Quantifying infection risks in incompatible living donor kidney transplant recipients

Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010 to 2015, categorized by desensitization intensity: none/compatible (n = 260), low (0-4 plasmaphereses, n = 47), moderate (5-9, n = 74), and high (≥10, n = 94). The 1-year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high-intensity desensitization (P < .001). The most common infections were UTI (33.5% of ILDKT vs. 21.5% compatible), opportunistic (21.9% vs. 10.8%), and bloodstream (19.1% vs. 5.4%) (P < .001). In weighted models, a trend toward increased risk was seen in low (wIRR = _0.771.40_2.56,P = .3) and moderately (wIRR = _0.881.35_2.06,P = .2) desensitized recipients, with a statistically significant 2.22-fold (wIRR = _1.332.22_3.72,P = .002) increased risk in highly desensitized recipients. Recipients with ≥4 infections were at higher risk of prolonged hospitalization (wIRR = _2.623.57_4.88, P < .001) and death-censored graft loss (wHR = _1.154.01_13.95,P = .03). Post–KT infections are more common in desensitized ILDKT recipients. A subset of highly desensitized patients is at ultra-high risk for infections. Strategies should be designed to protect patients from the morbidity of recurrent infections, and to extend the survival benefit of ILDKT across the spectrum of recipients.     

Multiple drug resistant non typhoidal salmonella spp associated with acute diarrheal disease

Rectal swabs/stool specimens from 115 children (0–5 years) suffering with acute diarrhea were screened for non typhoidal salmonella species. 7 (6%) patients were found to be positive for non typhoidal salmonella 4 (3.47%) were positive forS. paratyphi B and 3 (2.6%) were positive forS. typhimurium. Multidrug resistance was seen in 57 percent of the strains. All strains were sensitive to Ciprofloxacin. All strains were resistant to Ampicillin followed by Ciprofloxacin. All strains were resistant to Ampicillin followed by Gentamycin (43%), Kanamycin (43%), Tetracycline (43%), Streptomycin (28.5%) and Chloramphenicol (28.5%).     

Tetralogy of Fallot with Absent Pulmonary Valve and Bronchial Compression: Treatment with Endobronchial Stents

Absent pulmonary valve syndrome (APVS) is a rare congenital cardiac lesion. The lesion includes ventricular septal defect, overriding aorta, and absence of the pulmonary valve, with resultant pulmonary incompetence. It has been suggested that the pulmonary incompetence induces intrauterine dilatation of the pulmonary artery, which leads to tracheobronchial compression. One of the presenting features in infants with APVS is severe airway obstruction, which may be difficult to manage. We report an infant who benefited from bilateral endobronchial endoscopic stent placement.     

Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Antihyperlipidemic effect of Eugenia jambolana seed kernel on streptozotocin-induced diabetes in rats.

Abnormalities in lipid profile are one of the most common complications in diabetes mellitus, which is found in about 40% of diabetics. In the present study, anti-hyperlipidemic efficacy of Eugenia jambolana seed kernel (EJs-kernel) was evaluated in streptozotocin (STZ)-induced diabetic rats and the efficacy was compared with standard hypoglycemic drug, glibenclamide. The effect of oral administration of ethanolic extract of EJs-kernel (100 mg/kg body weight) was examined on the levels of cholesterol, phospholipids, triglycerides and free fatty acids in the plasma, liver and kidney tissues of STZ (55 mg/kg body weight)-induced diabetic rats. The plasma lipoproteins and tissues fatty acid composition were also monitored. STZ-induced diabetic rats, showed significant increase in the levels of cholesterol, phospholipids, triglycerides and free fatty acids which were considerably restored to near normal in EJs-kernel or glibenclamide treated animals. The plasma lipoproteins (HDL, LDL, VLDL-cholesterol) and fatty acid composition were altered in STZ-induced diabetic rats and these levels were also reverted back to near normalcy by EJs-kernel or glibenclamide treatment. It may be concluded that, EJs-kernel possesses hypolipidemic effect, which may be due to the presence of flavonoids, saponins, glycosides and triterpenoids in the extract. The hypolipidemic effect mediated by EJs-kernel may also be anticipated to have biological significance and provide a scientific rationale for the use of EJs-kernel as an anti-diabetic plant.     

In vitro and in vivo metabolism of a potent and selective integrin alpha v beta 3 antagonist in rats, dogs, and monkeys.

Compound A (3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyrindin-2-yl)propyl]-imidazolidin-1-yl]-3(S)-(6-methoxy-pyridin-3-yl)-propionic acid), a potent and selective antagonist of integrin alpha(v)beta(3) receptor, is under development for treatment of osteoporosis. This study describes metabolism and excretion of A in vivo in rats, dogs, and monkeys, and metabolism of A in vitro in primary hepatocytes from rats, dogs, monkeys, and humans. In all three animal species studied, A was primarily excreted as unchanged drug and, to a lesser degree, as phase I and phase II metabolites. Major biotransformation pathways of A included glucuronidation/glucosylation on the carboxylic group to form acyl-linked glucuronides/glucosides; and oxidation on the tetrahydronaphthyridine moiety to generate a carbinolamine and its further metabolized products. Minor pathways involved O-demethylation and hydroxylations on the alkyl chain. Only in rats, a glutathione adduct of A was also observed, and its formation is proposed to be via an iminium intermediate on the tetrahydronaphthyridine ring. Similar metabolic pathways were observed in the incubates of hepatocytes from the corresponding animals as well as from humans. CYP 3A and 2D subfamilies were capable of metabolizing A to its oxidative products. Overall, these in vitro and in vivo findings should provide useful insight on possible biotransformation pathways of A in humans.     

Acitretin‐Responsive Ichthyosis in Chanarin–Dorfman Syndrome with a Novel Mutation in the ABHD5/CGI‐58 Gene

Chanarin–Dorfman syndrome (CDS) is a rare nonlysosomal neutral lipid storage disorder characterized by congenital ichthyosis, lipid vacuoles in leukocytes (Jordan's anomaly), and hepatomegaly. The authors herein report an 18‐month‐old boy with ichthyosis and hepatomegaly diagnosed with CDS and confirmed to have a novel c.506–3C>G mutation in the ABHD5/CGI‐58 gene. Our case also illustrates that retinoids such as acitretin could be useful in the treatment of skin manifestations in CDS even in the presence of liver derangement.     

Mice with a conditional deletion of Talpid3 (KIAA0586) – a model for Joubert syndrome

Joubert syndrome (JS) is a ciliopathy associated with mutations in numerous genes encoding cilia components. TALPID3 encoded by KIAA0856 in man (2700049A03Rik in mouse) is a centrosomal protein essential for the assembly of primary cilia. Mutations in KIAA0856 have been recently identified in JS patients. Herein, we describe a novel mouse JS model with a conditional deletion of the conserved exons 11–12 of Talpid3 in the central nervous system which recapitulates the complete cerebellar phenotype seen in JS. Talpid3 mutant mice exhibit key hallmarks of JS including progressive ataxia, severely hypoplastic cerebellar hemispheres and vermis, together with abnormal decussation of the superior cerebellar peduncles. The Purkinje cell layer is disorganised with abnormal dendritic arborisation. The external granule layer (EGL) is thinner, lacks primary cilia, and has a reduced level of proliferation. Furthermore, we describe novel cellular defects including ectopic clusters of mature granule neurons, and abnormal parallel fibre-derived synapses and disorientation of cells in the EGL. The defective glial scaffold results in abnormal granule cell migration which manifests as ectopic clusters of granule neurons. In addition, we show a reduction in Wnt7a expression suggesting that defects may arise not only from deficiencies in the Hedgehog (Hh) pathway but also due to the additional roles of Talpid3. The Talpid3 conditional knockout mouse is a novel JS model which fully recapitulates the JS cerebellar phenotype. These findings reveal a role for Talpid3 in granule precursor cell migration in the cerebellum (either direct or indirect) which together with defective Hh signalling underlies the JS phenotype. Our findings also illustrate the utility of creating conditional mouse models to assist in unravelling the molecular and cellular mechanisms underlying JS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.