[Etiology, pathogenesis and management of senile inflammatory pulmonary diseases].
We studied the etiology, pathogenesis and management of therapy-resistant inflammatory pulmonary diseases. First, to understand the pathogenesis of rhinovirus (RV) infection-induced exacerbation of bronchial asthma, we infected cultured human tracheal epithelial cells with RV. The epithelial cells produced a variety of proinflammatory cytokines, intercellular adhesion molecules (ICAM-1) and low-density lipoprotein receptor, and increased the permeability across the epithelial cells. These findings suggest that these factors and the increased permeability may cause airway inflammation, resulting in the exacerbation of asthma. Glucocorticoid and bafilomycin inhibited RV infection in the epithelial cells by reducing ICAM-1 expression and RV RNA entry from the acidic endosomes to the cytoplasm. Second, we revealed the mechanisms of aspiration pneumonia induced by silent aspiration in patients with cerebral infarction. We also developed a pharmacologic treatment for preventing aspiration pneumonia with amantadine, which stimulates the dopaminergic neurons; the angiotensin-converting enzyme inhibitors, which decrease substance P catabolism; and cilostazol, which inhibits platelet aggregation and induces cerebral vasodilation. Third, we demonstrated that exhaled carbon monoxide concentrations caused by heme oxygenase-1 upregulation, may be a useful noninvasive means of monitoring airway inflammation and of controlling elderly patients with bronchial asthma. Finally, we demonstrated that microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema caused by cigarette smoke in Japanese patients with chronic pulmonary emphysema.


The T-type calcium channel enhancer SAK3 inhibits neuronal death following transient brain ischemia via nicotinic acetylcholine receptor stimulation.
The T-type calcium channel enhancer SAK3 (ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridin]-2-ene-3-carboxylate) promotes acetylcholine (ACh) release in mouse hippocampus, enhancing cognitive function. Here, we tested SAK3 neuroprotective activity in the context of transient brain ischemia using a 20-min bilateral common carotid arteries occlusion (BCCAO) mouse model. Mice were administered with SAK3 (0.1, 0.5 or 1.0 mg/kg, p.o.) 24 h after BCCAO ischemia. Oral SAK3 (0.5 or 1.0 mg/kg/day, p.o.) administration significantly blocked loss of hippocampal CA1 neurons and memory deficits seen in BCCAO mice. Treatment with α7 nicotinic ACh receptor (nAChR)-selective inhibitor methyllycaconitine (MLA: 6.0 mg/kg/day, i.p.) significantly antagonized both neuroprotection and improvement in memory promoted by SAK3 (0.5 mg/kg/day, p.o.). Acute SAK3 (0.5 mg/kg, p.o.) administration significantly enhanced protein kinase B (Akt) phosphorylation levels in CA1 of control and BCCAO mice. Importantly, treatment of control and BCCAO mice with the non-selective nAChR antagonist mecamylamine (MEC: 1.0 mg/kg, i.p.) or the α7-selective nAChR antagonist MLA (6.0 mg/kg, i.p.), but not the M1 muscarinic ACh receptor (mAChR) antagonist pirenzepine (PZ: 10 mg/kg, i.p.), blocked enhanced Akt activity elicited by SAK3 (0.5 mg/kg, p.o.). We also confirmed that decreased phosphorylated Akt immunoreactivities were rescued by SAK3 (0.5 mg/kg, p.o.) administration in NeuN-positive CA1 neurons of BCCAO mice, an effect blocked by MLA (6.0 mg/kg, i.p.). Finally, we observed α7 nAChR and phosphorylated Akt expression in CA1 pyramidal neurons. We conclude that the T-type calcium channel enhancer SAK3 is neuroprotective in the context of brain ischemia by stimulating nicotinic cholinergic neurotransmission.


Eco-friendly mixed metal (Mg-Ni) ferrite nanosheets for efficient electrocatalytic water splitting.
Eco-friendly and cost-effective catalysts with multiple active sites, large surface area, high stability and catalytic activity are highly desired for efficient water splitting as a sustainable green energy source. Within this line, a facile synthetic approach based on solventless thermolysis was employed for the simple and tunable synthesis of Ni1-xMgxFe2O4 (0 ≤ x ≤ 1) nanosheets. The characterization of nanosheets (via p-XRD, EDX, SEM, TEM, HRTEM, and SAED) revealed that the pristine ferrites (NiFe2O4 and MgFe2O4), and their solid solutions maintain the same cubic symmetry throughout the composition regulation. Elucidation of the electrochemical performance of the nanoferrite solid solutions showed that by tuning the local chemical environment of Ni in NiFe2O4 via Mg substitution, the intrinsic catalytic activity was enhanced. Evidently, the optimized Ni0.4Mg0.6Fe2O4 catalyst showed drastically enhanced HER activity with a much lower overpotential of 121 mV compared to the pristine NiFe2O4 catalyst. Moreover, Ni0.2Mg0.8Fe2O4 catalyst exhibited the best OER performance with a low overpotential of 284 mV at 10 mA/cm2 in 1 M KOH. This enhanced electrocatalytic activity could be due to improved electronic conductivity caused by the partial substitution of Ni2+ by Mg2+ in the NiFe2O4 matrix as well as the synergistic effect in the Mg-substituted NiFe2O4. Our results suggest a feasible route for developing earth-abundant metal oxide-based electrocatalysts for future water electrolysis applications.


Triple therapy after PCI - Warfarin treatment quality and bleeding risk.
A combination of warfarin, aspirin and clopidogrel is indicated after percutaneous coronary intervention (PCI) in some patients, despite the higher risk of bleeding inferred by this triple therapy. Whether the treatment quality of warfarin measured by iTTR (individual time within therapeutic INR range) is associated with bleeding complications during triple therapy after PCI. A retrospective register study consisting of 601 triple treated PCI patients from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). The cohort was cross-matched with the Swedish Patient Registry for background characteristics and bleeding complications up to 6 months after PCI using ICD10 codes, the Prescribed Drug Registry for ongoing medications, and the national oral anticoagulation registry Auricula for warfarin treatment quality. The patients were grouped into four iTTR groups: <50%, 50-69.9%, 70-84.9% and >85% as well as iTTR above or below 70%. Of 601 patients, 39 (6.5%) had a bleeding complication (type 2 according to BARC). Bleeding was more common for iTTR<70% compared to iTTR>70%, 28 (9.3%) vs. 11 (3.7%) (p = 0.005). The bleeding frequency increased gradually from the best group, iTTR>85% with four bleeders (3.3%) up to 17 bleeders (13.3%) in the worst group with iTTR<50% (p = 0.003), with a corresponding bleeding rate per 100 treatment years of 8.0 and 44.9, respectively. In multivariate analysis low BMI, HR 1.11 (95% CI 1.01-1.22), a medical history of anemia HR 3.17 (1.16-8.69) and iTTR < 70% HR 2.86 (1.25-6.53) increased the risk of bleeding. Triple therapy after PCI confers a high risk of bleeding events. Warfarin treatment quality measured by iTTR as well as a medical history of anemia are strong independent predictors of bleeding in these patients. Physicians should pay more attention to iTTR after PCI.


Phase function design of a diffraction grating lens for an optical imaging system from a Fraunhofer diffraction perspective.
The potential exists to apply diffraction gratings to optical imaging systems to improve camera resolution and shorten optical length. However, we have noted the generation of striped flare lights, which differ from unnecessary-order diffraction lights, under intense lighting. We have elucidated the generation principle of these new striped lights and have discovered that they are caused by narrow diffraction grating rings. In this paper, using an analysis based on Fraunhofer diffraction, we suggest a way of minimizing them by designing an appropriate phase function structure, and test the efficacy of this design using our own manufactured prototype.


Outcomes of Treatment of Spinal Fractures with the SpineJack System.
The use of "SpineJack" implants in patients with stable spinal fractures and without neurological deficits enables restoration of the shape of the fractured vertebra and significantly accelerates restoration of normal function. In unstable spinal fractures, additional posterior fixation is recommended. This is not recommended in patients with traumatic spinal stenosis. The aim of the study was to evaluate the surgical and functional outcomes of treatment of patients with the SpineJack implant. The objectives of this paper were accomplished on the basis of an evaluation of the outcomes of treatment of 39 patients operated on at the Orthopaedic Oncology Department in Brzozów and the Department of Orthopaedics and Traumatology in the District Hospital in Stalowa Wola in the years 2020-2021. 71% of patients were men; the mean age of women was 54 years and the mean age of men was 41 years. A total of 30 patients suffered traumatic fractures, while 9 patients suffered non-traumatic (pathological) fractures. Fractures were most often located in the lower parts of the thoracic and upper lumbar spine. Patient radiographs taken on the day before, the first day after and 3 months following the surgery were evaluated to assess the correction of vertebral wedging and cement leakage. Functional status was assessed using ODI, the quality of life was assessed with the EQ-VAS and the severity of pain was measured with a VAS. Pain intensity, measured with a VAS scale after the surgery, significantly decreased from the mean preoperative 6.9 to 2.4 three months post-op. The mean functional status of patients (ODI) before surgery was 74.4, compared to 14.8 at 3 months post-op. Mean Quality of life (EQ-VAS) was 56.4 before the surgery and 72.4 at 3 months post-op. The vertebral wedge angle decreased after surgical treatment, from a mean value of 15.8 degrees before surgery to 8.8 degrees after surgical treatment. At three months following the surgery, the mean loss of correction was 2.2 degrees and occurred in 4 patients. The most frequent complication was cement leakage into the disc and into the spinal canal, occurring in 4 and 2 patients, respectively. 1. The use of "SpineJack" implants in the treatment of stable vertebral fractures enables the restoration of the shape and reduction of the vertebral wedge angle. 2. The quality of life of patients after vertebral fracture treatment with "SpineJack" implants assessed using the EQ-VAS improved significantly. The severity of pain assessed on a VAS scale decreased significantly and the patients' functional status improved according to the ODI. 3.Complications observed during treatment with "SpineJack" implants include fractures of the vertebral endplate and cement leakage, mostly asymptomatic.


Respiratory symptoms and lung function in poultry confinement workers in Western Canada.
To determine whether poultry production methods impact respiratory health, and whether poultry farmers have more respiratory symptoms and lower lung function than comparison control groups. Cross-sectional study. Provinces of Saskatchewan, Alberta and Manitoba during the winters of 1997 to 1999. Three hundred three poultry workers, 241 grain farmers and 206 nonfarming control subjects were studied. Poultry workers were further classified according to the poultry housing type in which they worked, ie, workers who worked with poultry raised on the floor (floor-based operations), which included broiler/roaster, broiler/breeder and turkey operations (n=181), and workers who worked with poultry raised in a caged setting (cage-based operations), which included egg operations (n=122). Subjects completed a respiratory health questionnaire, which included questions on the poultry operation and work habits, and participated in lung function testing. Overall, this study indicated that poultry workers report greater prevalences of current and chronic respiratory symptoms than control populations, and that the type of production method (cage-based versus floor-based) appears to influence the prevalence of respiratory symptoms and lung function values. Workers from cage-based operations report greater prevalences of current cough and wheeze, as well as lower mean values for forced expiratory volume in the first second (FEV1), forced expiratory flow at 25% to 75% of vital capacity (FEF25-75) and FEV1/FVC than workers from floor-based facilities. Workers from cage-based facilities also reported greater prevalences of current and chronic cough and phlegm, as well as significantly lower FEF25-75 and FEV1/FVC values than nonfarming control subjects. Furthermore, grain farmers had lower FVC and FEV1 values than nonfarmers. The results suggest that the type of poultry production system (ie, floor- versus cage-based) appears to have an effect on the respiratory response of workers from these facilities. Further studies are required to understand the physiological mechanisms of respiratory dysfunction and the relationships concerning workplace exposure among poultry workers.


Antigen-containing liposomes engrafted with flagellin-related peptides are effective vaccines that can induce potent antitumor immunity and immunotherapeutic effect.
The bacterial protein flagellin can trigger immune responses to infections by interacting with TLR5 on APCs, and Ag-flagellin fusion proteins can act as effective vaccines. We report that flagellin-related peptides containing a His-tag and sequence related to conserved N-motif (aa 85-111) of FliC flagellin, purportedly involved in the interaction of flagellin with TLR5, can be used to target delivery of liposomal Ag to APCs in vitro and in vivo. When engrafted onto liposomes, two flagellin-related peptides, denoted as 9Flg and 42Flg, promoted strong liposome binding to murine bone marrow-derived dendritic cells and CD11c(+) splenocytes, and cell binding correlated with expression of TLR5. Liposomes engrafted with 9Flg or 42Flg induced functional MyD88-dependent maturation of dendritic cells in vivo. The vaccination of mice with 9Flg liposomes containing OVA induced OVA-specific T cell priming, increased the number of Ag-responsive IFN-gamma-producing CD8(+) T cells, and increased Ag-specific IgG(1) and IgG(2b) in serum. Importantly, the vaccination of C57BL/6 mice with syngeneic B16-OVA-derived plasma membrane vesicles, engrafted with 9Flg or 42Flg, potently inhibited tumor growth/metastasis and induced complete tumor regression in the majority of mice challenged with the syngeneic B16-OVA melanoma, in the lung and s.c. tumor models. Strong antitumor responses were also seen in studies using the s.c. P815 tumor model. Therefore, vaccination with Ag-containing liposomes engrafted with 9Flg or 42Flg is a powerful strategy to exploit the innate and adaptive immune systems for the development of potent vaccines and cancer immunotherapies.


Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis.
Cell-based therapies are attractive approaches to promote myelin repair. Recent studies demonstrated a reduction in disease burden in mice with experimental allergic encephalomyelitis (EAE) treated with mouse mesenchymal stem cells (MSCs). Here, we demonstrated human bone marrow-derived MSCs (BM-hMSCs) promote functional recovery in both chronic and relapsing-remitting models of mouse EAE, traced their migration into the injured CNS and assayed their ability to modulate disease progression and the host immune response. Injected BM-hMSCs accumulated in the CNS, reduced the extent of damage and increased oligodendrocyte lineage cells in lesion areas. The increase in oligodendrocytes in lesions may reflect BM-hMSC-induced changes in neural fate determination, since neurospheres from treated animals gave rise to more oligodendrocytes and less astrocytes than nontreated neurospheres. Host immune responses were also influenced by BM-hMSCs. Inflammatory T-cells including interferon gamma producing Th1 cells and IL-17 producing Th17 inflammatory cells and their associated cytokines were reduced along with concomitant increases in IL-4 producing Th2 cells and anti-inflammatory cytokines. Together, these data suggest that the BM-hMSCs represent a viable option for therapeutic approaches.


Cytoplasmic inheritance in Saccharomyces cerevisiae: comparison of zygotic mitochondrial inheritance patterns.
Mitochondrial movements in Saccharomyces cerevisiae (Sc) zygotes were monitored with phase-contrast microscopy and compared to known mitochondrial inheritance systems. The mitochondria of Sc were convincingly identified by integrated use of phase-contrast, cytochemical and electron microscopic observations. Mitochondria in Sc appear to move by saltatory jumps, which appear to be oriented towards movement of mitochondria into developing buds. Tracking of mitochondria of different genotypes was made possible by positive identification of each mitochondrial population before zygosis, and by the low degree of mixing (less than 10%) of mitochondrial populations before first bud septation. A grande by grande cross demonstrated equal numbers of mitochondria from each haploid moving into the first zygotic bud. A grande by neutral petite cross gave a 2:1 ratio of grande to petite mitochondria. However, a grande by suppressive petite cross gave equal numbers of grande and petite mitochondria. Using drug resistance systems, a comparison was made of highly biased (97%) and moderately biased (71%) chloramphenicol resistant inheritance patterns. In both cases, the ratios of drug resistant to sensitive mitochondria were 1:1. When numbers of mitochondria moving into an individual bud were compared to the phenotypic content of the clone of that bud, no model could be constructed which could predict the latter from the former. The data indicate (with the exception of the neutral petite by grande cross) that the numbers of each mitochondrial type "inserted" into the first zygotic bud are equal, regardless of the degree of asymmetry of inheritance of mitochondrial markers.


Antibiotic-resistant staphylococcus infections.
Strains of antibiotic-resistant staphylococci that develop in a hospital are becoming increasingly important as a cause of untoward complications of hospitalization. The hospital environment and hospital personnel present the chief reservoir of antibiotic-resistant strains; and they, as well as patients discharged after hospital stay, may represent the greatest source of antibiotic-resistant strains found in the community at large.Cross infection appears to be thwarted by rigid adherence to antiseptic techniques.


Comparing a series of 8-quinolinolato complexes of aluminium, titanium and zinc as initiators for the ring-opening polymerization of rac-lactide.
The preparation and characterization of a series of 8-hydroxyquinoline ligands and their complexes with Ti(IV), Al(III) and Zn(II) centres is presented. The complexes are characterized using NMR spectroscopy, elemental analysis and, in some cases, by single crystal X-ray diffraction experiments. The complexes are compared as initiators for the ring-opening polymerization of racemic-lactide; all the complexes show moderate/good rates and high levels of polymerization control. In the case of the titanium or aluminium complexes, moderate iso-selectivity is observed (Pi = 0.75), whereas in the case of the zinc complexes, moderate hetero-selectivity is observed (Ps = 0.70).


Resolving plant development in space and time with single-cell genomics.
Single-cell genomics technologies are ushering in a new research era. In this review, we summarize the benefits and current challenges of using these technologies to probe the transcriptional regulation of plant development. In addition to profiling cells at a single snapshot in time, researchers have recently produced time-resolved datasets to map cell responses to stimuli. Live-imaging and spatial transcriptomic techniques are rapidly being adopted to link a cell's transcriptional profile with its spatial location within a tissue. Combining these technologies is a powerful spatiotemporal approach to investigate cell plasticity and developmental responses that contribute to plant resilience. Although there are hurdles to overcome, we conclude by discussing how single-cell genomics is poised to address developmental questions in the coming years.


Topical cerium nitrate prevents postburn immunosuppression.
Suppression of cell-mediated immunity (CMI) follows a major thermal injury and is associated with an increased incidence of serious infections. Adult female CF-1 mice received a 20% full-thickness steam burn and were then treated with various topical antimicrobial creams in an attempt to alter the course of postburn immunosuppression. Topical agents included cerium nitrate (CE), silver sulfadiazine (SSD), mafenide (SML), silver nitrate (AG), and a mixture of CE and SSD (CE-SSD). CMI was determined in vivo by measuring ear swelling in response to 2,4-dinitrofluorobenzene (DNFB) challenge in previously sensitized mice. The usual nadir in CMI (ear swelling) when mice were sensitized at day 14 postburn did not occur in burned mice treated with CE or CE-SSD, AG was only modestly effective, and SML or SSD failed to restore CMI. These studies suggest that topical CE may have potential as an immunomodulator in the treatment of burns.


The series elastic component and the force-velocity relation in the anterior byssal retractor muscle of Mytilus edulis during active and catch contractions.
1. The length changes of the anterior byssal retractor muscle (ABRM) of Mytilus edulis, following step changes in load, were studied at various phases of active and catch contractions produced by acetylcholine. 2. The load-extension curves of the series elastic component (SEC) were found to be scaled down in proportion to the isometric tension immediately before step changes in load, but remain unchanged irrespective of whether the ABRM was in active or in catch contraction. 3. In hypertonic solutions the compliance of the SEC was reduced in the same manner as that of the SEC in frog skeletal muscle. 4. These results seem to favour the linkage hypothesis for the catch mechanism, though the SEC in the ABRM is suggested to be composed not only of the cross-linkages, but also of the compliance of the myofilaments.


Label-free rapid identification of tumor cells and blood cells with silver film SERS substrate.
The detection of circulating tumor cells (CTCs) from peripheral blood is considered as great significance for the diagnosis and prognosis of cancer patients. Raman spectroscopy is a highly sensitive optical detection technique that can provide fingerprint molecular identification information. In this paper, the silver film substrate surface-enhanced Raman scattering (SERS) was used to research several tumor cells, immortalized cells, clinical cancer cells isolated from cancer patient's tissue and blood cells. The results display that there is great difference for the nucleic acid characteristic peaks of those cells. The red blood cells have almost none nucleic acid characteristic peak and the SERS signals of white blood cells are only a slight increase. Except for immortalized cells and few tumor cells, the nucleic acid characteristic peaks of some tumor cells have huge enhancement. Nucleic acid characteristic peaks of clinical cancer cells also have greater enhancement. The discriminant model established by the intensity ratio of the nucleic acid characteristic peak 730 cm-1 to the substrate background peak 900 cm-1 shows that some tumor cells and clinical sample cells can be separated from white blood cells, but tumor cells with relatively low-DNA index cannot be differentiated from white blood cells. This study demonstrates that thin-film SERS technology can distinguish between blood cells and some types of tumor cells. This study opens up a new possible method for the detection of CTCs with label-free SERS spectra.


LDH isoenzymes and myocardial infarction in patients undergoing coronary bypass surgery: an excellent correlation.
To evaluate the efficacy of LDH isoenzymes in the detection of myocardial infarction in patients undergoing coronary bypass surgery, 73 patients were studied pre- and postoperatively by ECG, CPK, SGOT, total serum LDH, and LDH isoenzyme measurements. A reversal of the LDH1:LDH2 ratio was considered indicative of myocardial necrosis. Accordingly, the patients were separated into two groups: Group A (23 patients) who demonstrated an LDH1:LDH2 ratio exceeding 1.0 and Group B (50 patients) who failed to reveal an LDH1;LDH2 reversal. The two groups were similar in regard to preoperative evaluation and operative procedure performed. The postoperative ECG findings were significantly different. In Group A 18 of 23 patients (78 per cent) developed significant new Q waves. This occurred in only one patient in Group B. Significant arrhythmias occurred in 70 per cent of the patients in Group A as compared to 14 per cent of those patients in Group B. Severe congestive heart failure and/or clinical evidence of shock occurred in 39 per cent of Group A patients and in none in Group B. The results of our study indicate that the reversal of the LDH1:LDH2 ratio is a valuable tool for the evaluation of postoperative myocardial infarction.


Affinity labelling of alcohol dehydrogenases. Chemical modification of the horse liver and the yeast enzymes with alpha-bromo-beta(5-imidazolyl)-propionic acid and 1,3-dibromoacetone.
1. DL-alpha-Bromo-beta(5-imidazolyl)-propionic acid is a potential affinity labelling reagent for metallo-enzymes. It has been used with the alcohol dehydrogenases from liver and yeast. The liver enzyme is chemically modified and inactivated in a Michaelis-Menten-type reaction, where one molecule of the reagent is bound per subunit. The enzyme is protected from the inhibitor in a competitive manner by imidazole, 2,2'-dipyridyl, 1,10-phenanthroline and cyclohexanone, which all combine with the active-site zinc. The protection by chloride, acetate and NADH, which are considered to bind at the general anion binding site, is not strictly competitive. Inactivation has an optimum at pH 8.5. For the liver enzyme, the reagent was found to decrease the initial rate of ethanol oxidation. Prior to the irreversible alkylation of Cys-46, reversible binding is shown to occur at the active-site zinc atom. The yeast enzyme was extremely resistant to the reagent and no specific modification was found. 2. The potential affinity labelling and crosslinking reagent, symmetrical 1,3-dibromoacetone although unstable, has also been used for chemical modification. With the liver enzyme, concentrations below 5 mM gave a reaction of the Michaelis-Menten-type at pH 7.0. Several ligands known to complex with the active-site region protect the enzyme against the reagent. Dibromoacetone gave rapid inactivation of the yeast enzyme. Despite the fact that a pseudo-first-order reaction was observed with respect to enzyme as well as inhibitor, no saturating effect was found. In this work, dibromoacetone reacted like a monofunctional reagent.


SAS macros for point and interval estimation of area under the receiver operating characteristic curve for non-proportional and proportional hazards Weibull models.
For prediction of risk of cardiovascular end points using survival models the proportional hazards assumption is often not met. Thus, non-proportional hazards models are more appropriate for developing risk prediction equations in such situations. However, computer program for evaluating the prediction performance of such models has been rarely addressed. We therefore developed SAS macro programs for evaluating the discriminative ability of a non-proportional hazards Weibull model developed by Anderson (1991) and that of a proportional hazards Weibull model using the area under receiver operating characteristic (ROC) curve. Two SAS macro programs for non-proportional hazards Weibull model using Proc NLIN and Proc NLP respectively and model validation using area under ROC curve (with its confidence limits) were written with SAS IML language. A similar SAS macro for proportional hazards Weibull model was also written. The computer program was applied to data on coronary heart disease incidence for a Framingham population cohort. The five risk factors considered were current smoking, age, blood pressure, cholesterol and obesity. The predictive ability of the non-proportional hazard Weibull model was slightly higher than that of its proportional hazard counterpart. An advantage of SAS Proc NLP in terms of the example provided here is that it provides significance level for the parameter estimates whereas Proc NLIN does not. The program is very useful for evaluating the predictive performance of non-proportional and proportional hazards Weibull models.


Perception of toxicity and dose by 3- and 4-year-old children.
Three and 4-year-old children from two suburban preschools were individually interviewed to assess their knowledge of the effects of ingesting a household product, a candy, and a common drug. Most children understood that scouring cleanser was toxic. Children reported that candy was safe to eat, even in large amounts. However, vitamins were not perceived by all children as having a dose-related toxicity. This understanding developed with age, and boys were better than girls at differentiating between a usual and an excessive dose of vitamins. One overdose occurred, perhaps because of an increase in the child's interest in vitamins after the interview. More research is needed to broaden our understanding of children's knowledge of the toxicity of poisons. The results of the present study provided information needed for the formulation of educational objectives for a preschool poison prevention program. We believe the primary message is that nothing should be eaten unless it is approved by an adult.


Prevention of hospital payment errors and implications for case management: a study of nine hospitals with a high proportion of short-term admissions over time.
Since the publication of the first analysis of Medicare payment error rates in 1998, the Office of Inspector General and the Centers for Medicare & Medicaid Services have focused resources on Medicare payment error prevention programs, now referred to as the Hospital Payment Monitoring Program. The purpose of the Hospital Payment Monitoring Program is to educate providers of Medicare Part A services in strategies to improve medical record documentation and decrease the potential for payment errors through appropriate claims completion. Although the payment error rates by state (and dollars paid in error) have decreased significantly, opportunities for improvement remain as demonstrated in this study of nine hospitals with a high proportion of short-term admissions over time. Previous studies by the Quality Improvement Organization had focused on inpatient stays of 1 day or less, a primary target due to the large amount of Medicare dollars spent on these admissions. Random review of Louisiana Medicare admissions revealed persistent medical record documentation and process issues regardless of length of stay as well as the opportunity for significant future savings to the Medicare Trust Fund. The purpose of this study was to determine whether opportunities for improvement in reduction of payment error continue to exist for inpatient admissions of greater than 1 day, despite focused education provided by Louisiana Health Care Review, the Louisiana Medicare Quality Improvement Organization, from 1999 to 2005, and to work individually with the nine selected hospitals to assist them in reducing the number of unnecessary short-term admissions and billing errors in each hospital by a minimum of 50% by the end of the study period. Inpatient Short-Term Acute Care Hospitals. A sample of claims for short-term stays (defined as an inpatient admission with a length of stay of 3 days or less excluding deaths, interim bills for those still a patient and those who left against medical advice) occurring during the baseline and remeasurement time frames was examined. The baseline period consisted of 1 month's claims-the complete month just prior to the start of approved project activities. Remeasurement was performed by each hospital and reported to the Quality Improvement Organization on a monthly basis following implementation of the hospital's quality improvement plan. Each hospital was required to provide a monthly remeasurement report by indicator until it had met its stated goal(s) for improvement for 2 consecutive months; therefore, each hospital completed its required monthly reporting for a specific indicator in a different month. Results were calculated for the following indicators: INDICATOR 1: Proportion of unnecessary short-term admissions = number of unnecessary short-term inpatient admissions/total short-term inpatient admissions in time frame. INDICATOR 2: Proportion of errors in billed treatment setting, that is, outpatient observation billed as inpatient = number of errors in billed treatment setting/total short-term admissions in time frame.Six of the 9 hospitals were able to accomplish reduction of their error rates within 6 months from the beginning of the study. The seventh hospital reached its goals in the 7th month, with the 2 remaining hospitals making progress toward their goals by the conclusion of the study. 1 Case managers must be up-to-date with payor requirements regarding medical record documentation for medical necessity of services and timing of inpatient admission, e.g., for Medicare, the date and time of the written physician's order for admission to the inpatient care setting is the date and time of inpatient admission. 2 The balancing of clinical decisions and financial considerations required of case managers in hospital settings remains an ongoing challenge. 3 Senior leadership must be engaged in ensuring the success of the case management program by providing the resources required. 4 Managers of case management programs must have in place an effective process to address compliance with changes in federal and state regulations and maintain collaborative relationships with senior leaders responsible for clinical, financial, and strategic plans and goals for the organization. 5 The case management process must include all related services, e.g., admissions, nursing services, health information management, finance/business services, contracting, medical staff, etc.


Hemodynamic responses to magnetic stimulation of carotid sinus in normotensive rabbits.
Carotid baroreflex plays a crucial role in regulating arterial pressure. Based on this knowledge, electrical stimulation of carotid sinus was designed for treating resistant hypertension. However, the clinical implication of electrical stimulation of carotid sinus is largely restrained due to obvious invasiveness. This study aimed to evaluate the efficacy of magnetic stimulation of carotid sinus (MSCS), a noninvasive strategy, for lowering blood pressure in rabbits. MSCS with graded intensities and frequencies were systematically attempted in normotensive rabbits. Blood pressure was recorded dynamically. Sinoaortic denervation and plasma hormone level analyses were performed. When the right carotid sinus was stimulated at 1 Hz frequency, a dose-effect relationship was observed between stimulation intensity (100-250% motor threshold) and mean arterial pressure (MAP) decrement (3.6 ± 1.0 to 10.4 ± 2.3 mmHg). When stimulation intensity was fixed at 200% motor threshold, the median reduction of MAP in 1-Hz group [10.8 (8.6-14.9) mmHg] was significantly higher than that in other frequency groups (all P < 0.05). Heart rates declined transiently after the initiation of MSCS. Compared with baseline (33.9 ± 5.5 pg/ml), plasma epinephrine level increased during MSCS (88.1 ± 9.6, P = 0.002). After ipsilateral sinoaortic denervation, MAP decrement (7.0 ± 0.8 mmHg) was remarkably blunted compared with that in sham animals (13.0 ± 1.1 mmHg, P = 0.001). The current study demonstrated that MSCS treatment can lower the arterial pressure in normotensive rabbits. This preliminarily result warrants further studies to establish the efficacy of MSCS in treating refractory hypertension.


Combination of a novel heat shock protein 90-targeted photodynamic therapy with PD-1/PD-L1 blockade induces potent systemic antitumor efficacy and abscopal effect against breast cancers.
We previously demonstrated potent antitumor activity against human breast cancer xenografts using photodynamic therapy (PDT) targeting a novel tumor-specific photosensitizer (HS201), which binds heat shock protein 90 (HS201-PDT). However, induction of systemic antitumor immunity by HS201-PDT alone or by the combination strategy with immune checkpoint blockade has yet to be determined. Using unilateral and bilateral implantation models of syngeneic breast tumors (E0771, MM3MG-HER2, and JC-HER3) in mice, we assessed whether HS201-PDT could induce local and systemic antitumor immunity. In an attempt to achieve a stronger abscopal effect for distant tumors, the combination strategy with anti-PD-L1 antibody was tested. Tumor-infiltrating leukocytes were analyzed by single cell RNA-sequencing and receptor-ligand interactome analysis to characterize in more detailed the mechanisms of action of the treatment and key signaling pathways involved. HS201-PDT demonstrated greater tumor control and survival in immune competent mice than in immunocompromised mice, suggesting the role of induced antitumor immunity; however, survival was modest and an abscopal effect on distant implanted tumor was weak. A combination of HS201-PDT with anti-PD-L1 antibody demonstrated the greatest antigen-specific immune response, tumor growth suppression, prolonged mouse survival time and abscopal effect. The most significant increase of intratumoral, activated CD8+T cells and decrease of exhausted CD8+T cells occurred following combination treatment compared with HS201-PDT monotherapy. Receptor-ligand interactome analysis showed marked enhancement of several pathways, such as CXCL, GALECTIN, GITRL, PECAM1 and NOTCH, associated with CD8+T cell activation in the combination group. Notably, the expression of the CXCR3 gene signature was the highest in the combination group, possibly explaining the enhanced tumor infiltration by T cells. The increased antitumor activity and upregulated CXCR3 gene signature induced by the combination of anti-PD-L1 antibody with HS201-PDT warrants the clinical testing of HS201-PDT combined with PD-1/PD-L1 blockade in patients with breast cancer, and the use of the CXCR3 gene signature as a biomarker.


Predicting local adaptation in fragmented plant populations: implications for restoration genetics.
Understanding patterns and correlates of local adaptation in heterogeneous landscapes can provide important information in the selection of appropriate seed sources for restoration. We assessed the extent of local adaptation of fitness components in 12 population pairs of the perennial herb Rutidosis leptorrhynchoides (Asteraceae) and examined whether spatial scale (0.7-600 km), environmental distance, quantitative (Q(ST)) and neutral (F(ST)) genetic differentiation, and size of the local and foreign populations could predict patterns of adaptive differentiation. Local adaptation varied among populations and fitness components. Including all population pairs, local adaptation was observed for seedling survival, but not for biomass, while foreign genotype advantage was observed for reproduction (number of inflorescences). Among population pairs, local adaptation increased with Q(ST) and local population size for biomass. Q(ST) was associated with environmental distance, suggesting ecological selection for phenotypic divergence. However, low F(ST) and variation in population structure in small populations demonstrates the interaction of gene flow and drift in constraining local adaptation in R. leptorrhynchoides. Our study indicates that for species in heterogeneous landscapes, collecting seed from large populations from similar environments to candidate sites is likely to provide the most appropriate seed sources for restoration.


Effects of ionophores and antibiotics on in vitro hydrogen sulfide production, dry matter disappearance, and total gas production in cultures with a steam-flaked corn-based substrate with or without added sulfur.
Effects of 3 ionophores and 2 antibiotics on in vitro H(2)S production, IVDMD, total gas production, and VFA profile with or without added S were examined. In Exp. 1, ruminal fluid from 2 ruminally cannulated steers fed a steam-flaked corn-based diet (75% concentrate) without ionophore and antibiotics for 28 d before collection was used to inoculate in vitro cultures. Treatments were control (no ionophore or antibiotic), 3 ionophores (lasalocid sodium and monensin sodium at 5 mg/L or laidlomycin propionate at 1.65 mg/L), and 2 antibiotics (chlortetracycline hydrochloride at 5 mg/L and tylosin tartarate at 1.25 mg/L). Cultures also had 0 or 1.75 mg of S/L (from sodium sulfate). No S x ionophore-antibiotic treatment interactions were noted (P > 0.53) for IVDMD, total gas production, and H(2)S production. Hydrogen sulfide (mumol/g of fermentable DM) was increased (P < 0.001), and total gas production tended (P = 0.09) to be increased with additional S; however, IVDMD was not affected by added S (P = 0.90). Production of H(2)S was not affected by ionophores or antibiotics (P > 0.18). On average, IVDMD (P = 0.05) was greater for ionophores than for antibiotics, whereas total gas production was less for ionophores than for control (P < 0.001) and antibiotics (P < 0.001). Molar proportions of acetate (P < 0.01) and acetate:propionate (P < 0.01) were decreased and propionate was increased (P < 0.001) in ionophore treatments when no S was added, but when S was added there were no differences (P > 0.20) in acetate, propionate, or acetate:propionate between ionophores and control (S x treatment interaction, P = 0.03). In Exp. 2, the effects of ionophore-antibiotic combinations with added S were examined using the same procedures as in Exp. 1. Treatments were control, monensin plus tylosin (MT), and lasalocid plus chlortetracycline (LCTC), with concentrations of the ionophores and antibiotics as in Exp. 1. No differences were observed among treatments for H(2)S production (P > 0.55). Treatments MT and LCTC tended (P = 0.06) to increase IVDMD and decreased (P = 0.02) gas production vs. control. Proportion of acetate (P = 0.01) and acetate:propionate (P < 0.01) were decreased and propionate increased (P = 0.01) for both MT and LCTC compared with control. These data suggest that when S is approximately 0.42% of substrate DM, the 3 ionophores and 2 antibiotics we evaluated did not affect production of H(2)S gas in an in vitro rumen culture system.


Sarcoidosis complicating treatment with natalizumab for Crohn's disease.
Natalizumab is a humanised monoclonal antibody targeting the lymphocyte adhesion molecule a4 integrin, with proven efficacy in multiple sclerosis (MS) and Crohn's disease (CD). The development of sarcoidosis with extrapulmonary involvement is reported in two patients with refractory CD who had received maintenance therapy with natalizumab. This complication has not been previously reported. It is hypothesised that the effect of natalizumab in altering lymphocyte mucosal trafficking may underlie the development of sarcoidosis in these patients.


Advances in natural compound-based nanomedicine and the interaction with gut microbiota in ulcerative colitis therapy.
Ulcerative colitis (UC) is a chronic inflammatory bowel disorder of the large intestine. Previous studies have indicated that the gut microbiota plays an important role in the triggers, development, and treatment response of UC. Natural active molecules and their nanoformulations show huge potential for treating UC. The nanoparticles can regulate the gut microbiota and metabolites, whereas gut microbiota-mediated effects on nanomedicines can also bring additional therapeutic benefits. Therefore, this review aims to integrate current research on natural active molecule-based nanomedicines for UC therapy and their interaction with the gut microbiota. Here, this discussion focuses on the effects and functions of gut microbiota and metabolites in UC. The use of active molecules and the nanoformulation from natural compounds for UC therapy have been provided. The interactions between the gut microbiota and nanomedicines are derived from natural products and elucidate the possible biological mechanisms involved. Finally, the challenges and future directions for enhancing the therapeutic efficacy of nanomedicine in treating UC are proposed.


Young driver distraction: state of the evidence and directions for behavior change programs.
Adolescent drivers are overrepresented in distraction-related motor vehicle crashes. A number of potential reasons for such an elevated risk include driving inexperience, high adoption of communication technology, increased peer involvement, and tendency to take risks, which render young drivers particularly vulnerable. Major legislative efforts in Graduated Licensing Systems that include passenger restrictions have shown positive effects. Restrictions on cell phone use are also being introduced; however, it is challenging to enforce such regulations. This article argues that such contextual, legislative interventions are an essential prevention strategy, but there is an unfilled need to introduce behavior change programs that may target adolescents, parents, and friends. A theoretical framework is applied in which risk and protective factors are identified from research within the contexts of community and jurisdiction. In the literature on distraction, social context and normative influences are key elements used to inform program design for adolescent drivers, with parental monitoring informing interventions targeting parents. Following from this assessment of the message content assessment, the design of strategies to deliver the messages is reviewed. In the current literature, school-based programs, simulations, and Web-delivered programs have been evaluated with supplementary strategies delivered by physicians and parents. Such developments are still at an early stage of development, and ultimately will need controlled implementation and evaluation studies. Of course, there is no likely single approach to prevent adolescent driver distraction. Complementary approaches such as the further development of technological interventions to manage phone use are needed.


Investigating arsenic susceptibility from a genetic perspective in Drosophila reveals a key role for glutathione synthetase.
Chronic exposure to arsenic-contaminated drinking water can lead to a variety of serious pathological outcomes. However, differential responsiveness within human populations suggests that interindividual genetic variation plays an important role. We are using Drosophila to study toxic metal response pathways because of unrivalled access to varied genetic approaches and significant demonstrable overlap with many aspects of mammalian physiology and disease phenotypes. Genetic analysis (via chromosomal segregation and microsatellite marker-based recombination) of various wild-type strains exhibiting relative susceptibility or tolerance to the lethal toxic effects of arsenite identified a limited X-chromosomal region (16D-F) able to confer a differential response phenotype. Using an FRT-based recombination approach, we created lines harboring small, overlapping deficiencies within this region and found that relative arsenite sensitivity arose when the dose of the glutathione synthetase (GS) gene (located at 16F1) was reduced by half. Knockdown of GS expression by RNA interference (RNAi) in cultured S2 cells led to enhanced arsenite sensitivity, while GS RNAi applied to intact organisms dramatically reduced the concentration of food-borne arsenite compatible with successful growth and development. Our analyses, initially guided by observations on naturally occurring variants, provide genetic proof that an optimally functioning two-step glutathione (GSH) biosynthetic pathway is required in vivo for a robust defense against arsenite; the enzymatic implications of this are discussed in the context of GSH supply and demand under arsenite-induced stress. Given an identical pathway for human GSH biosynthesis, we suggest that polymorphisms in GSH biosynthetic genes may be an important contributor to differential arsenic sensitivity and exposure risk in human populations.


Mechanical signals as regulators of stem cell fate.
In recent years, stem cells have shown significant promise for their potential to provide a source of undifferentiated progenitor cells for therapeutic applications in tissue or organ repair. Significant questions still remain, however, as to the genetic and epigenetic signals that regulate the fate of stem cells. It is now well accepted that the micro-environment of the stem cell can have a significant influence on its differentiation and phenotypic expression. Although emphasis has been placed in previous work on the role of soluble mediators such as growth factors and cytokines on stem cell differentiation, there is now significant evidence, both direct and indirect, that mechanical signals may also regulate stem cell fate. We review a number of in vivo and in vitro studies that have provided evidence that mechanical factors have the ability to influence the differentiation of a number of cells that have been classified as either precursor, progenitor, or stem cells. Taken together, these studies show that specific mechanical signals may promote cell differentiation into a particular phenotype, potentially having an effect on embryonic development. The use of such mechanical signals in vitro in specially designed "bioreactors" may provide important adjuncts to standard biochemical signaling pathways for promoting engineered tissue growth. A further understanding of the biomechanical and biochemical pathways involved in mechanical signal transduction by stem cells will hopefully provide new insight for the improvement of stem-cell based therapies.


Identification and characterisation of new Campylobacter group III phages of animal origin.
Campylobacter-specific bacteriophages (phages) are considered as an alternative intervention strategy to decrease the level of poultry contamination with Campylobacter, a leading cause of gastroenteritis worldwide. Eradication efficiency depends primarily on phage-host interaction mediated by phage tail-spike proteins and bacterial receptors. Here, this interaction was characterised using tail-spike gene sequence analysis, phage neutralisation by antiserum and host range analysis of newly isolated group III Campylobacter phages with 68 Campylobacter jejuni and Campylobacter coli strains. Three different groups of phages were obtained using antibody neutralisation assay, and they were further divided according to polymorphisms observed within tail fibre sequences and host range. Only moderate congruence was observed between these criteria with notable exception of two phages. The infection relied on capsule in all phages isolated, and flagella were found to influence phage propagation on agar plates, but not in broth. Their specificity was more C. jejuni oriented with tendency to lyse human isolates more efficiently. Additionally, natural resistance of C. jejuni to phages did not correlate with their antibiotic resistance patterns. These findings provide new insights into Campylobacter-phage interaction.


Energetic radially polarized few-cycle pulse compression in gas-filled hollow-core fiber.
The compression of high-energy, radially polarized pulses in a gas-filled hollow-core fiber (HCF) is theoretically studied. The simulation results indicate that a 40-fs input pulse can be compressed to a full-width at half-maximum of less than 9 fs when the pulse energy reaches 7.0 mJ with a transmission efficiency of more than 67% after propagating through a 1-m-long, 500-μm diameter HCF filled with neon. Furthermore, the spatio-temporal intensity distributions of the compressed pulses with different initial input energies are studied, and the numerical results indicate that the spatio-temporal intensity distributions are more uniform for lower input pulse energies.


Handheld free space quantum key distribution with dynamic motion compensation.
Mobile devices have become an inseparable part of our everyday life. They are used to transmit an ever-increasing amount of sensitive health, financial and personal information. This exposes us to the growing scale and sophistication of cyber-attacks. Quantum Key Distribution (QKD) can provide unconditional and future-proof data security but implementing it for handheld mobile devices comes with specific challenges. To establish security, secret keys of sufficient length need to be transmitted during the time of a handheld transaction (~1s) despite device misalignment, ambient light and user's inevitable hand movements. Transmitters and receivers should ideally be compact and low-cost, while avoiding security loopholes. Here we demonstrate the first QKD transmission from a handheld transmitter with a key-rate large enough to overcome finite key effects. Using dynamic beam-steering, reference-frame-independent encoding and fast indistinguishable pulse generation, we obtain a secret key rate above 30kb/s over a distance of 0.5m.


Briaexcavatins M-P, four new briarane-related diterpenoids from cultured octocoral Briareum excavatum (Briareidae).
Four new briarane-related diterpenoids, designated as briaexcavatins M-P (1-4), were isolated from the cultured octocoral Briareum excavatum. The structures, including the relative configurations of natural products 1-4 were established on the basis of extensive spectral data analysis and by comparison with the spectral data from other known metabolites featuring a briarane carbon skeleton.


End-of-life care for cancer patients in Japanese acute care hospitals: A nationwide retrospective administrative database survey.
End-of-life (EOL) cancer care in Japanese acute care hospitals has not been well described. We aimed to assess the aggressiveness of EOL care and examine common treatments administered to cancer patients using a health administrative database. Subjects are adult cancer patients who died at acute care hospitals between April 2011 and March 2014. Data from the Japanese Diagnosis Procedure Combination database were analysed to measure the aggressiveness of care (chemotherapy, intensive care unit [ICU] admission and cardiopulmonary resuscitation [CPR]) and describe procedures and prescriptions administered in the last 14 and 30 days of life, disaggregated by hospital case volume: high, intermediate and low volumes. Of 248,978 cancer decedents, 170,024 died in high-, 70,231 in intermediate- and 8,723 in low-volume hospitals. Aggressive treatment in the last 14 days of life included chemotherapy (9.4%, 7.3%, and 5.4%, respectively), ICU admission (3.0%, 2.0%, and 2.4%) and CPR (5.8%, 6.4%, and 8.3%). Opioids were administered to 66.0%, 59.0% and 49.4% patients, while Palliative Care Team intervention was performed for 8.5%, 2.2% and 2.0% of patients, respectively in the last 30 days. In high-volume hospitals, radiotherapy and certified outpatient chemotherapy fees were more frequent. Catecholamines and hyperalimentation were more frequently administered in low-volume hospitals. This is the first study to assess EOL care among Japanese acute care hospitals. More frequent use of chemotherapy at high-volume hospitals may reflect a well-established cancer treatment system. The approach for low-volume hospitals might improve the EOL care for all cancer patients in Japan.


Cutis laxa: case report.
Cutis laxa is a rare inherited or acquired disorder of elastic tissue characterized by inelastic and loose skin. Congenital cutis laxa may present with internal organ involvement, determining a worse prognosis. The authors present the case of a female patient with clinical manifestations suggestive of the hereditary form of the disease, with consanguineous parents (second-degree cousins) and a brother who died with a similar clinical presentation. The genetic study of the FBLN5 gene was important to confirm the diagnosis, define the prognosis, and provide genetic counseling to the family.


[Embolization therapy of an arteriovenous fistula after percutaneous lithotripsy in combination with angioplasty of an ipsilateral kidney arterial stenosis].
We describe successful selective coil embolization therapy in a patient with renal hemorrhage caused by iatrogenic pseudoaneurysm after percutaneous nephrostomy and lithotripsy. In the same session, an incidentally detected severe renal artery stenosis that had caused moderate hypertension was treated by balloon angioplasty. No complications occurred. Coaxial micro-catheter technique and platinum microcoils were used for embolization and allowed targeted occlusion of the bleeding renal artery and preserved the surrounding renal parenchyma. Bleeding was controlled immediately and hematuria disappeared after embolization therapy.


The knowledge and attitude of rural children about poisonings.
Childhood poisonings are an important problem. The goal of the study was to implement and evaluate poisoning prevention training for primary school students. The study was carried out in 3 rural schools Kemalpasa, Izmir, Turkey. Fourth and 5th grade students completed age appropriate questionnaires pre- and post-education. There were significant differences in mean scores of the knowledge responses given pre- and post-test (p<0.05). with more questions answered correctly post-education.


[Relationship between the epithelium and the stroma of the small-intestinal mucosa during antigenic stimulation].
The state of cells and intercellular structures, as well as the pattern of interaction between the epithelium and the stroma of the small intestine mucosa following their exposure to microbic toxins were studied in experiments on rabbits using histological, histochemical and immunofluorescent methods. It was established that the immuno-barrier function of the intestine was implemented by the brush border, epithelial cells, their basal membrane, fibres and cells of lamina propia of the mucosa. Damage of the epithelial lining of the mucosa was accompanied by intensification of immunological processes in its stroma, which in the preliminary immunized animals contributed to an increase in the resistance of the epithelial lining to damaging factors of the lumen of the intestine. The lymphoid infiltration of the epithelium of the intestine mucosa represented a manifestation of immunological processes constantly proceeding therein. The epithelial basal membrane which fixed on its surface immunoglobulins coming from lamina propia, retained antigens passing through it from the lumen of the intestine into the thickness of the mucosa's stroma.


Enhancing psychosocial support for HIV positive adolescents in Harare, Zimbabwe.
There is a recognized gap in the evidence base relating to the nature and components of interventions to address the psycho-social needs of HIV positive young people. We used mixed methods research to strengthen a community support group intervention for HIV positive young people based in Harare, Zimbabwe. A quantitative questionnaire was administered to HIV positive Africaid support group attendees. Afterwards, qualitative data were collected from young people aged 15-18 through tape-recorded in-depth interviews (n=10), 3 focus group discussions (FGDs) and 16 life history narratives. Data were also collected from caregivers, health care workers, and community members through FGDs (n=6 groups) and in-depth interviews (n=12). Quantitative data were processed and analysed using STATA 10. Qualitative data were analysed using thematic analysis. 229/310 young people completed the quantitative questionnaire (74% participation). Median age was 14 (range 6-18 years); 59% were female. Self-reported adherence to antiretrovirals was sub-optimal. Psychological well being was poor (median score on Shona Symptom Questionnaire 9/14); 63% were at risk of depression. Qualitative findings suggested that challenges faced by positive children include verbal abuse, stigma, and discrimination. While data showed that support group attendance is helpful, young people stressed that life outside the confines of the group was more challenging. Caregivers felt ill-equipped to support the children in their care. These data, combined with a previously validated conceptual framework for family-centred interventions, were used to guide the development of the existing programme of adolescent support groups into a more comprehensive evidence-based psychosocial support programme encompassing caregiver and household members. This study allowed us to describe the lived experiences of HIV positive young people and their caregivers in Zimbabwe. The findings contributed to the enhancement of Africaid's existing programme of support to better promote psychological well being and ART adherence.


Inhaled anaesthetics have no effect on fertility in Drosophila melanogaster.
The potential effects of enflurane, isoflurane, halothane, fluroxene and nitrous oxide on mortality and fertility in Drosophila melanogaster were examined. The LD50 value 1 day after exposure for 1 h was the same for males and females and was about 8% for enflurane, isoflurane and halothane, about 20% for fluroxene, and greater than 100% for nitrous oxide. Male and female fertility, however, were not affected by any of the anaesthetics, even at concentrations well above those used clinically.


[Headspace analysis of volatile organic compounds (VOC) in drinking water by the method of gas chromatography].
In the paper there is presented a methodology of analysis of headspace 52 volatile organic compounds in drinking water by the method of gas chromatography with the use of the chromatograph "Crystal 5000.2" with three detectors and automatic attachment Lab Hut 200N NT-200 for the preparation of the sample water and vapor phase input. The lower limit of detection for all compounds in the 2-10 times lower than that of the corresponding standard value.


Genetic predisposition to pancreatic cancer.
Pancreatic adenocarcinoma (PC) is the most deadly of the common cancers. Owing to its rapid progression and almost certain fatal outcome, identifying individuals at risk and detecting early lesions are crucial to improve outcome. Genetic risk factors are believed to play a major role. Approximately 10% of PC is estimated to have familial inheritance. Several germline mutations have been found to be involved in hereditary forms of PC, including both familial PC (FPC) and PC as one of the manifestations of a hereditary cancer syndrome or other hereditary conditions. Although most of the susceptibility genes for FPC have yet to be identified, next-generation sequencing studies are likely to provide important insights. The risk of PC in FPC is sufficiently high to recommend screening of high-risk individuals; thus, defining such individuals appropriately is the key. Candidate genes have been described and patients considered for screening programs under research protocols should first be tested for presence of germline mutations in the BRCA2, PALB2 and ATM genes. In specific PC populations, including in Italy, hereditary cancer predisposition genes such as CDKN2A also explain a considerable fraction of FPC.


Maternal Smc3 protects the integrity of the zygotic genome through DNA replication and mitosis.
Aneuploidy is frequently observed in oocytes and early embryos, begging the question of how genome integrity is monitored and preserved during this crucial period. SMC3 is a subunit of the cohesin complex that supports genome integrity, but its role in maintaining the genome during this window of mammalian development is unknown. We discovered that, although depletion of Smc3 following meiotic S phase in mouse oocytes allowed accurate meiotic chromosome segregation, adult females were infertile. We provide evidence that DNA lesions accumulated following S phase in SMC3-deficient zygotes, followed by mitosis with lagging chromosomes, elongated spindles, micronuclei, and arrest at the two-cell stage. Remarkably, although centromeric cohesion was defective, the dosage of SMC3 was sufficient to enable embryogenesis in juvenile mutant females. Our findings suggest that, despite previous reports of aneuploidy in early embryos, chromosome missegregation in zygotes halts embryogenesis at the two-cell stage. Smc3 is a maternal gene with essential functions in the repair of spontaneous damage associated with DNA replication and subsequent chromosome segregation in zygotes, making cohesin a key protector of the zygotic genome.


Does whole-cell pertussis vaccine protect black South African infants? Assessment of post-vaccination events and antibody responses to pertussis toxin, filamentous haemagglutinin and agglutinogens 2 and 3.
The whole-cell pertussis vaccine currently used in South Africa has not been adequately evaluated for post-vaccination events and immunogenicity. A trial of this vaccine combined with diphtheria and tetanus toxoids (DTP) was undertaken in 115 black babies who received primary vaccination at 2, 4 and 6 months of age. Serological IgG responses to the major antigens of Bordetella pertussis, filamentous haemagglutinin (FHA), pertussis toxin (PT) and fimbriae (agglutinogens 2 and 3 (AGG 2 + 3), were evaluated by enzyme-linked immunosorbent assay in sera obtained at birth, and before vaccination at 2, 4 and 6 months and at 9 months. Surprisingly, after 3 doses of DTP, responses to PT and FHA were found merely to restore levels of IgG to PT and FHA to those found in cord blood. In contrast with the positive increases in these antibodies found in other series of whole-cell vaccination, the anti-PT seroconversion rate was only 19% and the anti-FHA rate only 24%. High levels of anti-AGG 2 + 3 were produced with 67.2% seroconversion. The frequency and nature of post-vaccination events were recorded. Incidences of all reactions to the vaccine were low (7.6%). Fever (3.2%) and excessive crying (2.4%) were the most frequently occurring minor events. The rate of neurological post-vaccination events (without sequelae) during the brief follow-up period was 2 hypotonic-hyporesponsive episodes (8.03/1,000 doses) and 1 convulsion (4.02/1,000 doses). Significant pertussis antibody levels were found in maternal and cord sera with levels in the latter frequently being higher.(ABSTRACT TRUNCATED AT 250 WORDS)


A double-blind, randomized, placebo-controlled multicenter study of oseltamivir phosphate for treatment of influenza infection in China.
To evaluate the efficacy and safety of oseltamivir phosphate as treatment for naturally acquired influenza infection. This study was conducted as a double-blind, randomized, placebo-controlled, multicenter trial during the influenza epidemic season from January to April 2001 at 7 centers in China. A total of 478 adults without other medical history, aged 18 to 65 years, were enrolled into the study. All subjects demonstrated febrile respiratory illness of no more than 36 hours' duration with a temperature of 37.8 degrees C or more plus at least two of the following symptoms: coryza/nasal congestion, sore throat, cough, myalgia/muscles aches and pain, fatigue, headache or chills/sweats. Individuals were randomized into either the oseltamivir phosphate or placebo group with identical-looking capsules. Either oral oseltamivir phosphate, 75 mg twice daily, or placebo was administered to the subjects for 5 days. A total of 451 individuals were analyzed for efficacy as the intent-to-treat population (ITT) (216 oseltamivir and 235 placebo) and 273 individuals were identified as influenza-infected through laboratory test, who were then defined as the intent-to-treat infected population (ITTI) (134 oseltamivir and 139 placebo). Four hundred and fifty nine individuals were included in the safety analysis. In the ITTI population, the cumulative alleviation proportion of oseltamivir group was significantly higher than that of the placebo group (P = 0.0466)). The median duration of illness was 91.6 h [95% confidence interval (CI) = 80.2 - 101.3 h] in the oseltamivir group and 95 h (95% CI = 84.5 - 105.3 h) in the placebo group. The median area under the curve of decreased total score was significantly higher in the oseltamivir group than in the placebo group, 1382.9 and 1236.7 score-hours, respectively (P = 0.0196). For the ITT population, similar results were observed. Adverse events (AE) were similarly reported in both the oseltamivir group and the placebo group. The main adverse events following test drug were gastrointestinal symptoms, neurological symptoms and rashes. Oseltamivir was effective and well tolerated as treatment of early naturally acquired influenza.


Safety and long-term efficacy of transduodenal excision for tumors of the ampulla of Vater.
Ampullary tumors should be resected because of the high incidence of malignancy and the unreliability of preoperative endoscopic diagnosis. Controversy exists about whether to perform a transduodenal excision (TDE) or a pancreatoduodenectomy. This study evaluated the safety and long-term efficacy of TDE. The records of 21 patients with a pathologic diagnosis of ampullary adenoma who underwent TDE were reviewed. Demographics, symptoms, pathologic findings, and outcomes were analyzed and long-term follow-up was ascertained. Twenty-one patients (mean age, 61 years) underwent TDE. Final pathology showed adenoma in all patients including 1 (5%) with invasive cancer, 2 (9%) with microinvasive cancer, 6 (28%) with high-grade dysplasia, and 1 (5%) with low-grade dysplasia. The overall survival was 85% (mean follow-up of 38 months). One of 3 late deaths was likely related to disease progression. Sixteen of the 18 remaining patients (89%) had no evidence of tumor recurrence. One benign ampullary recurrence was successfully treated endoscopically. One additional patient developed an ampullary cancer and underwent pancreatoduodenectomy. TDE of benign ampullary tumors, even those with varying grades of dysplasia, can be performed with acceptable morbidity and low rates of recurrence. Postoperative endoscopic surveillance is mandatory to identify recurrent tumors.


Aggregation and binding substances enhance pathogenicity in rabbit models of Enterococcus faecalis endocarditis.
We investigated the importance of enterococcal aggregation substance (AS) and enterococcal binding substance (EBS) in rabbit models of Enterococcus faecalis cardiac infections. First, American Dutch belted rabbits were injected intraventricularly with 10(8) CFU and observed for 2 days. No clinical signs of illness developed in animals given AS- EBS- organisms, and all survived. All rabbits given AS- EBS+ organisms developed signs of illness, including significant pericardial inflammation, but only one of six died. All animals given AS+ EBS- organisms developed signs of illness, including pericardial inflammation, and survived. All rabbits given AS+ EBS+ organisms developed signs of illness and died. None of the rabbits receiving AS+ EBS+ organisms showed gross pericardial inflammation. The lethality and lack of inflammation are consistent with the presence of a superantigen. Rabbit and human lymphocytes were highly stimulated in vitro by cell extracts, but not cell-free culture fluids, of AS+ EBS+ organisms. In contrast, cell extracts from AS- EBS- organisms weakly stimulated lymphocyte proliferation. Culture fluids from human lymphocytes stimulated with AS+/EBS+ enterococci contained high levels of gamma interferon and tumor necrosis factor alpha (TNF-alpha) and TNF-beta, which is consistent with functional stimulation of T-lymphocyte proliferation and macrophage activation. Subsequent experiments examined the abilities of the same strains to cause endocarditis in a catheterization model. New Zealand White rabbits underwent transaortic catheterization for 2 h, at which time catheters were removed and animals were injected with 2 x 10(9) CFU of test organisms. None of the animals given AS- EBS- organisms developed vegetations or showed autopsy evidence of tissue damage. Rabbits given AS- EBS+ or AS+ EBS- organisms developed small vegetations and had splenomegaly at autopsy. All rabbits given AS+ EBS+ organisms developed large vegetations and had splenomegaly and lung congestion at autopsy. Similar experiments that left catheters in place for 3 days revealed that all rabbits given AS- EBS- or AS+ EBS+ organisms developed vegetations, but animals given AS+ EBS+ organisms had larger vegetations and autopsy evidence of lung congestion. These experiments provide direct evidence that these two cell wall components play an important role in the pathogenesis of endocarditis as well as in conjugative plasmid transfer.


The impact of structural uncertainty on cost-effectiveness models for adjuvant endocrine breast cancer treatments: the need for disease-specific model standardization and improved guidance.
Structural uncertainty relates to differences in model structure and parameterization. For many published health economic analyses in oncology, substantial differences in model structure exist, leading to differences in analysis outcomes and potentially impacting decision-making processes. The objectives of this analysis were (1) to identify differences in model structure and parameterization for cost-effectiveness analyses (CEAs) comparing tamoxifen and anastrazole for adjuvant breast cancer (ABC) treatment; and (2) to quantify the impact of these differences on analysis outcome metrics. The analysis consisted of four steps: (1) review of the literature for identification of eligible CEAs; (2) definition and implementation of a base model structure, which included the core structural components for all identified CEAs; (3) definition and implementation of changes or additions in the base model structure or parameterization; and (4) quantification of the impact of changes in model structure or parameterizations on the analysis outcome metrics life-years gained (LYG), incremental costs (IC) and the incremental cost-effectiveness ratio (ICER). Eleven CEA analyses comparing anastrazole and tamoxifen as ABC treatment were identified. The base model consisted of the following health states: (1) on treatment; (2) off treatment; (3) local recurrence; (4) metastatic disease; (5) death due to breast cancer; and (6) death due to other causes. The base model estimates of anastrazole versus tamoxifen for the LYG, IC and ICER were 0.263 years, €3,647 and €13,868/LYG, respectively. In the published models that were evaluated, differences in model structure included the addition of different recurrence health states, and associated transition rates were identified. Differences in parameterization were related to the incidences of recurrence, local recurrence to metastatic disease, and metastatic disease to death. The separate impact of these model components on the LYG ranged from 0.207 to 0.356 years, while incremental costs ranged from €3,490 to €3,714 and ICERs ranged from €9,804/LYG to €17,966/LYG. When we re-analyzed the published CEAs in our framework by including their respective model properties, the LYG ranged from 0.207 to 0.383 years, IC ranged from €3,556 to €3,731 and ICERs ranged from €9,683/LYG to €17,570/LYG. Differences in model structure and parameterization lead to substantial differences in analysis outcome metrics. This analysis supports the need for more guidance regarding structural uncertainty and the use of standardized disease-specific models for health economic analyses of adjuvant endocrine breast cancer therapies. The developed approach in the current analysis could potentially serve as a template for further evaluations of structural uncertainty and development of disease-specific models.


A rapid, highly efficient and economical method of Agrobacterium-mediated in planta transient transformation in living onion epidermis.
Transient transformation is simpler, more efficient and economical in analyzing protein subcellular localization than stable transformation. Fluorescent fusion proteins were often used in transient transformation to follow the in vivo behavior of proteins. Onion epidermis, which has large, living and transparent cells in a monolayer, is suitable to visualize fluorescent fusion proteins. The often used transient transformation methods included particle bombardment, protoplast transfection and Agrobacterium-mediated transformation. Particle bombardment in onion epidermis was successfully established, however, it was expensive, biolistic equipment dependent and with low transformation efficiency. We developed a highly efficient in planta transient transformation method in onion epidermis by using a special agroinfiltration method, which could be fulfilled within 5 days from the pretreatment of onion bulb to the best time-point for analyzing gene expression. The transformation conditions were optimized to achieve 43.87% transformation efficiency in living onion epidermis. The developed method has advantages in cost, time-consuming, equipment dependency and transformation efficiency in contrast with those methods of particle bombardment in onion epidermal cells, protoplast transfection and Agrobacterium-mediated transient transformation in leaf epidermal cells of other plants. It will facilitate the analysis of protein subcellular localization on a large scale.


Changes in Muscle Stress and Sarcomere Adaptation in Mice Following Ischemic Stroke.
While abnormal muscle tone has been observed in people with stroke, how these changes in muscle tension affect sarcomere morphology remains unclear. The purpose of this study was to examine time-course changes in passive muscle fiber tension and sarcomeric adaptation to these changes post-ischemic stroke in a mouse model by using a novel in-vivo force microscope. Twenty-one mice were evenly divided into three groups based on the time point of testing: 3 days (D3), 10 days (D10), and 20 days (D20) following right middle cerebral artery ligation. At each testing time, the muscle length, width, and estimated volume of the isolated soleus muscle were recorded, subsequently followed by in-vivo muscle tension and sarcomere length measurement. The mass of the soleus muscle was measured at the end of testing to calculate muscle density. Two-way ANOVA with repeated measures was used to examine the differences in each of the dependent variable among the three time-point groups and between the two legs. The passive muscle stress of the impaired limbs in the D3 group (27.65 ± 8.37 kPa) was significantly lower than the less involved limbs (42.03 ± 18.61 kPa; p = 0.05) and the impaired limbs of the D10 (48.92 ± 14.73; p = 0.03) and D20 (53.28 ± 20.54 kPa; p = 0.01) groups. The soleus muscle density of the impaired limbs in the D3 group (0.69 ± 0.12 g/cm3) was significantly lower than the less involved limbs (0.80 ± 0.09 g/cm3; p = 0.04) and the impaired limbs of the D10 (0.87 ± 0.12 g/cm3; p = 0.02) and D20 (1.00 ± 0.14 g/cm3; p < 0.01) groups. The D3 group had a shorter sarcomere length (2.55 ± 0.26 μm) than the D10 (2.83 ± 0.20 μm; p = 0.03) and D20 group (2.81 ± 0.15 μm; p = 0.04). These results suggest that, while ischemic stroke may cause considerable changes in muscle tension and stress, sarcomere additions under increased mechanical loadings may be absent or disrupted post-stroke, which may contribute to muscle spasticity and/or joint contracture commonly observed in patients following stroke.


Berlin's medical students' smoking habits, knowledge about smoking and attitudes toward smoking cessation counseling.
Diseases associated with smoking are a foremost cause of premature death in the world, both in developed and developing countries. Eliminating smoking can do more to improve health and prolong life than any other measure in the field of preventive medicine. Today's medical students will play a prominent role in future efforts to prevent and control tobacco use. A cross-sectional, self-administered, anonymous survey of fifth-year medical students in Berlin, Germany was conducted in November 2007. The study explored the prevalence of smoking among medical students. We assessed their current knowledge regarding tobacco dependence and the effectiveness of smoking cessation methods. Students' perceived competence to counsel smokers and promote smoking cessation treatments was also explored. Analyses were based on responses from 258 students (86.6% response rate). One quarter of the medical students surveyed were current smokers. The smoking rate was 22.1% among women, 32.4% among men. Students underestimated smoking-related mortality and the negative effect of smoking on longevity. A considerable number of subjects erroneously assumed that nicotine causes coronary artery disease. Students' overall knowledge of the effectiveness of smoking cessation methods was inadequate. Only one third of the students indicated that they felt qualified to counsel patients about tobacco dependence. This study reveals serious deficiencies in knowledge and counseling skills among medical students in our sample. The curriculum of every medical school should include a tobacco module. Thus, by providing comprehensive training in nicotine dependence interventions to medical students, smokers will have access to the professional expertise they need to quit smoking.


Fe binding properties of two soybean (Glycine max L.) LEA4 proteins associated with antioxidant activity.
Late embryogenesis abundant (LEA) group 4 (LEA4) proteins play an important role in the water stress tolerance of plants. Although they have been hypothesized to stabilize macromolecules in stressed cells, the protective functions and mechanisms of LEA4 proteins are still not clear. In this study, the metal binding properties of two related soybean LEA4 proteins, GmPM1 and GmPM9, were tested using immobilized metal ion affinity chromatography (IMAC). The metal ions Fe(3+), Ni(2+), Cu(2+) and Zn(2+) were observed to bind these two proteins, while Ca(2+), Mg(2+) or Mn(2+) did not. Results from isothermal titration calorimetry (ITC) indicated that the binding affinity of GmPM1 for Fe(3+) was stronger than that of GmPM9. Hydroxyl radicals generated by the Fe(3+)/H(2)O(2) system were scavenged by both GmPM1 and GmPM9 in the absence or the presence of high ionic conditions (100 mM NaCl), although the scavenging activity of GmPM1 was significantly greater than that of GmPM9. These results suggest that GmPM1 and GmPM9 are metal-binding proteins which may function in reducing oxidative damage induced by abiotic stress in plants.


Do Smartphones Create a Coordination Problem for Face-to-Face Interaction? Leveraging Game Theory to Understand and Solve the Smartphone Dilemma.
Smartphone use changes the landscape of social interactions, including introducing new social dilemmas to daily life. The challenge of putting down one's smartphone is an example of a classic coordination problem from game theory: the stag hunt game. In a stag hunt game, there are two possible coordination points, one that involves big payoffs for both partners (e.g., working together to hunt large game like stag) and one that involves smaller payoffs for both partners (e.g., individually hunting small game like rabbits) but is safer because it does not require that your partner choose that option as well. This is similar to the challenges of putting down smartphones to have a face-to-face interaction: you and your interaction partner might both prefer the higher payoff option of having a face-to-face interaction, but neither of you wants to put down your phone and risk not having anything to do in the meantime. It is also discussed how new technological innovations are changing the payoffs of face-to-face conversation versus side-by-side smartphone scrolling. Insights that come from applying game theory to this "social media dilemma" are discussed here and potential solutions that come out of a game theoretic analysis are offered. Also see the video abstract here https://youtu.be/9esL578zM-E.


Towards a clarification of terminology in medicine taking behavior: compliance, adherence and concordance are related although different terms with different uses.
Medical terminology is at continuous process of change since the language of medicine needs the rapid incorporation of new terms or changing the existing ones to be in touch with new ideas, concepts and practices. The evolution of the terms "compliance", "adherence" and "concordance" in the field of medicine-taking represents a good example of this. Although these three terms are frequently used interchangeably generating some confusion, compliance, adherence and concordance mean different things and must be used in different ways. Compliance refers to the extent to which patients follow doctors' prescription about medicine taking; adherence refers to the extent to which patients follow through decisions about medicine taking; and concordance refers to the extent to which patients are successfully supported both in decision making partnerships about medicines and in their medicines taking. This terminology evolution may actually be more important than mere semantics since better adherence to a treatment regimen could be achieved through open-ended physician-patient communication, incorporating the beliefs and preferences of the patient in the decision-making process. At present time, concordance could be useful as a normative or aspirational term while compliance and adherence must be the terms used for scientific measurement in medicine-taking field.


Competency-based assessment in nutrition education: A systematic literature review.
A suitably prepared and qualified nutrition and dietetics workforce is part of the solution to combating the burden of disease. Competency-based assessment is a key part of the education of future workforces. Although there has been recent attention on competency-based assessment in dietetics, there is little exploration of competency-based education for the preparation of nutritionists. The present study aimed to understand how competency-based assessment is implemented and evaluated in nutrition education. A systematic literature review was carried out according to PRISMA guidelines. Four databases were initially searched in February 2020 using key words related to competenc* in combination with nutrition or dietetic and their synonyms. An updated search was completed again in March 2021. Studies that met eligibility criteria where the focus was on nutrition and involved a method of competency-based assessment were synthesised narratively. From a total of 6262 titles and abstracts, six studies on competency assessment in nutrition education were identified. The assessments focused on the development of key skills, including motivational interviewing and nutrition assessment, changes to knowledge and attitudes on food and culture, and self-perceived development of communication, collaboration, management, advocacy, scholarship and professional capabilities. No studies were found that assessed promotion of health and wellbeing or the food chain competencies. The lack of research in competency-based assessment must be addressed to ensure we are effectively preparing future nutritionists for work such that they can impact health outcomes.


"Before" and "after": Investigating the relationship between temporal connectives and chronological ordering using event-related potentials.
Sentence-initial temporal clauses headed by before, as in "Before the scientist submitted the paper, the journal changed its policy", have been shown to elicit sustained negative-going brain potentials compared to maximally similar clauses headed by after, as in "After the scientist submitted the paper, the journal changed its policy". Such effects may be due to either one of two potential causes: before clauses may be more difficult than after clauses because they cause the two events in the sentence to be mentioned in an order opposite the order in which they actually occurred, or they may be more difficult because they are ambiguous with regard to whether the event described in the clause actually happened. The present study examined the effect of before and after clauses on sentence processing in both sentence-initial contexts, like those above, and in sentence-final contexts ("The journal changed its policy before/after the scientist submitted the paper"), where an order-of-mention account of the sustained negativity predicts a negativity for after relative to before. There was indeed such a reversal, with before eliciting more negative brain potentials than after in sentence-initial clauses but more positive in sentence-final clauses. The results suggest that the sustained negativity indexes processing costs related to comprehending events that were mentioned out of order.


Autologous Cell Therapy for Aged Human Skin: A Randomized, Placebo-Controlled, Phase-I Study.
Skin ageing involves senescent fibroblast accumulation, disturbance in extracellular matrix (ECM) homeostasis, and decreased collagen synthesis. to assess a cell therapy product for aged skin (RCS-01; verum) consisting of ~25 × 106 cultured, autologous cells derived from anagen hair follicle non-bulbar dermal sheath (NBDS). For each subject in the verum group, 4 areas of buttock skin were injected intradermally 1 or 3 times at monthly intervals with RCS-01, cryomedium, or needle penetration without injection; in the placebo group RCS-01 was replaced by cryomedium. The primary endpoint was assessment of local adverse event profiles. As secondary endpoints, expression of genes related to ECM homeostasis was assessed in biopsies from randomly selected volunteers in the RCS-01 group taken 4 weeks after the last injection. -Results: Injections were well tolerated with no severe adverse events reported 1 year after the first injection. When compared with placebo-treated skin, a single treatment with RCS-01 resulted in a significant upregulation of TGFβ1, CTGF, COL1A1, COL1A2, COL3A1, and lumican mRNA expression. The cohort size was insufficient for dose -ranging evaluation and subgroup analyses of efficacy. RCS-01 therapy is well tolerated and associated with a gene expression response consistent with an improvement of ECM homeostasis.


Peripheral blood progenitor cell mobilization using stem cell factor in combination with filgrastim in breast cancer patients.
The safety and optimal dose and schedule of stem cell factor (SCF) administered in combination with filgrastim for the mobilization of peripheral blood progenitor cells (PBPCs) was determined in 215 patients with high-risk breast cancer. Patients received either filgrastim alone (10 microg/kg/d for 7 days) or the combination of 10 microg/kg/d filgrastim and 5 to 30 microg/kg/d SCF for either 7, 10, or 13 days. SCF patients were premedicated with antiallergy prophylaxis. Leukapheresis was performed on the final 3 days of cytokine therapy and, after high-dose chemotherapy and infusion of PBPCs, patients received 10 microg/kg/d filgrastim until absolute neutrophil count recovery. The median number of CD34+ cells collected was greater for patients receiving the combination of filgrastim and SCF, at doses greater than 10 microg/kg/d, than for those receiving filgrastim alone (7.7 v 3.2 x 10(6)/kg, P < .05). There were significantly (P < .05) more CD34+ cells harvested for the 20 microg/kg/d SCF (median, 7.9 x 10(6)/kg) and 25 microg/kg/d SCF (median, 13.6 x 10(6)/kg) 7-day combination groups than for the filgrastim alone patients (median, 3.2 x 10(6)/kg). The duration of administration of SCF and filgrastim (7, 10, or 13 days) did not significantly affect CD34+ cell yield. Treatment groups mobilized with filgrastim alone or with the cytokine combination had similar hematopoietic engraftment and overall survival after PBPC infusion. In conclusion, the results of this study indicate that SCF therapy enhances CD34+ cell yield and is associated with manageable levels of toxicity when combined with filgrastim for PBPC mobilization. The combination of 20 microg/kg/d SCF and 10 microg/kg/d filgrastim with daily apheresis beginning on day 5 was selected as the optimal dose and schedule for the mobilization of PBPCs.


Potential of pharmaceutical formulation based on Morinda citrifolia extract for the treatment of schistosomiasis.
Schistosomiasis is a parasitic disease that can be asymptomatic, but it can progress and cause serious damage, such as hospitalization and death. This work aimed to characterize and carry out the in vivo pharmacological test of the dry extract of Morinda citrifolia and obtain a pharmaceutical dosage form based on this extract for the treatment of schistosomiasis. The aqueous extract was characterized based on the evaluation of pH, dry residue and density. The aqueous extract was dried through the freeze-drying process. The obtained dry extract was characterized through phytochemical screening, rheological analysis, acute toxicity and in vivo pharmacology. Additionally, the pre-formulation development of a pharmaceutical dosage form was pursued with the dry extract. Through the HPLC chromatogram, characteristic rutin peaks were identified. The rheological behavior of the dry extract did not show good characteristics. Acute toxicity, at a dose of 2000 mg/kg, showed excitatory activity in the central and autonomous nervous system. The in vivo pharmacological test of the dry extract showed that, at a dose of 400 mg/kg, it was possible to reduce 67.5% of the total adult worms, 66% of female worms and 60% of the number of eggs. The pharmaceutical dosage form obtained was an oral solution that was clear, transparent, without the presence of lumps and precipitates, having a density of 1.1276 g mL-1 and pH of 5.92. The results obtained will provide parameters for the production of suitable pharmaceutical formulations, as well as for the quality control of products based on M. citrifolia, with promising schistosomicidal activity.


Strategies for reducing the risk of cardiovascular disease in patients with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is frequently accompanied by multimorbidities in affected patients. Even though the majority of these comorbidities are also related to advanced age and cigarette smoke, also COPD itself has significant impact on insurgence, or worsening of these conditions. As a consequence, COPD is regarded as a complex disease with pulmonary and extra-pulmonary involvement. According to current guidelines for the management of COPD patients, the comprehensive treatment of this condition should target respiratory symptoms as well as comorbidities. Cardiovascular disease is one of the most frequent comorbidities in COPD patients and there are several strategies for reducing the risk of cardiovascular disease in COPD patients. These include smoking cessation, pharmacologic prevention of cardiovascular disease, and the treatment of COPD. Beta-blockers for the prevention of cardiovascular disease have been traditionally limited in COPD patients, albeit current evidence supporting their efficacy and safety in these patients. With regard to COPD medications, corticosteroids are generally not recommended, except for exacerbations, while long-acting beta2-agonists have demonstrated an acceptable profile of cardiovascular safety. Long-acting anticholinergic bronchodilators, in particular tiotropium in the mist inhaler formulation, have been associated with an increased risk of major cardiovascular events and mortality. Data on this issue remain, however, controversial. Glycopyrronium, a recently introduced anticholinergic, demonstrated. a rapid and sustained relief of respiratory symptoms with a favorable safety profile and no increase in cardiovascular risk, in monotherapy and in combination with a long-acting beta2-agonist in a comprehensive trial program indicating a valid option for COPD patients with CV comorbidities.


Prevalence of inappropriate antibiotic prescriptions after the great east Japan earthquake, 2011.
Few studies have investigated the appropriateness of antibiotic use in postdisaster settings. We retrospectively evaluated clinical databases on health care delivered at clinics near shelters set up after the Great East Japan Earthquake, 2011. We defined appropriate, acceptable, and inappropriate antibiotic use for each diagnostic category, by applying and adopting precedent studies and clinical guidelines. From March to July, 2011, a total of 23,704 clinic visits occurred at 98 shelters with 7934 residents. Oral antibiotics were prescribed a total of 2253 times. The median age of the patients was 48.5 years old (range 0-97), and 43.7% were male. Of 2253 antibiotic prescriptions, 1944 were judged to be inappropriate (86.3% 95% CI 84.8%-87.7%). The most prescribed antibiotic was clarithromycin (646 times, 28.7%), followed by cefcapene pivoxil (644 times, 28.6%), levofloxacin (380, 16.9%), cefdinir (194, 8.6%), and cefditren pivoxil (98, 4.4%). The most frequent diagnosis for which antibiotics were prescribed was upper respiratory infection (URI, 1040 visits, 46.2%), followed by acute bronchitis (369, 16.4%), pharyngitis (298, 13.2%), traumatic injuries (194, 8.6%), acute gastroenteritis (136, 6.0%), urinary tract infections (UTIs, 123, 5.5%), and allergic rhinitis (5.1%). The majority of antibiotics prescribed at clinics after the Great East Japan Earthquake was inappropriate. Significant improvement of the use of antibiotics in postdisaster settings should be sought immediately in Japan.


Understanding the catalytic activity of nanoporous gold: Role of twinning in fcc lattice.
Nanoporous gold (NPG) prepared by de-alloying Al2Au exhibits correlation between the high catalytic reactivity towards CO oxidation and the density of twinning defects in the fcc lattice of NPG. It was also discovered that on the internal surface of NPG, quite common twinning defects can create close-packed rows of six-coordinated catalytically active Au atoms denoted as W-chains. In this work, using density functional theory methods, we investigate energy conditions for formation, thermal stability, and chemical reactivity of these active sites. The possibility of dioxygen chemisorption on various surface sites is studied in detail. A contribution from the dispersion interactions is also considered. The calculated surface density of the active six-coordinated atoms in NPG comparable with that of supported gold nanoparticle catalysts, exothermic chemisorption of dioxygen, and the energy profiles of reaction pathways for CO oxidation indicate that the six-coordinated sites created by twinning can significantly contribute to the catalytic activity of NPG.