Peripheral blood mononuclear cell mitochondrial enzyme activity is associated with parity and lactation performance in early lactation Holstein dairy cows.

Mitochondria are central to metabolism and are the primary energy producers for all biosynthesis, including lactation. The objectives of this study were to determine if high- and low-producing dairy cows exhibit differences in peripheral blood mononuclear cell mitochondrial enzyme activities of citrate synthase, complex I, complex IV, and complex V during early lactation and, thus, to determine whether those differences were related to differences in lactation performance in the dairy cow. Fifty-six Holstein cows were assigned to 1 of 4 groups: (1) primiparous high, (2) primiparous low, (3) multiparous high, or (4) multiparous low. Primiparous and multiparous cows were analyzed separately. Then, cows were divided into high or low production groups for each production parameter [peak milk, average milk, energy-corrected milk (ECM), fat-corrected milk (FCM), milk lactose, milk fat, milk protein, total solids (TS), solids-not-fat, feed efficiency, and somatic cell count (SCC)]. For all data analysis, production parameters are expressed as yields (kg/d) and SCC (103 cells/mL). High and low production groups were defined by their respective mean production parameters for the 56 cows, with below average cows defined as low and above average cows defined as high. Whole blood samples were collected at one time point, approximately 70 d in milk at 0800 h, and processed for crude mitochondrial extracts from peripheral blood mononuclear cells to determine the activity rates of mitochondrial enzymes. Milk samples were collected 9 times (3 d, 3 times per d) during the week of blood collection and analyzed for major components (fat, protein, lactose, TS, and SCC). Multiparous cows had lower citrate synthase activity than primiparous cows across all production parameters. High-producing cows had greater complex I activity for peak milk, milk yield, ECM, FCM, milk fat, TS, and feed efficiency, and greater complex V activity for ECM, FCM, milk lactose, milk fat, and TS across parities. These findings imply that the most influential respiratory chain enzymes on the level of milk production are those responsible for electron transport chain initialization and ATP production.

Glycaemic target attainment in people with Type 2 diabetes treated with insulin glargine/lixisenatide fixed-ratio combination: a post hoc analysis of the LixiLan-O and LixiLan-L trials.

AIMS: Both fasting (FPG) and postprandial plasma glucose (PPG) contribute to HbA1c levels. We investigated the relationship between achievement of American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) recommended FPG and/or PPG targets and glycaemic efficacy outcomes in two trials. METHODS: In this post hoc analysis, data from participants with Type 2 diabetes in the phase 3 LixiLan-O (NCT02058147) and LixiLan-L (NCT02058160) trials were evaluated to compare the relationship between achievement of society-recommended FPG and/or PPG targets and efficacy (HbA1c change, HbA1c goal attainment, weight change) and safety outcomes in the treatment groups. RESULTS: Across treatment arms, iGlarLixi achieved the highest proportion of participants meeting both ADA- and AACE-recommended FPG and PPG targets at study end in both trials. A higher proportion of participants in the iGlarLixi (fixed-ratio combination of insulin glargine and lixisenatide) vs. insulin glargine alone or lixisenatide alone treatment arms achieved HbA1c goals (P < 0.001 for overall comparisons), irrespective of ADA- or AACE-defined targets. Hypoglycaemia rates [any, documented symptomatic (plasma glucose ≤ 3.9 mmol/l), and clinically important (plasma glucose < 3.0 mmol/l)] were low across all groups. Participants treated with iGlarLixi tended to show weight loss or less weight gain compared with participants receiving insulin glargine alone. No differences were observed in average daily basal insulin dose at week 30 between the two treatment arms or across the different FPG and PPG target groups. CONCLUSION: Insulin glargine and lixisenatide as a fixed-ratio combination resulted in more participants reaching both FPG and PPG targets, leading to better HbA1c target attainment.

A review of the current public health practice for contact tracing in relation to laryngeal TB in England 2012-2016.

OBJECTIVES: Contact tracing following identification of tuberculosis (TB) is well established. However, evaluation of this activity, particularly for laryngeal TB, is limited. We compare contact tracing and outcomes in response to laryngeal TB with sputum-smear-positive pulmonary TB (ss + pTB) and consider the public health response in light of our findings. STUDY DESIGN: This study is a comparative secondary analysis of retrospective data, extracted from TB surveillance systems, to determine differences in contact tracing process and outcomes between two groups. METHODS: Cases of laryngeal TB (without ss + pTB) notified in England between 2012 and 2016 were selected and matched to ss + pTB controls. Number of contacts identified and screened, along with screening outcomes were gathered from local databases. RESULTS: There were 44 laryngeal TB cases who met inclusion criteria. The median number of contacts identified per case was 3 and 4 for controls (P = 0.04). Median number of contacts screened was 3 for cases and 4 for controls. The percentage of contacts with TB was 9.7 for cases and 20.3 for controls (P < 0.01). CONCLUSION: We observed a small difference, between case and control groups, in number of contacts identified but not number screened, indicative of a broadly similar approach to contact tracing. Conversely, the difference in screening outcomes between the groups was significant. These findings highlight a potential need to further understand infectivity of laryngeal TB; and consider possible implications for public health practice.

Technical note: An evaluation of technology-recorded rumination and feeding behaviors in dairy heifers.

Precision dairy monitoring technologies have become increasingly popular for recording rumination and feeding behaviors in dairy cattle. The objective of this study was to validate the rumination and feeding time functions of the CowManager SensOor (Agis, Harmelen, the Netherlands) against visual observation in dairy heifers. The study took place over a 44-d period beginning June 1, 2016. Holstein heifers equipped with CowManager SensOor tags attached according to manufacturer specifications (n = 49) were split into 2 groups based on age, diet, and housing type. Group 1 heifers (n = 24) were calves (mean ± SD) 2.0 ± 2.7 mo in age, fed hay and calf starter, and housed on a straw-bedded pack. Group 2 heifers (n = 25) were 17.0 ± 1.3 mo in age, fed a TMR, confirmed pregnant, and housed in freestalls. Visual observation shifts occurred at 1500, 1700, 1900, and 2100 h. Each heifer was observed for 2 hour-long periods, with both observation periods occurring on the same day. Visual observations were collected using a synchronized watch, and "start" and "stop" times were recorded for each rumination and feeding event. For correlations, data from CowManager SensOor tags and observations were averaged, so a single 1-h observation was provided per animal, reducing the potential for confounding repeated measures being collected for each animal. Concordance correlations (CCC; epiR package; R Foundation for Statistical Computing, Vienna, Austria) and Pearson correlations (r; CORR procedure; SAS Institute Inc., Cary, NC) were used to calculate association between visual observations and technology-recorded behaviors. Visually observed rumination time was correlated with the CowManager SensOor (r = 0.63, CCC = 0.55). Visually observed feeding time was also correlated with the CowManager SensOor (r = 0.88, CCC = 0.72). The difference between technology-recorded data and visual observation was treated as the dependent variable in a mixed linear model (MIXED procedure of SAS). Time of day, age in months, and group were treated as fixed effects. Individual heifers were treated as random and repeated effects. The effects of time of day, age, and group on rumination and feeding times were not significant. The CowManager SensOor was more effective at recording feeding behavior than rumination behavior in dairy heifers. The CowManager SensOor can be used to provide relatively accurate measures of feeding time in heifers, but its rumination time function should be used with caution.

Efficacy and safety of liraglutide, a once-daily human glucagon-like peptide-1 analogue, in Latino/Hispanic patients with type 2 diabetes: post hoc analysis of data from four phase III trials.

The aim of the present analysis was to evaluate the efficacy of the glucagon-like peptide-1 receptor agonist liraglutide in Latino/Hispanic individuals with type 2 diabetes, in addition to comparing its treatment effects with those observed in non-Latino/Hispanic individuals. Analyses were performed on patient-level data from a subset of individuals self-defined as Latino/Hispanic from four phase III studies, the LEAD-3, LEAD-4, LEAD-6 and 1860-LIRA-DPP-4 trials. Endpoints included change in glycated haemoglobin (HbA1c) and body weight from baseline. In Latino/Hispanic patients (n = 505; 323 treated with liraglutide) after 26 weeks, mean HbA1c reductions were significantly greater with both liraglutide 1.2 and 1.8 mg versus comparator or placebo in the LEAD-3 and LEAD-4 studies, and with 1.8 mg liraglutide in the 1860-LIRA-DPP-4 trial. In LEAD-3 both doses led to significant differences in body weight change among Latino/Hispanic patients versus the comparator. With 1.8 mg liraglutide, difference in weight change was significant only in the 1860-LIRA-DPP-4 trial versus sitagliptin. For both endpoints Latino/Hispanic and non-Latino/Hispanic patients responded to liraglutide similarly. In summary, liraglutide is efficacious for treatment of type 2 diabetes in Latino/Hispanic patients, with a similar efficacy to that seen in non-Latino/Hispanic patients.

Temporal and Spatial Development of Cercospora Leaf Spot of Faba Bean Influenced by In Situ Inoculum.

The temporal and spatial dynamics of Cercospora leaf spot on susceptible and resistant lines of faba bean grown in or at defined distances from soil with residues infested by Cercospora zonata were examined in South Australia in 2005 and 2006. The disease was first observed on susceptible seedlings 49 days after sowing (DAS) in soil that had been sown with faba bean every 3 years since 1997 (positive soil zone for C. zonata) but was delayed by 1 week in adjacent soil (0 to 16 m away) with no history of cultivation of faba bean (negative soil zone). The incidence of diseased seedlings from 49 to 63 DAS showed a gradient from 4 to 16 m from the infested soil and was significantly greater for susceptible plants grown in the positive versus negative soil zones in field trials conducted in 2005 and 2006 (92 versus 30% in 2005, χ21 = 32.2, P < 0.001; 98 versus 55% in 2006, χ21 = 12.1, P < 0.001). The incidence of Cercospora leaf spot on the resistant line 1322/2 was significantly less (χ26 = 171.7; P < 0.001) than on the susceptible line 'Farah' at that time in both years, with fewer than 5% of the seedlings showing the disease. However, a gradient was shown at 70 to 84 DAS, where disease incidence was significantly greater on line 1322/2 in the positive soil zone than on plants in the negative soil zone in both years (62 and 18%, respectively, with χ21 = 27.9, P < 0.001 in the 2005 trial; and 47 and 6%, respectively, with χ21 = 33.3, P < 0.001 in the 2006 trial). At peak disease severity on Farah, Cercospora leaf spot mean leaf area diseased (%LAD) was severe (85 ± 4.3%) on leaves of the three nodes closest to the soil surface, and much less severe (1 ± 0.6%) in the upper canopy. Defoliation combined with %LAD was used to describe the loss of photosynthetic leaf area (%LPLA) in both cultivars, on both soil zones, in each year. Nonlinear regression analyses using a logistic model described disease development over time on susceptible plants grown in infested soil (e.g., for +12-m blocks within infested soil, y = 2.66 + 46.08/[1 + exp(-0.23 × [X - 40.92])] in 2005 and y = 0.49 + 5.02/[1 + exp(-0.14 × [X - 28.30])] in 2006, where X = DAS and y = %LPLA, with both regressions significant at P < 0.001), whereas an exponential model (e.g., for -12-m blocks from infested soil, y = 0.23 + 0.77 × 1.04X in 2005 and y = 0.44 + 0.56 × 1.04X in 2006, both at P < 0.001) best described disease gradients with increasing distance from the inoculum source. Paired t tests of %LPLA at 77 and 98 DAS showed significant differences in disease severity in the positive versus negative soil zones and a steep gradient in %LPLA from 0 to 4 m from the inoculum source. The role of infested faba bean residue in survival of C. zonata over time was also examined using a pot-bioassay and in situ field assay. When residues were removed from the soil surface or depleted rapidly by animal grazing, the amount of C. zonata inoculum in the soil was significantly less (P < 0.001) than for soil with residue remaining on the soil surface. C. zonata survived in soil and remained infective for at least 30 months after harvest of an infected faba bean crop.

Notch-induced transcription factors are predictive of survival and 5-fluorouracil response in colorectal cancer patients.

BACKGROUND: The purpose of this study was to evaluate the expression of Notch-induced transcription factors (NTFs) HEY1, HES1 and SOX9 in colorectal cancer (CRC) patients to determine their clinicopathologic and prognostic significance. METHODS: Levels of HEY1, HES1 and SOX9 protein were measured by immunohistochemistry in a nonmalignant and malignant tissue microarray of 441 CRC patients, and the findings correlated with pathologic, molecular and clinical variables. RESULTS: The NTFs HEY1, HES1 and SOX9 were overexpressed in tumours relative to colonic mucosa (OR=3.44, P<0.0001; OR=7.40, P<0.0001; OR=4.08 P<0.0001, respectively). HEY1 overexpression was a negative prognostic factor for all CRC patients (HR=1.29, P=0.023) and strongly correlated with perineural and vascular invasion and lymph node (LN) metastasis. In 5-fluorouracil (5-FU)-treated patients, the tumour overexpression of SOX9 correlated with markedly poorer survival (HR=8.72, P=0.034), but had no predictive effect in untreated patients (HR=0.70, P=0.29). When HEY1, HES1 and SOX9 expression were combined to predict survival with chemotherapy, in treated patients there was an additive increase in the risk of death with each NTF overexpressed (HR=2.09, P=0.01), but no prognostic import in the untreated patient group (HR=0.74, P=0.19). CONCLUSION: The present study is the first to discover that HEY1 overexpression correlates with poorer outcome in CRC, and NTF expression is predictive of CRC patient survival with 5-FU chemotherapy. If confirmed in future studies, testing of NTF expression has the potential to enter routine pathological practice for the selection of patients to undergo chemotherapy alone or in combination with Notch inhibitors.

The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia.

The maintenance of normal glucose homeostasis requires a complex, highly integrated interaction among the liver, muscle, adipocytes, pancreas and neuroendocrine system. Recent studies have showed that the kidneys also play a central role in glucose homeostasis by reabsorbing all the filtered glucose, an adaptive mechanism that ensures sufficient energy is available during fasting periods. This mechanism becomes maladaptive in diabetes, however, as hyperglycaemia augments the expression and activity of the sodium-glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney. As a result, glucose reabsorption may be increased by as much as 20% in individuals with poorly controlled diabetes. SGLT2 is a low-affinity, high-capacity glucose transport protein that reabsorbs 90% of filtered glucose, while the high-affinity, low-capacity SGLT1 transporter reabsorbs the remaining 10%. SGLT2 represents a novel target for the treatment of diabetes. In animal studies, SGLT2 inhibition reduces plasma glucose levels, resulting in improved ß-cell function and enhanced insulin sensitivity in liver and muscle. Human studies have confirmed the efficacy of SLGT2 inhibitors in improving glucose control and reducing the A1c. Because the mechanism of SGLT2 inhibition is independent of circulating insulin levels or insulin sensitivity, these agents can be combined with all other antidiabetic classes, including exogenous insulin. Although the long-term efficacy and safety of SGLT2 inhibitors remain under study, the class represents a novel therapeutic approach with potential for the treatment of both type 2 and 1 diabetes.

Comparison of cultural growth and in planta quantification of Didymella pinodes, Phoma koolunga and Phoma medicaginis var. pinodella, causal agents of ascochyta blight on field pea (Pisum sativum).

The causal agents of ascochyta blight on field pea in South Australia, Didymella pinodes, Phoma medicaginis var. pinodella and Phoma koolunga, are isolated from a single plant within a crop, suggesting competition for space and nutrients. Interactions among these pathogens were investigated. Diameters of colonies of D. pinodes and of P. medicaginis var. pinodella were significantly reduced on PDA amended with filtrate from broth cultures of P. koolunga as were diameters of colonies of D. pinodes on PDA amended with filtrate from P. medicaginis var. pinodella or D. pinodes. This effect was negated when cultures were transferred to unamended PDA, indicating filtrates were fungistatic instead of fungicidal. The diameter of P. koolunga colonies was not influenced by filtrate from any of the three species. When pathogens were co-inoculated in pairs onto leaves on field pea plants, the quantity of DNA of D. pinodes and of P. medicaginis var. pinodella was significantly reduced if co-inoculated with P. koolunga. The quantity of DNA of P. koolunga was not influenced by co-inoculation. When co-inoculated onto excised leaf disks on sterile water the mean lesion diameter due to D. pinodes and to P. medicaginis var. pinodella was significantly reduced if co-inoculated with P. koolunga isolate DAR78535. Lesions caused by D. pinodes were significantly reduced when inoculum was self-paired. Conversely the diameter of lesions caused by P. koolunga DAR78535 increased when self-paired or when co-inoculated with P. medicaginis var. pinodella. Unlike leaf disks on sterile water, co-inoculation had no influence on lesion size or quantity of pathogen DNA in leaf disks on water agar. Antagonism, including self-antagonism, was detected among these species, leading to reduction in lesion size and quantity of pathogen DNA. The slower growing species, P. koolunga, was not self-antagonistic, and in a few instances the effect of co-inoculation was additive or synergistic.

Distribution and Survival of Ascochyta Blight Pathogens in Field-Pea-Cropping Soils of Australia.

Phoma koolunga, Didymella pinodes, and P. medicaginis var. pinodella were detected in DNA extracted from soil following field pea crops across four states in the southeastern and western regions of Australia. P. koolunga was commonly detected in soil from South Australia but rarely in other states whereas D. pinodes plus P. medicaginis var. pinodella were widespread in all regions tested. The quantity of DNA of these pathogens detected in soils prior to growing field pea was positively correlated with ascochyta blight lesions on field pea subsequently grown in infested soil in a pot bioassay and also on field pea in naturally infected field trials. The quantity of DNA of the soilborne pathogens was greatest following a field pea crop and gradually decreased in the following 3 years. The DNA tests were used to quantify the DNA of the pathogens in field pea plants sampled from naturally infected field trials in South Australia over two seasons. The combined results of DNA tests and pathogen isolation from the plants indicated that P. koolunga and D. pinodes were equally responsible for the ascochyta blight symptoms in the diseased trials, while P. medicaginis var. pinodella had a minor role in the disease complex.

Mid- and high-ratio premix insulin analogues: potential treatment options for patients with type 2 diabetes in need of greater postprandial blood glucose control.

Some patients with type 2 diabetes continue to have high postprandial blood glucose levels on twice-daily regimens of 'low-ratio' premix insulin formulations (up to 30% rapid-acting, with 70% protracted insulin). These patients require intensified insulin therapy, which can be provided by a twice- or thrice-daily regimen of mid-ratio (50% rapid-acting and 50% protaminated intermediate-acting insulin - human or analogue) or high-ratio (70% rapid-acting and 30% protaminated insulin - analogue only) premix insulin. Alternatively, a third daily injection of low-ratio premix insulin can be added to the regimen, with the option of incorporating one or more injections of mid- or high-ratio premix as required, and as an alternative to basal-bolus therapy. How these mid- and high-ratio formulations differ from the low-ratio premix insulins is reviewed here, with the aim of identifying the role of these formulations in diabetes management. Glucose clamp studies have shown that premix analogues give serum insulin levels proportional to their percentage of rapid-acting uncomplexed insulin: the higher the proportion, the greater the maximum level reached. Other pharmacokinetic parameters were not always significantly different between the mid- and high-ratio formulations. In clinical trials, postprandial plasma glucose and glycated haemoglobin A1c (HbA(1c)) levels were significantly reduced with thrice-daily mid- /high-ratio premix analogue when compared with twice-daily low-ratio biphasic human insulin (BHI) 30/70 or once-daily insulin glargine. Moreover, glycaemic control with mid-/high-ratio premix analogue was found to be similar to that with a basal-bolus therapy. Mid- and high-ratio premix regimens are generally well tolerated. The frequency of minor hypoglycaemia was reportedly higher with mid- /high-ratio premix analogues than with BHI 30, but nocturnal hypoglycaemia was less frequent. Although there is little evidence that clinical outcomes with mid-ratio premix analogues are different from those with high-ratio, they are useful additions to the low-ratio formulations for the management of diabetes, and addressing postprandial hyperglycaemia in particular.

Exercise training of late-pregnant and nonpregnant dairy cows affects physical fitness and acid-base homeostasis.

The objective was to determine if exercise training improves physical fitness of nonlactating, late-pregnant and nonpregnant multiparous Holstein cows and alters acid-base homeostasis during an exercise test on a treadmill. Twenty-six pairs (each pair having 1 late-pregnant and 1 nonpregnant) of cows were assigned to treatments of exercise training or no exercise. Exercise training was walking (1.25 to 1.5 h at 3.25 km/h) every other day in an outdoor mechanical walker for 70 d. Cows completed treadmill exercise tests on d 0, 30, and 60 of the experiment or about d 70, 40, and 10 before expected parturition of the pregnant cow of each pair. On d 0, physical fitness was similar among all cows based on durations of treadmill tests, heart rates, and acid-base measurements at given workloads (21.1 +/- 0.6 min; 144 +/- 2.2 beats per min; plasma lactate 3.1 +/- 1.9 mmol/L; and venous blood pH 7.44 +/- 0.0035, respectively). After 60 d of training, exercised cows walked longer during treadmill exercise tests compared with nonexercised cows (23.7 vs. 18.3 +/- 0.85 min, respectively), indicating greater physical fitness (pooled across pregnancy status). Heart rates and plasma lactate concentrations at given workloads were less (144 vs. 156 +/- 2.7 beats per min; and 1.4 vs. 3.2 +/- 0.24 mmol/L for exercised compared with nonexercised cows, respectively). Additionally, exercised cows more effectively maintained acid-base homeostasis during treadmill tests compared with nonexercised cows. Metabolic, endocrine, and nutritional demands associated with late pregnancy did not affect responses differently to exercise training for late-pregnant compared with nonpregnant cows. Overall, exercise training of late-pregnant and nonpregnant cows for 60 d improved physical fitness.

A new species of Phoma causes ascochyta blight symptoms on field peas (Pisum sativum) in South Australia.

Phoma koolunga sp. nov. is described, having been isolated from ascochyta blight lesions on field pea (Pisum sativum) in South Australia. The species is described morphologically and sequences of the internal transcribed spacer region compared with those of the accepted pathogens causing ascochyta blight of field peas. P. koolunga was distinct from Mycosphaerella pinodes (anamorph: Ascochyta pinodes), Phoma medicaginis var. pinodella and Ascochyta pisi. Under controlled conditions the symptoms on pea seedlings caused by P. koolunga were indistinguishable from those caused by M. pinodes, other than a 24 h delay in disease development. Isolates of P. koolunga differed in the severity of disease caused on pea seedlings.

Investigating a tuberculosis cluster among Filipino health care workers in a low-incidence country.

SETTING: Nearly 8% of adult tuberculosis (TB) cases in England, Wales and Northern Ireland (EW&NI) occur among health care workers (HCWs), the majority of whom are from high TB incidence countries. OBJECTIVES: To determine if a TB cluster containing multiple HCWs was due to nosocomial transmission. METHODS: A cluster of TB cases notified in EW&NI from 2009 to 2014, with indistinguishable 24-locus mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) profiles, was identified through routine national cluster review. Cases were investigated to identify epidemiological links, and occupational health (OH) information was collected for HCW cases. To further discriminate strains, typing of eight additional loci was conducted. RESULTS: Of the 53 cases identified, 22 were HCWs. The majority (n = 43), including 21 HCWs, were born in the Philippines. Additional typing split the cluster into three subclusters and seven unique strains. No epidemiological links were identified beyond one household and a common residential area. HCWs in this cluster received no or inadequate OH assessment. CONCLUSIONS: The MIRU-VNTR profile of this cluster probably reflects common endemic strains circulating in the Philippines, with reactivation occurring in the UK. Furthermore, 32-locus typing showed that 24-locus MIRU-VNTR failed to distinguish strain diversity. The lack of OH assessment indicates that latent tuberculous infection could have been identified and treated, thereby preventing active cases from occurring.

Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study.

PURPOSE: We performed a phase II study of combined cisplatin 100 mg/m2, given intravenously on day 1, and gemcitabine 1,000 mg/m2, given intravenously on days 1, 8, and 15 of a 28-day cycle for six cycles among patients with advanced measurable pleural mesothelioma. PATIENTS AND METHODS: Pleural tumor was measured at three levels on computed tomographic scans at study entry and before the second, fourth, and sixth cycles and every 2 months thereafter to disease progression. Of the 21 patients treated, 19 were male; the median age was 62 years (range, 46 to 74 years); 62% had epithelial tumors; and 18 were classified as tumor-node-metastasis system stage III or IV. Ninety-four cycles were given (median, six; mean, 4.5 per patient), with a mean relative dose intensity of cisplatin 96.7% and gemcitabine 82.5%. RESULTS: Best objective responses achieved were as follows: complete response, no patients; partial response, 10 patients (complete response + partial response, 47.6% [95% confidence interval, 26.2% to 69.0%]); no change, nine patients; and progressive disease, two patients. Median response duration was 25 weeks, progression-free survival was 25 weeks, and overall survival was 41 weeks. Nine of the 10 responders (90%) and three of nine patients with no change had significant symptom improvement. Serial measurements of vital capacity were performed on three of the responders; all showed a significant increase during the time of remission. Toxicity was mainly gastroenterologic and hematologic. Grade 3 nausea and vomiting occurred in 33% of patients, grade 3 leukopenia in 38%, grade 3 thrombocytopenia in 14%, and grade 4 thrombocytopenia in 19%. CONCLUSION: Combined cisplatin and gemcitabine is an active combination in malignant mesothelioma and produces symptomatic benefit in responding patients.

An assessment of hostility in a population of adolescents.

In the course of an epidemiological survey of adolescents, the Hostility and Direction of Hostility Questionnaire was administered to 6,709 persons aged 13 to 18 years, representing 89% of secondary school students in Hobart, Tasmania. Extrapunitiveness was found to decrease substantially between the ages of 15 and 17 years in both sexes. Intropunitiveness also decreased, although to a lesser extent. Girls were less extrapunitive and more intropunitive than boys over the whole age range. These findings are discussed in relation to their clinical relevance and to the understanding of psychiatric disorder in adolescents.

Sore throat in adults--does the introduction of a clinical scoring system improve the management of these patients in a secondary care setting?

OBJECTIVE: To audit sore throat management in adults, introduce proforma-based guidelines and to re-audit clinical practice. SETTING: Adult emergency department of an inner city teaching hospital. METHODS: A literature search was carried out to identify relevant guidelines. In stage one, patients presenting to the emergency department with sore throat were identified retrospectively from the emergency department attendance register. Proformas were completed retrospectively. In stage two, new guidelines were introduced and staff educated about the guidelines. In stage three, patients presenting with sore throat were identified at triage and proformas were completed at time of consultation. OUTCOME MEASURES: (1) appropriate clinical assessment of the likelihood of bacterial infection using the clinical scoring system, (2) appropriateness of antibiotic prescription, (3) recommendation of supportive treatments to patients. RESULTS: Introduction of a clinical scoring system reduced the inappropriate prescribing of antibiotics from 44 per cent to 11 per cent. Correct antibiotic prescription rose from 60 per cent to 100 per cent. Although the variety of advice given about supportive treatment increased, the actual number of patients receiving documented supportive advice fell from 67.8 per cent in stage one to 58 per cent in stage three. CONCLUSION: The introduction of clinically based guidelines for the diagnosis and management of sore throat in adults can reduce inappropriate antibiotic prescribing.

The treatment of type II diabetes in Texas. Current issues for managed care and employers.

In 1995, a forum was held in Dallas, Texas, to discuss the current state of treatment for type II diabetes and the issues facing managed care organizations (MCOs) and employers. Attendees included representatives from the American Diabetes Association (ADA), diabetologists, medical directors from leading MCOs in the area, benefits managers and employee representatives from large corporations in the region, diabetes educators, and a range of health care personnel directly involved in the care and treatment of patients with type II diabetes. The objectives of the forum were to discuss the state of diabetes treatment from the perspectives of MCOs and employers, to create a better understanding of the issues in treating diabetic patients, and to reach a consensus on the standards of care and the treatment guidelines for managed care patients with diabetes. Several needs were agreed on and identified by the attendees, including the need to develop minimum standards of care for the management of diabetes care, to improve patient and physician education programs and the communication between MCOs and employers, to acquire more sophisticated outcomes data, to pursue aggressive treatment of hyperglycemia, to increase emphasis on managing care to achieve long-term cost savings, and to stress greater patient responsibility for their own care.

Long-term titrated-dose alpha-glucosidase inhibition in non-insulin-requiring Hispanic NIDDM patients.

OBJECTIVE: To assess the long-term safety and effectiveness of a titrated dose of the alpha-glucosidase inhibitor miglitol (BAY m 1099) in Hispanic NIDDM patients. RESEARCH DESIGN AND METHODS: A 1-year double-blind randomized placebo-controlled study in which diet-treated or diet plus sulfonylurea-treated Hispanic NIDDM patients received either placebo (n = 131) or miglitol in doses of 50, 100, 150, 200 mg t.i.d. (n = 254), up-titrated and down-titrated based on tolerability. Efficacy parameters included changes from baseline in HbA1c, fasting and 2-h postprandial plasma glucose and serum insulin, fasting serum lipids, and urinary albumin-to-creatinine ratio (ACR). Safety assessments consisted primarily of tabulation of adverse events and intercurrent illnesses, and of periodic laboratory determinations. RESULTS: Reductions from baseline in HbA1c levels at the 6-month (primary efficacy) endpoint were significantly greater by 0.83% in the miglitol group than in the placebo group. HbA1c reductions in the miglitol treatment group significantly exceeded those in the placebo group by 0.63, 0.73, and 0.92% at 3, 9, and 12 months of treatment, respectively. Reductions in 120-min postprandial glucose and insulin levels were significantly greater in the miglitol group than in the placebo group at all postbaseline visits. There was little difference between treatments for changes in fasting insulin or lipid levels. Miglitol-associated reductions versus placebo in fasting plasma glucose (P = 0.0587 at 6 months) and in ACR (P = 0.0541 at 1-year) were nearly statistically significant. These efficacy results were not notably different between the 6-month endpoint, at which time the mean miglitol dose was 100 mg t.i.d., and the 1-year visit, when the mean miglitol dose was 149 mg t.i.d. Notable adverse events seen significantly more often in the miglitol group than in the placebo group were flatulence and diarrhea (or soft stools). The incidence of these gastrointestinal adverse events appeared to be dose dependent. CONCLUSIONS: Miglitol treatment of non-insulin-requiring Hispanic NIDDM patients at doses from 50 to 200 mg t.i.d. produced statistically and clinically significant reductions of HbA1c, primarily associated with reduction of glucose and insulin levels in the postprandial period, which were sustained over a year of treatment. Adverse events related to the drug's mechanism of action were common, but generally well tolerated. Doses above 100 mg t.i.d. were not associated with notably enhanced efficacy in most patients.

Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures.

Normal fasting subjects received regular insulin and mixtures of regular with NPH or lente to assess the effects of the combinations on serum insulin concentrations (SIC) and blood glucose responses (BGR). In addition, the influence of concentration, depth, and method and site of administration was investigated. In studies of mixtures of regular with NPH and with lente, it was observed that the regular: lente ratio needed to achieve peak SIC was higher than with the regular: NPH combination. Increased SIC, including either the peak and/or the time interval required to achieve the peak, were related to the depth and site (deltoid and abdominal greater than anterior thigh or buttocks). Assuming linear kinetics of absorption, significant quantities of insulin fail to reach the serum. Marked intra- and intersubject variations in SIC and BGR to regular, NPH, and lente insulins were observed.