Studies on the mechanism of bile salt-independent bile flow impairment in streptozotocin-induced hepatotoxicity.

The main factors involved in the impairment of formation of the bile salt-independent bile flow (BSIF) in streptozotocin (SZ)-treated rats were examined. Twenty-four hours after SZ injection (50 mg/kg body wt, i.v.) bile flow, bile salt output and biliary excretion of the major inorganic electrolytes (sodium, chloride and bicarbonate) were significantly diminished. The relationship between bile flow and bile salt output obtained during the administration of sodium taurocholate at stepwise-increasing rates indicated that bile salt-independent bile flow (y-intercept) was diminished by 37% in SZ-treated rats. The relationship between electrolyte output and bile salt output showed that the fractions of sodium, chloride and bicarbonate excreted independently of bile salt (y-intercept) decreased to 59%, 47% and 67% of the control values respectively, while the amount of electrolyte secreted per unit of bile salt secreted was unaffected in SZ-treated rats. The hepatic activity of Na+,K(+)-adenosine triphosphatase (Na+,K(+)-ATPase) was decreased by 59% (P less than 0.05) in SZ-treated rats. Nicotinamide administered prior to SZ prevented the hyperglycemia indicative of SZ-induced diabetes, but had no effect on the decrease in Na+,K(+)-ATPase activity caused by the drug. These results suggest that SZ itself, and not its diabetogenic effect, decreases the BSIF by a mechanism that involves impairment of the biliary electrolyte excretion, which could be the result of the inhibition of the hepatic Na+,K(+)-ATPase activity.     

Comparison of aceclofenac with diclofenac in the treatment of osteoarthritis

Summary A multicentre randomised, double-blind, parallel group, general practice study was undertaken to investigate the efficacy and safety of aceclofenac (200 patients, 100mg twice daily and placebo once daily) in comparison with diclofenac (197 patients, 50mg three times daily) in patients with osteoarthritis of the knee. The treatment period of twelve weeks was preceded by a washout period of two weeks duration. At end point, patients in both aceclofenac and diclofenactreated groups exhibited significant improvement in pain intensity (p=0.0001). Although both treatment groups showed significant improvement in all investigators' clinical assessments (joint tenderness, swelling, pain on movement, functional capacity, overall assessment), there were no significant differences between the groups. There was, however, a trend towards greater improvement in complete knee movement and reduced pain on movement with aceclofenac. In patients with initial flexion deformity, aceclofenac was significantly more effective than diclofenac in improving knee flexion after 2–4 weeks of treatment. Patients' subjective assessment of pain relief demonstrated significantly greater efficacy with aceclofenac. At end point, 71% of patients in the aceclofenac group reported improvement in pain intensity as compared to 59% treated with diclofenac (p=0.005). Tolerability of aceclofenac was better than with diclofenac as fewer patients experienced gastrointestinal adverse events. In particular, the incidence of treatment related diarrhoea was less with aceclofenac (1%) than with diclofenac (6.6%). In summary, this study supports a therapeutic role for aceclofenac in arthritis and suggests that it is an alternative NSAID to diclofenac in the treatment of osteoarthritis.     

Using discrete choice experiments to evaluate alternative electronic prescribing systems

Objective — To assess the relative importance to pharmacists and general practitioners (GPs) of different characteristics of electronic prescribing systems. Methods — A discrete choice experiment (DCE) was used to obtain preferences for the following attributes of an electronic prescribing scheme: “typical response time”, “frequency of slow responses”, “frequency of unscheduled downtime”, “length of unscheduled downtime”, “frequency of scheduled downtime”, and “frequency of lost/corrupted data”. Preferences of GPs and pharmacists were compared using the Likelihood ratio test and the Wald statistic. The rate at which respondents were willing to trade between attributes and benefit scores for different systems were estimated. Rationality of responses and theoretical validity of responses to the DCE were also assessed. Subjects and setting — 199 pharmacists and 197 GPs in Scotland. Key findings — The usable response rate for the DCE was 42.4 per cent. Preferences of pharmacists and GPs were significantly different. Given the units of measurement, the most important attribute for pharmacists was “length of unscheduled downtime” whereas for GPs it was “typical response time”. Evidence was found of rationality of responses and theoretical validity. Conclusions — All technical attributes of an electronic prescribing system assessed in this study were considered by the respondents to be important. Discrete choice experiments provide useful information on the relative importance and trade‐offs between attributes as well as benefit scores for different systems. The preferences of pharmacists and GPs are significantly different. Future research should investigate the nature of the benefit function, the assumption of trading across attributes and the external validity of the technique.     

Comparison of the effects of zinc delivered in a fortified food or a liquid supplement on the growth, morbidity, and plasma zinc concentrations of young Peruvian children

BACKGROUND: Zinc supplementation decreases morbidity from infections and increases growth of stunted children, but there is little information on functional responses to zinc delivered in fortified foods. OBJECTIVE: The aim was to examine the effects of zinc fortification on the growth, morbidity from infections, and plasma zinc concentrations of young children. DESIGN: We compared the physical growth, morbidity, and micronutrient status of 6-8-mo-old Peruvian children with initial length-for-age z score (LAZ) < -0.50 who were randomly assigned to receive one of the following treatments daily for 6 mo: 1) 30 g dry weight of an iron-fortified cereal porridge and a separate dose of an aqueous multivitamin (MV) supplement between meals (control group), 2) the same porridge and MV with 3 mg Zn added to the supplement dose (ZnSuppl group), or 3) the porridge with added zinc (150 mg/kg dry weight) and MV without zinc (ZnFort group). RESULTS: The children consumed a mean of 22-26 g dry porridge/d and 96% of the possible MV doses. After adjustment for small baseline differences in socioeconomic status and morbidity, no significant differences in weight or length increments were observed between the groups, even among the subset with an initial LAZ < -1.5, and no significant differences in the rates of common illnesses were observed. Mean plasma zinc concentrations decreased in the control group (-3.9 microg/dL), increased in the ZnSuppl group (4.3 microg/dL), and did not change significantly in the ZnFort group (-1.5 microg/dL; P < 0.001 for group-wise comparison). CONCLUSIONS: Provision of additional zinc, either in an aqueous supplement or a fortified porridge, did not significantly affect the children's physical growth or morbidity from infections, possibly because they were not sufficiently growth-restricted or zinc-deficient initially or because the level of zinc intake or absorption was inadequate. Additional studies of the functional effect of zinc-fortified foods are needed in populations that are known to respond to zinc supplements.     

Adherence to National Comprehensive Cancer Network ALK Testing Guidelines for Patients with Advanced Non-Small Cell Lung Cancer in U.S. Community Medical Centers

BackgroundNational Comprehensive Cancer Network (NCCN) guidelines recommend biomarker testing as the first step in the management of patients with advanced non‐small cell lung cancer (aNSCLC). We assessed anaplastic lymphoma kinase (ALK) testing rates and factors related to underuse in community medical systems between 2012 and 2019 to understand guideline adoption.MethodsA retrospective observational study using a nationwide electronic health record (EHR)‐derived deidentified database was conducted. Patients with aNSCLC diagnosed in community medical centers from January 2012 to May 2019 were included to describe the ALK testing trend. This cohort was further restricted to patients diagnosed after 2015 to understand factors associated with testing underuse using mixed‐effects multivariable logistic regression models.ResultsTrends for increased ALK testing rates by year were observed in both NCCN guideline‐eligible patients (59.5% in 2012 to 84.1% in 2019) and ‐ineligible patients (15.6% to 50.8%) in a cohort of 41,728 patients. Histology type and smoking status had the greatest impact on test use. Compared with patients with nonsquamous histology and no smoking history, patients with squamous histology and no smoking history (adjusted odds ratio [aOR], 7.6; 95% confidence interval [CI], 5.6–10.4), NSCLC histology not otherwise specified (NOS) with smoking history (aOR, 3.4; 95% CI, 2.8–4.2); NSCLC NOS/nonsmoker (aOR, 1.8; 95% CI, 1.1–3.2), and nonsquamous/smoker (aOR, 1.5; 95% CI, 1.3–1.7) were less likely to be tested. Factors related to underuse also included Eastern Cooperative Oncology Group performance status, stage at initial diagnosis, and demographics.ConclusionThis analysis of real‐world data shows increasing test use by year; however, one fifth of patients eligible for ALK testing still remain untested and potentially missing therapeutic options.Implications for PracticeAdvancement in treatment of lung cancer is accompanied by an increasing number of tests that should be run to determine potential therapy options for each patient. This study assessed adoption of testing recommendations for anaplastic lymphoma kinase rearrangements in a national database. Although test use increased over the time period studied (2012–2019), there is still room for improvement. Efforts are needed to increase test use in undertested groups, thus enabling eligible patients to benefit from novel lung cancer therapies.     

Physiological and psychological stress reactions in relation to classroom noise

OBJECTIVES: This study tested the hypothesis that classroom noise is related to stress reactions among primary school children. Stress was monitored via symptoms of fatigue and headache, systolic blood pressure, reduced diurnal cortisol variation, and indicators of emotional distress. METHODS: In three classrooms of pupils in the fourth grade (10 years of age), daily measurements of equivalent sound levels (Leq) were made during 4 weeks, evenly distributed from September to December. One day each week of the study, the pupils answered a questionnaire about disturbance and symptoms, and blood pressure and salivary cortisol were measured. In the first and fourth week, the children also performed a standardized drawing test concerning emotional indicators. RESULTS: Daily measurements of equivalent sound levels in the classes (Leq during schoolday) ranged from 59 to 87 dB(A). Equivalent sound-levels were significantly related to an increased prevalence of symptoms of fatigue and headache and a reduced diurnal cortisol variability. Blood pressure and emotional indicators were not significantly related to sound levels. CONCLUSIONS: Current sound levels in Swedish classrooms may have a negative health impact, being directly or indirectly related to stress reactions among children. This finding indicates that noise should be focused on as a risk factor in the school environment.     

Incidence and Elimination of R Plasmids in Vibrio cholerae

Of 124 strains of Vibrio cholerae, 32 were multiply resistant to antibiotics. This resistance appeared to be determined by R plasmids on the basis of their effective elimination by sodium dodecyl sulfate, acridine orange, ethidium bromide, and ultraviolet radiation.     

WISECARE+: Results of a European study of a nursing intervention for the management of chemotherapy-related symptoms

While the use of chemotherapy has significantly improved survival rates, the symptoms associated with chemotherapy remain a major burden for patients. Preventing or appropriately managing side effects significantly improves patients' functional status and quality of life, ultimately leading to greater patient acceptance of chemotherapy. However, symptom assessment and management are fraught with difficulties such as poor patient recall, retrospective assessment conducted by clinicians and lack of appropriate, clinically relevant and patient friendly symptom assessment and management tools. Furthermore the differences between clinician and patient perceptions of stresses and distress during chemotherapy are well recognised. This study aimed to evaluate the impact of a nursing intervention incorporating structured symptom assessment and management, facilitated by information technology, on chemotherapy-related symptoms, nausea, vomiting, fatigue and mucositis. This pan-European study, involved 8 clinical sites from Belgium, Denmark, England, Ireland and Scotland. Adults (n=249) receiving first line chemotherapy for breast, lung, ovarian or colorectal cancer, osteosarcoma, acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or lymphoma were recruited to the study. Patients completed daily symptom assessment questionnaires for 14 days following consecutive cycles of chemotherapy. Symptom outcomes were compared before and after the introduction of the intervention with positive impact on patients' experiences of nausea, vomiting and oral problems. Fatigue was not significantly improved.     

Cytokine gene polymorphism associations with congenital cytomegalovirus infection and sensorineural hearing loss

Cytomegalovirus (CMV) is the most common viral agent of congenital infections and a leading nongenetic cause of sensorineural hearing loss (SNHL). The host immunologic factors that render a developing foetus prone to intrauterine CMV infection and development of hearing loss are unknown. The aim of this study was to assess the potential associations between the polymorphisms within cytokine and cytokine receptors genes, and the risk of congenital CMV infection, and the hearing outcome. A panel of 11 candidate single nucleotide polymorphisms (SNPs): TNF rs1799964, TNF rs1800629, TNFRSF1A rs4149570, IL1B rs16944, IL1B rs1143634, IL10 rs1800896, IL10RA rs4252279, IL12B rs3212227, CCL2 rs1024611, CCL2 rs13900, CCR5 rs333 was genotyped in 470 infants (72 with confirmed intrauterine CMV infection and 398 uninfected controls), and related to congenital CMV infection, and the outcome. In multivariate analysis, the IL1B rs16944 TT and TNF rs1799964 TC genotypes were significantly associated with intrauterine CMV infection (aOR = 2.32; 95% CI, 1.11–4.89; p = 0.032, and aOR = 2.17, 95% CI, 1.25–3.77; p = 0.007, respectively). Twenty-two out of 72 congenitally infected newborns had confirmed SNHL. Carriers of CT or TT genotype of CCL2 rs13900 had increased risk of hearing loss at birth and at 6 months of age (aOR = 3.59; p = 0.028 and aOR = 4.10; p = 0.039, respectively). This is the first study to report an association between SNPs in IL1B, TNF, and CCL2, and susceptibility to congenital CMV infection (IL1B and TNF) and SNHL (CCL2).