Fetal volume blood flow and umbilical artery flow velocity waveform analysis: a comparison.
The estimation of fetal umbilical vein and aortic volume blood flow was compared with umbilical artery flow velocity-time waveform analysis in 42 pregnancies. The volume blood flow measurements were made with a combined linear array B-mode and pulsed Doppler ultrasound system. The umbilical artery flow velocity-time waveform analysis was made with either pulsed or continuous wave 2 MHz Doppler ultrasound and the systolic/diastolic (A/B) ratio was used as an index of flow resistance. There was no difference when continuous wave was compared to pulsed Doppler ultrasound as a method of recording flow velocity waveforms. Analysis of the umbilical artery flow velocity-time waveform was more sensitive (100%-50%) than the measurement of umbilical vein volume blood flow (ml/kg/min) in the detection of the small-for-gestational age (SGA) fetus. The predictive value of a positive test was higher (71%-45%) while specificity was similar (88%-81%). Descending aortic volume flow was reduced in only one SGA fetus. The increase in umbilical placental downstream resistance (high systolic/diastolic ratio) was associated with a reduction in the percentage of fetal aortic blood flow directed to the umbilical placental circulation.


Phase 1 pharmacokinetics and phase 3 efficacy of testosterone nasal gel in subjects with seasonal allergies.
NATESTO® testosterone nasal gel (TNG) is a liquid gel that is applied in the nose for the treatment of male hypogonadism. There is a reasonable concern that administration of TNG to patients with active rhinitis could modify absorption. Results from two clinical studies are reported wherein subjects with allergic rhinitis (AR) subjects are treated with TNG. The 24-hour pharmacokinetics (PK) and relative bioavailability of serum total testosterone (sTT) from TNG (11 mg tid ) were determined using a phase 1 Latin-square design with 18 eugonadal AR subjects crossed over between asymptomatic, symptomatic-untreated, and symptomatic-treated (oxymetazoline) conditions. Allergy symptoms, assessed using Total Nasal Symptom Score (TNSS), were induced using grass pollen in an allergy challenge chamber (ACC) prior to administration of TNG. The data are discussed in relation to results from a phase 3 study in 306 hypogonadal patients which compare clinical outcomes of AR and non-AR patients treated with TNG. PK analysis (Tmax, maximum observed concentration [Cmax], area under the curve [AUC]) of sTT showed no difference in the rate or extent of absorption of exogenous testosterone from TNG as a function of allergy symptoms. The relative bioavailability also showed all three conditions to be equivalent. However, pre-dose mean sTT in AR patients was 21-25% lower when symptomatic vs. asymptomatic, which is attributed to the allergic reaction. A large phase 3 study, based predominantly on PK measures of sTT, showed that clinical outcomes for AR and non-AR patients treated with TNG were identical, including the percentage of patients in the eugonadal range, hormone profiles, and adverse events. AR does not affect absorption of TNG. Patient outcomes for long-term treatment with TNG for up to one year are not dependent on AR history.


Paleontology. Feathers, or flight of fancy?
On page 2202, researchers describe the 220-million-year-old Longisquama insignis, a squat, mouse-sized reptile with at least six vanelike appendages up to 12 centimeters long sprouting from its spine. The authors argue that the appendages are feathers much like those of modern birds; outside the paper, they have touted the fossil as "an ideal bird ancestor." That conclusion has infuriated paleontologists--not just because it challenges the prevalent theory that birds evolved from theropod dinosaurs, but because they say it does so in an unscientific way.


Cytokine Clearances in Critically Ill Patients on Continuous Renal Replacement Therapy.
We sought to quantify any differences in cytokine clearance between continuous venovenous hemofiltration (CVVH-convective) compared to continuous venovenous hemodialysis (CVVHD-diffusive). We conducted a 20 patient, multicenter, prospective, open-label randomized trial (CVVH or CVVHD) at continuous renal -replacement therapy (CRRT) initiation. Blood, urine, and effluent were collected at 0, 4, 24, and 48 h after initiation of CRRT. Serum electrolytes, cytokines levels, and clearances were measured. Cytokines studies included IL-1β, IL-1RA, IL-6, IL-10, and TNFα. We randomized 20 patients to receive CRRT. After 4 h of CRRT there was no difference in total cytokine levels or change in cytokine concentrations across the 2 groups. With the exception of IL-1 RA, all cytokines levels decreased across patient groups regardless of modality. There was no significant difference in cytokine concentration across CRRT modality for any time point. Within the first 4 h of CRRT initiation, there is no significant difference between cytokine or solute clearance between CVVH and CVVHD.


Fused Projection-Based Point Cloud Segmentation.
Semantic segmentation is used to enable a computer to understand its surrounding environment. In image processing, images are partitioned into segments for this purpose. State-of-the-art methods make use of Convolutional Neural Networks to segment a 2D image. Compared to that, 3D approaches suffer from computational cost and are not applicable without any further steps. In this work, we focus on semantic segmentation based on 3D point clouds. We use the idea to project the 3D data into a 2D image to accelerate the segmentation process. Afterward, the processed image gets re-projected to receive the desired result. We investigate different projection views and compare them to clarify their strengths and weaknesses. To compensate for projection errors and the loss of geometrical information, we evolve the approach and show how to fuse different views. We have decided to fuse the bird's-eye and the spherical projection as each of them achieves reasonable results, and the two perspectives complement each other best. For training and evaluation, we use the real-world datasets SemanticKITTI. Further, we use the ParisLille and synthetic data generated by the simulation framework Carla to analyze the approaches in more detail and clarify their strengths and weaknesses. Although these methods achieve reasonable and competitive results, they lack flexibility. They depend on the sensor used and the setup in which the sensor is used.


Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans.
Experimentally renal tissue hypoxia appears to play an important role in the pathogenesis of chronic kidney disease (CKD) and arterial hypertension (AHT). In this study we measured renal tissue oxygenation and its determinants in humans using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) under standardized hydration conditions. Four coronal slices were selected, and a multi gradient echo sequence was used to acquire T2* weighted images. The mean cortical and medullary R2* values ( = 1/T2*) were calculated before and after administration of IV furosemide, a low R2* indicating a high tissue oxygenation. We studied 195 subjects (95 CKD, 58 treated AHT, and 42 healthy controls). Mean cortical R2 and medullary R2* were not significantly different between the groups at baseline. In stimulated conditions (furosemide injection), the decrease in R2* was significantly blunted in patients with CKD and AHT. In multivariate linear regression analyses, neither cortical nor medullary R2* were associated with eGFR or blood pressure, but cortical R2* correlated positively with male gender, blood glucose and uric acid levels. In conclusion, our data show that kidney oxygenation is tightly regulated in CKD and hypertensive patients at rest. However, the metabolic response to acute changes in sodium transport is altered in CKD and in AHT, despite preserved renal function in the latter group. This suggests the presence of early renal metabolic alterations in hypertension. The correlations between cortical R2* values, male gender, glycemia and uric acid levels suggest that these factors interfere with the regulation of renal tissue oxygenation.


Deposition of monodisperse particles in hollow models representing adult and child-size tracheobronchial airways.
A series of experiments was performed to determine deposition efficiencies of four sizes of radiolabeled monodisperse particles in custom-made hollow tracheobronchial models. The particles had geometric diameters of about 1, 5, 10, and 15 microm. The tracheobronchial models, consisting of a trachea and two or more additional generations, had dimensions representative of a typical adult, a 7-y-old child, and a 4-y-old child; the child-size models were appropriately scaled-down replicas of the adult-size model. Each deposition experiment was conducted using a steady inspiratory airflow representative of low physical activity for the appropriate age of individual: 20 L min(-1) for the adult; 9 L min(-1) for the 7-y-old; 5.5 L min(-1) for the 4-y-old. The results indicate that deposition efficiency of the particles increased substantially (up to 35 times) in all three models as particle diameter increased from 1-15 microm, undoubtedly as a result of particle impaction and sedimentation-related phenomena. An analysis of variance demonstrated the occurrence of statistically-significant (p < 0.05) main effects of hollow model size and particle size; the interaction between the two parameters was also significant. In general, deposition efficiencies of the various sizes of particles were greater in the child-size models than in the adult-size model; this effect may have risk assessment implications. In addition, the results obtained experimentally agreed more closely with those predicted using a radiation-protection mathematical particle deposition formulation as the particle size increased for each of the sizes of models.


[Diagnosing Alzheimer's disease: from research to clinical practice and ethics].
In 2011, the so-called Dubois criteria introduced the use of biomarkers in research (in particular, brain amyloid positron emission tomography imaging and the cerebrospinal fluid levels of tau/fosfo-tau and beta-amyloid 1-42) for the early or preclinical diagnosis of Alzheimer's disease. Even so, we are looking at an increased use of these markers in clinical practice. In the 1960s, Alzheimer's disease was considered a rare form of presenile dementia, but gradually it has been recognized as the prevalent form of old-age dementia. As a consequence, what was once regarded as an inevitable outcome of old age is now recognized as a true disease. Several factors contributed to this paradigm shift, in particular a longer lifespan, new techniques of in vivo study of the central nervous system, and the pressure exerted by the pharmaceutical industry and patient groups. The current lack of disease-modifying therapies and the high incidence of mild cognitive impairment, which is a risk factor for dementia, raise a series of clinical ethical problems ranging from how diagnosis is communicated to how resources are used. This article offers a conceptual scheme through which these issues can be addressed.


Mediation of emotional and external eating between dieting and food intake or BMI gain in women.
Dieting to control body weight is often associated with weight gain, particularly so in women; however, the underlying mechanisms are unclear. In a series of studies on women, we examined whether the relationship between dieting and weight gain can be explained by (serial) mediation of emotional eating (EE) and/or subsequent external eating (EX). In a pilot study (116 women), we first assessed this (serial) mediation between dieting or dietary restraint and actual food consumption in the laboratory. In Study 1, a four-year follow up on patients with newly diagnosed type 2 diabetes (51 women), we assessed this (serial) mediation between dietary restraint and change in BMI and intake of energy (Kcal; Food Frequency Questionnaire). In Study 2, a three-year follow up study in a representative Dutch sample (287 women), we assessed this (serial) mediation between dieting and change in BMI. There was consistent support for (serial) mediation: In the pilot study, frequency of dieting and dietary restraint were both indirectly associated with grams of crackers eaten through EE and EX. In study 1, dietary restraint had a significant (95% CI) indirect association with subsequent change in measured BMI and a marginally (90% CI) significant indirect association with intake of energy through EE and EX. In study 2, EE marginally (90% CI) acted as a mediator between frequency of dieting and subsequent self-reported change in BMI. In the subsample of overweight women (n = 146) frequency of dieting was indirectly associated with subsequent self-reported change in BMI through EE and EX. The possibility that female dieters may gain weight through EE and/or subsequent EX should be taken into account when treating women with overweight or obesity.


Fire ant decapitating fly cooperative release programs (1994-2008): two Pseudacteon species, P. tricuspis and P. curvatus, rapidly expand across imported fire ant populations in the southeastern United States.
Natural enemies of the imported fire ants, Solenopsis invicta Buren S. richteri Forel (Hymenoptera: Formicidae), and their hybrid, include a suite of more than 20 fire ant decapitating phorid flies from South America in the genus Pseudacteon. Over the past 12 years, many researchers and associates have cooperated in introducing several species as classical or self-sustaining biological control agents in the United States. As a result, two species of flies, Pseudacteon tricuspis Borgmeier and P. curvatus Borgmeier (Diptera: Phoridae), are well established across large areas of the southeastern United States. Whereas many researchers have published local and state information about the establishment and spread of these flies, here distribution data from both published and unpublished sources has been compiled for the entire United States with the goal of presenting confirmed and probable distributions as of the fall of 2008. Documented rates of expansion were also used to predict the distribution of these flies three years later in the fall of 2011. In the fall of 2008, eleven years after the first successful release, we estimate that P. tricuspis covered about 50% of the fire ant quarantined area and that it will occur in almost 65% of the quarantine area by 2011. Complete coverage of the fire ant quarantined area will be delayed or limited by this species' slow rate of spread and frequent failure to establish in more northerly portions of the fire ant range and also, perhaps, by its preference for red imported fire ants (S. invicta). Eight years after the first successful release of P. curvatus, two biotypes of this species (one biotype occurring predominantly in the black and hybrid imported fire ants and the other occurring in red imported fire ants) covered almost 60% of the fire ant quarantined area. We estimate these two biotypes will cover almost 90% of the quarantine area by 2011 and 100% by 2012 or 2013. Strategic selection of several distributional gaps for future releases will accelerate complete coverage of quarantine areas. However, some gaps may be best used for the release of additional species of decapitating flies because establishment rates may be higher in areas without competing species.


Genetic studies of autistic disorder and chromosome 7.
Genome-wide scans have suggested that a locus on 7q is involved in the etiology of autistic disorder (AD). We have identified an AD family in which three sibs inherited from their mother a paracentric inversion in the chromosome 7 candidate region (inv(7)(q22-q31.2)). Clinically, the two male sibs have AD, while the female sib has expressive language disorder. The mother carries the inversion, but does not express AD. Haplotype data on the family suggest that the chromosomal origin of the inversion was from the children's maternal grandfather. Based on these data, we have genotyped 76 multiplex (>/=2 AD affecteds/family) families for markers in this region of 7q. Two-point linkage analysis yielded a maximum heterogeneity lod score of 1.47 and maximum lod score (MLS) of 1.03 at D7S495. Multipoint MLS and NPL analyses resulted in peak scores of 1.77 at D7S2527 and 2.01 at D7S640. Examination of affected sibpairs revealed significant paternal (P = 0.007), but not maternal (P = 0. 75), identity-by-descent sharing at D7S640. Significant linkage disequilibrium was detected with paternal (P = 0.02), but not maternal (P = 0.15), transmissions at D7S1824 in multiplex and singleton families. There was also evidence for an increase in recombination in the region (D7S1817 to D7S1824) in the AD families versus non-AD families (P = 0.03, sex-averaged; and P = 0.01, sex-specific). These results provide further evidence for the presence of an AD locus on chromosome 7q, as well as provide evidence suggesting that this locus may be paternally expressed.


Evaluation of antioxidant and anti-inflammatory efficacy of caffeine in rat model of neurotoxicity.
Objective: The present study aims to investigate the neuroprotective effect of caffeine against aluminum chloride (AlCl3)-induced neurotoxicity in rats. Methods: Twenty-one male albino rats were divided into 3 groups: control, AlCl3-intoxicated group that received daily oral administration of AlCl3 (100 mg/kg for 30 days) and protected group injected daily with caffeine (20 mg/kg intraperitoneally) one hour before oral administration of AlCl3 for 30 days. Levels of lipid peroxidation, reduced glutathione, and nitric oxide and the activities of acetylcholinesterase (AchE) and Na+/K+-ATPase were measured spectrophotometrically. Tumor necrosis factor-α (TNF-α) was evaluated by ELISA kit. Results: The data revealed evidence of oxidative and nitrosative stress in the cerebral cortex, hippocampus, and striatum of AlCl3-intoxicated rats. This was indicated from the increased levels of lipid peroxidation and nitric oxide together with the decreased level of reduced glutathione. Moreover, the daily AlCl3 administration increased AchE and Na+/K+-ATPase activities and the level of TNF-α in the selected brain regions. Protection with caffeine ameliorated the oxidative stress induced by AlCl3 in the cerebral cortex, hippocampus, and striatum. In addition, caffeine restored the elevated level of TNF-α in the hippocampus and striatum. This was accompanied by an improvement in the activities of AchE and Na+/K+-ATPase in the studied brain regions. Discussion and conclusions: The present findings clearly indicate that caffeine provides a significant neuroprotection against AlCl3-induced neurotoxicity mediated by its antioxidant, anti-inflammatory, and anticholinesterase properties.


Tuberculosis recurrence after completion treatment in a European city: reinfection or relapse?
Tuberculosis (TB) recurrence can be due to reinfection or relapse. The contribution of each to TB incidence and the factors associated with recurrence are not well known. Effectiveness of TB control programs is assessed in part by recurrence rates. The aim of this study was to establish the recurrence rate of TB in Barcelona, the associated risk factors and the role of reinfection. A population-based retrospective longitudinal study was performed in Barcelona, Spain. TB patients with positive culture results who completed treatment between Jan 1(st), 2003 and Dec 31(st), 2006 were followed-up until December 31st, 2009 by the TB Control Program. The incidence rate of recurrence was calculated per person-year of follow-up (py). Kaplan-Meier and Cox regression methods were used for the survival analysis by calculating the hazard ratio (HR) with 95% confidence intervals (CI). Of the 1,823 TB cases identified, 971 fulfilled the inclusion criteria and 13 (1.3%) had recurrent TB. The recurrence rate was 341 cases per 100,000 py, 13 times higher than the TB incidence of the general population. Likelihood of TB recurrence at the 1st, 3rd and 5th year of follow-up was 0.1%, 1.4% and 1.6%, respectively. Factors associated with recurrence were HIV infection (HR: 4.7, CI: 1.4-15.7), living in the inner city district (HR: 3.9, CI: 1.3-11.8) and history of TB treatment (HR: 5.2, CI: 1.7-16.2). Genotyping results of recurrent cases were available for 6 patients (3 reinfections and 3 relapses). The rate of TB recurrence in Barcelona is low and most episodes occur within the first three years. Patients at higher risk of recurrence are co-infected with HIV, living in neighborhoods with high TB incidence or with a history of TB treatment. When available, genotyping results help determine whether the recurrence is due to reinfection or relapse.


Dynamic posturography in assessment of polyneuropathic disease.
Twenty-eight patients with polyneuropathy aged 49-82 years (mean 67 years) were assessed by dynamic posturography. The patient group was compared to a control group comprising 29 healthy controls aged 70 through 75 years (mean 73 years). The dynamic posturography method comprises a sensory organization part in which the platform and visual surround are either stable or referenced to the patient's sway; furthermore, the eyes are open or closed. In a movement coordination part the platform makes active movements. In the sensory organization part of the dynamic posturography the patient group showed significantly lower equilibrium performance compared to the control group in the test conditions with absent vision, sway-referenced surrounding, and, finally, sway referenced platform and surrounding. In these conditions the influx of somatosensory information is of paramount importance for stable posture. In the movement coordination test, the patient group showed prolonged muscular response latencies in both forward and backward platform perturbations compared to the control group. It is concluded that dynamic posturography is a valuable diagnostic tool in assessment of the dynamic equilibrium performance in patients with polyneuropathy.


Epigenome-wide association study of asthma and wheeze in childhood and adolescence.
Asthma heritability has only been partially explained by genetic variants and is known to be sensitive to environmental factors, implicating epigenetic modifications such as DNA methylation in its pathogenesis. Using data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), we assessed associations of asthma and wheeze with DNA methylation at 7.5 and 16.5 years, at over 450,000 CpG sites in DNA from the peripheral blood of approx. 1000 participants. We used Mendelian randomization (MR), a method of causal inference that uses genetic variants as instrumental variables, to infer the direction of association between DNA methylation and asthma. We identified 302 CpGs associated with current asthma status (FDR-adjusted P value < 0.05) and 445 with current wheeze status at 7.5 years, with substantial overlap between the two. Genes annotated to the 302 associated CpGs were enriched for pathways related to movement of cellular/subcellular components, locomotion, interleukin-4 production and eosinophil migration. All associations attenuated when adjusted for eosinophil and neutrophil cell count estimates. At 16.5 years, two sites were associated with current asthma after adjustment for cell counts. The CpGs mapped to the AP2A2 and IL5RA genes, with a - 2.32 [95% CI - 1.47, - 3.18] and - 2.49 [95% CI - 1.56, - 3.43] difference in percentage methylation in asthma cases respectively. Two-sample bi-directional MR indicated a causal effect of asthma on DNA methylation at several CpG sites at 7.5 years. However, associations did not persist after adjustment for multiple testing. There was no evidence of a causal effect of asthma on DNA methylation at either of the two CpG sites at 16.5 years. The majority of observed associations are driven by higher eosinophil cell counts in asthma cases, acting as an intermediate phenotype, with important implications for future studies of DNA methylation in atopic diseases.


Bond strengths of high-palladium content alloys.
Palladium-based alloys have had a significant import on the fabrication of ceramometal restorations. This article compares the bond strengths of four palladium-based alloys with that of a high-noble alloy. Tests were designed to closely represent clinical situations. Bond strengths of the palladium alloys compared favorably with the high-noble metals; palladium alloys containing up to 2% gold were the best.


Therapeutic bond judgments: Congruence and incongruence.
The present study had 2 aims: (a) to implement West and Kenny's (2011) Truth-and-Bias model to simultaneously assess the temporal congruence and directional discrepancy between clients' and therapists' ratings of the bond facet of the therapeutic alliance, as they cofluctuate from session to session; and (b) to examine whether symptom severity and a personality disorder (PD) diagnosis moderate congruence and/or discrepancy. Participants included 213 clients treated by 49 therapists. At pretreatment, clients were assessed for a PD diagnosis and completed symptom measures. Symptom severity was also assessed at the beginning of each session, using client self-reports. Both clients and therapists rated the therapeutic bond at the end of each session. Therapists and clients exhibited substantial temporal congruence in their session-by-session bond ratings, but therapists' ratings tended to be lower than their clients' across sessions. Additionally, therapeutic dyads whose session-by-session ratings were more congruent also tended to have a larger directional discrepancy (clients' ratings being higher). Pretreatment symptom severity and PD diagnosis did not moderate either temporal congruence or discrepancy at the dyad level; however, during sessions when clients were more symptomatic, therapist and client ratings were both farther apart and tracked each other less closely. Our findings are consistent with a "better safe than sorry" pattern, which suggests that therapists are motivated to take a vigilant approach that may lead both to underestimation and to attunement to fluctuations in the therapeutic bond.


Structure and dynamics of membrane-associated ICP47, a viral inhibitor of the MHC I antigen-processing machinery.
To evade the host's immune response, herpes simplex virus employs the immediate early gene product ICP47 (IE12) to suppress antigen presentation to cytotoxic T-lymphocytes by inhibition of the ATP-binding cassette transporter associated with antigen processing (TAP). ICP47 is a membrane-associated protein adopting an alpha-helical conformation. Its active domain was mapped to residues 3-34 and shown to encode all functional properties of the full-length protein. The active domain of ICP47 was reconstituted into oriented phospholipid bilayers and studied by proton-decoupled 15N and 2H solid-state NMR spectroscopy. In phospholipid bilayers, the protein adopts a helix-loop-helix structure, where the average tilt angle of the helices relative to the membrane surface is approximately 15 degrees (+/- 7 degrees ). The alignment of both structured domains exhibits a mosaic spread of approximately 10 degrees . A flexible dynamic loop encompassing residues 17 and 18 separates the two helices. Refinement of the experimental data indicates that helix 1 inserts more deeply into the membrane. These novel insights into the structure of ICP47 represent an important step toward a molecular understanding of the immune evasion mechanism of herpes simplex virus and are instrumental for the design of new therapeutics.


[An unusual case of hepatic abscess].
Right upper quadrant pain with chronic malaise and fever can be the clinical manifestation of a hepatic infection. An uncommon cause for the disease is hepatic actinomycosis. Actinomycosis was common in the preantibiotic era but is less frequent nowadays; consequently its timely recognition has become more difficult. The clinical and radiological findings often resemble other inflammatory and neoplastic lesions. We report a case of a mixed anaerobic liver abscess including fusobacteria and actinomycetes, without apparent predisposing factor. The diagnosis was obtained by CT-guided percutaneous aspiration of the hepatic mass, where microscopy revealed the presence of fusiform gramnegative bacteria and gram-positive branching filamentous rods consistent with Actinomyces species. The latter did not grow in culture, while the gram negatives were identified as fusobacterium nucleatum. The diagnosis of actinomycosis of the liver is confirmed in only a minority of cases by culture. The disease is usually treated with an extended course of antibiotics. Penicillin is the preferred choice.


Mother-child aspiration technique.
A 94-year-old woman underwent primary percutaneous coronary intervention for a total occlusion of the right coronary artery. A 6-Fr Ikari-left guiding catheter was inserted through the right radial artery. Initially, thrombectomy was performed with a conventional thrombus aspiration catheter. However, only small fragments of thrombus were aspirated and coronary blood flow was still obstructed. Subsequently, a 4.5-Fr straight guiding catheter was advanced through the 6-Fr guiding catheter into the coronary artery and aspiration was reinitiated. During the course of aspiration, the backflow of the blood was blocked. The inner catheter was pulled back slowly, maintaining suction. Just before it reached the tip of the 6-Fr guiding catheter, another vacuum syringe was attached to the side arm of the Y-connecter of the 6-Fr guiding catheter and additional aspiration with the outer guiding catheter was started. After complete retrieval of the 4.5-Fr catheter from the guiding catheter, thrombus was found in the vacuum syringes from both inner and outer guiding catheters. We consider that this double aspiration, with a mother-child catheter technique, is a simple and effective means of aspirating a larger thrombus, and may prevent the dislodgement of thrombus at the tip of the outer guiding catheter, which could cause systemic embolism.


A serial study of new MS lesions and the white matter from which they arise.
To compare MS normal-appearing white matter (NAWM) where new gadolinium-enhancing (Gd+) lesions do and do not arise. A total of 22 relapsing-remitting MS patients and 11 healthy control subjects completed as many as 12 monthly brain MRI sessions. Quantitative measures of gadolinium enhancement (GDR), water proton density (PDN), water proton T2 relaxation time constants (T2), magnetization transfer ratio (MTR), and T1-weighted signal intensity (T1N) were followed serially in healthy control and MS NAWM. A total of 129 new Gd+ lesions were identified in 11 patients. PDN, T2, MTR, and T1N were diffusely abnormal in MS NAWM. NAWM regions in which new Gd+ lesions arose have increased GDR, PDN, and T2, and reduced MTR and T1N compared with contralateral homologous NAWM regions in which no new Gd+ lesions arose. Differences between these NAWM regions preceded lesion appearance for at least several months. After lesions became visible, GDR returned to baseline within 2 months, and PDN and MTR had larger residual abnormalities than T2 or T1N. Quantitative MRI measures are diffusely abnormal in MS NAWM. These measures are, on average, more abnormal in NAWM regions in which new Gd+ lesions arise. After the appearance of Gd+ lesions, measures of PDN and MTR may provide more appealing markers of relatively irreversible tissue damage than measures of T2 and T1N.


Precursors and pathogenesis of ovarian carcinoma.
The ultimate goal of defining cancer specific precursors is to facilitate early detection and intervention before the development of invasive malignancy. Unlike other malignancies involving the female genital tract such as cervical or endometrial carcinomas, precursor lesions of ovarian carcinomas have not been well characterised, resulting in a failure to develop effective screening programs. Recent clinicopathological and molecular studies have provided new insight into the origin and pathogenesis of ovarian carcinomas. It has been shown that ovarian cancer is comprised of different tumour types differing not only in morphology, but also in pathogenesis, molecular alterations and clinical progression. A dualistic model of ovarian carcinogenesis has been proposed. Type I tumours which include low grade serous, low grade endometrioid, clear cell, mucinous carcinomas and Brenner tumours, are generally indolent and tend to be genetically stable, although clear cell carcinoma would probably belong to an intermediate category. They demonstrate a step-wise progression from a benign precursor such as a benign to borderline tumour or endometriosis and are characterised by genetic aberrations targeting specific cell signalling pathways. Type II tumours comprise high grade serous, high grade endometrioid, and undifferentiated carcinomas as well as malignant mixed mesodermal tumours. They are clinically aggressive and exhibit high genetic instability with frequent p53 mutations. Mounting evidence suggests that many high grade serous carcinomas originate from the epithelium of the distal fallopian tube, and that serous tubal intraepithelial carcinoma (STIC) represents the putative precursor of these neoplasms. Low grade serous carcinomas arise via transformation of benign and borderline serous tumours, thought to be derived from inclusion cysts originating from the ovarian surface or tubal epithelium. Recently it has been suggested that papillary tubal hyperplasia may be a putative precursor lesion for serous borderline tumours. Both endometrioid and clear cell carcinomas develop from endometriosis, via alterations affecting different genetic pathways. The origin of mucinous and transitional cell neoplasms is not well characterised, although new data suggest a possible origin from transitional cell nests present at the tubal-mesothelial junction. Likewise, the pathogenesis of carcinosarcomas is also not well established because of their rarity but there is accumulating evidence that the carcinomatous component determines the course of the disease and gives rise to the malignant mesenchymal component. This review discusses recent developments in the pathogenesis of ovarian carcinoma, with particular emphasis on the putative precursor lesions that give rise to the major histological subtypes. Recognition of these lesions is not only important in improving the understanding of ovarian carcinogenesis, but it will also influence our approach to prevent, detect and treat these tumours.


Integration of multimodality imaging data for radiotherapy treatment planning.
This paper describes computational techniques to permit the quantitative integration of magnetic resonance (MR), positron emission tomography (PET), and x-ray computed tomography (CT) imaging data sets. These methods are used to incorporate unique diagnostic information provided by PET and MR imaging into CT-based treatment planning for radiotherapy of intracranial tumors and vascular malformations. Integration of information from the different imaging modalities is treated as a two-step process. The first step is to determine the set of geometric parameters relating the coordinates of two imaging data sets. No universal method for determining these parameters is appropriate because of the diversity of contemporary imaging methods and data formats. Most situations can be handled by one of the four different techniques described. These four methods make use of specific geometric objects contained in the two data sets to determine the parameters. These objects are: (a) anatomical and/or fiducial points, (b) attached line markers, (c) anatomical surfaces, and (d) outlines of anatomical structures. The second step involves using the derived transformation to transfer outlines of treatment volumes and/or anatomical structures drawn on the images of one imaging study to the images of another study, usually the treatment planning CT. Solid modelling and image processing techniques have been adapted and developed further to accomplish this task. Clinical examples and phantom studies are presented which verify the different aspects of these techniques and demonstrate the accuracy with which they can be applied. Clinical use of these techniques for treatment planning has resulted in improvements in localization of treatment volumes and critical structures in the brain. These improvements have allowed greater sparing of normal tissues and more precise delivery of energy to the desired irradiation volume. It is believed that these improvements will have a positive impact on the outcome of radiation therapy.


[Unfounded doubt in laparoscopic cholecystectomy].
Laparoscopic cholecystectomy began to gain ground in the late eighties. The smaller incision led to less postoperative pain and faster recovery. By now, the method has become a matter of controversy: the laparoscopic operation took more time than the 'minilaparotomy'. This criticism can be refuted: laparoscopy gives faster recovery than the conventional large incision and a better view than the 'minilaparotomy'.


Effects of placebos without deception compared with no treatment: A systematic review and meta-analysis.
To investigate the clinical efficacy of open-label placebos compared with no treatment in a systematic review and meta-analysis. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations (OvidSP), EMBASE (OvidSP), and clinical trials registers and screened reference lists. The search was run on 27th April 2015. We included all randomized controlled trials of any medical condition with open-label placebo and no-treatment groups. Authors independently assessed records and extracted data. We excluded nonrandomized trials and nonclinical studies. Risk of bias was assessed using Cochrane criteria. We used random-effects model for meta-analysis. We screened 348 publications, assessed 24 articles for eligibility and identified five trials (260 participants) that met inclusion criteria. The clinical conditions were: irritable bowel syndrome, depression, allergic rhinitis, back pain, and attention deficit hyperactivity disorder. The risk of bias was moderate. We found a positive effect for nondeceptive placebos (standardized mean difference 0.88, 95% CI 0.62 to 1.14, P < 0.00001, I2 = 1%). Open-label placebos appear to have positive clinical effects compared to no treatment. Caution is warranted when interpreting these results due to the limited number of trials identified, lack of blinding, and the fact that positive messages were included alongside open-label placebos. Larger definitive trials are now warranted to explore the potential patient benefit of open-label placebos, to investigate the relative contributions of positive suggestions, and ethical implications.


Framing processes in public commentary on US federal tobacco control regulation.
Governmental health policy officials increasingly seek to promote public participation in expert and technical decisions regarding health regulation. The issues of what rôle the public plays in regulatory processes, and how health policy officials orient to public opinion, matter especially in the US context, where public commentary is a requisite component of federal rule-making. This paper examines written commentary as one specific, institutionalized form of public participation. To understand the relationship between scientific evidence and public commentary in public health regulation, we examine a US Food and Drug Administration (FDA) regulation, proposed in 1995, to restrict the promotion and sale of tobacco products to minors. We use recent work on collective action frames to analyse how the FDA framed the proposed regulation as a rational, science-based policy; the discursive practices employed in the public commentary either to embrace or to contest the FDA's framing; and how the agency presented the final version of its rule as responsive to that public commentary. Our content analyses reveal a significant disparity between the FDA's emphasis on scientific evidence and the commentators' emphases on political and ideological frames, which we analyse in terms of counter-framing. An orientation to the dynamics of framing and counter-framing contributes to an understanding of the relationship between scientific evidence and public commentary in the formulation of controversial health policy regulations.


A cost-effective pressure damage prevention strategy.
This article describes the development of a pressure ulcer prevention strategy, with the aim of establishing if the implementation of best practice would impact on the incidence of pressure ulcers in a healthcare setting. The strategy was piloted in a large 78-bedded nursing home. A full audit of the patients' notes and existing care pathways was conducted in order to inform the structure of the prevention plan. It was found that there were no protocols for the use of Cavilon barrier products and that it was not part of a standard care pathway. A prevention strategy was designed based on these findings and an education package delivered to all staff. Training in the appropriate use of Aderma (TM) Dermal Pads was also provided so that they could be put in place as an early preventative measure in patients at risk of pressure damage or those showing the symptoms. The results of the study showed that by establishing a best practice care pathway, the incidence of pressure ulcers could be reduced.


Haptic identification of common objects: effects of constraining the manual exploration process.
In this article, we address the effects on haptic recognition of common objects when manual exploration is constrained by using two kinds of rigid links--sheaths (Experiment 1A) and probes (Experiments 1B and 2). The collective effects of five different constraints are considered, including three from previous research (i.e., reducing the number of end effectors, wearing a compliant finger cover, and splinting the fingers; Klatzky, Loomis, Lederman, Wake, & Fujita, 1993) and from two current constraints (i.e., wearing a rigid finger sheath and using a rigid probe). The resulting impairments are interpreted in terms of the loss of somatosensory information from cutaneous and/or kinesthetic inputs. In addition, we relate the results to the design of haptic interfaces for teleoperation and virtual environments, which share some of the same reduction of sensory cues that we have produced experimentally.


Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade.
The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor-stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival. Checkpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy. This article is highlighted in the In This Issue feature, p. 2711.


Effect of interventions including provision of personalised cancer risk information on accuracy of risk perception and psychological responses: A systematic review and meta-analysis.
To synthesize the literature on the effect of provision of personalised cancer risk information to individuals at population level risk on accuracy of risk perception and psychological responses. A systematic review and random effects meta-analysis of articles published from 01/01/2000 to 01/07/2017. We included 23 studies. Immediately after provision of risk information 87% of individuals were able to recall the absolute risk estimate. Less than half believed that to be their risk, with up to 71% believing their risk to be higher than the estimate. Provision of risk information increased accuracy of perceived absolute risk immediately after risk information compared with no information (pooled RR 4.16 (95%CI 1.28-13.49), 3 studies). There was no significant effect on comparative risk accuracy (pooled RR 1.39 (0.72-2.69), 2 studies) and either no change or a reduction in cancer worry, anxiety and fear. These findings highlight the complex cognitive processes involved in the conceptualisation of risk. Individuals who appear to understand and are able to recall risk information most likely do not believe it reflects their own risk.


Monolayers of hard rods on planar substrates. I. Equilibrium.
The equilibrium properties of hard rod monolayers are investigated in a lattice model (where position and orientation of a rod are restricted to discrete values) as well as in an off-lattice model featuring spherocylinders with continuous positional and orientational degrees of freedom. Both models are treated using density functional theory and Monte Carlo simulations. Upon increasing the density of rods in the monolayer, there is a continuous ordering of the rods along the monolayer normal ("standing up" transition). The continuous transition also persists in the case of an external potential which favors flat-lying rods in the monolayer. This behavior is found in both the lattice and the continuum models. For the lattice model, we find very good agreement between the results from the specific DFT used (lattice fundamental measure theory) and simulations. The properties of lattice fundamental measure theory are further illustrated by the phase diagrams of bulk hard rods in two and three dimensions.


Level of family dysfunction and genetic influences on smoking in women.
An adoption study of alcoholism suggests that in women, the impact of genetic risk factors become greater in the presence of conflict in the family of origin. Is the same true for cigarette smoking (CS)? We obtained, in a sample of 1676 twins from female female twin pairs from a population-based register, a measure of maximum lifetime CS (divided into six ordinal categories) and family dysfunction (FD) assessed as the mean report of up to four informants (twin, co-twin, mother, father). Statistical analysis was conducted by traditional regression analysis and a moderator structural equation twin model using the computer program Mx. With increasing levels of FD, maximum CS increased substantially while correlations for CS in monozygotic (MZ) and dizygotic (DZ) twins decreased modestly. Regression analyses demonstrated reduced twin-pair resemblance for CS with increasing levels of FD. The best-fit structural equation model found high levels of heritability for CS and no evidence for a role of shared environment. With increasing levels of FD, the proportion of variance in CS due to genetic factors (i.e. heritability) decreased while that due to unique environmental effects increased. Several different statistical methods suggested that, contrary to prediction, heritability of CS decreased rather than increased with higher levels of dysfunction in the family of origin. The hypothesis that genetic effects for psychiatric and drug-use disorders become stronger in more adverse environments is not universally true.


[Organ pathology in chronic tissue-dwelling helminthic infections: role of blood and tissue eosinophilia, immunoglobulinemia E, G4, and immune response-inducing factors].
The results of earlier clinical, pathomorphological, and immunological studies of organic visceral and tissue lesions in helminthic infections [2, 3, 8, 10, 11, 14, 46] and present clinical and immunological ones [4-6, 44, 45] were analyzed and discussed in the light of a fundamental literature data review. The chronic visceral pathology in tissue-dwelling helminthic infections is associated with super- and reinfections [1, 2, 16, 36], with an inadequate immune response of humans to the invasion of zoonotic agents [2, 6, 13, 20] and with an individual invalidity of an immune response to infections [1, 2, 6, 16, 54]. The persistent course of infections, especially zoonotic, leads to organic pathology, sometimes irreversible [2, 13, 15, 21, 34, 46] if an individual (population) does not respond by immunity or by acquired (inherited) tolerance of invasion [1, 2, 3, 11, 16, 20, 36]. Transplacental transfer of Opisthorchis felineus antigens in the hyperendemic foci of the infection does not prevent superinfections, but does prevent the acute phase of disease and significantly mitigates the organic lesions in the chronic phase in spite of a very high intensity of infection [7, 10, 11]. Paramyosines (Pmes), proteins expressed on the tegument of Schistosoma mansoni and S. japonicum, show their immunogenic effect [42]. Antibodies to PM of Lumbricoidea and to a cardiac muscle myosin peptide (alpha-mp), known to induce experimental allergic myosites [55], were revealed in the sera of 32 trichinellosis, toxocarosis, opisthorchiasis, and hydatid echinococcosis patients with organic visceral abnormalities. The levels of antibodies against alpha-mp correlated with the severity of pathology [44]. S. mansoni PM peptide smp97 is a homologue of alpha-mp [25]. This fact suggests that there is a relationship between the development of an immune response to Pmes immunological processes in helminthiases. The relationship between organic visceral pathology and a competitive with serum IgE serum IgG4 hyperproduction at the early [6] and late stages of the studied helminthic infections was revealed. One may resume that this balance of production of these isotypes is not beneficial for the development of disease as IgG4-antibody hyperproduction is not beneficial for reinfection resistance [26, 28, 54]. One of the mechanisms may be serum IgG4 blocking the antibody-dependent cytotoxic effect, as it was supposed for unspecific IgE hyperproduction [47]. The selected development of cardiomyopathy or obstructive fibrosis in the lung after trichinellosis [2, 6, 45], endomyocardiofibrosis in the foci of filariases [21, 31] suggests that their development like resistance or susceptibility to infections [54] should be programmed.


Relationship Between Maximum Aerobic Speed Performance and Distance Covered in Rugby Union Games.
Swaby, R, Jones, PA, and Comfort, P. Relationship between maximum aerobic speed performance and distance covered in rugby union games. J Strength Cond Res 30(10): 2788-2793, 2016-Researchers have shown a clear relationship between aerobic fitness and the distance covered in professional soccer, although no research has identified such a relationship in rugby union. Therefore, the aim of the study was to identify whether there was a relationship between maximal aerobic speed (MAS) and the distance covered in rugby union games. Fourteen professional rugby union players (age = 26 ± 6 years, height = 1.90 ± 0.12 m, mass = 107.1 ± 24.1 kg) participated in this investigation. Each player performed a MAS test on 3 separate occasions during the preseason, to determine reliability and provide baseline data, and participated in 6 competitive games during the early stages of the season. Game data were collected using global positioning system technology. No significant difference (p > 0.05) in total distance covered was observed between games. Relationships between players' MAS and the average distance covered from 6 competitive games were explored using Pearson's correlation coefficients, with MAS performance showing a strong relationship with distance covered during match play (r = 0.746, p < 0.001). Significantly greater (p = 0.001, Cohen's d = 2.29) distances were covered by backs (6,544 ± 573 m) compared with the forwards (4,872 ± 857 m) during a game. Similarly, backs recorded a significantly (p = 0.001, Cohen's d = 2.20) higher MAS (4.9 ± 0.13 m·s) compared with the forwards (4.2 ± 0.43 m·s). Results of the study illustrate the importance of developing high levels of aerobic fitness to increase the distance that the athlete covers in the game.


Diagnosis, Evaluation, and Management of Patent Ductus Arteriosus in Preterm Neonates.
Patent ductus arteriosus (PDA) poses a diagnostic and therapeutic dilemma for clinicians. Diagnosis of persistent PDA and determination of its clinical and hemodynamic significance are challenging. Although the condition has been associated with substantial neonatal morbidities such as intraventricular hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis, most therapeutic approaches have failed to show improvement in these outcomes. As such, clinicians have tended toward conservative management strategies; however, the benefits and risks of such an approach are unclear. In this review, we explore various clinical diagnostic modalities, echocardiographic parameters for assessment of shunt presence, shunt volume and its effect on cardiovascular and hemodynamic status, and challenges in determining if a PDA is hemodynamically significant and clinically relevant. From the therapeutic aspect, we review current evidence on conservative, pharmacological, and mechanical (surgical or nonsurgical ligation) approaches to PDA closure. Dose, route, duration, and comparison of pharmacological strategies are reviewed, with implications for future research.


Two surgical procedures for esophagogastric variceal bleeding in patients with portal hypertension.
To determine the clinical value of a splenorenal shunt plus pericardial devascularization (PCVD) in portal hypertension (PHT) patients with variceal bleeding. From January 2008 to November 2012, 290 patients with cirrhotic portal hypertension were treated surgically in our department for the prevention of gastroesophageal variceal bleeding: 207 patients received a routine PCVD procedure (PCVD group), and 83 patients received a PCVD plus a splenorenal shunt procedure (combined group). Changes in hemodynamic parameters, rebleeding, encephalopathy, portal vein thrombosis, and mortality were analyzed. The free portal pressure decreased to 21.43 ± 4.35 mmHg in the combined group compared with 24.61 ± 5.42 mmHg in the PCVD group (P < 0.05). The changes in hemodynamic parameters were more significant in the combined group (P < 0.05). The long-term rebleeding rate was 7.22% in the combined group, which was lower than that in the PCVD group (14.93%), (P < 0.05). Devascularization plus splenorenal shunt is an effective and safe strategy to control esophagogastric variceal bleeding in PHT. It should be recommended as a first-line treatment for preventing bleeding in PHT patients when surgical interventions are considered.


Perfectly Alternating and Regioselective Copolymerization of Carbonyl Sulfide and Epoxides by Metal-Free Lewis Pairs.
The preparation of perfectly alternating and regioslective copolymers derived from the copolymerization of carbonyl sulfide (COS) and epoxides by metal-free Lewis pair catalysts composed of a Lewis base (amidine, guanidine, or quaternary onium salts) and a Lewis acid (triethyl borane) is described. Colorless and highly transparent copolymers of poly(monothiocarbonate) were successfully obtained with over 99 % tail-to-head content and high molecular weight (up to 92.5 kg mol-1 ). In most instances, oxygen-sulfur exchange reactions (O/S ERs), which would generate random thiocarbonate and carbonate units, were effectively suppressed. The turnover frequencies (TOF) of these Lewis pair catalyzed processes were as high as 119 h-1 at ambient temperature.


Effects of mutant and antisense RNA of phospholamban on SR Ca(2+)-ATPase activity and cardiac myocyte contractility.
The delayed cardiac relaxation in failing hearts has been attributed to a reduced activity of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2). Phospholamban (PLB) inhibits SERCA2 activity and is therefore a potential target to improve the cardiac performance in heart failure. Mutants of PLB (Adv/mPLB) or antisense RNA of PLB (Adv/asPLB) was expressed in cardiac myocytes by recombinant adenovirus, and their effects on SERCA2 activity and myocyte contractility were studied. One mPLB, K3E/R14E, pentamerized with endogenous PLB in neonatal myocytes and resulted in a 45% increase in the affinity of SERCA2 for Ca(2+) and 27% faster diastolic Ca(2+) decline as determined by SR (45)Ca uptake assays and by indo 1-facilitated Ca(2+) transient measurement, respectively. Edge-detection analysis of adult myocyte contractility showed a 74% increase in fractional shortening, accompanied by 115% increase in velocity of relengthening and 25% decrease in time to half-maximal relengthening. In parallel, infection of neonatal cardiac myocytes by Adv/asPLB decreased the endogenous PLB level by 54%, which was associated with a 35% increase in Ca(2+) affinity of SERCA2 and 21% faster diastolic Ca(2+) decline. However, in adult cardiac myocytes, Adv/asPLB failed to significantly alter the endogenous PLB level, the SERCA2 activity, or most of the contractile parameters. K3E/R14E is a dominant negative mutant of PLB that disrupts the structural integrity and function of the endogenous PLB and consequently enhances SERCA2 activity and myocyte contractility. In neonatal myocytes, the decrease in steady-state abundance of PLB by asPLB also leads to increased SERCA2 activity.


Association of disease activity with acute exacerbation of interstitial lung disease during tocilizumab treatment in patients with rheumatoid arthritis: a retrospective, case-control study.
The objective of the study was to identify risk factors for acute exacerbation of interstitial lung disease (ILD) during tocilizumab treatment in patients with rheumatoid arthritis (RA). This is a retrospective, case-control study. We reviewed 395 consecutive RA patients who received tocilizumab. First, we divided the patients according to the presence (RA-ILD) or absence of ILD (non-ILD) assessed by chest X-ray or high-resolution computed tomography, and compared them for characteristics relevant to RA-ILD. Subsequently, focusing on the patients with RA-ILD, we assessed their baseline characteristics and clinical courses comparing patients with acute exacerbation to those without. Comparing 78 with ILD and 317 without ILD, the following were identified as factors related to RA-ILD on multivariate analysis: age 60 years or older (OR 4.5, 95 % CI 2.2-9.4, P < 0.0001), smoking habit (OR 2.9, 95 % CI 1.5-5.5, P = 0.002), and high rheumatoid factor levels (OR 2.8, 95 % CI 1.4-5.5, P = 0.002). Of 78 RA-ILD patients, six developed acute exacerbation during tocilizumab treatment. The median duration between the initiation of tocilizumab treatment and the acute exacerbation occurrence was 48 weeks. While baseline characteristics did not differ between acute exacerbation and non-acute exacerbation groups, patients experiencing acute exacerbation had significantly higher Clinical Disease Activity Index (CDAI) at 24 weeks (20.8 vs. 6.2, P = 0.019). Univariate analysis showed that CDAI > 10 at 24 weeks was a risk factor for acute exacerbation (OR 4.7, 95 % CI 2.1-10.4, P = 0.02). Uncontrolled arthritis activity during tocilizumab treatment may be associated with acute exacerbation of RA-ILD, suggesting post-treatment monitoring of disease activity is important not only with respect to RA itself but also for RA-ILD.


[Chemobiokinetics of sarcolysin and its peptides with glutaminic acid].
A 14C study of chemobiokinetics of sarcolysin and its peptides of glutaminic acid, dosage and routes of administration was conducted in intact rats and those bearing Walker's carcinoma. Similar in shape for peptides, kinetic curves differed from those found for sarcolysin. The rates of absorption and excretion of sarcolysin peptides in intraperitoneal and, particularly, oral administration were lower than those of sarcolysin. Tumor appeared to play a role in a higher rate of peptide excretion. While sarcolysin and its peptides distribution in organs and tissues was generally identical, time of peak radioactive concentration build-up was different. Time needed for accumulation and excretion of peptides from tumor was much longer than from other organs or tissues. Sarcolysin went chiefly to urine while peptides--to faeces.


Evaluation of the effect of calcium hydroxide and endodontic irrigants on the push-out bond strength of fiber post - an in vitro study.
In recent years, fibre-reinforced composite posts have been proposed for the restoration of root filled teeth as an alternative to pre-fabricated posts or metal dowels. The aim of the study was to analyze the effect of endodontic irrigants used for removal of calcium hydroxide on the push-out bond strength of fiber posts to root canal dentin. Forty human permanent single-rooted mandibular premolars with relatively straight roots were taken and access cavities were prepared and biomechanical preparation done using Rotar Y protaper file till size F2. The samples were divided into Experimental group and Control group. In Experimental groups Intracanal dressing of calcium hydroxide was removed by 2.5% NaOCl and 17% EDTA (Group1), MTAD (Group II) and Qmix (Group III). Control group did not receive Intracanal calcium hydroxide dressing. Canals were obturated using size F2 protaper gutta-percha points and AH plus sealer. After storage for 24 hours, post space was prepared. Forty Tenax fiber post (Coltene) were cemented with Rely X U200 resin. The roots were then transversally sectioned into 3 slices of 1mm thickness corresponding to cervical, middle and apical third. The slices obtained were subjected to micro-push-out bond strength test using a universal testing machine. The data obtained was subjected to statistical analysis using One-Way ANOVA test. P value of .05 was considered as statistically significant level. The mean push-out bond strength values for controls, NaOCl/EDTA, MTAD and QMIX group at cervical third were 10.17, 15.84, 20.39 and 20.98 whereas at apical third 4.78, 8.85, 11.66 and 12.10. Qmix showed higher push-out bond strength values followed by MTAD and NaOCl/EDTA. All the groups showed lowest push-out bond strength values in the apical third followed by middle and the maximum in the cervical region.


Localization of cell division protein FtsK to the Escherichia coli septum and identification of a potential N-terminal targeting domain.
Escherichia coli cell division protein FtsK is a homolog of Bacillus subtilis SpoIIIE and appears to act late in the septation process. To determine whether FtsK localizes to the septum, we fused three N-terminal segments of FtsK to green fluorescent protein (GFP) and expressed them in E. coli cells. All three segments were sufficient to target GFP to the septum, suggesting that as little as the first 15% of the protein is a septum-targeting domain. Localized fluorescence was detectable only in cells containing a visible midcell constriction, suggesting that FtsK targeting normally occurs only at a late stage of septation. The largest two FtsK-GFP fusions were able at least partially to complement the ftsK44 mutation in trans, suggesting that the N- and C-terminal domains are functionally separable. However, overproduction of FtsK-GFP resulted in a late-septation phenotype similar to that of ftsK44, with fluorescent dots localized at the blocked septa, suggesting that high levels of the N-terminal domain may still localize but also inhibit FtsK activity. Interestingly, under these conditions fluorescence was also sometimes localized as bands at potential division sites, suggesting that FtsK-GFP is capable of targeting very early. In addition, FtsK-GFP localized to potential division sites in cephalexin-induced and ftsI mutant filaments, further supporting the idea that FtsK-GFP can target early, perhaps by recognizing FtsZ directly. This hypothesis was supported by the failure of FtsK-GFP to localize in ftsZ mutant filaments. In ftsK44 mutant filaments, FtsA and FtsZ were usually localized to potential division sites between the blocked septa. When the ftsK44 mutation was incorporated into the FtsK-GFP fusions, localization to midcell ranged between very weak and undetectable, suggesting that the FtsK44 mutant protein is defective in targeting the septum.


Molecular cytogenetic and phenotypic characterization of ring chromosome 13 in three unrelated patients.
We report on the cytogenetic and molecular investigations of constitutional de-novo ring chromosome 13s in three unrelated patients for better understanding and delineation of the phenotypic variability characterizing this genomic rearrangement. The patient's karyotypes were as follows: 46,XY,r(13)(p11q34) dn for patients 1 and 2 and 46,XY,r(13)(p11q14) dn for patient 3, as a result of the deletion in the telomeric regions of chromosome 13. The patients were, therefore, monosomic for the segment 13q34 → 13qter; in addition, for patient 3, the deletion was larger, encompassing the segment 13q14 → 13qter. Fluorescence in situ hybridization confirmed these rearrangement and array CGH technique showed the loss of at least 2.9 Mb on the short arm and 4.7 Mb on the long arm of the chromosome 13 in patient 2. Ring chromosome 13 (r(13)) is associated with several phenotypic features like intellectual disability, marked short stature, brain and heart defects, microcephaly and genital malformations in males, including undescended testes and hypospadias. However, the hearing loss and speech delay that were found in our three patients have rarely been reported with ring chromosome 13. Although little is known about its etiology, there is interesting evidence for a genetic cause for the ring chromosome 13. We thus performed a genotype-phenotype correlation analysis to ascertain the contribution of ring chromosome 13 to the clinical features of our three cases.


An intergenerational androgenic mechanism of female intrasexual competition in the cooperatively breeding meerkat.
Female intrasexual competition can be intense in cooperatively breeding species, with some dominant breeders (matriarchs) limiting reproduction in subordinates via aggression, eviction or infanticide. In males, such tendencies bidirectionally link to testosterone, but in females, there has been little systematic investigation of androgen-mediated behaviour within and across generations. In 22 clans of wild meerkats (Suricata suricatta), we show that matriarchs 1) express peak androgen concentrations during late gestation, 2) when displaying peak feeding competition, dominance behaviour, and evictions, and 3) relative to subordinates, produce offspring that are more aggressive in early development. Late-gestation antiandrogen treatment of matriarchs 4) specifically reduces dominance behaviour, is associated with infrequent evictions, decreases social centrality within the clan, 5) increases aggression in cohabiting subordinate dams, and 6) reduces offspring aggression. These effects implicate androgen-mediated aggression in the operation of female sexual selection, and intergenerational transmission of masculinised phenotypes in the evolution of meerkat cooperative breeding.


[A multicenter study to test the reliability and validity of the frailty assessment scale for elderly patients with inguinal hernia and to evaluate the value of clinical application].
Objectives: To verify the reliability and validity of the frailty assessment scale for elderly patients with inguinal hernia and to evaluate the value of its clinical application. Methods: A convenience sampling method was used to collect 129 geriatric patients who underwent inguinal hernia surgery from January 2018 to January 2023 in nine hospitals in Liaoning Province. There were 120 males and 9 females, of whom 89 patients were 60 to <75 years old, 33 patients were 75 to <85 years old and 7 patients were ≥85 years old. The 129 patients included 11 elderly patients with inguinal hernia who had recovered from preoperative infection with COVID-19. Statistical methods such as Cronbach's coefficient, Kaiser-Meyer-Olkin test, Bartlett's test, Pearson's correlation analysis, etc. were calculated to verify the reliability indexes such as feasibility, content validity, structural validity, criterion-related validity, internal consistency reliability, and re-test reliability. Taking the 5-item modified frailty index (5-mFI) as the gold standard, the area under the curve was used to analyze the ability of the two scales to predict the occurrence of postoperative acute urinary retention, postoperative delirium, poor incision healing, operative hematoma seroma, and postoperative complications. Results: The frailty assessment scale for elderly patients with inguinal hernia showed good reliability and validity (valid completion rate of 99.2%; item content validity index of 1.000, and the scale content validity index of 1.000; exploratory factor analysis extracted a total of 1 principal component, and factor loadings of each item of 0.565 to 0.873; the AUC for frailty diagnosis using 5-mFI as the gold standard of 0.795 (P<0.01) Cronbach's coefficient of 0.916, retest reliability coefficient of 0.926), it could effectively predict postoperative acute urinary retention, delirium, hematoma seroma in the operative area and total complications (AUC of 0.746, 0.870, 0.806, and 0.738, respectively; all P<0.05), and prediction efficiency was higher than that of 5-mFI (AUC of 0.694, 0.838, 0.626 and 0.641, P<0.05 for delirium only), but both scales were inaccurate in predicting poor incision healing (AUC of 0.519, P=0.913 for the frailty assessment scale and 0.455, P=0.791 for the 5-mFI). Conclusions: The frailty assessment scale for elderly patients with inguinal hernia is reliable and significantly predicts the occurrence of postoperative adverse events in elderly inguinal hernia patients. The scale can also be used for preoperative frailty assessment in elderly patients with inguinal hernia after rehabilitation from COVID-19 infection.


Differential response of bone and kidney to ACEI in db/db mice: A potential effect of captopril on accelerating bone loss.
The components of renin-angiotensin system (RAS) are expressed in the kidney and bone. Kidney disease and bone injury are common complications associated with diabetes. This study aimed to investigate the effects of an angiotensin-converting enzyme inhibitor, captopril, on the kidney and bone of db/db mice. The db/db mice were orally administered by gavage with captopril for 8weeks with db/+ mice as the non-diabetic control. Serum and urine biochemistries were determined by standard colorimetric methods or ELISA. Histological measurements were performed on the kidney by periodic acid-schiff staining and on the tibial proximal metaphysis by safranin O and masson-trichrome staining. Trabecular bone mass and bone quality were analyzed by microcomputed tomography. Quantitative polymerase chain reaction and immunoblotting were applied for molecular analysis on mRNA and protein expression. Captopril significantly improved albuminuria and glomerulosclerosis in db/db mice, and these effects might be attributed to the down-regulation of angiotensin II expression and the expression of its down-stream profibrotic factors in the kidney, like connective tissue growth factor and vascular endothelial growth factor. Urinary excretion of calcium and phosphorus markedly increased in db/db mice in response to captopril. Treatment with captopril induced a decrease in bone mineral density and deterioration of trabecular bone at proximal metaphysis of tibia in db/db mice, as shown in the histological and reconstructed 3-dimensional images. Even though captopril effectively reversed the diabetes-induced changes in calcium-binding protein 28-k and vitamin D receptor expression in the kidney as well as the expression of RAS components and bradykinin receptor-2 in bone tissue, treatment with captopril increased the osteoclast-covered bone surface, reduced the osteoblast-covered bone surface, down-regulated the expression of type 1 collagen and transcription factor runt-related transcription factor 2 (markers for osteoblastic functions), and up-regulated the expression of carbonic anhydrase II (marker for bone resorption). Captopril exerted therapeutic effects on renal injuries associated with type 2 diabetes but worsened the deteriorations of trabecular bone in db/db mice; the latter of which was at least in part due to the stimulation of osteoclastogenesis and the suppression of osteogenesis by captopril.


Bridging steady-state and stick-slip fracture propagation in glassy polymers.
Both an experimental and a theoretical investigation of fracture propagation mechanisms acting at the process zone scale in glassy polymers are presented. The main aim is to establish a common modeling for different kinds of glassy polymers presenting either steady-state fracture propagation or stick-slip fracture propagation or both, depending on loading conditions and sample shapes. From the experimental point of view, new insights are provided by the in situ AFM measurements of viscoplastic strain fields acting within the micrometric process zone in a brittle epoxy resin, which highlight an extremely slow unexpected steady-state regime with finite plastic strains of about 30% around a blunt crack tip, accompanied by propagating shear lips. From the theoretical point of view, we apply to glassy polymers some recently developed models for describing soft dissipative fracture that are pertinent with the observed finite strains. We propose a unified modeling of fracture energy for both the steady-state and stick-slip fracture propagation based on the evaluation of energy dissipation density at a characteristic strain rate induced in the process zone by a competition between the crack propagation velocity and the macroscopic sample loading rate.


The importance of lipid type in the diet after burn injury.
The effects of different types of dietary lipids were tested in burned guinea pigs. All diets were identical except for the type of lipid, with total energy intake from lipids equaling 10%. All animals received a 30% total body surface area (TBSA) flame burn and were fed identically by pump-controlled gastrostomy feedings for 14 days. When compared to safflower oil (74% linoleic acid) as well as linoleic acid alone, fish oil (18% eicosapentaenoic acid or EPA) administration resulted in less weight loss, better skeletal muscle mass, lower resting metabolic expenditure, better cell mediated immune responses, better opsonic indices, higher splenic weight, lower adrenal weight, higher serum transferrin, and lower serum C3 levels. With the exception of better cell mediated immune responses in the animals fed linoleic acid, the administration of indomethacin made little difference. These findings can be explained by a reduction in the synthesis of the dienoic prostaglandins that are derived from the omega 6 series of fatty acids, some of which are significantly immunosuppressive. Regulation of dietary lipids may be an important therapeutic advance in nutritional support after burn injury, and controlled trials should be considered.


A cohort study of stomach cancer in a high-risk American population.
Demographic, smoking and dietary information was obtained from a cohort of 17,633 white American men, largely of Scandinavian and German descent, who responded to a mailed questionnaire in 1966. After 20 years of follow-up, 50% to 90% increases in mortality from stomach cancer (75 deaths) were found among foreign-born, their children, and among residents of the North Central states. An association was seen with low educational attainment and laboring or semiskilled occupations, primarily among immigrants and their children. Risk was evaluated in subjects who regularly smoked cigarettes (RR = 2.6, 95% CI = 1.1 to 5.8). A significant dose-response trend was observed, with subjects who smoked 30 or more cigarettes per day having more than a five-fold increased risk compared with those who never smoked. Elevated risks were also found for pipe smoking and smokeless tobacco use, but not for alcohol consumption. Analysis of dietary consumption of nine food groups revealed no significant associations with stomach cancer. However, total carbohydrate intake and a few individual food items (salted fish, bacon, cooked cereal, milk, and apples) were associated with increased risk. The findings of this prospective study of a high-risk population add to the limited evidence relating tobacco consumption to stomach cancer risk and suggest clues to ethnic, geographic, and dietary risk factors.


Phylogenesis of relapsing fever Borrelia spp.
The phylogenetic relationships of 20 relapsing fever (RF) Borrelia spp. were estimated on the basis of the sequences of rrs genes. Complete sequences were aligned and compared with previously published sequences, and the similarity values were found to be 97.7 to 99.9%. Phylogenetic trees were constructed by using the three neighbor-joining, maximum-parsimony, and maximum-likelihood methods. The results of the comparative phylogenetic analysis divided the RF Borrelia spp. into three major clusters. One cluster included Borrelia crocidurae, Borrelia duttonii, Borrelia recurrentis, and Borrelia hispanica. Another cluster comprised tow main branches with Borrelia coriaceae, Borrelia lonestari, and Borrelia miyamotoi on one side and Borrelia parkeri, Borrelia turicatae, and Borrelia hermsii on the other side. Borrelia anserina constituted the third cluster. The phylogenetic position of Borrelia persica was more uncertain. These results suggested that the taxonomy of these spirochetes should be revised. To overcome the problems of culturing the spirochetes, RF Borrelia primers were defined. Following PCR amplification of the rrs gene, restriction length fragment polymorphism could be used to distinguish between RF Borrelia strains.


Engineering Yarrowia lipolytica for sustainable ricinoleic acid production: A pathway to free fatty acid synthesis.
Ricinoleic acid (C18:1-OH, RA) is a valuable hydroxy fatty acid with versatile applications. The current industrial source of RA relies on the hydrolysis of castor bean oil. However, the coexistence of the toxic compound ricin and the unstable supply of this plant have led to an exploration of promising alternatives: generating RA in heterologous plants or microorganisms. In this study, we engineered the oleaginous yeast Yarrowia lipolytica to produce RA in the form of free fatty acids (FFA). First, we overexpressed fungal Δ12 oleate hydroxylase gene (CpFAH12) from Claviceps purpurea while deleting genes related to fatty acid degradation (MEF1 and PEX10) and oleic acid desaturation (FAD2). Since Δ12 oleate hydroxylase converts oleic acid (C18:1) located at the sn-2 position of phosphatidylcholine (PC), we next focused on increasing the PC pool containing oleic acid. This objective was achieved thorough implementing metabolic engineering strategies designed to enhance the biosynthesis of PC and C18 fatty acids. To increase the PC pool, we redirected the flux towards phospholipid biosynthesis by deleting phosphatidic acid phosphatase genes (PAH1 and APP1) and diacylglycerol acyltransferase gene (DGA1), involved in the production of diacylglycerol and triacylglycerol, respectively. Furthermore, the PC biosynthesis via the CDP-DAG pathway was enhanced through the overexpression of CDS1, PSD1, CHO2, and OPI3 genes. Subsequently, to increase the oleic acid content within PC, we overexpressed the heterologous fatty acid elongase gene (MaC16E) involved in conversion of C16 to C18 fatty acids. As RA production titer escalated, the produced RA was mainly found in the FFA form, leading to cell growth inhibition. The growth inhibition was mitigated by inducing RA secretion via Triton X-100 treatment, a process that simultaneously amplified RA production by redirecting flux towards RA synthesis. The final engineered strain JHYL-R146 produced 2.061 g/L of free RA in a medium treated with 5% Triton X-100, constituting 74% of the total free fatty acids produced. Generating free RA offers the added benefit of bypassing the hydrolysis stage required when employing castor bean oil as an RA source. This achievement represents the highest level of RA synthesis from glucose reported thus far, underscoring the potential of Y. lipolytica as a host for sustainable RA production.


Estrogen action on the prostate gland: a critical mix of endocrine and paracrine signaling.
Although modern biotechnology has provided us with a greater understanding of the molecular events in endocrine-related diseases, such as benign prostatic hyperplasia and prostate cancer, these conditions continue to be a significant healthcare problem world-wide. As the number of men afflicted by these diseases will only continue to grow with the aging population, finding new strategies and new therapeutic options for the treatment of both of these diseases is crucial. A better knowledge of the mechanisms of hormone action is pivotal to making progress in the development of new hormone-based therapies. This is fundamental to increasing our understanding of the endocrine, paracrine, and autocrine signaling mechanisms in the prostate and in prostate disease, distinguishing the effects and role of each, and identifying where and how this communication goes wrong.


Classifying the estrogen receptor status of breast cancers by expression profiles reveals a poor prognosis subpopulation exhibiting high expression of the ERBB2 receptor.
Recent work using expression profiling to computationally predict the estrogen receptor (ER) status of breast tumors has revealed that certain tumors are characterized by a high prediction uncertainty ('low-confidence'). We analyzed these 'low-confidence' tumors and determined that their 'uncertain' prediction status arises as a result of widespread perturbations in multiple genes whose expression is important for ER subtype discrimination. Patients with 'low-confidence' ER+ tumors exhibited a significantly worse overall survival (P=0.03) and shorter time to distant metastasis (P=0.004) compared with their 'high-confidence' ER+ counterparts, indicating that the 'high-' and 'low-confidence' binary distinction is clinically meaningful. We then discovered that elevated expression of the ERBB2 receptor is significantly correlated with a breast tumor exhibiting a 'low-confidence' prediction, and this association was subsequently validated across multiple independently derived breast cancer expression datasets employing a variety of different array technologies and patient populations. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ER, a large proportion of the perturbed genes in the 'low-confidence'/ERBB2+ samples are not known to be estrogen responsive, and a recently described bioinformatic algorithm (DEREF) was used to demonstrate the absence of potential estrogen-response elements (EREs) in their promoters. We propose that a significant portion of ERBB2's effects on ER+ breast tumors may involve ER-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the 'low-confidence' breast tumor subtype.


Sexual Orientation Differences in Satisfaction with Healthcare: Findings from the Behavioral Risk Factor Surveillance System, 2014.
In the United States, the Affordable Care Act and marriage equality may have eased sexual orientation-based differences in access to healthcare coverage, but limited research has investigated sexual orientation-based differences in healthcare satisfaction. The purpose of this study was to examine whether satisfaction with healthcare varied by sexual orientation in a large population-based sample of adults. Data are from the 2014 Behavioral Risk Factor Surveillance System, including items about sexual orientation and healthcare (n = 113,317). Healthcare coverage included employer-based insurance; individually purchased insurance; Medicare; Medicaid; or TRICARE, VA, or military care. Respondents indicated whether they were "very satisfied, somewhat satisfied, or not at all satisfied" with healthcare. After adjusting for several sociodemographic covariates, lesbian, gay, and bisexual status was associated with lower satisfaction with healthcare with individually purchased insurance (adjusted odds ratio = 1.49, 95% confidence interval = 1.24-1.80). Efforts are needed to examine and reduce sexual orientation differences in satisfaction with healthcare.


No difference in 1RM strength and muscle activation during the barbell chest press on a stable and unstable surface.
Exercise or Swiss balls are increasingly being used with conventional resistance exercises. There is little evidence supporting the efficacy of this approach compared to traditional resistance training on a stable surface. Previous studies have shown that force output may be reduced with no change in muscle electromyography (EMG) activity while others have shown increased muscle EMG activity when performing resistance exercises on an unstable surface. This study compared 1RM strength, and upper body and trunk muscle EMG activity during the barbell chest press exercise on a stable (flat bench) and unstable surface (exercise ball). After familiarization, 13 subjects underwent testing for 1RM strength for the barbell chest press on both a stable bench and an exercise ball, each separated by at least 7 days. Surface EMG was recorded for 5 upper body muscles and one trunk muscle from which average root mean square of the muscle activity was calculated for the whole 1RM lift and the concentric and eccentric phases. Elbow angle during each lift was recorded to examine any range-of-motion differences between the two surfaces. The results show that there was no difference in 1RM strength or muscle EMG activity for the stable and unstable surfaces. In addition, there was no difference in elbow range-of-motion between the two surfaces. Taken together, these results indicate that there is no reduction in 1RM strength or any differences in muscle EMG activity for the barbell chest press exercise on an unstable exercise ball when compared to a stable flat surface. Moreover, these results do not support the notion that resistance exercises performed on an exercise ball are more efficacious than traditional stable exercises.


Proteolysis in the rat lung: hypoxia and evidence for an inhibitor of proteolysis.
We labeled proteins with [14C]phenylalanine in rats breathing air and assessed the rate of proteolysis in the isolated ventilated lung by measuring the accumulation of [14C]phenylalanine in the medium perfusing the lung. Ventilation with 0% O2 decreased the rate of proteolysis and the ATP content in the lung 60%. Medium from lungs ventilated with 0% O2, when used to perfuse lungs ventilated with 95% O2, decreased the rate of proteolysis 60% without lowering the ATP content of the lung. Correcting the pH of "used" medium or dialyzing used medium did not decrease its ability to inhibit proteolysis. Used medium from nonhypoxic lungs, or exogenous lactate (50 mM), diminished proteolysis only 20%. In a cell-free system the degradation by cathepsin D of radioactive lung proteins and radioactive hemoglobin was decreased by used medium from hypoxic lungs. We conclude that the hypoxic perfused lung releases a factor(s) that decreases the rate of proteolysis in nonhypoxic lungs and that this factor may be a protease inhibitor.


Use of a pharmacy-based GP video consultation service: a mixed methods study.
Little is known about private general practice appointment services offered via video. This study aimed to explore which patients are using a video pharmacy-based general practitioner (GP) appointment service, including patterns of use, reasons for using the service, and satisfaction with the service. Descriptive statistics and parametric and nonparametric tests were used to conduct a retrospective cross-sectional analysis of routinely collected data on consultations, and postconsultation questionnaires. Interviews were conducted with patients and GPs. A total of 7,928 consultations were included in the analysis. More than half of appointments were booked for the same day, with lunchtime appointments being popular. The most common health condition was respiratory conditions, and 9% of consultations were used by patients using the service more than once. At least one prescription was issued in over half of all consultations. Overall, satisfactions of consultations were high. The characteristics of those patients using the video consultation service match data on who uses online services in general practice. This study shows that some patients are willing to pay to use this private service because they feel it is more convenient, NHS services do not have capacity to see them at the time they need, or they do not have access to regular GP services.


[A questionnaire study on the necessity of approval for revaccination of the pneumococcal polysaccharide vaccine].
To clarify the current situation of revaccination with pneumococcal polysaccharide vaccine (PPV) and the adverse effects caused by revaccination with PPV in the elderly in Japan, a questionnaire study was carried out among the 989 members of the directors and councillors of the Japanese Respirology Society and the Japanese Association for Infectious Diseases. Of 385 evaluable respondents, 290 who had had experience giving PPV immunization were regarded as the study subjects. Of whom 46 subjects (15.9%) had had experience of PPV revaccination. However, 252 subjects (86.9%) recognized that PPV revaccination is necessary. In addition, of the 290 subjects, 114 subjects (49.7%) had experienced a patient refusing the first vaccination with PPV because of contraindications for PPV revaccination. Of 46 subjects with experience of PPV vaccination, 4 subjects found adverse effects in the recipients of PPV revaccination. The adverse effects found were not serious. The present study demonstrated that most of the study subjects recognized the necessity of PPV revaccination, and in part, those subjects implementing PPV revaccination were responding to requests by patients or their family. It was also suggested that the contraindication for PPV revaccination could prevent the increase of the coverage rate of PPV.


[Sarcosporidiosis in sheep (author's transl)].
Histological examination of the masseter muscle, diaphragm, oseophagus and heart showed that about 18 per cent of approximately eight-month-old sheep in the Netherlands were infected with Sarcocystis. The masseter muscle obviously was the site of predilection.


Induction of tumor-specific T-cell responses by vaccination with tumor lysate-loaded dendritic cells in colorectal cancer patients with carcinoembryonic-antigen positive tumors.
Dendritic cells (DCs) are the most effective antigen-presenting cells. In the last decade, the use of DCs for immunotherapy of cancer patients has been vastly increased. High endocytic capacity together with a unique capability of initiating primary T-cell responses have made DCs the most potent candidates for this purpose. Although DC vaccination occasionally leads to tumor regression, clinical efficacy, and immunogenicity of DCs in clinical trials has not been yet clarified. The present study evaluated the safety and effectiveness of tumor-lysate loaded DC vaccines in advanced colorectal cancer (CRC) patients with carcinoembryonic antigen (CEA) positive tumors. Six patients HLA-A*0201-positive were vaccinated with autologous DCs loaded with tumor lysates (TL) together with tetanus toxoid antigen, hepatitis B, and influenza matrix peptides. Two additional patients were injected with DCs that were generated from their sibling or parent with one haplotype mismatch. All patients received the vaccines every 2 weeks, with a total of three intra-nodal injections per patient. The results indicated that DC vaccination was safe and well tolerated by the patients. Specific immune responses were detected and in some patients, transient stabilization or even reduction of CEA levels were observed. The injection of haplotype mismatched HLA-A*0201-positive DCs resulted in some enhancement of the anti-tumor response in vitro and led to stabilization/reduction of CEA levels in the serum, compared to the use of autologous DCs. Altogether, these results suggest that TL-pulsed DCs may be an effective vaccine method in CRC patients. Elimination of regulatory mechanisms as well as adjustment of the vaccination protocol may improve the efficacy of DC vaccination.


Colonic cancer in pregnancy.
We have described a case of adenocarcinoma of the descending colon in a 29-year-old pregnant woman, and have reviewed the problems of diagnosis and management and the role of reproductive and hormonal factors in relation to colonic cancer. Ours is the 20th reported case of colonic cancer during pregnancy.


Sulphation of N-linked oligosaccharides of vesicular stomatitis and influenza virus envelope glycoproteins: host cell specificity, subcellular localization and identification of substituted saccharides.
The presence of sulphate groups on various saccharide residues of N-linked carbohydrate units has now been observed in a number of glycoproteins. To explore the cell specificity of this post-translational modification, we evaluated sulphate incorporation into virus envelope glycoproteins by a variety of cells, since it is believed that assembly of their N-linked oligosaccharides is to a large extent dependent on the enzymic machinery of the host. Employing the vesicular stomatitis virus (VSV) envelope glycoprotein (G protein) as a model, we noted that the addition of [35S]sulphate substituents into its complex carbohydrate units occurred in Madin-Darby canine kidney (MDCK), Madin-Darby bovine kidney, LLC-PK1 and BHK-21 cell lines but was not detectable in BRL 3A, BW5147.3, Chinese hamster ovary, HepG2, NRK-49F, IEC-18, PtK1 or 3T3 cells. The sulphate groups were exclusively located on C-3 of galactose [Gal(3-SO4)] and/or C-6 of N-acetylglucosamine [GlcNAc(6-SO4)] residues in the N-acetyllactosamine sequence of the branch chains. Moreover, we observed that the pronounced host-cell-dependence of the terminal galactose sulphation was reflected by the 3'-phosphoadenosine 5'-phosphosulphate:Gal-3-O-sulphotransferase activity assayed in vitro. Comparative studies carried out on the haemagglutinin of the influenza virus envelope formed by MDCK and LLC-PK1 cells indicated that sulphate in this glycoprotein was confined to its complex N-linked oligosaccharides where it occurred as Gal(3-SO4) and GlcNAc(6-SO4) on peripheral chains as well as on the mannose-substituted N-acetylglucosamine of the core. Since sulphation in both internal and peripheral locations of the virus glycoproteins was found to be arrested by the alpha1-->2 mannosidase inhibitor, kifunensine, as well as by the intracellular migration block imposed by brefeldin A, it was concluded that this modification is a late biosynthetic event which most likely takes place in the trans-Golgi network.


Does use of a government service depend on distance from the health facility?
To reduce mortality from common childhood illnesses such as diarrhoea and upper respiratory infections, it is important that health services are available and used appropriately. Physical accessibility to a health facility may influence its use, particularly in rural areas. We assessed whether use of government services for treatment of the three most common acute childhood illnesses (fever, diarrhoea and upper respiratory infections) was influenced by the physical accessibility of the government primary health care centres. We analyzed data from a household survey which was collected between November 1992 and January 1993, from 139 randomly selected villages located around 14 government facilities in Thatta, a rural district of Pakistan. There were 691 children under 5 years of age who suffered from the three acute illnesses; 85% of these children used either a government or a private service. Children living at less than 4 km from a government facility made 22% less use of that facility than those living 4 km or more away. After controlling for the effects of distance from a private facility and treatment cost in a multiple logistic regression model, children living less than 4 km from a government facility were no more likely to use the facility than those living 4 km or more away (Adjusted Odds Ratio: 1.01, 95% Confidence Interval: 0.68-1.50). These results suggest that factors other than distance are the primary determinants of use of government services for treating children in the Thatta district. To increase the use of government health services, policymakers should assess carefully the factors determining the use of existing facilities, before they plan the building of more health facilities. Further studies are needed to examine the management of health facilities and the clients' perception of health-care providers.


Two direct (nonchromatographic) assays for 25-hydroxyvitamin D.
We describe direct, nonchromatographic assays for 25-hydroxyvitamin D3 in which we use either rat vitamin D-binding protein or rabbit antibodies to 25-hydroxyvitamin D3-3-hemisuccinate-bovine serum albumin as binding protein. Nonspecific interferences in serum could be eliminated by an appropriate extraction method or in obtaining data for the calibration curve, by using vitamin D-free human serum. The latter is prepared by affinity chromatography with use of immobilized antibodies against human vitamin D-binding protein. Values obtained by the direct assays and those obtained by two different chromatographic methods correlated well (r greater than 0.95). The direct competitive protein-binding assay overestimated the true 25-hydroxyvitamin D3 concentration by about 20%, but this percentage was constant from 5 to 600 micrograms/L. Overestimation by the direct radioimmunoassay was less than 10%. These two direct assays for 25-hydroxyvitamin D3 allow reliable, rapid, and simple screening for vitamin D deficiency or excess.