Pharmacokinetics and pulmonary distribution of gamithromycin after intravenous administration in foals.

The long-acting azalide antibiotic gamithromycin is marketed for intramuscular treatment of bovine and swine infections. Off-label use in foals leads to severe local lesions likely caused by hyperosmolality of the injected solution. We provide evidence from a pharmacokinetic study in 10 warm-blooded healthy foals for intravenous bolus injection of gamithromycin diluted in distilled water to be a safe and well tolerated alternative. By intravenous dosing, markedly higher plasma exposure and better penetration into bronchoalveolar lavage cells but lower distribution into epithelial lining fluid are achieved as after intramuscular or subcutaneous administration. Intravenously injected gamithromycin was tolerated without any adverse drug reactions. The protocols for treatment of equine pulmonary infections caused by Rhodococcus equi should be revised accordingly.

Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer.

BACKGROUND: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PATIENTS AND METHODS: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. RESULTS: Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. CONCLUSIONS: DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. CLINICAL TRIAL NUMBER: NCT01335958.

Single locus sex determination and female heterogamety in the basket willow (Salix viminalis L.).

Most eukaryotes reproduce sexually and a wealth of different sex determination mechanisms have evolved in this lineage. Dioecy or separate sexes are rare among flowering plants but have repeatedly evolved from hermaphroditic ancestors possibly involving male or female sterility mutations. Willows (Salix spp.) and poplars (Populus spp.) are predominantly dioecious and are members of the Salicaceae family. All studied poplars have sex determination loci on chromosome XIX, however, the position differs among species and both male and female heterogametic system exists. In contrast to the situation in poplars, knowledge of sex determination mechanisms in willows is sparse. In the present study, we have for the first time positioned the sex determination locus on chromosome XV in S. viminalis using quantitative trait locus mapping. All female offspring carried a maternally inherited haplotype, suggesting a system of female heterogamety or ZW. We used a comparative mapping approach and compared the positions of the markers between the S. viminalis linkage map and the physical maps of S. purpurea, S. suchowensis and P. trichocarpa. As we found no evidence for chromosomal rearrangements between chromosome XV and XIX between S. viminalis and P. trichocarpa, it shows that the sex determination loci in the willow and the poplar most likely do not share a common origin and has thus evolved separately. This demonstrates that sex determination mechanisms in the Salicaceae family have a high turnover rate and as such it is excellent for studies of evolutionary processes involved in sex chromosome turnover.

Percutaneous cholecystostomy in critically ill patients with acute cholecystitis: complications and late outcome.

AIM: To evaluate the outcome of percutaneous cholecystostomy in critically ill patients with acute cholecystitis. MATERIALS AND METHODS: The study group included critically ill patients who underwent percutaneous cholecystostomy for acute cholecystitis at a tertiary medical centre in 2007-2011. Data on complications, morbidities, surgical outcome, and imaging findings were collected from the medical files and radiology information system. RESULTS: There were 48 women (59.3%) and 33 men (40.7%), with a median age of 82 years (range 47-99 years). Seventy-one (88%) had calculous cholecystitis and 10 (12%), acalculous cholecystitis. The drain was successfully inserted in all cases with no immediate major procedural complications. Fifteen patients (18.5%) died in-hospital within 30 days, mainly (93%) due to septic shock (14/15), another 20 patients (24.7%) died during the study period of unrelated co-morbidities. Of the remaining 46 patients, 36 (78.2%) had surgical cholecystectomies. In patients with acalculous cholecystitis, the drain was removed after cessation of symptoms. Transcystic cholangiography identified five patients with additional stones in the common bile duct. They were managed by pushing the stones into the duodenum via the cystostomy access, sparing them the need for surgical exploration. CONCLUSIONS: Early percutaneous gallbladder drainage is safe and effective in critically ill patients in the acute phase of cholecystitis, with a high technical success rate. Surgical results in survivors are better than reported in patients treated surgically without drainage. Bile duct stones can be eliminated without creating an additional access.

Intestinal and hepatic contributions to the pharmacokinetic interaction between gamithromycin and rifampicin after single-dose and multiple-dose administration in healthy foals.

BACKGROUND: Standard treatment of foals with severe abscessing lung infection caused by Rhodococcus equi using rifampicin and a macrolide antibiotic can be compromised by extensive inhibition and/or induction of drug metabolising enzymes (e.g. CYP3A4) and transport proteins (e.g. P-glycoprotein), as has been shown for rifampicin and clarithromycin. The combination of rifampicin with the new, poorly metabolised gamithromycin, a long-acting analogue of azithromycin and tulathromycin with lower pharmacokinetic interaction potential, might be a suitable alternative. OBJECTIVES: To evaluate the pharmacokinetic interactions and pulmonary distribution of rifampicin and gamithromycin in healthy foals, and to investigate the cellular uptake of gamithromycin in vitro. STUDY DESIGN: Controlled, four-period, consecutive, single-dose and multiple-dose study. METHODS: Pharmacokinetics and lung distribution of rifampicin (10 mg/kg) and gamithromycin (6 mg/kg) were measured in nine healthy foals using LC-MS/MS. Enzyme induction was confirmed using the 4ß-OH-cholesterol/cholesterol ratio. Affinity of gamithromycin to drug transport proteins was evaluated in vitro using equine hepatocytes and MDCKII-cells stably transfected with human OATP1B1, OATP1B3 and OATP2B1. RESULTS: Rifampicin significantly (P<0.05) increased the plasma exposure of gamithromycin (16.2 ± 4.77 vs. 8.57 ± 3.10 µg × h/mL) by decreasing the total body clearance. Otherwise, gamithromycin significantly lowered plasma exposure of single- and multiple-dose rifampicin (83.8 ± 35.3 and 112 ± 43.1 vs. 164 ± 96.7 µg × h/mL) without a change in metabolic ratio and half-life. Gamithromycin was identified as an inhibitor of human OATP1B1, OATP1B3 and OATP2B1 and as a substrate of OATP2B1. In addition, it was extracted by equine hepatocytes via a mechanism which could be inhibited by rifampicin. MAIN LIMITATIONS: Influence of gamithromycin on pulmonary distribution of rifampicin was not evaluated. CONCLUSION: The plasma exposure of gamithromycin is significantly increased by co-administration of rifampicin which is most likely caused by inhibition of hepatic elimination.

Pharmacological indices and pulmonary distribution of rifampicin after repeated oral administration in healthy foals.

BACKGROUND: The treatment of equine lung infections by Rhodococcus equi with rifampicin is empirically based because pharmacokinetic/pharmacodynamic (PK/PD) indices and pivotal clinical outcome data are not available. OBJECTIVES: To evaluate the pharmacokinetics and pulmonary distribution of rifampicin into epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALC) to predict antimicrobial activity in the lung using PK/PD indices. STUDY DESIGN: Controlled, randomised, two-period, crossover, repeated-dose study with an initial arm to measure disposition after i.v. administration of rifampicin. METHODS: Pharmacokinetics and lung distribution were evaluated in six healthy foals treated with 10 mg/kg bwt rifampicin i.v. (initial arm) and with repeated oral doses of rifampicin at 10 mg/kg bwt and 20 mg/kg bwt once per day for 10 days (crossover arms). ELF and BALC were sampled by bronchoalveolar lavage 24 h after the last oral dosing. Rifampicin and 25-O-desacetyl rifampicin were quantified using liquid chromatography tandem-mass spectrometry. Enzyme induction by rifampicin was confirmed by evaluation of plasma 4ß-OH-cholesterol:cholesterol ratios. RESULTS: The distribution volume of rifampicin administered i.v. was ~0.85 L/kg. Terminal elimination half-life was ~11 h. Orally given rifampicin was slowly absorbed (Tmax , range: 2.5-8.0 h) and eliminated with apparent half-lives of ~6-8 h. Trough concentrations in ELF and BALC were 1.01 ± 0.20 µg/mL and 1.25 ± 0.29 µg/mL, respectively, after 10 mg/kg bwt rifampicin and 2.71 ± 1.25 µg/mL and 3.09 ± 1.63 µg/mL, respectively, after 20 mg/kg bwt rifampicin. The average ratios of area under the plasma concentration time curve during an administration interval of 24 h (AUC0-24 h ) to minimum inhibitory concentration (MIC) were 145 and 322 h, respectively, for less susceptible strains of R. equi (MIC90 : 0.5 µg/mL). MAIN LIMITATIONS: The clearance and bioavailability of rifampicin after repeated oral dosing were not evaluated. CONCLUSIONS: Treatment with rifampicin at 10 mg/kg bwt administered once per day is suitable to generate drug concentrations above the MIC90 in the ELF and BALC of foals. Future clinical studies with rifampicin in combination with macrolide antibiotics with low drug interaction potential are required to translate the PK/PD indices into protocols for the treatment of R. equi lung infections.

Effect of altitude on hand-held peak flowmeters.

OBJECTIVE: To quantify the effect of altitude on the operational characteristics of hand-held peak flowmeters. DESIGN: Altitude simulation within a hypobaric chamber combined with five constant simulated peak flows delivered from a computerized pump were used to test commercially available peak flowmeters. SETTING: F.G. Hall Hyperbaric/Hypobaric facilities located at Duke University School of Medicine. MEASUREMENTS: Two each of nine models of commercially available hand-held peak flowmeters and a volume spirometer were tested at six simulated altitudes (100, 500, 1,000, 1,500, 2,000, and 3,000 m) using five target peak flows. Each peak flow was injected into each meter twice. Forward stepwise regression was used to check for nonlinear relationships between altitude and peak expiratory flowmeter readings. Linear regression equations were fit to the data at each target flow across altitude. Effect of absolute peak flow was tested by analysis of covariance. RESULTS: For these altitudes, linear relationships were found between altitude and measured peak flow. For all meters tested, the average decrease in peak flow ranged from -8.7% at the lowest target flow (123 L/min) to -6.5% at the highest target flow (702 L/min) for each 100 mm Hg decrease in barometric pressure (PB). Individual meters ranged from -12.3% at the lowest target flow to -4.4% at the highest target flow for 100 mm Hg decrease in PB. The spirometer had no significant changes associated with changes in PB. In all cases, the magnitude of the altitude effect, measured by percent change, decreased with increasing peak flow. CONCLUSIONS: Peak expiratory flowmeters underread PEF as a function of both increasing altitude and increasing target peak flow.

Pulmonary hemorrhage: clinical course and outcomes among very low-birth-weight infants.

OBJECTIVE: To describe the clinical course, neonatal morbidity, and neurodevelopmental outcomes of very low-birth-weight (<1500 g) children who develop pulmonary hemorrhage. DESIGN: A retrospective case-control study in which 58 very low-birth-weight infants who developed pulmonary hemorrhage during 1990 through 1994, of whom 29 survived, were each matched to the next admitted infant who required mechanical ventilation for respiratory distress syndrome and was of the same sex, race, and birth weight (within 250 g). SETTING: A regional tertiary neonatal intensive care unit and follow-up clinic for high-risk infants at University Hospitals of Cleveland, Cleveland, Ohio. MAIN OUTCOME MEASURES: Survival, neonatal morbidity, and neurodevelopmental outcome at 20 months' corrected age. RESULTS: Pulmonary hemorrhage occurred in 5.7% of the total population of very low-birth-weight infants. Despite similar severity of lung disease, significantly more infants who developed pulmonary hemorrhage received surfactant therapy compared with controls (91% vs 69%, P = .005). Infants with pulmonary hemorrhage who died had a lower birth weight and gestational age compared with those who survived (766 g vs 1023 g; 25 weeks vs 28 weeks, P<.001) and more received surfactant therapy (100% vs 83%, P = .05). Survivors with pulmonary hemorrhage did not differ significantly from controls in rates of oxygen dependence at 36 weeks corrected age (52% vs 38%), grade 3 to 4 periventricular hemorrhage (28% vs 17%), or necrotizing enterocolitis (3% vs 7%), but tended to have more seizures (24% vs 3%, P = .05), periventricular leucomalacia (17% vs 0%, P = .06), and patent ductus arteriosus (79% vs 55%, P =.09). There were no significant differences in neurodevelopmental outcomes at 20 months' corrected age, (cerebral palsy, 16% vs 14%; subnormal [<70] Bayley Mental Developmental Index, 59% vs 43%; and deafness, 13% vs 10%). CONCLUSION: Although mortality is high, pulmonary hemorrhage does not significantly increase the risk of later pulmonary or neurodevelopmental disabilities among those who survive.

Rate of CO uptake by canine erythrocytes as a function of PO2.

We used a continuous-flow rapid-mixing apparatus with spectroscopic analysis to measure the rate of CO uptake by canine erythrocytes at 37 degrees C at five different PO2 values from 0 to 553 Torr. Fresh blood from five different dogs was used for the experiments. PCO approximated 80 Torr. Corrections for the lower capillary PCO during a measurement of the diffusing capacity of lung CO, as made by Roughton and Forster in 1957 (J. Appl. Physiol. 11: 290-302, 1957), were not used. The regression equation for 1/theta, where theta is milliliters of CO combining for each milliliter of whole blood (capacity 0.2 ml/ml) per minute for a PCO of 1 Torr was 1/theta = 1.45 +/- 0.0042 PO2. This equation is very similar to that for human erythrocytes under the same conditions.

Venous drainage of the femur permits passage of 100-micron particles.

Iatrogenic metastasis of bone tumor is reportedly increased if aggregates of tumor cells enter the circulation. The current study used a previously developed animal model to explore the movement of 25-, 50-, and 100-micron-diameter particles from an experimental femur biopsy site into the circulation. The results indicate that cell aggregate-sized particles can enter the circulation from the femur at a rate similar to that of the 15-micron particles used in previous studies. Arterial blood samples collected during and after the injection of particles contained no 50- or 100-micron particles, suggesting that the lung is an effective filter for these larger particles.

Comprehensive individualised nonpharmacological treatment programme for hypertension in physician-nurse clinics: two year follow-up.

A comprehensive programme of nonpharmacological control of hypertension (balanced nutrition, satisfactory weight, enhanced physical activity, relaxation technique, smoking cessation) by primary care physician-nurse (PN) teams who were instructed and routinely advised by a paramedical professional (PP) team (psychologist, nutritionist and physical activity instructor) was developed with the aim of increasing long-term compliance. To evaluate effectiveness, 52 mild and moderate hypertensives without target organ damage were randomly allocated to six weekly meetings of individual intensive instruction by PN teams alone, or direct group instructions by PP teams (24 and 28 patients, respectively). The respective results at 11 months and 24 months follow-up compared with baseline were: (1) 56.9% and 58.8% showed minimal satisfactory reduction of weight, (2) 49% and 58.8% showed minimal satisfactory increase in physical activity, (3) the reported increase in physical activity at 11 months follow-up was validated by significantly correlated improved performance in ergometry, (4) 75% and 40% of the patients performed relaxation vs. 2% at baseline and (5) 71% and 59% needed no medication or reduced dose to control BP, and these changes were significantly (P < 0.02) correlated with weight reduction and increased physical activity. As no differences were found between the two modes of treatment, we conclude that our programme can be successfully applied by the PN primary care teams to increase adherence to nonpharmacological measures in the control of hypertension.

Partial cost-benefit analysis of two different modes of nonpharmacological control of hypertension in the community.

In the Dan and Ashkelon areas of Israel, 28 male and 24 female mild to moderate hypertensives without target organ damage aged 35-65 years were randomly assigned to treatment programmes (based on nutritional management, exercise and stress management techniques) either on an individual basis administered by physician-nurse teams (PN) or on a group basis from a team of paramedical professionals (PP) consisting of a psychologist, nutritionist and physical activity instructor. At 11 and 24 months follow-up, there were similar significant improvements in both treatment modes for such risk factors as body mass index, caloric intake and physical activity levels. There was a significant decrease in drug use from $36.28 a month at baseline to $18.94 a month at 11 month follow-up (P = 0.01) and to an estimated $20.48 at 24 months. Mean BP remained unchanged, despite the reduction in drug use, indicating a reduction in the underlying BP. The net present value (NPV) of the reduction in drug utilisation totalled $740 per person over a five year time horizon and a 7.5% discount rate. The total extra costs of treatment, training, case-note writing, travelling and follow-up booster sessions, amounted to $95 per patient for the PN mode and $234 per patient for the PP mode, yielding benefit to cost ratios of 7.79/1 and 3.16/l, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of abnormal glucose metabolism in chronic pancreatitis by administration of pancreatic polypeptide.

Chronic pancreatitis, induced in dogs by pancreatic duct ligation, is associated with glucose intolerance due to insulin deficiency, reduced hepatic sensitivity to insulin, and a marked deficiency of pancreatic polypeptide. Treatment with a 14 day continuous subcutaneous infusion of pancreatic polypeptide resulted in improved oral glucose tolerance and improved hepatic glucose responses to insulin in dogs with chronic pancreatitis. No effect of continuous subcutaneous infusion of pancreatic polypeptide was seen in the control dogs. The time course of the effect of continuous subcutaneous infusion on the hepatic response to insulin was relatively immediate, whereas the effects on improvement in oral glucose tolerance were prolonged. We conclude that pancreatic polypeptide may function physiologically to enhance the hepatic glucose response to insulin and that alterations in glucose metabolism seen in chronic pancreatitis may be due, in part, to a deficiency in pancreatic polypeptide. Since treatment with continuous subcutaneous infusion of pancreatic polypeptide restored the hepatic response to insulin and oral glucose tolerance to more normal levels in our animal model, administration of pancreatic polypeptide may play a therapeutic role in the treatment of certain forms of pancreatogenic diabetes.

Magnetic resonance imaging of the cardiovascular system and airway.

Cardiovascular MR imaging is unique in its ability to combine anatomic, physiologic, and functional information in a single examination. Established applications in the pediatric population include the evaluation of the child with a suspected thoracic aortic arch anomaly, vascular compression of the airway, coarctation of the aorta, pulmonary arterial and venous abnormalities, and cardiac or paracardiac masses. The increasing availability of radiologists with the knowledge and commitment to cardiac imaging will allow this exciting technique to thrive in the future, to the benefit of our patients.

Silicone elastomer microshards in fluid from a painful metatarsophalangeal implant site. A case report.

Histopathologic studies have demonstrated microshards from silicone elastomer metatarsophalangeal joint implants in adjacent tissues in a setting of chronic inflammation and in inguinal lymph nodes. Cytologic smears of synovial fluid from symptomatic implanted joints should show these refractile, nonpolarizing microshards in the reactive inflammatory context. Nonspecific enzymatic inflammatory activity contributes to further destabilization of the implants, eventuating in symptoms and signs requiring prosthesis removal. Cytopathologic examination of aspirated fluid from the vicinity of a symptomatic implanted joint demonstrates foreign body reaction to silicone elastomer, predicting a need for intervention before the local damage is severe and disabling.

Women and autonomy: using structural analysis of social behavior to find autonomy within connections.

In their work to construct psychological theories about women's development, Carol Gilligan and Jean Baker Miller both highlight the centrality of interpersonal connections in women's lives. As they describe how women's senses of self and morality are organized around relationships, Gilligan and Miller tend to contrast affiliation with autonomy. The message that readers often take from this view is that autonomy has no meaning for women--is somehow beneath them, beyond them, or unnatural to them. Although Miller and Gilligan dichotomize affiliation and autonomy, they also provide numerous examples in which women's feelings of worth, ability, and self-consideration enhance relatedness. We argue that autonomy can be understood as a sense of freedom and personal integrity that encompasses these same characteristics, and we use the Structural Analysis of Social Behavior to clarify how autonomy makes critical contributions to interpersonal connections.

Development of clinical standards in industrial rehabilitation.

Before discussing adjustments in the fees for the clinical services of industrial rehabilitation, the Medical Free Guide Committee of the Maryland Industrial Commission requested a copy of the clinical standards for these services. However, there were no multidisciplinary standards for industrial services that had state-wide approval. Therefore, a committee was formed to write the standards. Following a review of the literature and unpublished work from other associations and state organizations, standards were developed. Constructive criticism was solicited from national and local professionals and organizations with demonstrated interest and experience in providing or using these services or with experience writing standards. Further comment was solicited from individuals in the state of Maryland before final editing. Because of the dearth of outcome studies supporting the efficacy of clinical services in industrial rehabilitation, the standards describing a level of expectation from clinical services have become important for state organizations responsible for making decisions on reimbursement for clinical services. This paper summarizes the process used for the development of clinical standards of industrial rehabilitation services.

Gender, coping, and psychological well-being in spouses of older adults with chronic dementia.

Relationships among gender, types of coping strategies, and psychological well-being were examined in 61 spousal caregivers of older adults with chronic dementia. Gender emerged as a significant correlate of well-being (with women reporting higher levels of distress), although not of related coping strategies. Implications for research into interactions among biological, psychological, and social factors contributing to women's psychological distress are discussed.

Statistical analysis of 307,601 tumors and other lesions of the foot.

This laboratory study is limited to lesions submitted from office procedures and makes no claims or comparison regarding statistical data from hospitals, where most malignancies are excised. This study is ongoing, and will be updated regularly to observe trends and alert practitioners to changing patterns of incidence.

Kaposi's sarcoma of the foot. A review and report of 156 cases.

The authors identify the incidence of Kaposi's sarcoma in the foot, and discuss the increasing incidence of AIDS-related cases, and the increasing chance of mortality when this lesion is seen in patients under the age of 50.