Distinct B cell profiles characterise healthy weight and obesity pre- and post-bariatric surgery.

BACKGROUND/OBJECTIVES: Obesity-associated metabolic dysfunction and inflammation can be ameliorated by bariatric surgery. While obesity is also linked to impaired B cell activation, differentiation, and persistence in response to infection and vaccination little is known about post-operative immune B cell compartment and to what extent dysregulation in B cell pathways can be reversed. To bridge this gap in knowledge, we carried out in-depth evaluation of B cell composition in individuals with obesity prior to and following bariatric surgery compared to lean controls. SUBJECTS/METHODS: We recruited individuals with obesity (BMI at least 35 kg/m2) before bariatric surgery (n = 21) and followed them up 6 months post-operatively (n = 17). As controls we recruited age- and sex-matched lean (BMI < 25) individuals (n = 18). We carried out comprehensive immunophenotyping of peripheral blood B cells as well as interrogated their association with inflammatory and metabolic parameters. RESULTS: In obesity the balance of antigen-inexperienced and memory B cells in the peripheral blood is altered, with an expansion of naïve and a reduction in total memory B cells. 6 months following bariatric surgery this balance is restored. However, post-operative patients are uniquely characterised by an increase in B cell subsets associated with chronic inflammation - CD11c+CXCR5-IgD-CD27- double negative 2 (DN2) B cells and CD27+CD38++ plasmablasts. Correlations between B cells subsets, inflammatory and metabolic parameters were distinct in lean people and individuals with obesity pre- and post-bariatric surgery. CONCLUSIONS: Bariatric surgery patients display a unique B cell profile 6 months post-operatively; this bears minimal resemblance to that of pre-operative patients and only partially overlaps with that of lean controls. Post-operative differences in the B cell compartment compared to lean controls are detected despite global amelioration of inflammation and restoration of metabolic health. Collectively, this indicates that bariatric surgery creates a specific immunometabolic state with potential implications for health outcomes.

The Global Leadership Mentoring Community: building capacity across seven global regions.

AIM: The purpose of this paper is to report on the evaluation of the online Global Leadership Mentoring Community, a programme designed to build relationships across seven global regions and promote leadership development for emerging nurse leaders. BACKGROUND: There is a pressing need and opportunity for sustainable global leadership mentoring programmes. This programme of Sigma Theta Tau International (Sigma) brought mentors and mentees together from across the world to build leadership capacity, understand global leadership issues and build networks. Community coordinators purposively selected mentors from each of Sigma's seven Global Regions, and mentees were chosen through a process of snowball sampling. Mentors and mentees met monthly with quarterly group calls. METHODS: The study followed a programme evaluation, outcomes-focused approach. All eleven pairs of mentors-mentees were invited to complete online surveys at the outset and end of programme capturing both quantitative and qualitative data. Quantitative data were analysed using descriptive statistics and for qualitative data, a thematic analysis. FINDINGS: Quantitative data confirmed that all 22 participants gained from the experience. From qualitative analysis, themes emerged illustrating the scope of achievements: 1. facilitation of successful outcomes for both mentors and mentees, 2. challenges of global mentoring and 3. strategies for successful global mentoring. DISCUSSION/CONCLUSION: Participants reported that creating global leadership is a longitudinal process that needs sustained attention to effect change. This evaluation identified many strengths of the programme and recommended its continuation to help further development of global leaders, particularly through focusing more purposefully on policy issues. IMPLICATIONS FOR NURSING POLICY: Empowerment of nurses globally through a Global Leadership Mentoring Community can improve leadership at all levels, thus emboldening their voices to influence nursing and health policy and ultimately improve patient care.

Patient understanding of genetic information influences reproductive decision making in retinoblastoma.

BACKGROUND: Retinoblastoma is the most common malignant tumour of the eye in childhood, with nearly all bilateral tumours and around 17% to 18% of unilateral tumours due to an oncogenic mutation in the RB1 gene in the germline. Genetic testing enables accurate risk assessment and optimal clinical management for the affected individual, siblings, and future offspring. MATERIAL AND METHODS: We carried out the first UK-wide audit of understanding of genetic testing in individuals with retinoblastoma. A total of 292 individuals aged 16 to 45 years were included. RESULTS: Patients with bilateral disease were significantly more likely to understand the implications of retinoblastoma for siblings and children. There was a significant association between not knowing the results of genetic testing or not understanding the implications and not having children, particularly in women. Surprisingly, this was also true for individuals treated for unilateral disease with a low risk of retinoblastoma for their offspring. CONCLUSION: We are concerned that individuals may be making life choices based on insufficient information regarding risks of retinoblastoma and reproductive options. We suggest that improvement in transition care is needed to enable individuals to make informed reproductive decisions and to ensure optimal care for children born at risk of retinoblastoma.

CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells.

Regulatory B cells (Breg) express high levels of CD1d that presents lipid antigens to invariant natural killer T (iNKT) cells. The function of CD1d in Breg biology and iNKT cell activity during inflammation remains unclear. Here we show, using chimeric mice, cell depletion and adoptive cell transfer, that CD1d-lipid presentation by Bregs induces iNKT cells to secrete interferon (IFN)-γ to contribute, partially, to the downregulation of T helper (Th)1 and Th17-adaptive immune responses and ameliorate experimental arthritis. Mice lacking CD1d-expressing B cells develop exacerbated disease compared to wild-type mice, and fail to respond to treatment with the prototypical iNKT cell agonist α-galactosylceramide. The absence of lipid presentation by B cells alters iNKT cell activation with disruption of metabolism regulation and cytokine responses. Thus, we identify a mechanism by which Bregs restrain excessive inflammation via lipid presentation.

Pharmacokinetics and Relative Bioavailability of Orally Administered Innovator-Formulated Itraconazole Capsules and Solution in Healthy Dogs.

BACKGROUND: Itraconazole is commonly used for treatment of systemic and cutaneous mycoses in veterinary medicine. Two formulations, capsule and solution, are used interchangeably in dogs. However, marked differences in bioavailability have been reported in other species. Similar investigations have not been performed in dogs. OBJECTIVE: To determine and compare pharmacokinetics of itraconazole in dogs after oral administration of commercially available capsule and solution formulations intended for use in humans. ANIMALS: Eight healthy, adult, purpose-bred dogs. METHODS: Dogs received approximately 10 mg/kg of innovator-formulated itraconazole solution and capsule PO in randomized, crossover design with a 10-day washout period. To ensure maximal absorption, solution was administered to fasted dogs, whereas capsules were co-administered with food. Blood samples were collected at predetermined time points, and plasma drug concentrations were measured using high-pressure liquid chromatography. Pharmacokinetic parameters were determined with compartmental analysis. RESULTS: The mean relative bioavailability of the capsule was 85% that of the solution, but drug absorption was variable, and overall drug concentrations were similar between formulations. Mean elimination half-lives of both formulations were nearly identical at approximately 33 hours. Regardless of formulation, simulations suggest that a loading dose of 20 mg/kg, followed by 10 mg/kg once every 24 hours, will result in plasma concentrations considered to be adequate in most dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Contrary to findings reported in other species, overall drug exposures after capsule and solution administration are not substantially different in dogs. Despite some pharmacokinetic differences between itraconazole capsule and solution, formulation-specific dosages do not appear to be necessary.

Homozygotes and heterozygotes for ciliary neurotrophic factor null alleles do not show earlier onset of Huntington's disease.

The CAG repeat number on Huntington's disease (HD) chromosomes accounts for about 60% of the variance in the age at onset of HD. However, distinct familial factors may also influence the age at onset. HD is associated with loss of medium-sized GABA-ergic striatal output neurons. Intracerebral administration of human ciliary neurotrophic factor (CNTF) protects striatal output neurons in excitotoxic rodent and primate models of HD induced by intrastriatal quinolinic acid injection. We have examined the effect of a common null mutation in the human CNTF gene on the age of onset of HD using a multiple regression approach that takes into account the CAG repeat number on HD chromosomes. We failed to detect an earlier onset of HD in nine homozygotes and 71 heterozygotes with this CNTF mutation compared with 203 homozygotes with wild-type alleles.

Geleophysic dysplasia: a report of three affected boys--prenatal ultrasound does not detect recurrence.

Geleophysic dysplasia is characterized by short stature with short limbs and brachydactyly, a "happy" facial appearance, and joint contractures. Infiltration of heart valves and liver with a mucopolysaccharide-like substance has been demonstrated in some patients. A metabolic pathogenesis is suspected, but has not yet been identified. We report on 3 boys with the condition, 2 of whom are brothers. Serial ultrasound scans were performed on 2 of the cases during pregnancy, but short limbs did not become obvious until after 28 weeks of gestation, making it an uninformative procedure for prenatal diagnosis.

Bacterial population and histologic changes in dogs with perianal fistula.

Ages of 44 dogs with perianal fistula, ranged from 6 months to 13 years (mean, 5.2 years). German Shepherd Dogs and Irish Setters were statistically (P less than 0.01) over-represented compared with those breeds in a canine hospital population (n = 22,047) for the same period. There was a 2:1 male-to-female ratio, with 38 (86.4%) of dogs sexually intact and 6 (13.6%) of dogs neutered. Eleven types of bacterial organisms were recovered from deep perianal tissues of which Escherichia coli, Staphylococcus aureus, beta-hemolytic streptococci, and Proteus mirabilus were most common. Organisms were not recovered from 7 dogs. Of 93 isolates, 88.3% were susceptible to gentamicin, 80.5% to cephalothin, 79.2% to chloramphenicol, and 74% to trimethoprim-sulfamethoxazole. Fifty-one biopsy specimens from 44 dogs were classified as having early, intermediate-, and late-stage lesions based on the amount of fibrosis, severity of the inflammatory response, and, if present, depth of sinus tracts. In most biopsy specimens, all 3 stages were represented in the same histologic section. In 45 specimens, most inflamed lesions were in the dermis of the zona cutanea. Hidradenitis was present in 22 biopsy specimens and was associated with the formation of epithelial-lined sinus tracts.

Thyroid and immunologic status of dogs with perianal fistula.

Lymphocyte-proliferation responses, absolute lymphocyte counts, and thyrotropin-stimulation responses were determined in 33 dogs with perianal fistula; serum immunoglobulin values also were determined in 15 of the 33 dogs. Lymphocytes were stimulated with concanavalin A, pokeweed mitogen, and phytohemagglutinin and were cultured with medium containing normal pooled canine serum or fresh patient's autologous serum. Initially, lymphocytes from 9 dogs (27.3%) had depressed stimulation responses to greater than or equal to 1 phytomitogen, and 4 of the 9 dogs had absolute lymphopenia. One month after recovery in these 9 dogs, lymphocytes from 4 dogs (66.7%) had normal proliferation responses. Of immunoglobulin determinations in 15 dogs, serum IgA values were 32 to 185 mg/dl (mean, 69 +/- 10 mg/dl) and were low in 2 dogs (13%), and serum IgM values were 48 to 610 mg/dl (mean, 263 to 46 mg/dl) and were high in 8 dogs (53%). Serum IgG values were 1,050 to 3,220 mg/dl (mean, 2,339 +/- 165 mg/dl) and were high in 10 dogs (71%). After thyrotropin stimulation, 1 dog was considered hypothyroid. Neither pathogenesis nor prognosis of canine perianal fistula was clarified via immunoglobulin concentrations or absolute lymphocyte counts. Based on lymphocyte-proliferation assays, suppression of cell-mediated immunity was probably a result of perianal fistula, rather than a cause of the fistula.

Type-1 hypersensitivity reactions to Malassezia pachydermatis extracts in atopic dogs.

OBJECTIVE: To investigate the potential allergenic role of the yeast Malassezia pachydermatis in dogs with clinical diagnosis of atopic dermatitis. ANIMALS: 5 clinically normal nonatopic dogs, 10 atopic dogs with cytologic evidence of Malassezia dermatitis, and 12 atopic dogs without cytologic evidence of Malassezia dermatitis. PROCEDURE: A crude yeast extract was produced by disrupting the cell wall of M pachydermatis. The crude extract and 8 of its fractions, which were generated by fractionation in a high-performance liquid chromatography column, were injected along with 46 commercial allergens for intradermal allergy testing of normal and atopic sample populations. Significant difference between atopic populations was evaluated, using a threshold concentration of crude yeast extract that failed to induce wheal-and-flare responses in normal nonatopic dogs. RESULTS: Atopic dogs with cytologic evidence of Malassezia dermatitis had significantly greater wheal-and-flare reactions to intradermal injection of crude extract of M pachydermatis than did atopic dogs without cytologic evidence of Malassezia dermatitis. CONCLUSIONS: It is concluded that M pachydermatis is capable of promoting type-1 hypersensitivity reactions in dogs with an atopic dermatitis phenotype. CLINICAL RELEVANCE: Currently, Malassezia dermatitis is principally managed by use of antifungal chemotherapy. Because the yeast appears to be a contributing allergen in dogs with atopic dermatitis, hyposensitization with M pachydermatis extracts may offer a future alternative to extended or repeated episodic administration of antifungals for extended control of recurrent infections.

Lethal acrofacial dysostosis, pre- and post-axial defects of the hands, and bilateral renal agenesis.

We report a female fetus with a previously undescribed form of mandibulofacial dysostosis with mesomelic limb abnormalities, pre- and post-axial defects of the hands, bilateral renal agenesis, bicornuate uterus, and a single umbilical artery.

Serum and tissue fluid norfloxacin concentrations after oral administration of the drug to healthy dogs.

Norfloxacin, a 4-quinolone antibiotic, was administered orally to 4 healthy dogs at dosages of 11 and 22 mg/kg of body weight, every 12 hours for 4 days, with a 4-week interval between dosing regimens. Serum and tissue cage fluid (TCF) norfloxacin concentrations were measured at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after the first and seventh dose of each dosing regimen. When administered at a dosage of 11 mg/kg, the mean peak serum concentration (Cmax) was 1.0 microgram/ml at 1 hour, the time of mean peak concentration (Tmax) after the first dose. After the seventh dose, the Cmax was 1.4 micrograms/ml at Tmax of 1.5 hours. The Tmax for the TCF concentration was 5 hours, with Cmax of 0.3 microgram/ml and 0.7 microgram/ml after the first and seventh dose, respectively. When administered at a dosage of 22 mg/kg, the serum Tmax was 2 hours after the first dose, with Cmax of 2.8 micrograms/ml. After the seventh dose, the serum Tmax was 1.5 hours, with Cmax of 2.8 micrograms/ml. The Tmax for the TCF concentration was 5 hours after the first and seventh doses, with Cmax of 1.2 micrograms/ml and 1.6 micrograms/ml, respectively. After the seventh dose, the serum elimination half-life was 6.3 hours for a dosage of 11 mg/kg and was 6.7 hours for a dosage of 22 mg/kg. For serum concentration, the area under the curve from 0 to 12 hours (AUC0----12) was 8.77 micrograms.h/ml and 18.27 micrograms.h/ml for dosages of 11 mg/kg and 22 mg/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Nance-Sweeney chondrodysplasia--a further case?

A 52-year-old male with short stature due to short limbs, a cleft palate and subcutaneous calcification was described by Nance and Sweeney in 1970. His parents were consanguineous and two female sibs and two cousins were said to be similarly affected, thus the authors proposed that this was a previously undescribed recessively inherited chondrodystrophy. We describe a patient with short stature due to short limbs, subcutaneous calcification, and a cleft palate with features similar to those described by Nance and Sweeney.

Serpentine fibula syndrome: expansion of the phenotype with three affected siblings.

We describe three siblings, one of whom has serpentine fibula syndrome (SFS) and has many facial and skeletal features in common with two deceased brothers, making it highly likely that they too had the condition. The karyotype of one of the deceased males was 47,XXY. These are the first affected sibs with SFS, and the first affected males. They all have other abnormalities which have not previously been described as part of the condition, namely congenital heart disease, inguinal herniae (two sibs), intestinal malrotation (two sibs) and coloboma (one sib). Facially they resemble the cases described by ter Haar et al. (1983), who also had congenital heart disease and a skeletal dysplasia though did not have the characteristic bowing of the fibulae. There are also features in common with Hadju-Cheney syndrome.

Effects of propofol anesthesia on intradermally injected histamine phosphate in clinically normal dogs.

OBJECTIVE: To compare skin test reactivity of ID injected histamine phosphate in clinically normal dogs that were physically restrained or anesthetized with propofol. ANIMALS: 12 clinically normal adult dogs. PROCEDURE: Nonanesthetized dogs (group 1) were restrained and shaved on the right side of the thorax. A single injection of sterile buffered saline solution (negative control) and 5 serial dilutions of histamine phosphate (0.05 ml each) were injected ID. Wheal size was measured after 15 minutes. Propofol anesthetized dogs (group 2) were shaved, and saline solution and histamine were administered ID. Wheal size was measured as for nonanesthetized dogs. Hemoglobin saturation, heart and respiratory rates, and times to sternal recumbency and standing were recorded for anesthetized dogs. Twenty-four hours later, groups were reversed, and testing was repeated on the left side of the thorax. RESULTS: Mean wheal size was significantly (P < 0.05) less in dogs during propofol anesthesia. Heart and respiratory rates were well maintained but hemoglobin saturation decreased during the first 6 minutes of anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Although statistically significant, the difference in mean wheal size may not be clinically important. Propofol anesthesia may be used during ID skin testing in atopic dogs. Further studies to assess effects of propofol on the reactivity of ID injected aeroallergens should be performed before recommending its use.

Pharmacokinetics of L-thyroxine after its oral administration in dogs.

Twelve mature (5 sexually intact males, 4 castrated males, and 3 females) mixed-breed dogs were surgically thyroidectomized and used in a Latin-square design pharmacokinetic study of orally administered L-thyroxine. The dogs were treated with 44, 22, and 11 micrograms of L-thyroxine/kg as a single morning dose or in divided doses, morning and evening. Serum concentration of thyroxine (T4) was evaluated to determine a number of pharmacokinetic variables for comparison. Mean steady-state concentrations (Css) were determined from the area under the curve. Variables were analyzed for comparisons between dosages by use of ANOVA. Concentration at steady state was highest for dogs of the 44-micrograms/kg of body weight once-daily group and was lowest for dogs of the group given 11 micrograms/kg in 2 daily doses. Single daily administration resulted in higher Css, except at the 22-micrograms/kg/d dosage. Clearance was faster for the 22- and 44-micrograms/kg/d dosages than for the 11-micrograms/kg/d dosage. The half-life (t1/2) and mean residence time (MRT) also were shorter for the 44-micrograms/kg/d dosage, possibly indicating more rapid elimination of the drug at higher doses and dose-dependent kinetics. Perhaps, as the dogs' metabolism increased with higher iodothyronine concentrations, hormone degradation was accelerated. Interval (divided vs single dose) caused some expected changes: maximal concentration was higher and minimal concentration was lower when single administration was used. These undulations resulted in iodothyronine concentrations above the physiologic range for a number of hours, whereas concentration closer to physiologic ranges was achieved by use of divided doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum and tissue cage fluid concentrations of ciprofloxacin after oral administration of the drug to healthy dogs.

Ciprofloxacin, a fluoroquinolone antimicrobial agent, was administered orally to 4 healthy dogs at dosage of approximately 11 and 23 mg/kg of body weight, every 12 hours for 4 days, with a 4-week interval between dosing regimens. Serum and tissue cage fluid (TCF) concentrations of ciprofloxacin were measured after the first and seventh dose of each dosing regimen. The peak concentration was greatest in the serum after multiple doses of 23 mg/kg (mean +/- SEM; 5.68 +/- 0.54 micrograms/ml) and least in the TCF after a single dose of 11 mg/kg (0.43 +/- 0.54 micrograms/ml). The time to peak concentration was not influenced by multiple dosing or drug dose, but was longer for TCF (6.41 +/- 0.52 hour) than for serum (1.53 +/- 0.52 hour). Accumulation of ciprofloxacin was reflected by the area under the concentration curve from 0 to 12 hours after administration (AUC0----12). The AUC0----12 was greatest in the serum after multiple doses of 23 mg/kg (31.95 +/- 1.90 micrograms.h/ml) and least in the TCF after a single dose of 11 mg/kg (3.87 +/- 1.90 micrograms.h/ml). The elimination half-life was not influenced by multiple dosing or dose concentration, but was greater for TCF (14.59 +/- 1.91 hours) than for serum (5.14 +/- 1.91 hours). The percentage of TCF penetration (AUCTCF/AUCserum) was greater after multiple doses (95.76 +/- 6.79%) than after a single dose (55.55 +/- 6.79%) and was not different between doses of 11 and 23 mg/kg. Both dosing regimens of ciprofloxacin resulted in continuous serum and TCF concentrations greater than 90% of the minimal inhibitory concentration for the aerobic and facultative anaerobic clinical isolates tested, including Pseudomonas aeruginosa.

Physiologic features of the canine esophagus: effects of tranquilization on esophageal motility.

Esophageal motility was studied in clinically normal dogs. Mean values as to the time and pressure functions of esophageal peristaltic pressure curves are presented. Effects of two dosage levels of tranquilization on the time and pressure functions are reported.

Three patients with the osteochondrodysplasia and hypertrichosis syndrome--Cantu syndrome.

Cantu syndrome is a rare condition whose main features are hypertrichosis, cardiac anomalies and wide ribs. Four children have been described and we now present details of a further three. The parents of one of these are first cousins, adding weight to Cantu's theory that the condition is an autosomal recessive disease.

Diagnosis of food allergy in dogs.

The diagnosis of food allergy was confirmed in 51 dogs while the responsiveness to a 60-day home-cooked restricted dietary trial (elimination-diet trial) was evaluated. The primary clinical sign of allergy detected and evaluated in all dogs was persistent and nonseasonally pruritic skin disease. The duration of time between starting the elimination-diet trial and remission of clinical signs was recorded. Dogs were then reexposed to diets that had been fed before testing, and the duration of time before pruritus recurred was recorded. The elapsed time during which dogs were being fed an elimination diet before remission of clinical signs was 1 to 3 weeks in 13 dogs, 4 to 6 weeks in 25 dogs, 7 to 8 weeks in 10 dogs, and 9 to 10 weeks in 3 dogs. Findings indicated that the recommendation of a 3-week elimination-diet trial for diagnosis of food allergy was adequate for only 25% of the dogs. It is recommended that test diets be fed for at least 10 weeks before a food allergy is ruled out.