgery (OHNS), to organize them by categorization, and to establish a consensus among surgeons regarding the importance and difficulty of each skill. Improvement of fundamental surgical skills is the core of surgical education; however, surgical skills are not yet organized, and consensus in any surgical field remains uncertain. Fundamental surgical skills during OHNS were collected from surgical textbooks, real surgeries, and expert interviews. The items were analyzed to calculate the frequency of words and were categorized by 2 expert surgeons. After consensus on the importance and difficulty of each item was established by 15 expert surgeons using a Delphi survey, principal component (PC) analysis was performed to integrate importance and difficulty into a single parameter. Sixty skills were verbalized and categorized into 7 categories: "skin flap elevation (n = 6)," "vessel management (n = 9)," "nerve preservation (n = 8)," "instrument handling (n = 11)," "counter traction (n = 7)," "tissue exposure (n = 9)," and "flow and planning (n = 10)." In the Delphi survey, expert consensus was established after 2 voting rounds (Cronbach's α ≥ 0.80). The "counter traction" and "flow and planning" categories had high PC scores, which indicate priority in surgical education. Fundamental OHNS skills were verbalized, categorized, and evaluated via expert consensus. Assessment of surgeons' skills by the structured items hereby developed will help standardize the quality of OHNS and improve patient outcomes.


mTOR signaling in disease.
The target of rapamycin (TOR) is a highly conserved serine/threonine kinase and a central controller of cell growth, metabolism and aging. Mammalian TOR (mTOR) is activated in response to nutrients, growth factors and cellular energy. Dysregulated mTOR signaling has been implicated in major disease. Here we review recent findings on the role of mTOR in cancer, metabolic disorders, neurological diseases, and inflammation.


Elimination of PPV and PNRSV through thermotherapy and meristem-tip culture in nectarine.
The plum pox virus (PPV) and prunus necrotic ringspot virus (PNRSV) cause serious disease problems in stone-fruit trees. In this work, the possibility of obtaining plant material free from these viruses through thermotherapy and meristem-tip culture from infected nectarine shoots (Prunus persica var. nectarina Max, cv. 'Arm King') was studied. In addition, the detection of these viruses in in vitro cultures and young acclimatized plantlets with double antibody sandwich-enzyme-linked immunosorbent assay (DAS-ELISA) and multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) was studied. Meristem-tip explants (0.8-1.3 mm) derived from sprouted buds of winter wood and spring shoots from field grown plants had a 2-5% regeneration response. However, application of thermotherapy to potted nectarine trees (3 weeks at a maximum temperature of 35 degrees C) facilitated excision of longer meristem tips (1.3-2.0 mm) that resulted in a significantly higher regeneration response (38%) in woody plant medium (WPM) without plant growth regulators. Such explants formed multiple shoots with the addition of 8 microM benzylaminopurine and 0.8 microM indoleacetic acid. When they were tested for the presence of PPV and PNRSV, 86% and 81% were found to be virus-free as detected by DAS-ELISA and multiplex RT-PCR, respectively. Individual shoots excised from virus-free cultures readily rooted in vitro (half-strength WPM plus 2 microM indolebutyric acid) and grew to plantlets. The combination of an efficient protocol for virus elimination and the establishment of highly sensitive diagnostics resulted in the production of nectarine plants free from PPV and PNRSV.


AFFECT: a prospective, open-label, multicenter trial to evaluate the feasibility and safety of a short-term treatment with subcutaneous certoparin in patients with persistent non-valvular atrial fibrillation.
Patients with persistent atrial fibrillation (AF) scheduled for electrical cardioversion need immediate anticoagulation. Unfractionated heparin (UFH) is often used for early anticoagulation in these patients before oral anticoagulation becomes effective. However, dose adjustment is required to achieve a two- to three-fold prolongation of the activated partial thromboplastin. Low molecular weight heparins, given in body weight-adjusted or independent fixed dosage, require less laboratory monitoring and are also effective within hours of first dosing. They seem to be an attractive alternative to UFH. Previous evidence has shown that these drugs are safe and effective in this indication. In this prospective, open-label, multicenter pilot study, 203 patients were enrolled with persistent non-valvular AF scheduled for electrical cardioversion. Patients received a fixed dose of 8000 U anti-Xa certoparin twice daily starting immediately after enrolment and before cardioversion was performed. Patients with AF > 48 h underwent transoesophageal echocardiography (TEE) before cardioversion to exclude intra-atrial thrombi. After cardioversion, overlapping oral anticoagulation was started. Treatment with certoparin was stopped only after two consecutive days with INR values >2. The objective was to document the feasibility and safety of a short-term treatment with a fixed, body weight-independent certoparin regimen (2 x 8000 U anti-Xa). Out of 203 patients enrolled, 200 received at least one dose of certoparin and were included in the analysis (safety population). Median treatment duration with certoparin was 7 days. Bleedings were observed in 8 patients (4.0%) and were classified as major (1.5%) or minor (2.5%). Cerebral ischemia was reported for 1 patient (0.5%). One patient showed mild thrombocytopenia (0.5%). There were no reports of venous thromboembolism or death during the treatment period. Certoparin administered at 8000 U anti-Xa twice daily independent of body weight was safe and appeared to be effective in patients with non-valvular AF undergoing electrical cardioversion. Its ease of use and the possibility of treatment on an outpatient basis make it an attractive option for early anticoagulation in AF.


Copper perchlorate and tetrafluoridoborate compounds with the ligand 1,4,5-triazanaphthalene. Gradual transformation of mononuclear Cu(II) compounds via polynuclear mixed-valence Cu(II)/Cu(I) species to dinuclear Cu(I); syntheses, characterizations and X-ray structures.
When the ligand 1,4,5-triazanaphthalene (abbreviated as tan) is reacted with Cu(II) BF(4)(-) and ClO(4)(-) salts, a variety of mononuclear compounds has been found, all with the [Cu(tan)(4)] unit and varying amounts of weakly coordinating axial ligands and lattice solvents. Reproducible compounds formed include two purple compounds, analyzing as [Cu(tan)(4)](ClO(4))(2)(CH(3)OH)(2)(H(2)O) (1) and [Cu(tan)(4)](BF(4))(2)(CH(3)OH)(1.5)(H(2)O) (3), and two blue compounds, analyzing as [Cu(tan)(4)](ClO(4))(2)(H(2)O)(2) (2) and [Cu(tan)(4)](2)(BF(4))(2)(H(2)O)(2) (4). Upon standing at room temperature, red-coloured, mixed-valence dinuclear-based 3D coordination polymers are formed by conversion of the purple/blue products, of which [Cu(2)(tan)(4)](n)(BF(4))(3n) (5) and the isomorphic methanol-water adduct [Cu(tan)(4)](n)(BF(4))(3n)(CH(3)OH)(n)(H(2)O)(5n) (5A) are presented in this paper. In addition a fully reduced dinuclear Cu(I) compound of formula [Cu(2)(tan)(3)(ClO(4))(2)] (7) has been observed, and structurally characterized, as a rare three-blade propeller structure, with a Cu-Cu distance of 2.504 Å.


Prevalence and genetic diversity of Theileria equi from horses in Xinjiang Uygur Autonomous region, China.
Theileria equi is a tick-borne intracellular apicomplexan protozoan parasite that causes equine theileriosis (ET). ET is an economically important disease with a worldwide distribution that significantly impacts international horse movement. Horses are an essential part of the economy in Xinjiang which is home to ∼10% of all the horses in China. However, there is very limited information on the prevalence and genetic complexity of T. equi in this region. Blood samples from 302 horses were collected from May to September 2021 in Ili, Xinjiang, and subjected to PCR examination for the presence of T. equi. In addition, a Bayesian latent class model was employed to estimate the true prevalence of T. equi, and a phylogenetic analysis was carried out based on the 18S rRNA gene of T. equi isolates. Seventy-two horses (23.8%) were PCR positive. After accounting for the imperfect PCR test using a Bayesian latent class model, the estimated true prevalence differed considerably between age groups, being 10.8% (95%CrI: 5.8% - 17.9%) in ≤ 3-year-old horses and 35.7% (95%CrI: 28.1% - 44.5%) in horses that were > 3 year-old. All T. equi isolates had their 18S rRNA gene (430bp) sequenced and analyzed in order to identify whether there were multiple genotypes of T. equi in the Xinjiang horse population. All of the 18S rRNA genes clustered into one phylogenetic group, clade E, which is thus probably the dominant genotype of T. equi in Xinjiang, China. To summarize, we monitored the prevalence of T. equi in horses of Xinjiang, China, with a focus on the association between age and the occurrence of T. equi by Bayesian modelling, accompanied by the genotyping of T. equi isolates. Obtaining the information on genotypes and age structure is significant in monitoring the spread of T. equi and studying the factors responsible for the distribution.


Novel birch pollen specific immunotherapy formulation based on contiguous overlapping peptides.
Synthetic contiguous overlapping peptides (COPs) may represent an alternative to allergen extracts or recombinant allergens for allergen specific immunotherapy. In combination, COPs encompass the entire allergen sequence, providing all potential T cell epitopes, while preventing IgE conformational epitopes of the native allergen. Individual COPs were derived from the sequence of Bet v 1, the major allergen of birch pollen, and its known crystal structure, and designed to avoid IgE binding. Three sets of COPs were tested in vitro in competition ELISA and basophil degranulation assays. Their in vivo reactivity was determined by intraperitoneal challenge in rBet v 1 sensitized mice as well as by skin prick tests in volunteers with allergic rhinoconjunctivitis to birch pollen. The combination, named AllerT, of three COPs selected for undetectable IgE binding in competition assays and for the absence of basophil activation in vitro was unable to induce anaphylaxis in sensitized mice in contrast to rBet v 1. In addition no positive reactivity to AllerT was observed in skin prick tests in human volunteers allergic to birch pollen. In contrast, a second set of COPs, AllerT4-T5 displayed some residual IgE binding in competition ELISA and a weak subliminal reactivity to skin prick testing. The hypoallergenicity of contiguous overlapping peptides was confirmed by low, if any, IgE binding activity in vitro, by the absence of basophil activation and the absence of in vivo induction of allergic reactions in mouse and human. ClinicalTrials.gov NCT01719133.


Vascular polyps of ureter associated with megacalycosis and nephrolithiasis.
Multiple benign vascular polyps of the ureter are rare, and the associated congenital megacalycosis and nephrolithiasis are very uncommon. Herein we report a case with vascular polyps of the right ureteropelvic junction dissociated with extensive hydronephrosis which was considered to be megacalycosis. Clinical features and treatment modalities are reviewed.


Cholinergic nerves in the thyroid gland.
The cholinergic innervation of the thyroid gland has been studied in the human. AChE positive nerve fibers are localized in the wall of the thyroid artery, arranged in two plexuses, a superficial (adventitial) and a deep one (medial). The glandular tissue is provided with cholinergic nerve fibers, localized between and around thyroid follicles. The present results suggest that the endocrine activity of the thyroid gland is also under the control of the autonomic nervous system.


Unmanned aerial vehicles (UAVs) with thermal infrared (TIR) sensors are effective for monitoring and counting threatened Vietnamese primates.
Monitoring the population size of threatened primate species with minimal disturbance is becoming an outstanding requirement for conservation and wildlife management. Drones with thermal infrared (TIR) and visible spectrum (RGB) imaging are increasingly used to survey arboreal primates, but ground-truthing is still required to assess the effectiveness of drone-based count estimates. Our pilot study aims to assess the ability of a drone with both TIR and RGB sensors to detect, count, and identify semi-wild population of four endangered species of langurs and gibbon in the Endangered Primate Rescue Center (EPRC) in northern Vietnam. We found that TIR imagery enabled higher detection rates compared to RGB imagery and obtained an accurate count with the TIR only after four drone flights. We could identify langurs species based on thermal signature at a flight height of 50 m from the ground level (max tree height = 15 m), via size and shape of the body. With TIR imagery, we were able to record inconspicuous behaviors such as foraging and play. While some individuals initially showed flight or avoidance behaviors when the drone was sighted, these behaviors decreased or were absent on following drone surveys. Our study suggests that monitoring and precisely counting langur and gibbon species populations could be successful with the use of thermal drones only.


Correlative studies of serum digitalis levels and the arrhythmias of digitalis intoxication.
Correlative studies of serum digoxin levels, cardiac rhythm and related clinical laboratory data were carried out in 114 patients. Seventy-three patients who presented with 79 episodes of arrhythmias typical of digitalis intoxication could be separated into a normokalemic group of 55 patients whose serum digoxin level was 6.68 +/- 0.17 ng/ml (mean +/- standard error of the mean), and a hypokalemic group of 24 with a mean serum digoxin level of 1.13 +/- 0.04 ng/ml (P less than 0.001). Of 45 consectutive normokalemic patients with a high serum digoxin level (more than 2 mg/ml) who underwent serial studies, 17 had arrhythmias. Serial studies in 10 hypokalemic patients revealed an inconsistent relation between presence of arrhythmia and serum digoxin level. During repletion of serum potassium in seven of these patients with an arrhythmia, the arrhythmia disappeared without a significant change in serum digoxin level in four patients. A group of seven patients had 16 episodes of serum digoxin level greater than 2.2 ng/ml, but an arrhythmia occurred during only 3 of these episodes. A sharp border between toxic and therapeutic serum digoxin values was not found in these groups of study patients. The serum digoxin level at which arrhythmias occurred appeared to be variable for both groups and individual patients. However, correlative studies utilizing serum digoxin levels can define existing thresholds for therapeutic and toxic effects and may often be more useful than isolated observations.


Cadmium governance in Europe's phosphate fertilizers: Not so fast?
The European Union has been concerned about cadmium (Cd), because of its toxic nature, since the 1970s. While many anthropogenic sources of Cd were regulated early on at the community level, and most member states later established national limits, Cd content in widely used mineral fertilizers remains uncontrolled across the EU. In 1997, the European Commission first suggested phased Cd limit values in mineral fertilizers as a promising approach to reducing Cd content in soils and harmonising national measures. For over 20 years, however, no harmonised measures have been adopted because confusion remains about the basis for, and level of, such limits. We comment on the latest deadlock over the revision of the Fertilisers Regulation and strengthen assumptions as to why such limits are timely, pertinent, and possible.


Fixation of bilateral acetabular fractures using the modified Stoppa approach: Two-year clinical outcomes.
This study aims to evaluate the two-year clinical results of bilateral acetabular fractures operated via a single incision with the modified Stoppa approach. Between January 2013 and January 2020, a total of 22 acetabular fractures of 11 patients (7 males, 4 females; mean age: was 42.9±13.7 years; range, 19 to 62 years) who were operated via the modified Stoppa approach were retrospectively analyzed. The medical records were analyzed in terms of time to surgery, fracture patterns, Injury Severity Score (ISS), operation duration, blood loss, reduction quality, perioperative complications and concomitant injuries. Reduction quality was assessed according to Matta's criteria. The Harris Hip Score (HHS) and modified Merle d'Aubigne score (MDS) were utilized for functional assessment. The mean follow-up was 49±15 (range, 30 to 79) months. The mean ISS was 28.2±7.2. The mean modified MDS was 15.90±1.57. The mean HHS was 84.27±8.85. For both sides, reduction was anatomical-anatomical (63.6%) in seven patients, anatomical-imperfect in three (27.3%) patients, and imperfectpoor in one (9.1%) patient. According to the Kellgren-Lawrence radiological evaluation at 24 months of follow-up bilaterally, Grade 0-1 osteoarthritis was observed in six (54.5%) patients, Grade 1-1 in four (36.4%) patients, and Grade 1-2 osteoarthritis in one (9.1%) patient. The modified Stoppa approach in bilateral acetabular fractures seems to be more preferable than other approaches, as it can be performed with a single incision and provides less bleeding, shorter operation duration, and satisfactory results.


Direct separation of drug enantiomers by high-performance liquid chromatography with chiral stationary phases.
The development of chiral stationary phases for HPLC has resulted in renewed interest in methods for the separation of drug enantiomers. This paper provides a brief overview of some of the more recent approaches to the direct resolution of drug enantiomers by HPLC with particular emphasis on their quantification in biological fluids.


Potentiation and inhibition by clonidine of PAF-acether-induced human platelet activation.
PAF-acether (platelet-activating factor) and adrenaline synergized to induce aggregation of human platelets in whole blood and in platelet-rich plasma (PRP) irrespective of the use of citrate, of heparin or acid-citrate dextrose (ACD) as anticoagulants, whereas the partial adrenoceptor agonist clonidine imitated adrenaline in a limited number of cases and only when blood was collected in ACD. Whether added to ACD-PRP or ingested by the blood donors, aspirin suppressed the synergic effect of clonidine plus PAF-acether in plasma but failed to block the potentiated aggregation of adrenaline plus PAF-acether. Clonidine alone had no effect on plasma-free platelet suspensions and also failed to synergize with PAF-acether under conditions where the latter's association to adrenaline consistently induced full aggregation. Added before adrenaline or before adrenaline plus PAF-acether, clonidine reduced the aggregation to the level of that due to PAF-acether alone irrespective of cyclooxygenase inhibition with aspirin. The alpha 2-adrenoceptor antagonist yohimbine blocked the synergistic effects of adrenaline or clonidine associated to PAF-acether, reducing aggregation to that due to PAF-acether alone. Clonidine has dual effects on human platelets, since it can imitate adrenaline and synergize with PAF-acether in some subjects, and can also block aggregation induced by adrenaline alone or in combination with PAF-acether.


Resection of inverted papilloma in nasal cavity with transseptal access and crossing multiple incisions minimizes bleeding and reveals the tumor pedicle.
Sinonasal inverted papilloma can be resected endoscopically, but has a risk of recurrence. This risk can be minimized by identifying the pedicle of the tumor and ensuring complete resection. Intraoperative bleeding, particularly from the tumor, decreases endoscopic visualization and contributes to failure to identify the tumor pedicle, and piecemeal resection with dissection of the non-tumoral mucosa makes it impossible to distinguish the tumor pedicle. Previously reported transseptal access with crossing multiple incisions (TACMI) increases mobility of an inverted papilloma within the otherwise restricted nasal cavity. This technique often allows en bloc resection complete with the pedicle and control of bleeding. We retrospectively reviewed our patients who underwent endoscopic resection of inverted papilloma with or without TACMI and compared the operating times, estimated blood loss, and en bloc resection and recurrence rates between the two groups. Thirty-five patients underwent endoscopic resection of inverted papilloma (Krouse stage 2-4) with (n = 23) or without (n = 12) TACMI. The operating time was longer in the TACMI group (218±68 min) than in the non-TACMI group (129±33 min). Estimated blood loss was less in the TACMI group (72±103 mL vs. 120±136.5 mL) but this finding was not significant. En bloc resection was achieved in 19 patients (83%) in the TACMI group but not in any patient in the non-TACMI group. There were no recurrences in the TACMI group. Multivariate analysis showed significant relationships between estimated amount of blood loss and operating time according to Krouse stage and whether or not TACMI was performed. Endoscopic resection of inverted papilloma with TACMI may achieve better treatment results with less blood loss.


Quantum mechanics and 3D-QSAR studies on thienopyridine analogues: inhibitors of IKKβ.
Inhibitor of kappa B kinase subunit β (IKKβ) is a main regulator of nuclear factor kappa B (NF-κB) and has received considerable attention as an attractive therapeutic target for the treatment of lung cancer or other inflammatory disease. A group of diversified thienopyridine derivatives exhibited a wide range of biological activity was used to investigate its structural requirements by using DFT and 3D-Quantitative structure activity relationship. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were established using the experimental activity of thienopyridine derivatives. The cross-validation coefficient (q2) values for CoMFA and CoMSIA are 0.671 and 0.647 respectively, were achieved, demonstrating high predictive capability of the model. The contour analysis indicate that presence of hydrophobic and electrostatic field is highly desirable for biological activity. The results indicate that substitution of hydrophobic group with electron withdrawing effect at R4 and R6 position have more possibility to increase the biological activity of thienopyridine derivatives. Subsequently molecular docking and DFT calculation were performed to assess the potency of the compounds.


Specifications of the ACMG/AMP guidelines for ACADVL variant interpretation.
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is a relatively common inborn error of metabolism, but due to difficulty in accurately predicting affected status through newborn screening, molecular confirmation of the causative variants by sequencing of the ACADVL gene is necessary. Although the ACMG/AMP guidelines have helped standardize variant classification, ACADVL variant classification remains disparate due to a phenotype that can be nonspecific, the possibility of variants that produce late-onset disease, and relatively high carrier frequency, amongst other challenges. Therefore, an ACADVL-specific variant curation expert panel (VCEP) was created to facilitate the specification of the ACMG/AMP guidelines for VLCADD. We expect these guidelines to help streamline, increase concordance, and expedite the classification of ACADVL variants.


A comparative prospective randomized clinical study of MTA and IRM as root-end filling materials in single-rooted teeth in endodontic surgery.
Randomized clinical prospective study to evaluate the application of MTA and IRM as retrograde sealers in surgical endodontics. One hundred single-rooted teeth were surgically treated. After randomization, MTA or IRM was used as a retrosealer. Radiographs were taken 1 week, 3 months, and 1 year postoperatively. Assessment was performed by 2 independent assessors 1 year after surgery. Both treatment groups were homogeneous in their composition, and clinical features and radiographic findings were classified according to Rud's classification. Complete healing was observed in 64% of the MTA-treated teeth vs 50% of the IRM-treated teeth. Incomplete healing was seen in 28% (MTA) vs 36% (IRM), and unsatisfactory in 6% (MTA) vs 14% (IRM). Only 1 failure was seen (MTA). No statistically significant differences were found between the 2 retrofilling materials. As root-end filling materials in this clinical prospective randomized design on single rooted teeth, MTA and IRM had the same clinical effectiveness.


Nitric oxide synthase inhibition attenuates phencyclidine-induced disruption of cognitive flexibility.
Schizophrenia encompasses, amongst other symptoms, a heavy load of cognitive dysfunctionality. Using the psychotomimetic agent, phencyclidine (PCP), we have previously found that PCP-induced disruptions of cognitive function in translational rodent models of schizophrenia are dependent on nitric oxide (NO) production. In the present study, male Sprague-Dawley rats were subjected to a Morris water maze task designed to assess cognitive flexibility (i.e. the ability to cope with an increasingly demanding cognitive task) by means of a "constant reversal learning paradigm". Experiments were conducted to evaluate the effects of the NO synthase inhibitor, L-NAME (10 mg/kg), on PCP-induced (2 mg/kg) impairments. Control animals significantly improved their learning over the first 3 consecutive days, whereas PCP-treated animals failed to show any significant learning. Pretreatment with L-NAME normalized the PCP-induced disruption of learning to control levels. These findings suggest that PCP-induced disruptions of cognitive flexibility (i.e. ability to modify behaviour according to an increasingly demanding cognitive task) are dependent upon NO production. These observations, together with accumulated clinical findings, suggest that the NO system is a potential treatment target for cognitive dysfunctions in schizophrenia.


Determination of ceftazidime in plasma using high-performance liquid chromatography and electrochemical detection. Application for individualizing dosage regimens in elderly patients.
This study describes a sensitive HPLC-electrochemical detection method for the analysis of ceftazidime, a third-generation cephalosporin, in human plasma. The extraction procedure involved protein precipitation with 30% trichloroacetic acid. The separation was achieved on a reversed-phase column (250X4.6 mm I.D., 5 microm) packed with C18 Kromasil with isocratic elution and a mobile phase consisting of acetonitrile-25 mM KH2PO4-Na2HPO4 buffer, pH 7.4 (10:90, v/v). The proposed analytical method is selective, reproducible and reliable. The assay has a precision of 0.2-15.1% (C.V.) in the range of 5-200 microg mil(-1). (corresponding to 0.5 to 20 ng of ceftazidime injected onto the column), and is optimised for assaying 50 microl of plasma. The extraction recovery from plasma was approximately 100%. The method was highly specific for ceftazidime and there was no interference from either commonly administered drugs or endogenous compounds. This assay was used to measure ceftazidime in elderly patients for therapeutic drug monitoring.


Acute microwave injury to the hand.
An acute microwave oven burn injury to the hand resulting in second- and third-degree burns to the left long finger is presented. Excision and coverage using a cross-finger flap resulted in full return of function. Because of the difficulty in evaluating the extent of tissue necrosis, we recommend hospitalization for most microwave injuries where obvious soft tissue damage has been sustained.


Intratracheal dopamine attenuates pulmonary edema and improves survival after ventilator-induced lung injury in rats.
Clearance of alveolar oedema depends on active transport of sodium across the alveolar-epithelial barrier. beta-Adrenergic agonists increase clearance of pulmonary oedema, but it has not been established whether beta-agonist stimulation achieves sufficient oedema clearance to improve survival in animals. The objective of this study was to determine whether the increased pulmonary oedema clearance produced by intratracheal dopamine improves the survival of rats after mechanical ventilation with high tidal volume (HVT). This was a randomized, controlled, experimental study. One hundred and thirty-two Wistar-Kyoto rats, weighing 250 to 300 g, were anaesthetized and cannulated via endotracheal tube. Pulmonary oedema was induced by endotracheal instillation of saline solution and mechanical ventilation with HVT. Two types of experiment were carried out. The first was an analysis of pulmonary oedema conducted in six groups of 10 rats ventilated with low (8 ml/kg) or high (25 ml/kg) tidal volume for 30 or 60 minutes with or without intratracheally instilled dopamine. At the end of the experiment the animals were exsanguinated and pulmonary oedema analysis performed. The second experiment was a survival analysis, which was conducted in two groups of 36 animals ventilated with HVT for 60 minutes with or without intratracheal dopamine; survival of the animals was monitored for up to 7 days after extubation. In animals ventilated at HVT with or without intratracheal dopamine, oxygen saturation deteriorated over time and was significantly higher at 30 minutes than at 60 minutes. After 60 minutes, a lower wet weight/dry weight ratio was observed in rats ventilated with HVT and instilled with dopamine than in rats ventilated with HVT without dopamine (3.9 +/- 0.27 versus 4.9 +/- 0.29; P = 0.014). Survival was significantly (P = 0.013) higher in animals receiving intratracheal dopamine and ventilated with HVT, especially at 15 minutes after extubation, when 11 of the 36 animals in the HVT group had died as compared with only one out of the 36 animals in the HVT plus dopamine group. Intratracheal dopamine instillation increased pulmonary oedema clearance in rats ventilated with HVT, and this greater clearance was associated with improved survival.


Polymer folding through active processes recreates features of genome organization.
From proteins to chromosomes, polymers fold into specific conformations that control their biological function. Polymer folding has long been studied with equilibrium thermodynamics, yet intracellular organization and regulation involve energy-consuming, active processes. Signatures of activity have been measured in the context of chromatin motion, which shows spatial correlations and enhanced subdiffusion only in the presence of adenosine triphosphate. Moreover, chromatin motion varies with genomic coordinate, pointing toward a heterogeneous pattern of active processes along the sequence. How do such patterns of activity affect the conformation of a polymer such as chromatin? We address this question by combining analytical theory and simulations to study a polymer subjected to sequence-dependent correlated active forces. Our analysis shows that a local increase in activity (larger active forces) can cause the polymer backbone to bend and expand, while less active segments straighten out and condense. Our simulations further predict that modest activity differences can drive compartmentalization of the polymer consistent with the patterns observed in chromosome conformation capture experiments. Moreover, segments of the polymer that show correlated active (sub)diffusion attract each other through effective long-ranged harmonic interactions, whereas anticorrelations lead to effective repulsions. Thus, our theory offers nonequilibrium mechanisms for forming genomic compartments, which cannot be distinguished from affinity-based folding using structural data alone. As a first step toward exploring whether active mechanisms contribute to shaping genome conformations, we discuss a data-driven approach.


Suitability of nanoparticles for gamma-ray applications.
While measuring the relative gamma-to-electron conversion efficiencies of nanoparticles by incorporating them into plastic scintillator and comparing the number of counts in pulse height spectrum for gamma-rays from 241Am, WO3, and PbO nanocomposites offered lesser scintillation counts than their unloaded counterparts. As investigated, these nanoparticles absorb a major portion of outgoing electron energy such that exiting electrons turn incapable of scintillating the medium. This observation hints why only selected species of nanoparticles successfully enhance the gamma-counting efficiency of plastic scintillators.


Analysis and use of the serum albumin binding domains of streptococcal protein G.
Streptococcal protein G is an IgG-binding receptor with a molecular weight of 63 kDa as predicted from the sequence of the corresponding gene. Here we show that a truncated recombinant protein of 23 kDa still has IgG-binding capacity and also interacts specifically with human serum albumin (HSA). This demonstrates that protein G is a bifunctional receptor. To investigate the structures needed for IgG- and albumin-binding, different parts of the receptor molecule were produced in E. coli using a coupled expression/secretion system. Affinity chromatography, using IgG or HSA immobilized on Sepharose, showed that the two binding activities are structurally separated. From these experiments, it was concluded that a region of 64 amino acid residues is sufficient for albumin-binding. The structure of this part of the protein suggests either a divalent or a trivalent binding capacity. The specific interaction to albumin was used to purify a heterologous protein by affinity chromatography to yield a pure fusion protein in a one-step procedure. The implication of this novel affinity system as a tool to facilitate protein immobilization and purification is discussed.


Cochlear implantation has a positive influence on quality of life, tinnitus, and psychological comorbidity.
To determine the effect of cochlear implantation (CI) on health-related quality of life (HRQoL), tinnitus, and psychological comorbidity in patients with severe to profound postlingual hearing loss and to analyze the relationship between these parameters. Prospective study. Using six validated questionnaires, we evaluated the pre-CI and post-CI scores of HRQoL, tinnitus, perceived stress, symptoms of depression and anxiety, and coping strategies in 43 patients implanted unilaterally with a multichannel implant for at least 6 months. In addition to improvements in hearing, speech understanding, and disease-specific HRQoL, psychological comorbidity was reduced and coping strategies were improved following CI. In the 39 tinnitus patients, their tinnitus was reduced. We found negative correlations between HRQoL and stress, depression, and anxiety. Pre-CI, tinnitus severity did not correlate with HRQoL and psychological comorbidity. However, patients with a high-level tinnitus had lower HRQoL as well as a higher level of perceived stress and anxiety symptoms than patients with a low-level tinnitus and no/incidental tinnitus before CI. Moreover, patients with severe hearing loss had a higher level of perceived symptoms of stress and depression than patients with profound hearing loss before CI. The present study provides evidence that tinnitus and psychological comorbidity may play an important role in the rehabilitation of CI patients, and that there is a correlation between HRQoL and these parameters. In addition to hearing tests, tinnitus, stress, and psychological comorbidity should be assessed using validated questionnaires before and after CI. This will help to improve the rehabilitation process.