Quantitative in vivo islet potency assay in normoglycemic nude mice correlates with primary graft function after clinical transplantation

Reliable assays are critically needed to monitor graft potency in islet transplantation (IT). We tested a quantitative in vivo islet potency assay (QIVIPA) based on human C-peptide (hCP) measurements in normoglycemic nude mice after IT under the kidney capsule. QIVIPA was initially tested by transplanting incremental doses of human islets. hCP levels in mice were correlated with the number of transplanted islet equivalents (r(2) = 0.6, P<0.01). We subsequently evaluated QIVIPA in eight islet preparations transplanted in type 1 diabetic patients. Conversely to standard criteria including islet mass, viability, purity, adenosine triphosphate content, or glucose stimulated insulin secretion, hCP in mice receiving 1% of the final islet product was correlated to primary graft function (hCP increase) after IT (r(2)=0.85, P<0.01). QIVIPA appears as a reliable test to monitor islet graft potency, applicable to validate new methods to produce primary islets or other human insulin secreting cells.     

Roll and pitch set-up errors during volumetric modulated arc delivery

Purpose

The purpose of this work was to investigate whether adapting gantry and collimator angles can compensate for roll and pitch setup errors during volumetric modulated arc therapy (VMAT) delivery.

Methods

Previously delivered clinical plans for locally advanced head-and-neck (H&N) cancer (n?=?5), localized prostate cancer (n?=?2), and whole brain with simultaneous integrated boost to 5 metastases (WB + 5M, n?=?1) were used for this study. Known rigid rotations were introduced in the planning CT scans. To compensate for these, in-house software was used to adapt gantry and collimator angles in the plan. Doses to planning target volumes (PTV) and critical organs at risk (OAR) were calculated with and without compensation and compared with the original clinical plan. Measurements in the sagittal plane in a polystyrene phantom using radiochromic film were compared by gamma (γ) evaluation for 2 H&N cancer patients.

Results

For H&N plans, the introduction of 2°-roll and 3°-pitch rotations reduced mean PTV coverage from 98.7 to 96.3?%. This improved to 98.1?% with gantry and collimator compensation. For prostate plans respective figures were 98.4, 97.5, and 98.4?%. For WB + 5M, compensation worked less well, especially for smaller volumes and volumes farther from the isocenter. Mean comparative γ evaluation (3?%, 1 mm) between original and pitched plans resulted in 86?% γ <?1. The corrected plan restored the mean comparison to 96?% γ <?1.

Conclusion

Preliminary data suggest that adapting gantry and collimator angles is a promising way to correct roll and pitch set-up errors of <?3° during VMAT for H&N and prostate cancer.

     

The Effect of Roux-en-Y Gastric Bypass Surgery in Morbidly Obese Patients on Pharmacokinetics of (Acetyl)Salicylic Acid and Omeprazole: the ERY-PAO Study

Background

Data on the absorption of orally administered drugs following Roux-en-Y gastric bypass (RYGB) surgery in obese patients are limited and inconclusive. As it is difficult to predict changes in absorption, studies on frequently used drugs in this population are necessary. Acetylsalicylic acid (ASA) and omeprazole are two commonly prescribed drugs in obese patients.

Methods

In this repeated measures study, omeprazole and salicylic acid (SA) serum concentrations were measured before and after RYGB in 34 morbidly obese subjects. Time to maximum concentration (Tmax), lag time (Tlag), maximum concentration (Cmax), and area under the serum concentration versus time curve (AUC) were calculated for both drugs to determine possible differences in drug absorption after the procedure.

Results

For SA, Tmax significantly decreased after RYGB, while both Cmax and AUC_0–24 significantly increased. For omeprazole, both Tmax and Tlag significantly decreased after RYGB, while Cmax significantly increased. Mean AUC_0–12 significantly decreased post-surgery. The difference in AUC_0–12 before and after surgery varied between subjects.

Conclusions

Our study shows a faster absorption of both ASA and omeprazole after RYGB. The exposure to ASA is higher post-surgery, but the standard dose of 80 mg does not need to be modified, considering its range in effective dose. The exposure to omeprazole is, on average, decreased after surgery. Clinicians should be aware to increase the dose of omeprazole if symptoms suggest inadequate response.

     

Hearing impairment in Dutch patients with connexin 26 (GJB2) and connexin 30 (GJB6) mutations

OBJECTIVE: Despite the identification of mutations in the connexin 26 (GJB2) gene as the most common cause of recessive nonsyndromic hearing loss, the pattern of hearing impairment with these mutations remains inconsistent. Recently a deletion encompassing the GJB6 gene was identified and hypothesized to also contribute to hearing loss. We hereby describe the hearing impairment in Dutch patients with biallelic connexin 26 (GJB2) and GJB2+connexin 30 (GJB6) mutations. METHODS: The audiograms of patients who were screened for GJB2 and GJB6 mutations were analysed retrospectively. Standard statistical testing was done for symmetry and shape, while repeated measurement analysis was used to assess the relation between mutation and severity. Progression was also studied via linear regression analysis. RESULTS: Of 222 hearing-impaired individuals, 35 exhibited sequence variations; of these 19 had audiograms for study. Hearing loss in patients with biallelic "radical" (i.e. deletions, nonsense and splice site) mutations was significantly worse than in the wild type and heterozygotes (SAS proc GENMOD, p=0.013). The presence of at least one missense mutation in compound heterozygotes tends to lead to better hearing thresholds compared to biallelic radical mutations (p=0.08). One patient with the [35delG]+[del(GJB6-D13S1830)] genotype was severely impaired. Non-progressive hearing impairment was demonstrated in five 35delG homozygotes in individual longitudinal analyses. However a patient with the [299A>C]+[416G>A] genotype showed significant threshold progression in the lower frequencies. Findings on asymmetry and shape were inconclusive. CONCLUSIONS: Our data support the hypothesis that severity is a function of genotype and its effect on the amino acid sequence. A bigger cohort is required to establish non-progressivity more definitively.     

Cholestatic pruritus: a retrospective analysis on clinical characteristics and treatment response

Background: Chronic cholestatic pruritus (ChP) is caused by various hepatobiliary disorders. This retrospective study describes the distribution of underlying diseases, clinical characteristics and treatment efficacy in a consecutive collective of patients with ChP. Patients and methods: Extensive data from 60 patients with ChP (30 women, 30 men; mean age: 58.0 ± 17.0 years) were retrospectively statistically analyzed concerning demographic data, pruritus characteristics, and response to therapy. Results: In this study population, 40.0% of the patients suffered from hepatitis B or C. Regarding the overall population, pruritus started in 50% of patients after diagnosis of the underlying hepatobiliary disorder. Only in patients with immune‐mediated liver diseases did pruritus more often occur before diagnosis (p < 0.05). Only 23.3% of the patients reported an initial palmoplantar pruritus. Along with other drugs, anticonvulsants proved to be an effective treatment regime. Conclusions: In this study, viral pathogenesis was the most common cause of ChP. Other underlying diseases were represented to a lower extent in the total study population. Overall, the collected clinical parameters in each group were comparable. Thus, it was difficult to draw conclusions on the pathogenesis.     

B-cell chronic lymphocytic leukaemia cells express and release transforming growth factor-β

Summary Transforming growth factor-β (TGF-β) has been described as a potent inhibitor of various cell types, among others of primitive haematopoietic progenitors in vitro, and as a negative autocrine regulator of normal B lymphocyte growth and differentiation. In the present study we investigated TGF-β gene expression in peripheral blood mononuclear cells (PBMC) and in B cells from patients with B-cell chronic lymphocytic leukaemia (B-CLL) and from normal controls. Monocyte depleted B-CLL cells expressed constitutively mRNA for TGF-β1 and secreted low amounts of TGF-β activity into the culture medium. Stimulation of cells by phorbol ester noticeably enhanced mRNA levels as well as protein secretion in most cases. TGF-β activity was of the same magnitude as in normal controls. We next analysed TGF-β in highly enriched B lymphocytes from B-CLL (95100% CD19+), and found that TGF-β secretion was up to 3 times higher than in the original PBMC population. It is discussed that B-CLL cells might escape from negative regulation by TGF-β and, on the other hand, inhibit normal haematopoietic cell proliferation and thereby achieve a growth advantage in the haematopoietic tissues.     

Prevalence of lactose malabsorption among patients with functional bowel disorders

To investigate the prevalence of lactose malabsorption among patients with functional gastrointestinal disturbances we prospectively evaluated all patients referred to a gastrointestinal outpatient clinic over a period of 18 months. All patients had a breath hydrogen test following oral lactose in addition to the standard diagnostic procedures. In 37 of the total of 64 patients no organic cause of the gastrointestinal complaints was found. In 9 of these 37 patients (24%) the breath hydrogen test indicated lactose malabsorption. Three to 6 month later most of the patients with lactose malabsorption showed a significant reduction of gastrointestinal complaints after they had maintained a lactose-poor diet. In comparison, patients with functional disturbances but without lactose malabsorption reported nor or only minor improvement of symptoms; most of these patients had consulted another physician since the last visit in the clinic.     

Whole genome sequencing identifies variants associated with sarcoidosis in a family with a high prevalence of sarcoidosis

Clinical Rheumatology - We studied genetic risk factors associated with sarcoidosis within a family with a high prevalence of this disease. We studied 41 members of a family with a high rate of...     

Leflunomide

Leflunomide is a low-molecular weight, synthetic, oral agent specifically developed for immunosuppression. Because of activity in animal models, leflunomide was tested in rheumatoid arthritis(RA). These investigations have demonstrated that leflunomide reduces the clinical symptoms and signs of RA, improves health related quality of life, and retards structural damage. Leflunomide has been evaluated in RA patients as monotherapy and in combination with methotrexate. Close monitoring for adverse events with particular attention for monitoring liver enzymes for hepatic toxicity is important during treatment with leflunomide.