Outcomes of bisphosphonate therapy in kidney transplant recipients: a systematic review and meta‐analysis

Mineral and bone disorders that precede kidney transplantation are exacerbated in the post‐transplant setting by tertiary hyperparathyroidism and immunosuppressive regimens. Bone mineral density (BMD) decreases following transplantation, leading to increased fracture risk. The effect of bisphosphonates on fracture is unknown. The aim of this study was to update estimates of change in BMD and fracture rates in bisphosphonate‐treated kidney transplant recipients through meta‐analysis. Studies comparing bisphosphonate therapy to standard of care were included if follow‐up duration was more than 6 months. We performed random‐effects meta‐analysis to determine the effect of bisphosphonates on lumbar spine and femoral neck BMD and fracture rates. Bisphosphonates improved femoral neck and lumbar spine BMD compared with controls (0.055 g/cm², 95% CI 0.012–0.099 and 0.053 g/cm², 95% CI 0.032–0.074, respectively) without adversely affecting serum creatinine or calcium. This corresponded to an unweighted improvement in BMD of 6.0% and 7.4%, respectively. There was no difference in fracture incidence in the two groups. Bisphosphonate therapy in kidney transplant recipients is associated with a statistically significant improvement in BMD at the lumbar spine and femoral neck. There was no difference in fracture incidence. Bisphosphonates did not adversely affect allograft dysfunction or serum calcium levels.     

Wilson's disease presenting as isolated obsessive-compulsive disorder

Wilson's disease (WD) is a genetic neurodegenerative disorder; it exhibits wide heterogeneity in symptoms and usually presents with liver disease and/ or neuropsychiatric manifestations. The common neurological manifestations observed are dysarthria, gait disturbance, dystonia, rigidity, tremor, dysphagia and chorea. The frequent psychiatric manifestations reported are personality and mood changes, depression, phobias, cognitive impairment, psychosis, anxiety, compulsive and impulsive behavior. Isolated obsessive-compulsive disorder (OCD) is a rare presentation of WD. Reported herein is a case of a 17-year-old boy with isolated OCD. He presented to the psychiatrist with symptoms of contamination obsessions and washing compulsions, along with compulsion of repeated feet tapping and was treated with adequate doses of fluoxetine for 6 months but did not improve. Later on, he was diagnosed as a case of WD and showed improvement with chelating and behavior therapy. This implies the importance of the occurrence of isolated psychological symptoms in WD.     

Species differences in bile acids II. Bile acid metabolism

One of the mechanisms of drug‐induced liver injury (DILI) involves alterations in bile acid (BA) homeostasis and elimination, which encompass several metabolic pathways including hydroxylation, amidation, sulfation, glucuronidation and glutathione conjugation. Species differences in BA metabolism may play a major role in the failure of currently used in vitro and in vivo models to predict reliably the DILI during the early stages of drug discovery and development. We developed an in vitro cofactor‐fortified liver S9 fraction model to compare the metabolic profiles of the four major BAs (cholic acid, chenodeoxycholic acid, lithocholic acid and ursodeoxycholic acid) between humans and several animal species. High‐ and low‐resolution liquid chromatography–tandem mass spectrometry and nuclear magnetic resonance imaging were used for the qualitative and quantitative analysis of BAs and their metabolites. Major species differences were found in the metabolism of BAs. Sulfation into 3‐O‐sulfates was a major pathway in human and chimpanzee (4.8%–52%) and it was a minor pathway in all other species (0.02%–14%). Amidation was primarily with glycine (62%–95%) in minipig and rabbit and it was primarily with taurine (43%–81%) in human, chimpanzee, dog, hamster, rat and mice. Hydroxylation was highest (13%–80%) in rat and mice followed by hamster, while it was lowest (1.6%–22%) in human, chimpanzee and minipig. C6‐β hydroxylation was predominant (65%–95%) in rat and mice, while it was at C6‐α position in minipig (36%–97%). Glucuronidation was highest in dog (10%–56%), while it was a minor pathway in all other species (<12%). The relative contribution of the various pathways involved in BA metabolism in vitro were in agreement with the observed plasma and urinary BA profiles in vivo and were able to predict and quantify the species differences in BA metabolism. In general, overall, BA metabolism in chimpanzee is most similar to human, while BA metabolism in rats and mice is most dissimilar from human.     

Hollow Microparticles as a Superior Delivery System over Solid Microparticles for the Encapsulation of Peptides

Purpose

Peptides are gaining significant interests as therapeutic agents due to their high targeting specificity and potency. However, their low bioavailability and short half-lives limit their massive potential as therapeutics. The use of dense, solid particles of biodegradable polymer as a universal carrier for peptides also has its challenges, such as inefficient peptide release and low bioactivity. In this paper, it was established that hollow microparticles (h-MPs) instead of solid microparticles (s-MPs), as peptide carriers, could improve the release efficiency, while better preserving their bioactivity.

Methods

Glucagon like Peptide-1 (GLP-1) was encapsulated as a model peptide. Mass loss, average molecular weight changes, intraparticle pH, polymer-peptide interaction and release studies, together with bioactivity assessment of the peptide for s-MPs and h-MPs were systematically analyzed and evaluated for efficacy.

Results

The intraparticle pH of s-MPs was as low as 2.64 whereas the pH of h-MPs was 4.99 by day 7. Consequently, 93% of the peptide extracted from h-MPs was still bioactive while only 58% of the peptide extracted from s-MPs was bioactive. Likewise, the cumulative release of GLP-1 by day 14 from h-MPs showed a cumulative amount of 88?±?8% as compared to 33?±?6% for s-MPs.

Conclusions

The cumulative release of peptide can be significantly improved, and the bioactivity can be better preserved by simply using h-MPs instead of s-MPs as carriers.

     

Case report of a uniocular topography guided laser-assisted in situ keratomileusis enhancement following an incorrectly treated astigmatic axis

A 23-year-old male presented to us wanting spectacle removal for cosmetic purposes. He underwent bilateral wavefront optimized (WFO) laser-assisted in situ keratomileusis (LASIK) on the Alcon Wavelight^® EX-500 excimer laser with an incorrectly treated astigmatism axis for left eye due to a manual data entry error in the laser. WFO LASIK treats the sphere and cylinder only. LASIK enhancement with topographic-guided ablation resulted in the elimination of all refractive errors and gave excellent results. Wavelight^® topographic-guided treatment can perform two separate layers of correction in the same ablation: The first is to treat the corneal irregularities for the higher order aberration (HOA) removal, the second one meant to treat the sphere and cylinder if indicated.