Scheduling nab-paclitaxel combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.

BACKGROUND: Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial. METHODS: Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers. RESULTS: In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47-0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65-1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13-0.70). CONCLUSIONS: SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. CLINICAL TRIAL REGISTRATION: ISRCTN71070888; ClinialTrials.gov (NCT03529175).

Effects of exposure to fine particulate matter in elderly hospitalizations due to respiratory diseases in the South of the Brazilian Amazon.

Exposure to air pollution is an important cause of hospital admissions due to respiratory diseases. Nevertheless, few studies use pollutant concentration data estimated by mathematical models. A time-series ecological study was developed, using data from hospitalizations due to respiratory diseases in people over 60 years of age, residents of Cuiabá, Brazil, during 2012, obtained from the Brazilian Ministry of Health. The independent variables were the concentrations of fine particulate matter (PM2.5) and carbon monoxide (CO) estimated by mathematical modeling, minimum temperature, and relative humidity (obtained from the Brazilian Meteorological Agency), and the number of forest fires. The generalized linear regression model of Poisson was used, with lags of 0 to 7 days. The coefficients obtained were transformed into relative risk of hospitalization, with respective 95% confidence intervals; alpha=5% was adopted. In that year, 591 hospitalizations were evaluated, with a daily average of 1.61 (SD=1.49), the PM2.5 average concentration was 15.7 µg/m3, and the CO average concentration was 144.2 ppb. Significant associations between exposure to these contaminants and hospitalizations in lags 3 and 4 in 2012 were observed. There was a hospitalization risk increase of 31.8%, with an increase of 3.5 µg/m3 of PM2.5 concentrations and an increase of 188 in the total number of hospitalizations, with an expense of more than ≈US$ 96,000 for the Brazilian Public Health System. This study provided information on the cost of air pollution to the health system and the feasibility of using a mathematical model to estimate environmental concentration of air pollutants.

Effects of exposure to fine particulate matter in elderly hospitalizations due to respiratory diseases in the South of the Brazilian Amazon

Exposure to air pollution is an important cause of hospital admissions due to respiratory diseases. Nevertheless, few studies use pollutant concentration data estimated by mathematical models. A time-series ecological study was developed, using data from hospitalizations due to respiratory diseases in people over 60 years of age, residents of Cuiabá, Brazil, during 2012, obtained from the Brazilian Ministry of Health. The independent variables were the concentrations of fine particulate matter (PM2.5) and carbon monoxide (CO) estimated by mathematical modeling, minimum temperature, and relative humidity (obtained from the Brazilian Meteorological Agency), and the number of forest fires. The generalized linear regression model of Poisson was used, with lags of 0 to 7 days. The coefficients obtained were transformed into relative risk of hospitalization, with respective 95% confidence intervals; alpha=5% was adopted. In that year, 591 hospitalizations were evaluated, with a daily average of 1.61 (SD=1.49), the PM2.5 average concentration was 15.7 µg/m3, and the CO average concentration was 144.2 ppb. Significant associations between exposure to these contaminants and hospitalizations in lags 3 and 4 in 2012 were observed. There was a hospitalization risk increase of 31.8%, with an increase of 3.5 µg/m3 of PM2.5 concentrations and an increase of 188 in the total number of hospitalizations, with an expense of more than ≈US$ 96,000 for the Brazilian Public Health System. This study provided information on the cost of air pollution to the health system and the feasibility of using a mathematical model to estimate environmental concentration of air pollutants.

A qualitative exploration of stakeholder perceptions of the implementation of place-based working and its potential to reduce health inequality.

Background: Local authorities (LAs) have statutory responsibility to reduce health inequalities and improve public health. Place-based approaches may positively influence service provision yet little is known about their implementation and potential for reducing inequality through health and wellbeing improvements. An English LA implemented a place-based working (PBW) pilot in a small geography during austerity measures in the north of England. This involved three strands (early intervention, estate services and community intelligence) which were introduced separately and covered overlapping geographies. Predominantly focusing on early intervention, this qualitative study investigates stakeholders' perceptions of the pilot and its potential to improve health and wellbeing by reducing inequality. Methods: In total, 15 face-to-face qualitative interviews with stakeholders were completed. Thematic analysis produced context, mechanism and outcome configurations in a process adapted from realist evaluation methodology. Results: Stakeholders described PBW as holistic, upstream and cutting across departmental boundaries to engage staff and the community. Collaborative working was considered important and was aided by PBW in our study. Conclusions: PBW has the potential to reduce health inequalities by improving health and wellbeing. LAs deliver services that affect health and wellbeing and PBW may help develop a more coordinated response to improve outcomes and potentially save money.

The extra-articular impacts of rheumatoid arthritis: moving towards holistic care.

Although treat-to-target has revolutionised the outcomes of patients with rheumatoid arthritis (RA) there is emerging evidence that attaining the target of remission is insufficient to normalise patients' quality of life, and ameliorate the extra-articular impacts of RA. RA has a broad range of effects on patient's lives, with four key "extra-articular" impacts being pain, depression and anxiety, fatigue and rheumatoid cachexia. All of these are seen frequently; for example, studies have reported that 1 in 4 patients with RA have high-levels of fatigue. Commonly used drug treatments (including simple analgesics, non-steroidal anti-inflammatory drugs and anti-depressants) have, at most, only modest benefits and often cause adverse events. Psychological strategies and dynamic and aerobic exercise all reduce issues like pain and fatigue, although their effects are also only modest. The aetiologies of these extra-articular impacts are multifactorial, but share overlapping components. Consequently, patients are likely to benefit from management strategies that extend beyond the assessment and treatment of synovitis, and incorporate more broad-based, or "holistic", assessments of the extra-articular impacts of RA and their management, including non-pharmacological approaches. Innovative digital technologies (including tablet and smartphone "apps" that directly interface with hospital systems) are increasingly available that can directly capture patient-reported outcomes during and between clinic visits, and include them within electronic patient records. These are likely to play an important future role in delivering such approaches.

Downregulation of specific miRNAs in hyperdiploid multiple myeloma mimics the oncogenic effect of IgH translocations occurring in the non-hyperdiploid subtype.

Currently, multiple myeloma (MM) patients are broadly grouped into a non-hyperdiploid (nh-MM) group, highly enriched for IgH translocations, or into a hyperdiploid (h-MM) group, which is typically characterized by trisomies of some odd-numbered chromosomes. We compared the micro RNA (miRNA) expression profiles of these two groups and we identified 16 miRNAs that were downregulated in the h-MM group, relative to the nh-MM group. We found that target genes of the most differentially expressed miRNAs are directly involved in the pathogenesis of MM; specifically, the inhibition of hsa-miR-425, hsa-miR-152 and hsa-miR-24, which are all downregulated in h-MM, leads to the overexpression of CCND1, TACC3, MAFB, FGFR3 and MYC, which are the also the oncogenes upregulated by the most frequent IgH chromosomal translocations occurring in nh-MM. Importantly, we showed that the downregulation of these specific miRNAs and the upregulation of their targets also occur simultaneously in primary cases of h-MM. These data provide further evidence on the unifying role of cyclin D pathways deregulation as the key mechanism involved in the development of both groups of MM. Finally, they establish the importance of miRNA deregulation in the context of MM, thereby opening up the potential for future therapeutic approaches based on this molecular mechanism.

Comparative population genetics of a parasitic nematode and its host community: the trichostrongylid Neoheligmonella granjoni and Mastomys rodents in southeastern Senegal.

Contrasting host and parasite population genetic structures can provide information about the population ecology of each species and the potential for local adaptation. Here, we examined the population genetic structure of the nematode Neoheligmonella granjoni at a regional scale in southeastern Senegal, using 11 microsatellite markers. Using the results previously obtained for the two main rodent species of the host community, Mastomys natalensis and Mastomys erythroleucus, we tested the hypothesis that the parasite population structure was mediated by dispersal levels of the most vagile host. The results showed similar genetic diversity levels between host and parasite populations, and consistently lower levels of genetic differentiation in N. granjoni, with the exception of one outlying locus with a high F(ST). The aberrant pattern at this locus was primarily due to two alleles occurring at markedly different frequencies in one locality, suggesting selection at this locus, or a closely linked one. Genetic differentiation levels and isolation by distance analyses suggested that gene flow was high and random in N. granjoni at the spatial scale examined. The correlation between pair-wise genetic differentiation levels in the parasite and its main host was consistent with the hypothesis tested. Models of local adaptation as a function of the dispersal rates of hosts and parasites suggest that opportunities for local adaptation would be low in this biological system.

Use of short tandem repeats loci to study the genetic structure of several populations from Zulia State, Venezuela.

Genetic relationships between populations can be studied by comparing genotypic and allelic similarities. This investigation aims to demonstrate that selected autosomal microsatellite markers could be used to study the genetic structures of different populations living in northwest Venezuela, in Zulia State. Seven autosomal systems (CSF1PO, TPOX, TH01, vWA, D7S820, D13S317, and D5S818) were tested by PCR in a multiplex format on 688 different chromosomes from unrelated individuals living in Maracaibo, "Isla de Toas," and "San José de Heras," and from two Amerindian populations from the "Sierra de Perijá," Barí' and Yukpa. Allele frequencies, Hardy-Weinberg equilibria, genetic distances, phylogenetic trees, and ethnic admixtures were estimated. The study shows the existence of a clear genetic difference among these populations in accordance with their historic evolution. The populations of Maracaibo and "Isla de Toas" showed a triracial origin, with a large European contribution, followed by an Amerindian component and a small African component. The indigenous groups, Barí' and Yukpa, showed exclusively an Amerindian component, and "San José de Heras" showed only an African component. These results indicate that microsatellite markers are useful for molecular anthropology in a regional and worldwide context and provide important genetic information about contemporary populations of Venezuela.

Noninvasive ventilation in cystic fibrosis patients with acute or chronic respiratory failure.

The experience of using noninvasive ventilation (NIV) in 113 adult cystic fibrosis (CF) patients with chronic respiratory failure, during episodes of acute deterioration in respiratory function is reported. The patients aged 15-44 yrs were divided into three groups. Group A consisted of 65 patients (median forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) 0.7/1.4 L) who were on a lung transplant waiting list. Group B consisted of 25 patients (median FEV1/FVC 0.7/1.4 L) who were being evaluated for lung transplantation. Group C consisted of 23 patients (median FEV1/FVC 0.6/1.2 L) who were not being considered for lung transplantation. The mean duration of NIV support for groups A, B and C was 61 (range: 1-600) days, 53 (1-279) days and 45 (0.5-379) days respectively. Twenty-three patients in group A subsequently received lung transplantation and 12 of these patients had a median survival of 39 months postsurgery. Thirty-nine patients died and three awaited transplantation. Five patients in group B received a transplant four of whom survived; thirteen patients died and seven awaited transplantation. Twenty patients in group C died. Noninvasive ventilation improved hypoxia but failed to correct hypercapnia in these cystic fibrosis patients. Noninvasive ventilation is useful in the treatment of acute episodes of respiratory failure in cystic fibrosis patients with end-stage lung disease who have been accepted, or are being evaluated, for lung transplantation. For these patients, there is a possibility of prolonging life if they are successfully treated for their acute episode of respiratory failure until transplantation. In this group, treatment is not merely prolonging the process of dying.

Identification of the amino acid residue involved in rabbit hemorrhagic disease virus VPg uridylylation.

The virus genome-linked protein (VPg) coding region from rabbit hemorrhagic disease virus (RHDV) (isolate AST/89) was expressed in Escherichia coli by using a glutathione S-transferase-based vector. The recombinant polypeptide could be purified in good yields and was uridylylated in vitro from [alpha-32P]UTP in a reaction catalyzed by the recombinant RNA-dependent RNA polymerase from RHDV in the absence of added template RNA. The use of deletion and point mutants allowed the identification of Tyr-21 as the residue involved in uridylylation and consequently in the linkage between VPg and the viral genome. These data constitute the first report on the identity of the amino acid residue involved in VPg uridylylation in a member of the Caliciviridae family.

A joint health and social services initiative for children with disabilities.

The children's disability team in Cambridge provides an integrated health and social care service for children with complex learning and physical disabilities and their families. The team uses a multidisciplinary and multi-agency teamwork approach to care provision. The effectiveness of the team was evaluated using a cooperative review of its functions, in which all the 'subjects' were active participants in defining and delivering the evaluation. This was combined with individual questionnaires regarding the team's perceived strengths and weaknesses. Particular implications for training and supervision emerged from the findings. This article discusses the ways in which the team has successfully refined its practice of collaborative working in a developmental way between 1992-1998.

Mixed gonadal dysgenesis: a syndrome of broad clinical, cytogenetic and histopathologic spectrum.

Mixed gonadal dysgenesis (MGD) is an abnormality of sexual differentiation (ASD), which encompasses an heterogeneous group of different gonadal and phenotypic abnormalities. This study describes the main clinical features found in 16 patients with MGD, relating the clinical presentation with cytogenetic evaluation and histopathological findings. For purpose of this study, MGD was considered in those patients who fulfilled the following diagnostic criteria: 1) müllerian and/or wolfflan derivatives; 2) any of the following gonadal characteristics: a) bilateral intrabdominal or scrotal immature testicular tissue; b) intrabdominal or scrotal immature testicular tissue with contralateral streak gonad. Patients were selected from an ASD study which was carried out in Medical Genetic Unit of University of Zulia (UGM-LUZ), Maracaibo, Venezuela, from 1980 to 1997. The following information was extracted from the medical history at UGM-LUZ: age, gender which patient was reared, clinical presentation, cytogenetic evaluation, laparoscopic findings and gonadal biopsy. Sixteen patients fulfilled the diagnostic criteria and ranged in age from 1.2 to 39.4 years with an average of 12.65 years. Only 5 patients were reared as males. Twelve patients consulted for genital ambiguity. Chromosomal evaluation was as following: 8 patients with 45,X/46,XY mosaicism: 5 had a 46,XY normal male karyotype and the remaining patients: 46,XX; 46,XX/46,XY and 45,X/46,Xi(Xq) karyotypes, respectively. All patients showed müllerian derivatives and occasionally wolffian derivatives. Gonadal tumors were present in 2 patients. Molecular studies of genes that govern gonadal development are necessary for a better understanding of the wide heterogeneity present in MGD.

Cloning and expression in Escherichia coli of a Fasciola hepatica gene encoding a calcium-binding protein.

A Fasciola hepatica cDNA clone of 994 bp was isolated from an adult worm cDNA expression library using a rabbit serum against the excretory-secretory antigens. The nucleotide sequence of the cDNA clone revealed the presence of an open reading frame of 572 bp which encoded a 22 kDa polypeptide (Fh22) showing putative EF-hand domains. This gene was expressed in Escherichia coli and the recombinant protein used for the production of specific antibodies. Immunoblotting studies using the anti-Fh22 serum showed the presence of a polypeptide of similar molecular mass in the excretory-secretory extract of the adult parasite. The recombinant Fh22 polypeptide showed calcium-dependent electrophoretic mobility (decreased with Ca2(+)-ions and increased with EGTA). The observed behaviour of recombinant Fh22 in gel filtration experiments also suggested calcium-induced conformational changes.

[Analysis of Bcl I polymorphism of factor VIII gene in the molecular diagnosis of female hemophilia A carriers in families from northwestern Venezuela]. / Análisis del polimorfismo Bcl I del gen del factor VIII en el diagnóstico molecular de portadoras de Hemofilia A en familias del noroccidente de Venezuela.

PURPOSE: To identify carrier females in segregant families of haemophilia A from Zulia state-Venezuela. PATIENTS AND METHODS: The polymorphisms' analysis linked to the gene, independently of the mutation nature is the most suitable method to identify carriers, because it permits to track the mutated gene. This study is comprised of 139 ADN samples distributed in 20 families affected by haemophilia A. The diagnosis of carrier was made by polymerase chain reaction (PCR), a fragment of 142 pb corresponding to intron 18 of the factor VIII gene, which shows a restriction polymorphism for the Bcl I enzyme. RESULTS: The frequency of the Bcl I alleles in the 43 unrelated individuals was 0.35 and 0.65 for the 142 pb and 99 + 43 pb, respectively. In the 35 women that required diagnosis, we were able to establish the carrier status for 11, and 4 were excluded to be. CONCLUSIONS: The Bcl I polymorphism at the FVIII gene was useful in the 43% (15/35) of the women that required diagnosis. It's possible to identify carriers for haemophilia A in most of the families from Zulia state-Venezuela employing several polymorphisms at the Factor VIII gene.