Assessment of drinking water fortification with iron plus ascorbic Acid or ascorbic Acid alone in daycare centers as a strategy to control iron-deficiency anemia and iron deficiency: a randomized blind clinical study.
Assess drinking water fortification with iron and/or ascorbic acid as a strategy to control iron-deficiency anemia and iron deficiency. Randomized blind clinical study, fortifying drinking water to 153 pre-school children during 3 months, with iron and ascorbic acid (A), ascorbic acid (B) or plain water (C). Hemoglobin (Hb), mean corpuscular volume (MCV) and ferritin were measured. Within the groups, Hb raised in all three groups, MCV in A and B and ferritin in A. The difference between time points 0 and 1 was significant between A and B for Hb, when A and B were compared with C for MCV and when A was compared with either B or C for ferritin. Water fortification is efficient in controlling iron deficiency and anemia. Iron stores' recovery depends on a more effective offer of iron. Water fortification must be preceded by a careful assessment of the previous nutritional status.


Cloning and expression of retinoblastoma-binding protein 4 gene in embryo diapause termination and in response to salinity stress from brine shrimp Artemia sinica.
Retinoblastoma binding protein 4 (RBBP4) is a nuclear protein with four WD-repeat sequences and thus belongs to a highly conserved subfamily of proteins with such domains. This retinoblastoma-binding protein plays an important role in nucleosome assembly and histone modification, which influences gene transcription and regulates cell cycle and proliferation. Artemia sinica (brine shrimp) undergoes an unusual diapause process under stress conditions of high salinity and low temperature. However, the role of RBBP4 in diapause termination of embryo development in A. sinica remains unknown. Here, the full-length cDNA of the As-rbbp4 gene was obtained from A. sinica and found to contain 1411 nucleotides, including a 1281 bp open reading frame (ORF), 63 bp 5'-untranslated region (UTR) and a 67-bp 3'-UTR, which encodes a 427 amino acid (48 kDa) protein. Bioinformatic analysis indicated As-RBBP4 to be mainly located in the nucleus, with a theoretical isoelectric point of 4.79. Protein sequence domain analysis showed that As-RBBP4 is a conserved protein, especially in the WD40 domain. No specificity in expression of this gene was observed in tissues or organs by in situ hybridization. Real-time quantitative PCR and Western blot analyses of As-RBBP4 gene and protein expression, respectively, showed notably high levels at 10 h and a subsequent downward trend. Obvious trends in upregulation of As-RBBP4 were observed under conditions of low temperature and high salinity stress. As-E2F1 and As-CyclinE also presented similar trends as that of As-RBBP4 in Western blots. Analysis of the RBBP4 expression in early embryonic development of A. sinica indicated that this protein plays an important role in diapause termination and cell cycle regulation.


Pharmacokinetics and Bioequivalence of 2 Oral Formulations of Domperidone After Single-Dose Administration in Healthy Chinese Subjects.
To evaluate the pharmacokinetic properties and bioequivalence of 2 oral formulations of domperidone in healthy Chinese subjects, a randomized, open-label, 2-way crossover study was conducted under fasting and fed states. All 96 healthy subjects were randomized to receive a single oral dose of a 10-mg generic domperidone tablet (test) or branded domperidone tablet (reference). Blood samples were collected at specified time intervals and analyzed for domperidone using liquid chromatography-tandem mass spectrometry. In the fasting test, 90% CIs of geometric mean ratios were 86.7% to 105.8% for maximum concentration, 96.7% to 106.1% for area under the concentration-time curve (AUC) from time 0 to the time of the last measurable plasma concentration, and 97.1% to 106.1% for AUC from time 0 extrapolated to infinity. In the fed test, the 90% CIs were 90.8% to 121.1%, 99.7% to 109.4%, and 99.4% to 109.1%, respectively. All 90% CIs were within the bioequivalence range of 80% to 125%, indicating that the 2 formulations were bioequivalent. In addition, the values of time to maximum concentration, terminal-phase elimination half-life, and AUC were significantly higher in the fed group than in the fasting group, suggesting that a high-fat meal slowed down the absorption and elimination of domperidone and significantly increased domperidone exposure.


Safety, efficacy and repeatability of a novel house dust mite allergen challenge technique in the Fraunhofer allergen challenge chamber.
Efficacy testing of immunotherapy in field studies is often hampered by variation of airborne allergens. Standardized allergen exposure in challenge chamber settings might be an alternative. Therefore, we developed a universal technique to create an atmosphere loaded with allergen particles of adjustable size from aqueous solutions of licensed allergen extracts. The aim of this study was to apply this technique and test the safety and efficacy of challenges with house dust mite (HDM) allergen in the Fraunhofer allergen challenge chamber. Aerosol particles carrying HDM allergen were produced by spray-drying of an aqueous solution containing HDM allergen and lactose. In a monocenter, placebo-controlled, single-blind, dose-escalation pilot study, 18 subjects with perennial allergic rhinitis and sensitization to HDM were exposed to HDM allergen for 4 h at either 250, 500, 1000 SQE/m3 or lactose alone (0 SQE/m3 ) 7 days apart. The dose of 500 SQE/m³ was repeated to investigate reproducibility. Total nasal symptom score (TNSS) was the primary endpoint. Exposure to HDM increased TNSS (mean ± SD) to 3.4 ± 1.8, 3.3 ± 2.1, and 3.6 ± 2.0 at 250, 500 and 1000 SQE/m3 , respectively, while lactose alone did not change TNSS (0.7 ± 0.6). The results were reproducible at 500 SQE/m3 . Pulmonary function and adverse event frequency did not change with escalation of allergen dose. This HDM allergen particle generation is safe, specific and reproducible and can therefore be used for efficacy testing of immunotherapy and for basic clinical research.


Breast Cancer Screening in Patients With Newly Diagnosed Lung and Colorectal Cancer: A Population-Based Study of Utilization.
To assess breast cancer screening utilization in Medicare beneficiaries with colorectal and lung cancer versus cancer-free controls. Female fee-for-service Medicare beneficiaries who were ≥67 years old and diagnosed with lung or colorectal cancer between 2000 and 2011 and who reported to a Surveillance, Epidemiology, and End Results (SEER) registry (case group) were followed for 2 years after their diagnoses, unless death, a diagnosis of breast cancer, or the end of 2013 came first. A similar number of cancer-free controls were individually matched to cases by age, race, registry region, and follow-up time. Screening utilization was defined as the percentage of women with ≥1 screening mammogram during follow-up. Overall, 104,164 cases (48% colorectal, 52% lung; 30% advanced cancer) and 104,164 controls were included. Among women with lung or colorectal cancer, 22% underwent ≥1 screening mammogram versus 26% of controls (odds ratio [OR] 0.80; 95% confidence interval [CI] 0.78-0.82). Stratified by cancer type, 28% of colorectal cancer cases versus 29% of controls (OR 0.98; 95% CI 0.95-1.01) and 17% of lung cancer cases versus 23% of controls (OR 0.63; 95% CI 0.60-0.65) received ≥1 mammogram. When stratified by stage, 8% with advanced cancer versus 18% of controls (OR 0.33; 95% CI 0.31-0.35) and 30% with early-stage cancer versus 30% of controls (OR 1; 95% CI 0.97-1.02) underwent ≥1 mammogram. Screening mammography utilization rates are similar between Medicare beneficiaries with early-stage cancer versus controls. Although the majority of patients with advanced-stage cancer appropriately do not pursue screening mammography, a small number (8%) continue with screening.


Role of cytoskeletal elements in cytochalasin E-induced superoxide production by human polymorphonuclear leukocytes.
The release of superoxide anions from human polymorphonuclear leukocytes induced by cytochalasin E was greatly enhanced by the pretreatment of the cells either with deuterium oxide or with concanavalin A. Colchicine, vinblastine and cyclic AMP inhibited the release. Cytochalasins A and B also suppressed the superoxide release. These observations suggest the involvement of microfilament-microtubule system in the production and release of superoxide anions induced by cytochalasin E.


State-dependent capital and income breeding: a novel approach to evaluating individual strategies with stable isotopes.
Species-specific strategies for financing the costs of reproduction are well understood, forming a continuum ranging from high to low reliance on stored nutrients. Animals relying mostly on stored reserves are termed 'capital breeders', whereas 'income breeders' rely mostly on concurrent intake when financing the costs of reproduction. The role and adaptive value of individual variation in these strategies remain elusive. Life-history theory posits that capital breeding should be favoured when offspring reproductive value peaks, typically occurring early in the season, and that current income should increasingly be used with progressing season. Because resource limitation may hamper flexible resource allocation, a corollary prediction is that only good-condition individuals may show the expected seasonal shift in resource use. To test this prediction, we examined stable isotopes (δ(13)C and δ(15)N) in blood and lipid-free egg yolk of breeding eider females (Somateria mollissima) from the Baltic Sea to assess the role of individual variation in the use of proteins from local diet vs. stored reserves. We show for the first time that individuals from a single population differ in their utilization of stored reserves and concurrent intake to finance the costs of reproduction. Consistent with our prediction, heavy females predominantly used stored reserves for producing egg yolks early in the season, increasingly relying on local feeding with later onset of breeding, whereas light females showed no seasonal change in allocation strategy. Stable isotope profiling at the individual level is a powerful tool for monitoring relative changes in investment strategies through time, showing promise as an early warning indicator of ecological change in food webs.


The impact of different alignment strategies on bone cuts for neutral knee phenotypes in total knee arthroplasty.
The purpose of this study was to simulate and visualise the influence of the alignment strategy on bone resection in neutral knee phenotypes. It was hypothesised that different amounts of bone resection would be required depending on the alignment strategy chosen. The hypothesis was that by visualising the corresponding bone cuts, it would be possible to assess which of the different alignment strategies required the least change to the soft tissues for the chosen phenotype but still ensured acceptable component alignment and could, therefore, be considered the most ideal alignment strategy. Simulations of the different alignment strategies (mechanical, anatomical, restricted kinematic and unrestricted kinematic) regarding their bone resections were performed on four common exemplary neutral knee phenotypes. NEUHKA0° VARFMA 90° VALTMA90°, NEUHKA0° NEUFMA 93° NEUTMA87°, NEUHKA0° VALFMA 96° NEUTMA87° and NEUHKA0° VALFMA 99° VARTMA84°. The phenotype system used categorises knees based on overall limb alignment (i.e. hip knee angle) but also considers joint line obliquity (i.e. TKA and FMA) and has been used globally since its introduction in 2019. These simulations are based on long leg weightbearing radiographs. It is assumed that a change of 1° in the alignment of the joint line corresponds to correspond to 1 mm of distal condyle offset. In the most common neutral phenotype NEUHKA0° NEUFMA 93° NEUTMA87°, with a prevalence of 30%, bone cuts remain below 4 mm regardless of alignment strategy. The greatest changes in the obliquity of the joint line can be expected for the mechanical alignment of the phenotype NEUHKA0° VALFMA 99° VARTMA84° where the medial tibia is raised by 6 mm and the lateral femur is shifted distally by 9 mm. In contrast, the NEUHKA0° VARFMA 90° VALTMA90° phenotype requires no change in joint line obliquity if the mechanical alignment strategy is used. Illustrations of alignment strategies help the treating surgeon to estimate the postoperative joint line obliquity. When considering the alignment strategy, it seems reasonable to prefer a strategy where the joint line obliquity is changed as little as possible. Although for the most common neutral knee phenotype the choice of alignment strategy seems to be of negligible importance, in general, even for neutral phenotypes, large differences in bone cuts can be observed depending on the choice of alignment strategy.


A potential prognostic marker in primitive lung neuroendocrine tumor: A case report.
The diagnosis and monitoring of primitive lung neuroendocrine tumors (lung pNETs) are usually performed by the measurement of serum chromogranin A (CgA) and urinary 5-hydroxyindolacetic acid (5-HIAA) levels. However, imaging techniques are necessary due to the poor diagnostic efficiency of the laboratory tests. A total-body computed tomography and bone scintigraphy scans showed multiple hepatic and bone metastases of a 55-year-old man affected by well-differentiated lung pNETs without severe initial symptoms. After diagnosis, he started therapy and was monitored with serum, urinary markers, and imaging techniques. During follow-up, the urinary 5-HIAA levels did not significantly increase, while serum CgA and urinary para-hydroxyphenylacetic acid (pHPAA) levels (urinary organic acid physiologically present in the urines of healthy subjects) showed significant increases related to worsening clinical condition. The early increase in urinary pHPAA levels-usually not dosed in pNET patient monitoring-could be a promising prognostic marker.


Transacromial approach to obtain fusion of unstable os acromiale.
The purpose of this study was to identify possible causes for the low union rate for surgically stabilized os acromiale. Between February 1990 and November 1995, fusion of an os acromiale was attempted in 15 shoulders in 12 patients at our institution. All patients were men. The mean age was 54 years (range 37 to 63 years). All shoulders had an os mesoacromiale considered too large for simple resection. An associated lesion of the rotator cuff ranging from partial-to full-thickness tear was present in all patients. Eleven had an unfused acromial epiphysis in both shoulders. Two different surgical approaches were used. Seven shoulders were approached through an anterior deltoid-off approach, thus potentially devascularizing the os acromiale. Eight shoulders were approached transacromially, preserving the deltoid origin and hence the terminal branches of the thoracoacromial artery. The technique of internal fixation (tension band wiring) was the same for both groups. The mean follow-up was 44 months (range 13 to 72 months). Union, as demonstrated by axial radiographic views, occurred in 3 out of 7 cases with a devascularized os acromiale and in 7 out of 8 shoulders with a perfused os acromiale (P = .017), respectively. Patients with a united os acromiale had a significantly better functional outcome as measured by the Constant score (P = .0169). In conclusion, aiming at a stable fusion of a sizable and hypermobile os acromiale is probably desirable because it enhances the overall functional result. Obtaining consolidation was possible when the vascularity of the acromial epiphysis was respected.


Alterations in CRY2 and PER3 gene expression associated with thalamic-limbic community structural abnormalities in patients with bipolar depression or unipolar depression.
Objectives The current study aimed to identify shared and distinct brain structure abnormalities and their relationships with the expression of circadian genes in patients with bipolar or unipolar depression. Method A total of 93 subjects participated in this study, including 32 patients with bipolar depression (BDP), 26 patients with unipolar depression (UDP) and 35 age- and sex-matched healthy controls. Brain structural magnetic resonance imaging scans were obtained, and optimized voxel-based morphometry was used to explore group differences in regional gray matter volume (GMV). The mRNA expression levels of circadian genes in peripheral blood were measured using reverse transcription quantitative real-time polymerase chain reaction. Results Our results showed that the GMV in brain regions in the thalamus-limbic pathways had significantly increased in the BDP patients compared to controls, while the increased GMV in UDP patients compared to controls was limited to the thalamus. The mRNA expression levels of circadian-related genes decreased significantly in patients with BDP, but increased in patients with UDP, compared to controls. In addition, the GMV in the right thalamus in the patients with UDP was positively associated with mRNA levels of CRY2, while the GMV in the right hippocampus in the patients with BDP was negatively associated with mRNA levels of PER3. Conclusion Our study suggested that patients with BDP or MDD shared GMV abnormalities in the right thalamus. The PER3 and CRY2 genes might be critical to right hippocampal dysfunction in BDP and right thalamic dysfunction in UDP, respectively. The result provided potentially important molecular targets for the treatment of mood disorders.


Cytomegalovirus-related Complications and Management in Facial Vascularized Composite Allotransplantation: An International Multicenter Retrospective Cohort Study.
There is a paucity of data on the impact of cytomegalovirus (CMV) serostatus and CMV infection on outcomes in facial vascularized composite allotransplantation. This international, multicenter, retrospective cohort study presents data on CMV and basic transplant-related demographics, including pretransplant viral D/R serostatus, and duration of antiviral prophylaxis. CMV-related complications (viremia, disease), allograft-related complications (rejection episodes, loss), and mortality were analyzed. We included 19 patients, 4 of whom received CMV high-risk transplants (D+/R-). CMV viremia was noted in 6 patients (all 4 D+/R- patients and 2 D-/R+), mostly within the first-year posttransplant, shortly after discontinuation of antiviral prophylaxis (median 2 mo). CMV disease occurred in 2 D+/R- patients. The high-risk group experienced relatively more rejection episodes per month follow-up. None of D+/R- patients suffered allograft loss due to rejection (longest follow-up: 121 mo). D+/R- patients were at increased risk of CMV-related complications. Although a higher number of rejections was noted in this group, none of the D+/R- patients lost their allograft or died because of CMV or rejection. Thus, CMV D+/R- face transplantation can likely be safely performed with prophylaxis, active surveillance, and prompt treatment.


Interaction of HydSL hydrogenase from Thiocapsa roseopersicina with cyanide leads to destruction of iron-sulfur clusters.
The effects of cyanide on enzymatic activity and absorption spectra in the visible and mid-IR (2150-1850cm-1) regions were characterized for purified HydSL hydrogenase from the purple sulfur bacterium Thiocapsa (T.) roseopersicina BBS. Prolonged incubation (over hours) of T. roseopersicina hydrogenase with exogenous cyanide was shown to result in an irreversible loss of activity of the enzyme in both the oxidized (as isolated) and H2-reduced states. The frequency position of the active site CO and CN- ligand stretching bands in the Fourier transform infrared (FTIR) spectrum of the oxidized form of hydrogenase was not influenced by cyanide treatment. The 410-nm absorption band characteristic of hydrogenase iron‑sulfur clusters showed a bleaching concomitantly with cyanide inactivation. A new band at 2038cm-1 was present in the FTIR spectrum of the cyanide-inactivated preparation, which band is assignable to ferrocyanide as a possible product of a destructive interaction of hydrogenase with cyanide. The results are interpreted in terms of a slow destruction of iron‑sulfur clusters of hydrogenase in the presence of cyanide accompanied by a release of iron ions in the form of ferrocyanide into the surrounding solution. Such a slow and irreversible cyanide-dependent inactivation seems to be complementary to a recently described rapid, reversible inhibitory reaction of cyanide with the active site of hydrogenases [S.V. Hexter, M.-W. Chung, K.A. Vincent, F.A. Armstrong, J. Am. Chem. Soc. 136 (2014) 10470-10477].


Tolerability and dose proportional pharmacokinetics of pasireotide administered as a single dose or two divided doses in healthy male volunteers: a single-center, open-label, ascending-dose study.
Pasireotide is a multireceptor-targeted somatostatin analogue with high binding affinity for somatostatin receptor subtypes SST 1, 2, 3, and 5. To evaluate the safety profile, tolerability, and pharmacokinetic profile of pasireotide in single- and divided-dose regimens in healthy volunteers. A single-center, open-label, ascending-dose study was performed in healthy volunteers. Pasireotide, 900, 1200, and 1500 μg SC, was administered as either a single dose or as two divided doses given 12 hours apart, with a 7-day washout period between treatments. Seventeen men (median age, 26 years) were enrolled. Their median weight was 81 kg, and 65% were white. One participant dropped out because of a grade 2 adverse event; most other adverse events were mild and affected the gastrointestinal tract. Blood glucose concentration increased after pasireotide administration, but returned to normal within 10 hours. After single-dose administration, pasireotide plasma concentration peaked rapidly at 15 minutes to 1 hour after dosing, followed by a tri-exponential (α, β, and γ phases) decline over time. Mean t(½) values during the α, β, and γ phases were approximately 2 to 3, 12 to 17, and 54 to 97 hours, respectively. In the single-dose cohort, the mean (SD) AUC(∞) was 110 (29), 149 (42), and 188 (52) h · ng/mL in the 900-, 1200-, and 1500-μg groups, respectively. Time to reach C(max) was 0.69 (0.41), 0.59 (0.38), and 0.56 (0.18) hours in the 900-, 1200-, and 1500-μg groups, respectively. AUC(∞) values were similar in the single-dose and divided-dose cohorts. Mean total body clearance was 8 to 9 L/h across the dosage groups and dosing regimens, indicating a linear pharmacokinetic profile between doses. When administered as a single- or divided-dose regimen, pasireotide had a favorable tolerability profile in this selected group of healthy male volunteers. Its pharmacokinetic profile indicated rapid absorption, low clearance, high volume of distribution, and a long terminal half-life.


Prioritization of realignment associated with superior clinical outcomes for surgical cervical deformity patients.
To optimize quality of life in patients with cervical deformity (CD), there may be alignment targets to be prioritized. To prioritize the cervical parameter targets for alignment. Included: CD patients (C2-C7 Cobb >10°°, C2-C7 lordosis [CL] >10°°, cSVA > 4 cm, or chin-brow vertical angle >25°°) with full baseline (BL) and 1-year (1Y) radiographic parameters and Neck Disability Index (NDI) scores; patients with cervical (C) or cervicothoracic (CT) Primary Driver Ames type. Patients with BL Ames classified as low CD for both parameters of cSVA (<4 cm) and T1 slope minus CL (TS-CL) (<15°°) were excluded. Patients assessed: Meeting Minimal Clinically Important Difference (MCID) for NDI (<-15 ΔNDI). Ratios of correction were found for regional parameters categorized by Primary Ames Driver (C or CT). Decision tree analysis assessed cut-offs for differences associated with meeting NDI MCID at 1Y. Seventy-seven CD patients (62.1 years, 64%F, 28.8 kg/m2). 41.6% met MCID for NDI. A backward linear regression model including radiographic differences as predictors from BL to 1Y for meeting MCID for NDI demonstrated an R 2= 0.820 (P = 0.032) included TS-CL, cSVA, MGS, C2SS, C2-T3 angle, C2-T3 sagittal vertical axis (SVA), CL. By primary Ames driver, 67.5% of patients were C, and 32.5% CT. Ratios of change in predictors for MCID NDI patients for C and CT were not significant between the two groups (P > 0.050). Decision tree analysis determined cut-offs for radiographic change, prioritizing in the following order: ≥42.5° C2-T3 angle, >35.4° CL, <-31.76° C2 slope, <-11.57 mm cSVA, <-2.16° MGS, >-30.8 mm C2-T3 SVA, and ≤-33.6° TS-CL. Certain ratios of correction of cervical parameters contribute to improving neck disability. Prioritizing these radiographic alignment parameters may help optimize patient-reported outcomes for patients undergoing CD surgery.


Sequence alterations in the YBX2 gene are associated with male factor infertility.
To investigate YBX2 gene alterations in men with severe defects in spermatogenesis, including azoospermia or severe oligozoospermia, and protamine deregulation. MSY2 has been identified as a central component in the regulation of spermatogenesis in mice, but the potential role of its human orthologue, YBX2 or "Contrin," in human infertility is not known. A prospective cohort study. University infertility clinic and associated research laboratory. A total of 288 men were evaluated. Diagnoses were made of complete azoospermia, severe oligozoospermia, and protamine deregulation, or men were of known paternity. Deoxyribonucleic acid (from peripheral blood) and semen samples were collected and analyzed for gene mutations and semen parameters respectively. YBX2 gene alterations. YBX2 sequence analysis revealed 15 polymorphic sites, of which seven polymorphisms were present at a statistically higher frequency in one or both of the patient populations than in controls. Of these seven, two resulted in an amino acid substitution in the highly conserved cold shock domain and one resulted in a highly significant synonymous change in exon 8 of infertile patients. The frequency of single nucleotide polymorphisms was significantly elevated in patients with infertility, particularly in men with abnormal protamine expression. These data indicate a significant association between gene alterations in the YBX2 gene and abnormal spermatogenesis in humans, including a potential role in altering protamine expression, and implicate YBX2 gene alterations as a potential cause of male factor infertility.


Salmonella invasion of a cell is self-limiting due to effector-driven activation of N-WASP.
Salmonella Typhimurium drives uptake into non-phagocytic host cells by injecting effector proteins that reorganize the actin cytoskeleton. The host actin regulator N-WASP has been implicated in bacterial entry, but its precise role is not clear. We demonstrate that Cdc42-dependent N-WASP activation, instigated by the Cdc42-activating effector SopE2, strongly impedes Salmonella uptake into host cells. This inhibitory pathway is predominant later in invasion, with the ubiquitin ligase activity of the effector SopA specifically interfering with negative Cdc42-N-WASP signaling at early stages. The cell therefore transitions from being susceptible to invasion, into a state almost completely recalcitrant to bacterial uptake, providing a mechanism to limit the number of internalized Salmonella. Our work raises the possibility that Cdc42-N-WASP, known to be activated by numerous bacterial and viral species during infection and commonly assumed to promote pathogen uptake, is used to limit the entry of multiple pathogens.


Facilitators and barriers to clinicians' use of COPD action plans in self-management support: A qualitative study.
Written action plans for patients with chronic obstructive pulmonary disease (COPD) aim at early recognition of exacerbations and self-initiation of interventions. Previous research suggest underuse of COPD action plans. We wanted to 1) examine which factors clinicians in specialist healthcare perceived as influencing clinicians' use of written action plans in COPD-self management support and 2) propose a framework for understanding the factors affecting clinicians' use of action plans in routine practice. We performed a theory-driven retrospective qualitative study. Documentary data were collected to describe the COPD action plan in context. In-depth interviews with clinicians (n = 8) were carried out. Interview data were thematically analyzed, using a predetermined model for understanding behavior. Our study revealed that a number of factors influenced clinicians' use of action plans, including their capabilities (knowledge and skills to identify "the right patient" and to individualize the plan template) and motivations (beliefs, reinforcements, and emotions s.a. frustration, fear, and distrust), together with organizational and social opportunities (resources, patient, and GP preferences). A multilevel understanding of factors that affect clinicians' use of action plans in self-management support is needed. The proposed framework can be used to guide future initiatives to promote targeted self-management support.


Translocation of preproinsulin across the endoplasmic reticulum membrane. The relationship between nascent polypeptide size and extent of signal recognition particle-mediated inhibition of protein synthesis.
Signal recognition particle (SRP) induces elongation arrest of nascent presecretory proteins as the signal peptide protrudes from the large ribosomal subunit. To examine the relationship between the size of the precursor and extent of SRP mediated inhibition of polypeptide chain elongation, we performed in vitro translation experiments in the presence of SRP using a series of truncated preproinsulin mRNA molecules. These precursors possessed the same NH2 terminus as native preproinsulin followed by progressively shorter COOH termini. SRP inhibited translation of precursors as short as 64 amino acids in length, however, the extent of inhibition diminished for shorter precursors. This correlated with a reduction in the time required for ribosomes to transit through the mRNA encoding the shortened precursors. By exploiting a chimeric protein comprising the first 71 residues of preproinsulin fused to the bacterial cytoplasmic enzyme chloramphenicol acetyltransferase, we demonstrate that the largest size a nascent chain can reach and still be susceptible to SRP-mediated elongation arrest is approximately 17 kDa. Our data support the model that SRP binding to the signal peptide is a reversible process even in the absence of microsomal membranes, and that SRP can arrest polypeptide chain elongation at multiple stages during translation.


Microscopic theory of modified spontaneous emission in a dielectric.
The modification of the radiative decay rate of a source atom embedded in a uniform, isotropic dielectric is calculated to first order in the density of the dielectric atoms using a microscopic approach. In contrast to the recent results of Crenshaw and Bowden [Phys. Rev. Lett. 85, 1851 (2000)]], the decay rate is found to be consistent with macroscopic theories based on quantization of the field in the dielectric.


Transcriptional regulation of IL-15 expression during hematopoiesis.
Dendritic cells (DCs) are the most commonly studied source of the cytokine IL-15. Using an IL-15 reporter transgenic mouse, we have recently shown previously unappreciated differences in the levels of IL-15 expressed by subsets of conventional DCs (CD8⁺ and CD8⁻). In this study, we show that IL-15 promoter activity was differentially regulated in subsets of hematopoietically derived cells with IL-15 expression largely limited to myeloid lineages. In contrast, mature cells of the lymphoid lineages expressed little to no IL-15 activity. Surprisingly, we discovered that hematopoietic stem cells (lineage⁻Sca-1⁺c-Kit⁺) expressed high levels of IL-15, suggesting that IL-15 expression was extinguished during lymphoid development. In the case of T cells, this downregulation was Notch-dependent and occurred in a stepwise pattern coincident with increasing maturation and commitment to a T cell fate. Finally, we further demonstrate that IL-15 expression was also controlled throughout DC development, with key regulatory activity of IL-15 production occurring at the pre-DC branch point, leading to the generation of both IL-15⁺CD8⁺ and IL-15(⁻/low)CD8⁻ DC subsets. Thus, IL-15 expression is coordinated with cellular fate in myeloid versus lymphoid immune cells.


Effect of temozolomide in patients with metastatic bronchial carcinoids.
Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value. All patients with progressive metastatic bronchial carcinoid treated with temozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1. There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11 (52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxicities grade 3-4 were noted in 4 patients, thrombocytopenia (n = 3) and leukopenia (n = 1). Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining temozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients.


Peptide-based inhibitors of the hepatitis C virus serine protease.
Hexapeptide DDIVPC-OH is a competitive inhibitor of the hepatitis C virus (HCV) NS3 protease complexed with NS4A cofactor peptide. This hexapeptide corresponds to the N-terminal cleavage product of an HCV dodecapeptide substrate derived from the NS5A/5B cleavage site. Structure-activity studies on Ac-DDIVPC-OH revealed that side chains of the P4, P3 and P1 residues contribute the most to binding and that the introduction of a D-amino acid at the P5 position improves potency considerably. Furthermore, there is a strong preference for cysteine at the P1 position and conservative replacements, such as serine, are not well tolerated.


Linkage to BRCA2 region in hereditary male breast cancer.
Breast cancer is rare in men, and family history of the disease is a risk factor. The recently discovered BRCA2 gene on chromosome 13q is thought to account for some families with increased risk of breast cancer, including male breast cancer. We describe a family with multiple cases of male breast cancer but, interestingly, no increase in female breast cancer. Linkage to the BRCA2 region is demonstrated and all the affected men share the same haplotype for the BCRA2 markers and loss of the other alleles in their tumours.


Altered resting-state functional connectivity and its association with executive function in adolescents with borderline personality disorder.
Adolescents with borderline personality disorder (BPD) may have impaired executive functions. There are few functional MRI (fMRI) studies in adolescents with BPD and the neuroimaging markers of this disorder are unknown. The aim of this study was to investigate the functional connectivity (FC) of BPD in adolescents, and to explore the relationship between FC changes and executive function in adolescents with BPD. 50 adolescents aged 12 to 17 years with BPD and 21 gender-and-age matched healthy controls (HC) were enrolled into the study. Brain MRI scan including a 3D-T1 weighted structural sequence and a resting-state fMRI was acquired. A seed-based FC analysis was performed. We used the Stroop color-word test (SCWT) and the trail making test (TMT) to evaluate the executive function of the participants. Correlative analysis of FC alterations with executive function and clinical symptoms was also performed. Compared to the HCs, adolescents with BPD showed increased FC in the limbic-cortical circuit, such as the FC between the left hippocampus and right parahippocampal gyrus, between the right middle occipital gyrus and the left middle temporal gyrus, and between the left medial superior frontal gyrus and the right inferior temporal gyrus. FC in the default mode network (DMN) was decreased between the left angular gyrus and the left precuneus but increased between the left angular gyrus and the right anterior cingulate cortex (voxel P < 0.001, cluster P < 0.05, FWE corrected). The BPD group demonstrated significantly lower cognitive testing scores than the HC group on the SCWT-A (P < 0.001), SCWT-B (P < 0.001), and SCWT-C (P = 0.034). The FC alterations between limbic system and cortical regions were associated with SCWT and TMT (P < 0.05). FC alterations were noted in both limbic-cortical circuit and DMN in adolescents with BPD, which were associated with impaired executive function. This study implicated the FC alterations as the neural correlates of executive functioning in adolescents with BPD.


[Postmortem imaging of the lung in cases of COVID-19 deaths].
COVID-19 is a new viral disease that is associated with inflammatory pulmonary changes which can be detected in computed tomography (CT). So far postmortem CT (PMCT) has not been used as a screening instrument for the evaluation of deaths with and without autopsy. In this respect, its validity has to be proved in comparison to clinical-radiological experiences. Postmortem CT METHODICAL INNOVATIONS: So far, PMCT can be regarded as a methodological innovation that has not yet been sufficiently evaluated for pneumonia. CT in clinical routine has a high sensitivity for pneumonia. However, to what extent postmortem artifacts are relevant to PMCT still has to be determined. There is still no standard procedure for the postmortem radiological diagnosis of COVID-19 disease. Despite postmortem artifacts, PMCT can provide valuable information about the presence of pneumonia with interstitial character, especially without autopsy. PMCT is particularly useful in the assessment of suspected cases of COVID-19 pneumonia for morphological assessment in the context of monitoring deaths in the current pandemic situation.


Osteoarthrosis of the antebrachiocarpal joint of 7 riding horses.
Osteoarthrosis (OA) of the antebrachiocarpal joint from 7 riding horses is described. The horses were old mares and developed severe OA, with ankylosis in some of the joints. The lesions were bilateral, and the owners noticed the lameness in a late event. The cause of severe OA in these mares is not clear. The fact that OA was bilateral indicates that a single traumatic injury is unlikely as an etiologic factor. Considering the severe joint lesions it took long time before the horse-owners noticed the lameness. It is discussed if the threshold of pain is higher in the antebrachiocarpal joint compared with the middle carpal joint.


The pattern, change and driven factors of vegetation cover in the Qin Mountains region.
The Qin Mountains region is one of the most important climatic boundaries that divide the North and South of China. This study investigates vegetation covers changes across the Qin Mountains region over the past three decades based on the Landsat-derived Normalized Difference Vegetation Index (NDVI), which were extracted from the Google Earth Engine (GEE). Our results show that the NDVI across the Qin Mountains have increased from 0.624 to 0.776 with annual change rates of 0.0053/a over the past 32 years. Besides, its abrupt point occurred in 2006 and the change rates after this point increased by 0.0094/a (R2 = 0.8159, p < 0.01) (2006-2018), which is higher than that in 1987-1999 and 1999-2006. The mean NDVI have changed in different elevation ranges. The NDVI in the areas below 3300 m increased, such increased is especially most obviously in the cropland. Most of the forest and grassland locate above 3300 m with higher increased rate. Before 2006, the temperature and reference evapotranspiration (PET) were the important driven factors of NDVI change below 3300 m. After afforestation, human activities become important factors that influenced NDVI changes in the low elevation area, but hydro-climatic factors still play an important role in NDVI increase in the higher elevations area.


Standardized karyotype of deer mice, Peromyscus (Rodentia). The Committee for Standardization of Chromosomes of Peromyscus.
A standard G-band karyotype is proposed for the genus Peromyscus. G-banded chromosomes of Peromyscus boylii glasselli (NF=56), numbered and arranged according to euchromatic lengths, serve as the standard. It is suggested that rearrangements of the standard pattern which occur in other species of Peromyscus be described using the general methods of the PARIS CONFERENCE (1971).


Enantiomeric separation of metolachlor and its metabolites using LC-MS and CZE.
The stereoisomers of metolachlor and its two polar metabolites [ethane sulfonic acid (ESA) and oxanilic acid (OXA)] were separated using liquid chromatography-mass spectrometry (LC-MS) and capillary zone electrophoresis (CZE), respectively. The separation of metolachlor enantiomers was achieved using a LC-MS equipped with a chiral stationary phase based on cellulose tris(3,5-dimethylphenyl carbamate) and an atmospheric pressure chemical ionization source operated under positive ion mode. The enantiomers of ESA and OXA were separated using CZE with gamma-cyclodextrin (gamma-CD) as chiral selector. Various CZE conditions were investigated to achieve the best resolution of the ESA and OXA enantiomers. The optimum background CZE electrolyte was found to consist of borate buffer (pH=9) containing 20% methanol (v/v) and 2.5% gamma-CD (w/v). Maximum resolution of ESA and OXA enantiomers was achieved using a capillary temperature of 15 degrees C and applied voltage of 30 kV. The applicability of the LC-MS and CZE methods was demonstrated successfully on the enantiomeric analysis of metolachlor and its metabolites in samples from a soil and water degradation study that was set up to probe the stereoselectivity of metolachlor biodegradation. These techniques allow the enantiomeric ratios of the target analytes to be followed over time during the degradation process and thus will prove useful in determining the role of chirality in pesticide degradation and metabolite formation.


Headaches in hospitalized cocaine users.
We reviewed the medical records of 283 cocaine users consecutively admitted to a municipal hospital and identified 37 patients (13.1%) complaining of headaches. These patients were divided into three groups. Three patients had migraine-like headaches and transient hemiparesis associated with cocaine use. Five patients had headaches associated with cocaine withdrawal. In 29 patients headaches were not clearly associated with cocaine. Twenty-two of the 29 had chronic daily headaches; nine of these patients were depressed. Three had focal brain lesions with chronic daily headache or acute onset global headache. The four remaining patients had other headaches. Based on these findings, we conclude that: (1) Headache is a common complaint in hospitalized cocaine users; (2) Cocaine may occasionally trigger a syndrome which resembles hemiplegic migraine. The potential mechanisms of this syndrome will be discussed; (3) Hospitalized cocaine users who present with headaches most frequently have depression with suicidal ideation, often associated with cocaine withdrawal; and (4) Structural brain disease in these patients may result from a variety of causes.


Arabidopsis Micro-grafting to Study the Systemic Signaling of Nutrient Status.
Grafting enables the study of systemic signals that plants use to maintain their homeostasis at the level of the whole organism. Several protocols of Arabidopsis grafting have been published over the years. These methods are limited because they either affect the overall behavior of the plant, or their throughput is low. The method presented here is based on grafting 3- to 4-days-old seedlings directly on an agar plate, without the use of hormone or collar, and can produce consistently over a hundred grafted plants per day and operator.


Chemical method to enhance transungual transport and iontophoresis efficiency.
Transungual transport is hindered by the inherent small effective pore size of the nail even when it is fully hydrated. The objectives of this study were to determine the effects of chemical enhancers thioglycolic acid (TGA), glycolic acid (GA), and urea (UR) on transungual transport and iontophoresis efficiency. In vitro passive and iontophoretic transport experiments of model permeants mannitol (MA), UR, and tetraethylammonium (TEA) ion across the fully hydrated, enhancer-treated and untreated human nail plates were performed in phosphate-buffered saline. The transport experiments consisted of several stages, alternating between passive and anodal iontophoretic transport at 0.1mA. Nail water uptake experiments were conducted to determine the water content of the enhancer-treated nails. The effects of the enhancers on transungual electroosmosis were also evaluated. Nails treated with GA and UR did not show any transport enhancement. Treatment with TGA at 0.5M enhanced passive and iontophoretic transungual transport of MA, UR, and TEA. Increasing the TGA concentration to 1.8M did not further increase TEA iontophoresis efficiency. The effect of TGA on the nail plates was irreversible. The present study shows the possibility of using a chemical enhancer to reduce transport hindrance in the nail plate and thus enhance passive and iontophoretic transungual transport.


Small intestinal perforation secondary to metastasis from skin squamous cell carcinoma: A case report and literature review.
Primary and metastatic carcinoma of the small intestine are rare. While most of these malignancies are adenocarcinomas, squamous cell carcinoma (SCC) of the gastrointestinal tract is uncommon. We present a case report of a rare occurrence of skin SCC metastasizing to the ileum, highlighting diagnostic challenges and clinical implications. An 83-year-old female had a history of cutaneous SCC excision in the right temporal region two years prior to the current emergency department visit, followed by metastatic recurrence in a right intra-parotid lymph node treated with radiotherapy. The patient exhibited septic shock and an acute abdomen, and an abdominal computed tomography scan revealed signs of intestinal perforation. Emergency exploratory laparotomy confirmed purulent peritonitis and perforation of the terminal ileum. Subsequently, a 20 cm intestinal resection was performed. Histopathological examination of the resected specimen revealed a 4 cm perforated SCC of the small intestine (pT4 pN0 L0 V1 Pn0 R0). Metastases of the small intestine are rare. The primary sites for these metastases are typically the uterus, cervix, colon, lung, breast, or melanoma. SCC of the small intestine is particularly rare and poses challenges in diagnosis owing to non-specific symptoms. The prognosis for SCC of the small intestine is generally poor, and the potentially aggressive behavior of some skin SCC emphasizes the need for increased awareness and vigilance in managing such cases. This case report underscores the importance of considering metastatic disease in the small bowel of patients with a history of skin SCC who present with new-onset abdominal symptoms.


Diastolic versus systolic coronary computed tomography angiography derived fractional flow reserve for the identification of lesion-specific ischemia.
To investigate the measurement discrepancy of coronary computed tomography angiography (CTA)-derived fractional flow reserve (FFR) between diastolic (CT-FFR-D) and systolic (CT-FFR-S) phases using FFR as the reference standard. Participants, suspected of coronary artery disease and indicated for invasive coronary angiography (ICA) and FFR and coronary CTA and CT-FFR, were enrolled in this study (Clinicaltrials.gov:NCT03692936) from September 2018 to October 2019. For every participant, coronary CTA of both systolic and diastolic phases was postprocessed to calculate CT-FFR-S and CT-FFR-D, respectively. Diagnostic sensitivity, specificity, accuracy, and the area under the receiver operating characteristic (ROC) curve were compared. A total of 181 lesions from 151 participants (mean age 54.5 ± 7.8 years, 113 males) were analyzed. Of these, 129 lesions from 110 participants were successfully measured both in diastolic and systolic phases. Sensitivity, specificity, and accuracy of CT-FFR-D and CT-FFR-S on per-patient level were 88.9%, 91.3%, 90.1% and 66.7%, 87.7%, 76.7%, on per-vessel level were 89.5%, 91.5%, 90.6% and 66.7%, 87.0%, 77.9%, respectively. The ROC curve of CT-FFR-D was significantly higher than that of CT-FFR-S on both per-patient and per-vessel levels (0.938 vs. 0.771, 0.935 vs. 0.772, both p < 0.0001). In severe hemodynamic lesions (FFR ≤ 0.7), the absolute difference between CT-FFR-S and FFR was significantly higher than that between CT-FFR-D and FFR [0.1636, inter-quartile range (IQR): 0.0662-0.2586 vs. 0.0953, IQR: 0.0496-0.1702, p = 0.035]. CT-FFR derived in diastole was superior to that derived in systole in detecting coronary ischemic lesions. For lesions with FFR < 0.7, CT-FFR measured in the diastolic phase was noted to be more closely approximated to FFR.


Systematic review on first trimester three-dimensional placental volumetry predicting small for gestational age infants.
A systematic review and pooled analysis was carried out to estimate (i) the reference values and (ii) the potential value of measuring the first-trimester 3D-placental volume (PV) for predicting small for gestational age (SGA) infants. A comprehensive literature search for relevant studies was conducted using the PubMed and Web of Knowledge databases. A simulation model was generated to calculate the detection rate (DR) of the PV for SGA infants. A random variable was generated having the same number of cases, and the same means and standard deviation as those reported in the articles considered for the analysis. For the evaluation of the normal values of PV, 12 studies met the inclusion criteria. Four also produced an equation for PV estimation at 11 to 14 weeks. The weighted mean PV [±standard error of mean (SEM)] of 7519 cases was 59.40 ± 1.533 mL. For the estimation of PV performance in predicting SGA, five studies were included. The DR of the PV was 24.7% (19.3-30.1) at a 10% false-positive rate. The mean PV estimation of the studies analyzed was burdened by a high degree of heterogeneity. Instead, discordant results were reported for the possible prediction of SGA infants using PV. Surprisingly, just two articles reported the DR for SGA infants and also had proper statistical power. The discriminatory ability of using PV alone for predicting SGA appears to be modest, but could successfully be integrated into a multivariable screening method for SGA infants.


Surgical correction in mirror-image atrial arrangement or left atrial isomerism with systemic venous return to the left-sided atrium.
We have recently encountered three patients with the hemodynamics of complete transposition accompanied by unusual atrial arrangements. The flow patterns produced all required correction by means of a "mirror-image" Mustard operation. Two of the patients had left atrial isomerism as evidenced by the finding of bilateral atrial appendages of morphologically left type. In both patients the systemic venous return was to the left-sided atrium and the pulmonary venous return to the right-sided atrium. The major effect of the isomerism was to reduce the volume of the left-sided chamber. This initially produced concern, since we now try to avoid enlargement of the pulmonary venous atrium when performing Mustard's operation. However, despite the small volume, it was possible to place the baffle without producing postoperative pulmonary or systemic venous obstruction. The other significant effect of left atrial isomerism is to deviate the position of the sinus node, but thus far we have not encountered any postoperative rhythm problems. The third patient had a mirror-image arrangement of the atrial chambers and the venous connections (situs inversus), and the anatomy was corrected by straightforward mirror-image reversal of our current technique for Mustard's procedure.


Impact of hypertension and apolipoprotein E4 on poststroke cognition in subjects >75 years of age.
The apolipoprotein E4 allele (APOE4) associates with increased dementia risk, and hypertension may associate with mild cognitive deficits. We examined whether nondemented stroke patients with (1) a prestroke history of hypertension and (2) APOE4 were more cognitively impaired at 3 months after stroke. A total of 257 participants were genotyped and outcomes from neuropsychological evaluations analyzed using regression. Total Cambridge Assessment for Mental Disorders in the Elderly (CAMCOG) and speed of working memory significantly associated with hypertension. No outcomes significantly associated with APOE4. Subjects with prestroke hypertension had more impaired global cognition and slower access to information held in working memory.


Information compression in biological systems.
In biological systems a high coordination between their individual parts occurs. The concept of coordination can be given a rigorous mathematical basis by the concept of order parameters and the slaving principle. We calculate the information of the total system in terms of order parameters and slaved subsystems. When qualitative changes of a system happen, the information change is given by that of the order parameters alone and may amount to few bits only.


Clinical perspectives and outcomes of the giant breast phyllodes tumor and sarcoma: a real-world retrospective study.
Giant breast malignant phyllodes tumor or sarcoma (GBPS) are rare entities with diameter larger than 10 cm and variously histological pleomorphisms. This disease poses a significant threat to the quality of life of individuals, and its prognosis remains unclear. This study aimed to explore the differential diagnosis, treatment, and prognosis of GBPS in a real-world retrospective cohort. We collected GBPS (diameter > 10 cm, n = 10) and BPS (diameter ≤ 10 cm, n = 126) from patients diagnosed with sarcoma or malignant phyllodes tumor between 2008 and 2022. We analyzed clinical characteristics, histological status, treatment, and local recurrence using the Fisher's exact test between GBPS (diameter > 10 cm) and BPS (diameter ≤ 10 cm) cohort. We described overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier curves and identified risk factors for local recurrence using logistic regression. The tumor size, age at diagnosis, and differential immunohistochemistry markers of breast sarcoma or phyllodes tumor to determine the prognosis of GBPS. In our retrospective analysis of breast malignancies, we identified 10 cases of GBPS and 126 cases of BPS, corresponding to a GBPS prevalence of 0.17% (10/6000). The median age was 38.5 years (inter-quartile range, IQR: 28.25-48.5 years). During the follow-up of period (median: 80.5 months, IQR: 36.75-122 months), the local recurrence (LR) rate was 40% and 20.6%, respectively. Clinical characteristics of young age (HR:2.799, 95%CI -00.09276-0.017, p < 0.05) and cytological characteristics of marked stromal atypia (HR:0.88, 95% CI 0.39-1.40, p < 0.05) were risk factors for the poor prognosis of GBPS by COX regression model analysis. The Kaplan-Meier curves of GBPS 5-year disease-free survival (DFS) and overall survival (OS) were 31.5 months and 40 months, respectively, and were not associated with adjuvant radiation or chemotherapy. We recommend mastectomy with a clear surgical margin as the preferred treatment for GBPS. Age and stromal atypia are significantly associated with recurrence. Adjuvant radiation therapy is advised; however, there was no improvement in overall survival. There is no consensus on the effectiveness of adjuvant chemotherapy and genetic methods, highlighting the need for further research into this aggressive tumor. We recommend a multidisciplinary approach involving a dedicated team for the management of GBPS.


Challenges for tuberculosis control at selected primary healthcare centers in Bangladesh: A mixed-method study.
The national tuberculosis control program in Bangladesh is progressing to end tuberculosis (TB) epidemic by 2035. Despite improved diagnostic and treatment facilities, the disease burden remains high. This mixed-method study aimed to identify existing challenges for successfully implementing the tuberculosis control program in primary healthcare centers (PHCs) of Bangladesh. Qualitative data were collected by observing six PHCs and interviewing TB patients (n = 12) and healthcare providers (n = 12). Quantitative data were collected by interviewing 94 TB patients. Data were integrated through a narrative approach. Mean patient and health system delay were 99.0 (SD = 98.7) and 42.9 (SD = 79.9) days respectively. Patient delay was related to poor care-seeking behavior, unfamiliarity with tuberculosis symptoms, and unavailability of healthcare facilities. About 74 percent of patients sought initial treatment from village doctors or drug vendors. Health system delay was related to inadequate manpower, unskilled staff, and limited diagnostic facilities. Every second patient reported non-adherence to the directly observed treatment short-course (DOTS) guideline. DOTS provider's inaccessibility, inadequate incentive, and unreasonable patient demand lead to non-adherence. Insufficient administrative and structural facilities for infection control were observed at the selected facilities. This study provides an insight into the recent challenges in TB control at PHCs in Bangladesh.


Meiosis activating sterols derived from diosgenin.
Continuing research based on the meiosis activation properties of the endogenous sterol FF-MAS is reported. The synthesis and SAR of 16- and 26-substituted sterols are described, utilising diosgenin as starting material. Selected sterols were tested for their ability to induce oocyte maturation in hypoxanthine arrested mouse oocytes in vitro.


Should ACR/EULAR criteria be revised changing the RF and ACPA scores?
Current classification criteria for rheumatoid arthritis (RA) encompass clinical and immunological items and are capable of correctly identifying the majority of symptomatic RA patients. The presence of positive rheumatoid factor (RF) and/or and anti-cyclic citrullinated protein/peptide antibodies (ACPA) gaining increasing importance according to their serological titer eases the recognition of RA, yet the debate is open on whether this scoring system ought to be optimized by hierarchizing ACPA or the combination of ACPA and RF over single positivity, prioritizing specificity over sensitivity. The risk of misdiagnosis and misclassification are often entangled, yet they are not the same. In fact, while ideal diagnosis requires 100% sensitivity and specificity, classification criteria are conceived to gather a homogeneous patient population, favoring specificity over sensitivity. Nevertheless, as they are frequently summoned to support the diagnostic process in clinical practice, issues arise on how comprehensive those should be and on how frequently they should be updated in light of novel acquisitions regarding measurable RA-related abnormalities. In this viewpoint two different views on the topic are confronted, discussing the performance of available criteria and the potentiality and pitfalls of their refinement according to novel data on ACPA and RF contribution and emergence of newly discovered specificities.


Review article: treatment of the gastrointestinal manifestations of AIDS.
The Acquired Immune Deficiency Syndrome (AIDS) is frequently associated with infections, infestations, or diseases of the gastrointestinal tract. This review describes the practical aspects of treating oral and oesophageal disease, the management of weight loss and diarrhoea, the role for zidovudine, and the management of Kaposi's sarcoma.


Methanol and formate kinetics during treatment with fomepizole.
Methanol is metabolized by alcohol dehydrogenase to formaldehyde, and further to formic acid, which is responsible for the toxicity in methanol poisoning. Fomepizole (4-methylpyrazole) is a potent competitive inhibitor of alcohol dehydrogenase and is used as an antidote to treat methanol poisonings. We report serum methanol kinetics in eight patients treated with bicarbonate and fomepizole only. Prospective case series study of eight patients with methanol poisoning, who were selected to fomepizole and bicarbonate treatment only, because of moderate metabolic acidosis. Three of the patients were later dialyzed, because of high serum methanol concentrations and very slow methanol elimination. Upon admission the median pH was 7.27 (range 7.12-7.50), median base deficit was 15 mmol/L (5-22 mmol/L) and median serum methanol was 20.4 mmol/L (65 mg/dL) (range 8.4-140.6 mmol/L). The kinetics of methanol during fomepizole treatment in six patients was best described by a first-order elimination one-compartment model. The mean correlation coefficient (R2) describing the first-order elimination model in all eight patients was 0.95 (range 0.90-0.99). The mean plasma half-life (t(1/2)) of methanol during fomepizole treatment was 52 h (range 22-87); the higher the serum methanol, the longer the T(1/2). Mean half-life of serum formate was 2.6 h, when methanol metabolism was assumed blocked by fomepizole and no folinic acid was given. This rapid formate elimination in nonacidotic patients may be explained by high renal excretion of formate. Based on our data, methanol-poisoned patients with moderate metabolic acidosis and methanol levels up to 19 mmol/L (60 mg/L) may safely be treated with bicarbonate and fomepizole only, without dialysis.


Leukemia cell differentiation: cellular and molecular interactions of retinoids and vitamin D.
1. The conventional approach to treatment of acute myeloid leukemia has been the use of chemotherapy, which although being cytotoxic to malignant clones, is also cytodestructive to normal cells. In addition, some leukemia cells develop resistance to chemotherapy and are therefore difficult to eradicate. 2. Differentiation therapy, whereby immature cells are induced to attain a mature phenotype by differentiation agents, has provided an alternative strategy in the treatment of hyperproliferative disorders. This has been highlighted by the use of all-trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL). 3. Another differentiation agent, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), directs monocytic maturation of normal and leukemic cells. Cellular studies have revealed that combinations of vitamin D derivatives and retinoids such as ATRA and 9-cis retinoic acid (9-cis RA) exhibit cooperative effects on differentiation in established leukemia cell lines such as HL-60, U937, and NB4. Furthermore, vitamin D compounds, although not able to induce apoptosis when used alone, potentiate apoptosis induced by 9-cis RA in HL-60 cells and differentially regulate the expression of the apoptosis-related gene products bcl-2 and bax. The molecular mechanisms involved in regulating differentiation and apoptosis by these agents are mediated through the interactions of the nuclear receptors for vitamin D (VDR), ATRA (RAR), and 9-cis RA (RXR), which are able to form homo- or heterodimeric complexes and transcriptionally activate or repress target gene expression. 4. There is evidence to suggest that nitric oxide may also play a role in leukemic cell differentiation and that 1,25(OH)2D3 may influence endogenous nitric oxide production either by directly increasing tumor necrosis factor-alpha (TNF-alpha) or through a secondary mediator such as the C-type lectin CD23.


Hypothesis driven drug design: improving quality and effectiveness of the design-make-test-analyse cycle.
In drug discovery, the central process of constructing and testing hypotheses, carefully conducting experiments and analysing the associated data for new findings and information is known as the design-make-test-analyse cycle. Each step relies heavily on the inputs and outputs of the other three components. In this article we report our efforts to improve and integrate all parts to enable smooth and rapid flow of high quality ideas. Key improvements include enhancing multi-disciplinary input into 'Design', increasing the use of knowledge and reducing cycle times in 'Make', providing parallel sets of relevant data within ten working days in 'Test' and maximising the learning in 'Analyse'.


Matrix formulation for the propagation of light beams with orbital and spin angular momenta.
Jones matrices describe the polarization, or spin angular momentum, of a light beam as it passes through an optical system. We devise an equivalent of the Jones matrix formulation for light possessing orbital angular momentum. The matrices are then developed to account for light that has both spin and orbital angular momentum.


Spatial pattern of atmospherically deposited radiocesium on the forest floor in the early phase of the Fukushima Daiichi Nuclear Power Plant accident.
Spatial patterns of atmospherically deposited radiocesium on the forest floor and the temporal evolution were measured in two Japanese cedar stands and a secondary mixed broad-leaved forest in the early phase of the Fukushima Daiichi Nuclear Power Plant accident. In situ measurements of the 137Cs gamma count were made using a portable germanium gamma ray detector. These measurements revealed that the forest floors were contaminated with radionuclides derived from the accident. In the cedar stands, the inter-canopy area had higher 137Cs count rate relative to the under-canopy area, whereas no clear relationship was found between the radiocesium pattern and canopy cover in the mixed broad-leaved forest. Repeated radiocesium measurements revealed that the spatial pattern of radiocesium activity on the forest floor did not substantially change following additional deposition inputs. Furthermore, the magnitude of canopy cover partially explained spatial variability of the 137Cs on the forest floor in cedar stands. These results suggest that canopy structure affected the genesis of the horizontal variability of atmospherically deposited radiocesium on the forest floor during the early phase of the Fukushima accident.


Immunomodulatory molecules of Fasciola hepatica: candidates for both vaccine and immunotherapeutic development.
The liver fluke, Fasciola hepatica, causes fascioliasis in domestic animals (sheep, cattle), a global disease that is also an important infection of humans. As soon as the parasite invades the gut wall its interaction with various host immune cells (e.g. dendritic cells, macrophages and mast cells) is complex. The parasite secretes a myriad of molecules that direct the immune response towards a favourable non-protective Th2-mediate/regulatory environment. These immunomodulatory molecules, such as cathepsin L peptidase (FhCL1), are under development as the first generation of fluke vaccines. However, this peptidase and other molecules, such as peroxiredoxin (FhPrx) and helminth defence molecule (FhHDM-1), exhibit various immunomodulatory properties that could be harnessed to help treat immune-related conditions in humans and animals.


Does percutaneous endoscopic gastrostomy prevent gastro-oesophageal reflux during the enteral feeding of elderly patients?
Percutaneous endoscopic gastrostomy (PEG) is reported to be a safe method for enteral feeding, although its ability to prevent gastro-oesophageal reflux (GOR) during enteral feeding remains controversial. In 12 elderly patients fed enterally to avoid the risk of tracheal aspiration, we have compared two 24-h oesophageal pH profiles, one recorded when enteral feeding was delivered at first via a nasogastric tube (NGT), and the other via a PEG. The second recording was always performed at least 8 days after gastrostomy placement. Enteral nutrition consisted of 500 ml of a polymeric diet delivered 3 times a day at 08:00, 13:00 and 18:00. After gastrostomy placement, enteral feeding was associated with a pathological acid reflux in 8 out of 12 patients. In all of these 8 patients, GOR was mostly related to a high number of reflux episodes. In 4 out of 8 patients, GOR occurred only during the 3 h following the administration of the nutritive diet. In 4 of the patients, GOR did not occur any more after removal of the NGT, whilst gastrostomy placement was followed by GOR in 5 patients. GOR during enteral feeding via PEG is common in elderly subjects. We have shown that a chronological relationship existed in some patients between the endoscopic procedure and the onset of a pathological GOR.


Arrhythmia knowledge: a qualitative study.
The objective is to identify and describe critical care nurses' perception of arrhythmia knowledge. In addition, this study is the first step in developing levels of arrhythmia competency. A qualitative research design was used. Focus group technique using a semistructured group session, with a moderator, was used to gather data. Data were analyzed by the constant comparative method. The subjects were critical care nurses who work in acute care settings where they read electrocardiographic data and make treatment decisions. Five focus groups were conducted over a period of 12 months. Group size ranged from four to eight participants. Participants were asked to describe their perceptions of arrhythmia knowledge and to assign a rating score related to the level of knowledge needed to identify specific arrhythmias. Basic, intermediate, and advanced levels of arrhythmia knowledge were identified. This study revealed a deficit in nurses' ability to recognize and identify specific arrhythmias including heart block, aberrant conduction, and tachyarrhythmias. Understanding of lead placement concepts varied greatly among participants. The insight and perspective of critical care nurses related to the level of arrhythmia knowledge are needed for the development of competency measures and evidence-based teaching strategies.


Assays for the rapid and specific identification of North American Yersinia pestis and the common laboratory strain CO92.
We present TaqMan-minor groove binding (MGB) assays for an SNP that separates the Yersinia pestis strain CO92 from all other strains and for another SNP that separates North American strains from all other global strains.


Adjuvant and Neoadjuvant Therapy, Treatment for Advanced Disease, and Genetic Considerations for Adrenocortical Carcinoma: An Update from the SSO Endocrine and Head and Neck Disease Site Working Group.
This is the second of a two-part review on adrenocortical carcinoma (ACC) management. While margin-negative resection provides the only potential cure for ACC, recurrence rates remain high. Furthermore, many patients present with locally advanced, unresectable tumors and/or diffuse metastases. As a result, selecting patients for adjuvant therapy and understanding systemic therapy options for advanced ACC is important. Herein, we detail the current literature supporting the use of adjuvant mitotane therapy, consideration of adjuvant radiation therapy, and utility of cytotoxic chemotherapy in patients with advanced disease. Ongoing investigation into molecular targeted agents, immunotherapy, and inhibitors of steroidogenesis for the treatment of ACC are also highlighted. Lastly, the importance of genetic counseling in patients with ACC is addressed as up to 10% of patients will have an identifiable hereditary syndrome.


Atypical drug-induced hypersensitivity syndrome with multiple organ failure rescued by combined acute blood purification therapy: a case report.
Drug-induced hypersensitivity syndrome (DIHS), including Stevens-Johnson syndrome (SJS), is a severe rash that often develops 2-6 weeks after the intake of the causative drug; however, its diagnosis is sometimes difficult. This article describes a case in which a patient with DIHS-induced multiple organ failure was successfully treated with blood purification therapy. A male patient in his 60s was admitted to our hospital with autoimmune encephalitis. The patient was treated with steroid pulse therapy, acyclovir, levetiracetam, and phenytoin. From the 25th day, he presented with fever (≥ 38 °C) as well as miliary-sized erythema on the extremities and trunk, followed by erosions. DIHS and SJS were suspected; accordingly, levetiracetam, phenytoin, and acyclovir were discontinued. On the 30th day, his condition further deteriorated, and he was admitted to the intensive care unit for ventilatory management. The next day, he developed multi-organ failure and was started on hemodiafiltration (HDF) for acute kidney injury. Although he presented with hepatic dysfunction and the appearance of atypical lymphocytes, he did not meet the diagnostic criteria for DIHS or SJS/toxic epidermal necrolysis. Therefore, he was diagnosed with multi-organ failure caused by severe drug eruption and underwent a 3-day treatment with plasma exchange (PE) in addition to HDF. Accordingly, the patient was diagnosed with atypical DIHS. After being started on blood purification therapy, the skin rash began to disappear; moreover, the organ damage improved, with a gradual increase in urine output. Eventually, the patient was weaned off the ventilator and transferred to the hospital on the 101st day. HDF + PE could effectively treat multi-organ failure caused by atypical DIHS, which is difficult to diagnose.


Highly regiocontrolled Pd-catalyzed cross-coupling reaction of terminal alkynes and allenylphosphine oxides.
The cross-coupling of a variety of terminal alkynes 1 with allenylphosphine oxides 2 catalyzed by a Pd(OAc)(2)-TDMPP system provided conjugated endo-enynes 3 solely, while the TCPC-catalyzed reaction of the same regents led to the exclusive formation of exo-isomers 4. The mechanistic rationale for these selective transformations was proposed. Synthetic usefulness of the prepared exo-enyne 4 was demonstrated in the synthesis of multisubstituted diarylbenzylphosphine oxides 5 via the Pd-catalyzed [4+2]-benzannulation reaction.


[The adaptive value of cyclomorphic spine production in Brachionus calyciflorus pallas (rotatoria) : I. Predator-prey relationships in short term experiments].
In the rotifer Brachionus calyciflorus there occurs a cyclomorphic variation concerning the absence or the presence of a pair of postero-lateral spines. If present, these spines may vary up to lorica length. The production of these spines is induced by starvation, low temperature, or a peptide substance released into the medium by the predacious rotifer Asplanchna. The first two factors apparently induce spines only up to a relative short length, while extremely long spines appear to be induced only by the Asplanchna substance. 1. Existing hypotheses with regard to possible adaptive values of the cyclomorphic spine production are discussed and rejected with the exception of two, which are tested by laboratory experiments. 2. The hypothesis of Erman, that spined Brachionus calyciflorus swim more slowly and filter the nourishment more effectively as a consequence of the resistance of the spines to friction, is disproved experimentally (see Table 1 and 2). 3. The hypothesis of Beauchamp and of Gilbert, that spines form a protection against the predacious Asplanchna, is tested in detail. a) The components of the predator-prey relationship of Asplanchna and the influences of the spines on these components are studied in short term experiments (stopped after the first catch; see Fig. 2 and Table 3): The number of accidental collisions with Asplanchna is not influenced by spine length. However, by increasing spine length the rate of catches per collision and the rate of swallowed prey per catch decrease, and the time spent in swallowing the prey increases. The timespan from the start of the experiment to the moment when the first prey is just being swallowed shows a marked increase with growing spine length (see Table 3: g). b) In experiments of longer periods of exposition (up to one hour; see Table 5) the long-spined B. calyciflorus are again nearly completely unassailable. In these cases the advantage of short-spined animals (compared with spineless ones) is reduced. The reason for this is a more rapid saturation of the Asplanchna by unarmed prey. This causes a quicker relaxation of the predator's activities (decrease of the swimming speed, number of prey caught per collision, and number of prey swallowed per catch). In Asplanchna feeding on short-spined prey, saturation is slower but at the same time the predator's activities decrease more slowly, too (see Fig. 4). By extending the periods of exposition the survival chances of spined and spineless animals become more similar. c) In the presence of spineless animals (Brachionus rubens) as an alternative prey, the protection of the spines (in relation to spineless controls) becomes more important, because in this case the unarmed alternative prey makes a higher proportion of the predator's diet. This is true over a wide range of predation pressure (see Tables 6 and 7). d) Protective spinesara also present in juvenile B. calyciflorus. However, the juveniles are in all of their categories of spine length more sensitive to predator attacks than are corresponding adult females. The reason for this is the smaller overall body size of these animal (Tables 3, 4, 5, 6, Fig. 4). 4. The connexions between the inductive factors and the adaptive values of the cyclomorphic spine production are reviewed and discussed.


Saccadic disorders caused by cooling the superior colliculus or the frontal eye field, or from combined lesions of both structures.
We used reversible cold lesions to explore the oculomotor consequences of separate and combined dysfunction of the superior colliculus (SC) and the frontal eye field (FEF). Two monkeys were trained to fixate visual targets. In one we measured visually driven saccades while cooling the right SC, first alone, then in combination with bilateral FEF ablation. Two cryodes in the other subject permitted measurement of eye movements during cooling of either the right FEF or the right SC, or both structures together. Cooling FEF mainly caused a neglect. Raising the cryode temperature slightly alleviated the neglect and uncovered a subtle saccadic deficit. It consisted of a slight reduction in saccadic amplitude and increase in saccadic reaction time. Cooling the SC alone lengthened saccadic reaction time and reduced saccadic amplitude more dramatically, causing the monkeys' initial saccade to miss the target. Some correction occurred but a targeting error persisted to the end of the trial. Combined lesions of FEF and SC greatly increased reaction times, reduced saccadic amplitude, and caused large and persistent targeting errors. The changes in saccadic amplitude and the targeting errors were a function of the monkey's eye position. Combined lesions also truncated the ocular range of the monkeys.


Yeast mannan structure necessary for co-aggregation with Lactobacillus plantarum ML11-11.
Lactic acid bacteria (LAB) Lactobacillus plantarum ML11-11, an isolate from Fukuyama pot vinegar, and yeast Saccharomyces cerevisiae form significant mixed-species biofilm with direct cell-cell contact. Co-aggregation of L. plantarum ML11-11 and S. cerevisiae cells, mediated by the interaction between surface protein(s) on L. plantarum ML11-11 cells and surface mannan of S. cerevisiae cells, contributes significantly to mixed-species biofilm formation. In this study, co-aggregation activities of yeast mutants that were deleted of genes related to mannan biosynthesis were investigated to clarify the mannan structures essential for interaction with L. plantarum ML11-11. Among the 12 deletion mutants which had various incomplete mannan structures, only the mnn2 mutant lost the co-aggregation activity. In the mnn2 mutant, the gene coding the activity of attaching first branching mannose residue to mannan main chain is deleted and therefore the mnn2 mutant has unbranched mannan. From this result, it is clarified that the specific structure, consisted of mannan main chain to which are attached side chains containing one or more mannose residues, is critical for co-aggregation with L. plantarum ML11-11.


Long-term Outcomes of Patients with Acute Myocardial Infarction Presenting to Regional and Remote Hospitals.
Acute myocardial infarction (AMI) has poorer outcomes in disadvantaged populations such as those in regional and remote locations. We compared long-term outcomes associated with presentation to regional or remote hospitals among AMI patients. Administrative claims data from New South Wales (27% regional and remote residents) was used to identify patients >18 years admitted to any NSW hospital with a principal diagnosis of AMI (ICD10 codes: I21·0-I21·4) between 01/07/2004 and 30/06/2008. Hospital of presentation location with a population of <250,000 was defined as regional and remote while hospitals with a population >250,000 were deemed urban. Receipt of revascularisation and mortality were analysed and adjusted for age, comorbidities and previous revascularisation. Patients were censored at death or end of the follow-up period (31 December 2009). 39,798 patients were identified with 9,393 (23.6%) regional and remote presenters. In multivariable models, regional and remote presentation was associated with reduced rates of revascularisation (OR 0.30 95%CI 0.28-0.32; p<0.001), no impact on overall mortality (HR 1.04 95%CI 0.99-1.02; p=0.11), but with increased mortality for patients presenting with STEMI (HR 1.14; 95% CI 1.06-1.23; p<0.001). The propensity analysis was consistent with these findings. Presentation to a regional and remote hospital was associated with lower revascularisation rates following AMI, but with a higher long-term mortality if presenting with ST segment elevation.


Efficacy of selected food-safe compounds to prevent infestation of the ham mite, Tyrophagus putrescentiae (Schrank) (Acarina: Acaridae), on southern dry-cured hams.
Tyrophagus putrescentiae (Schrank) is a serious mite pest of dried meats and cheeses. Infestations of T. putrescentiae are controlled with the fumigant methyl bromide, which is an ozone-depleting substance and is currently being banned in most countries. Effective alternatives to methyl bromide are needed. The objective of this research was to use laboratory assays to investigate the effectiveness of food-safe compounds for preventing infestation of T. putrescentiae on dry-cured hams. Ham pieces dipped in solutions of either propylene glycol (1,2-propanediol), lard, ethoxyquin or butylated hydroxytoluene prevented or significantly reduced mite population growth. Behavioral assays revealed that more mites oriented to the untreated control ham cubes, and more eggs were laid on these untreated ham cubes, compared with cubes treated with various dips. Our results also indicated that a combination of carrageenan + propylene glycol alginate + 40% propylene glycol was effective in reducing mite numbers on whole aging hams compared with untreated whole hams. Several food-safe compounds can prevent infestation of T. putrescentiae on dry-cured hams and may represent alternatives for managing this pest. © 2015 Society of Chemical Industry.


Trust-region filtered sequential convex programming for multi-UAV trajectory planning and collision avoidance.
This paper presents an trust-region filtered sequential convex programming (TRF-SCP) to reduce computational burdens of multi-UAV trajectory planning. In TRF-SCP, the trust-region based filter is proposed to remove the inactive collision-avoidance constraints of the convex programming subproblems for decreasing the complexity. The inactive constraints are detected based on the intersection relations between trust regions and collision-avoidance constraints. The trust-region based filter for different types of obstacles are tailored to address complex scenarios. An adaptive trust-region updating mechanism is also developed to mitigate infeasible iteration in TRF-SCP. The sizes of the trust regions are automatically adjusted according to the constraint violation of the optimized trajectory during the SCP iterations. TRF-SCP is then tested on several numerical multi-UAV formation scenarios involving cylindrical, spherical, conical, and polygon obstacles, respectively. Comparative studies demonstrate that TRF-SCP eliminates a large number of collision-avoidance constraints in the entire iterative process and outperforms SCP and Guaranteed Sequential Trajectory Optimization in terms of computational efficiency. The indoor flight experiments are presented to further evaluate the practicability of TRF-SCP.


Phosphoryl Transfer Reaction Snapshots in Crystals: INSIGHTS INTO THE MECHANISM OF PROTEIN KINASE A CATALYTIC SUBUNIT.
To study the catalytic mechanism of phosphorylation catalyzed by cAMP-dependent protein kinase (PKA) a structure of the enzyme-substrate complex representing the Michaelis complex is of specific interest as it can shed light on the structure of the transition state. However, all previous crystal structures of the Michaelis complex mimics of the PKA catalytic subunit (PKAc) were obtained with either peptide inhibitors or ATP analogs. Here we utilized Ca(2+) ions and sulfur in place of the nucleophilic oxygen in a 20-residue pseudo-substrate peptide (CP20) and ATP to produce a close mimic of the Michaelis complex. In the ternary reactant complex, the thiol group of Cys-21 of the peptide is facing Asp-166 and the sulfur atom is positioned for an in-line phosphoryl transfer. Replacement of Ca(2+) cations with Mg(2+) ions resulted in a complex with trapped products of ATP hydrolysis: phosphate ion and ADP. The present structural results in combination with the previously reported structures of the transition state mimic and phosphorylated product complexes complete the snapshots of the phosphoryl transfer reaction by PKAc, providing us with the most thorough picture of the catalytic mechanism to date.


Sudden Cardiac Death Following Thrombolysis in a Young Woman with Spontaneous Coronary Artery Dissection: A Case Report.
BACKGROUND Spontaneous coronary artery dissection (SCAD) is a well-known cause of acute coronary syndrome. ST-segment elevation myocardial infarction (STEMI) is the most common presentation of SCAD, which can be complicated by sudden cardiac death (SCD). Conservative management is the cornerstone of treatment except in case of ongoing ischemia or large myocardial compromise. CASE REPORT A 34-year-old woman presented with an anterior STEMI, diagnosed by the Emergency Medical Service (EMS) team, which performed fibrinolysis. SCD resulting from ventricular fibrillation occurred soon after thrombolysis was started. Her pulsed was palpable following defibrillation, and she was immediately intubated. A coronary angiogram (CA) showed total occlusion with dye staining contrast of the proximal left anterior descending (LAD) coronary artery. Echocardiogram showed a severe drop in the left ventricular ejection fraction (LVEF 20%). She was treated with dobutamine and intra-aortic balloon pump implantation because of her poor hemodynamic status. Rescue angioplasty was performed with a drug-eluting stent implanted from the left main stem toward the proximal LAD. However, she developed hemorrhagic shock due to active liver bleeding that was surgically treated. At 3 months, she was asymptomatic, her LVEF had improved (45%), and elective CA showed quite normal coronary arteries. Optical coherence tomography showed residual hematoma as "lunar crescent" and stent under-expansion. The latter was fixed by post-dilatations. CONCLUSIONS Our case adds to the evidence that thrombolysis leads to poor outcomes in patients with SCAD, as reported in numerous reports. OCT was used to confirm, a posteriori, the diagnosis of SCAD. Rescue angioplasty was necessary in our patient due to poor hemodynamic status following unsuccessful fibrinolysis.


The societal burden of poor persistence to treatment of osteoporosis in Sweden.
Poor persistence to prescribed treatment regimens is a well-documented health problem. The issue is of particular importance in treatment of chronic diseases, such as osteoporosis. The objective of this study was to estimate the annual societal burden of real-world persistence to treatment of osteoporosis in Sweden. A second aim was to estimate the monetary net benefit of improved persistence. The annual societal burden was evaluated in relation to perfect persistence to a five-year treatment duration and performed using a published Markov model by Ström and colleagues. The target population was extracted from the Swedish Prescribed Drug Register and based on all treatment-naïve patients who started therapy of primary osteoporosis in Sweden during 2009. Five hypothetical interventions were investigated, with improvements in the persistent proportion of between 10% and 50%. Annually, a total of 1018 fractures were estimated to be caused by non-persistence to treatment of osteoporosis in Sweden. These fractures resulted in a substantial waste of health care resources related to morbidity (€26 million annually) and a loss, in total, of 771 quality-adjusted life-years (QALYs). Using a societal willingness-to-pay for a QALY of €60000, the total annual societal burden, incorporating both monetary consequences and health effects, was estimated at €62.76 million. Given current Swedish cost-effectiveness guidelines, between approximately €225 and €1130 could be spent per patient to increase persistence, depending on the level of improvement (between 10% and 50%). The total annual societal burden of current, real-world persistence was estimated at €63 million. The estimated additional fracture-related costs associated with poor persistence were larger than the current total annual expenditure on all osteoporosis medications in Sweden. Poor persistence to treatment of osteoporosis should consequently be acknowledged as an important and costly health problem, and be taken into account when evaluating osteoporosis interventions.


Structural basis for the interaction of isoDGR with the RGD-binding site of alphavbeta3 integrin.
Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I5) generates isoDGR, an alphavbeta3 integrin-binding motif regulating endothelial cell adhesion and proliferation. By NMR and molecular dynamics studies, we analyzed the structure of CisoDGRC (isoDGR-2C), a cyclic beta-peptide mimicking the FN-I5 site, and compared it with NGR, RGD, or DGR-containing cyclopeptides. Docking experiments show that isoDGR, exploiting an inverted orientation as compared with RGD, favorably interacts with the RGD-binding site of alphavbeta3, both recapitulating canonical RGD-alphavbeta3 contacts and establishing additional polar interactions. Conversely, NGR and DGR motifs lack the fundamental pharmacophoric requirements for high receptor affinity. Therefore, unlike NGR and DGR, isoDGR is a new natural recognition motif of the RGD-binding pocket of alphavbeta3. These findings contribute to explain the different functional properties of FN-I5 before and after deamidation, and provide support for the hypothesis that NGR --> isoDGR transition can work as a molecular timer for activating latent integrin-binding sites in proteins, thus regulating protein function.


The usefulness of mesenterium thickness as an index of visceral fat accumulation.
Visceral fat syndrome, which includes visceral fat accumulation, glucose intolerance, hyperlipidemia, and hypertension, refers to a highly atherogenic state with a cluster of risk factors secondary to visceral fat accumulation. Although X-ray computed tomography (CT) is used commonly in diagnosis of visceral fat accumulation, it is expensive and exposes the patient to radiation. Some indices obtained using ultrasonography, which is fast and easy to use, have been reported. The ratio of the maximum thickness of preperitoneal fat (P) to the minimum thickness of subcutaneous fat (S), the abdominal wall fat index (P/S), is widely used in ultrasonographic diagnosis, however, this ratio tends to vary largely according to examiners. To establish a more reliable ultrasonographic index of visceral fat accumulation, we measured the thickness of the mesenterium, and tried to examine the relation between its thickness and maximum thickness of preperitoneal fat, minimum thickness of subcutaneous fat, and abdominal wall fat index, as well as body mass index, systolic and diastolic blood pressure, and levels of serum triglyceride, high-density lipoprotein cholesterol, total cholesterol, and blood sugar. The subjects were 131 individuals, 98 males and 33 females, averaging 47.0±7.9 years, with a mean body mass index of 24.1±2.6. The mesenterium was measured with a 3.5 or 3.75 MHz convex probe by longitudinal scanning on the left side of the umbilicus of the patient in the supine position. The thickness of the mesenterium correlated positively with maximum thickness of the preperitoneal fat, abdominal wall fat index, body mass index, and levels of serum triglyceride, total cholesterol, and blood sugar, and negatively with levels of high-density lipoprotein cholesterol. When the subjects were divided into a high-M group and a normal-M group, body mass index, triglyceride level, and blood sugar levels in the high-M group were significantly higher and level of high-density lipoprotein cholesterol was significantly lower than in the normal-M group. These results suggest that the thickness of mesenteium measured by ultrasonography may be useful in the diagnosis of accumulation of visceral fat.


Mastery learning improves simulated central venous catheter insertion by emergency medicine teaching faculty.
Routine competency assessments of procedure skills, such as central venous catheter (CVC) insertion, do not occur beyond residency training. Evidence suggests variable, suboptimal attending physician procedure skills. Our study aimed to assess CVC insertion skill by academic emergency physicians, determine whether a simulation-based mastery learning (SBML) intervention improves performance and investigate for variables that predict competence. This is a pretest-posttest study that evaluated simulated CVC insertion by emergency medicine (EM) faculty physicians. We assessed 44 volunteer participants at a large academic medical center over a 1-month period using a published 29-item checklist. Our primary outcome was the difference in assessment score before and after a SBML intervention. A secondary analysis evaluated predictors of pretest performance. A total of 44 subjects participated. Only four of 44 (9.1%) of subjects met a predefined minimum passing score on pretest. Mean assessment scores increased by 21.5% following the SBML intervention (95% confidence interval [CI] of the difference = 18.1% to 24.8%, p < 0.001). In a regression model, pretest scores increased by 10.8% (95% CI = 2.9 to 18.7%, p = 0.009) if subjects completed postgraduate training within 5 years. Frequency of CVC insertion did not predict performance, but 25 of 44 (56.8%) faculty members had no documented performance or supervision of a CVC insertion within 1 year of assessment. SBML is a promising method to assess and improve CVC insertion performance by EM faculty physicians. Recent completion of postgraduate training was a significant predictor of CVC insertion performance. Our results require validation in larger cohorts of EM physicians across other academic institutions.


Does a complex model help to understand grasping?
Several studies have demonstrated a peculiar effect of initial aperture on the grip formation in reach-to-grasp movements. We compare these findings with the predictions of two models for prehension. The first is a very simple model that only describes the movements of the end-effectors. The second model is rather complex and takes postural constraints into account. Both models can account for many aspects of human grasping when the movement starts with the digits in contact. We compare the models' performance with published data on other initial configurations. Both models predict an effect of initial aperture that was not present in the data. The model that considers postural constraints does not perform better than the simple model. We conclude that such constraints are not responsible for the main characteristics of the reach-to-grasp movement.


Docetaxel (Taxotere) in advanced renal cell cancer. A phase II trial of the EORTC Early Clinical Trials Group.
Docetaxel (Taxotere), an analogue of paclitaxel, was tested in a phase II study in advanced renal cell carcinoma. Consenting patients with measurable lesions, adequate organ functions and no prior chemotherapy received 100 mg/m2 of docetaxel as a 1-h infusion every 3 weeks. No premedication to avoid hypersensitivity reactions or nausea and emesis was given. 32 eligible patients received 100 treatment cycles. Short-lasting neutropenia was the dose-limiting toxicity. Acute hypersensitivity reactions (HSR), oedema and skin changes were other important side-effects. HSRs regressed spontaneously or were treated with antihistamines with or without corticosteroids. One partial remission was documented. At the dose and schedule used, docetaxel has only low activity against renal cell carcinoma.