Zonal distribution of glomerular collapse in renal allografts: possible role of vascular changes

Collapsing glomerulopathy (CG), an aggressive variant of focal segmental glomerular sclerosis, is a renal disease with severe proteinuria and rapidly progressive renal failure. The pathogenesis of CG is unknown. It strongly resembles human immunodeficiency virus (HIV)-associated nephropathy, but the patients are HIV negative. The characteristic glomerular lesion is capillary loop collapse with prominent podocytes filling Bowman's space. Interestingly, these glomerular changes are usually associated with severe tubulointerstitial injury, including tubular epithelial degenerative changes, microcystic dilation of several tubules, and interstitial inflammatory cell infiltrate. Recently, it became evident that the morphologic pattern of CG may appear not only in native kidneys, but also de novo in renal allografts, and that the pattern of CG in renal transplants is not always associated with severe proteinuria. Studies describing CG in renal allografts are all based on biopsies. We report 3 allograft nephrectomy specimens that showed a zonal distribution of the characteristic collapsing glomerular changes with associated tubulointerstitial injury. All 3 kidneys had obliterative vascular changes. One nephrectomy specimen had chronic obliterative transplant arteriopathy, 1 had acute vascular rejection, and 1 had thrombotic microangiopathy. None of the patients had severe proteinuria. Our cases suggest that the morphologic pattern of CG in renal allografts may not represent the same disease process as CG in native kidneys and provide further evidence that collapsing glomerular changes do not define the disease entity of CG, but rather represent a pattern of renal injury. Among other factors, hemodynamic disturbance may play a role in the development of the pattern of CG in renal allografts.     

Heme oxygenase isoform-specific expression and distribution in the rat kidney

BACKGROUND: The heme oxygenase (HO) genes, HO-1 and HO-2, are the limiting steps in heme degradation and in the regulation of renal heme-dependent enzymes. Previously we reported that selective overexpression of renal HO-1 resulted in a decrease of microsomal heme and the cytochrome P450-dependent arachidonic acid metabolite, 20 HETE, a vasoconstrictor. The present study was undertaken to explore the relative expression and contribution of each of the HO isoforms to HO activity in the rat kidney. METHODS AND RESULTS. Renal HO activity increased above control levels after an injection of the inducers of HO activity, heme or SnCl2. Stannous Mesoporphyrin (SnMP), a nonselective inhibitor of HO, when used alone or in combination with heme or SnCl2, decreased HO activity. Heme alone and combined with SnCl2 decreased the levels of heme content by 13 and 35%, respectively. Western blot analysis showed that both SnCl2 and heme readily induced HO-1 protein, whereas HO-2 was constitutively expressed. Immunohistochemistry showed the distribution of the HO-1 isoform primarily in proximal convoluted tubules. Western blot analysis exhibited relatively higher levels of HO-1 in isolated proximal tubules and relatively higher HO-2 levels in the thick ascending limbs of the loop of Henle and preglomerular arterioles. In vivo administration of HO-1 and HO-2 antisense oligodeoxynucleotides further confirmed that HO-2, but not HO-1, contributed to the basal HO activity; however, following induction of HO with heme, antisense to HO-1, but not to HO-2, inhibited the induced levels of HO activity. CONCLUSION: These results suggest that HO-2 is constitutively expressed in the rat kidney mainly within tubular and arteriolar structures, and its activity may modulate physiological function under basal conditions. On the other hand, the basal levels of expression of HO-1 in the rat kidney are relatively low, and its contribution to HO activity and the regulation of hemoproteins such as cytochrome P450 become apparent only under pathophysiological conditions causing HO induction.     

A comparison of the laryngeal tube-S and Proseal laryngeal mask during outpatient surgical procedures

BACKGROUND AND OBJECTIVE: The Laryngeal Tube Sonda (LTS) and the ProSeal Laryngeal Mask Airway (PLMA) are two new devices introduced for maintaining the airway during controlled ventilation under general anaesthesia. The present investigation compared their performance in a randomized controlled study. METHODS: One hundred ASA I-II patients, aged 18-60 yr undergoing elective minor surgery, were randomized to receive either an LTS (n = 50) or PLMA (n = 50) for airway management. After induction of general anaesthesia, the devices were inserted, its correct placement was verified and airway leak pressure was measured. Ease of insertion, quality of airway seal, fibre-optic view and postoperative pharyngeal morbidity were examined. RESULTS: There were no differences in patient characteristics for both groups. First-time and second-time success rates were comparable for both groups (86 vs. 88% and 96 vs. 98% in LTS and PLMA groups, respectively). The airway of one patient in each group could not be managed with these devices after three attempts. Time until delivery of first tidal volume for LTS and PLMA was 24.5 +/- 6.9 and 28.8 +/- 10.3 s. Fixation and manipulation time was 54.9 +/- 15.2 and 73.2 +/- 25 s, respectively (P < 0.05). Airway seal pressure (cm H(2)O) for LTS and PLMA was 20 +/- 8.6 and 24.1 +/- 10.8, respectively (P = 0.04). Patients were questioned on a variety of postoperative pharyngeal morbidities. Only hoarseness was more frequent in the LTS group. CONCLUSIONS: Both devices provide a secure airway, are similar in clinical utility and are easy to insert. Better airway seal was detected in the PLMA group.     

Home glucometer monitoring markedly improves diagnosis of post renal transplant diabetes mellitus in renal transplant recipients

BACKGROUND: Definitions of de novo posttransplant diabetes mellitus (PTDM) have varied widely in the renal transplant literature, and most have not used the American Diabetes Association (ADA) definition of diabetes (fasting plasma glucose [FPG] > or = 126 mg/dl on two occasions, or a casual plasma glucose level >200 mg/dl). Most patients are monitored for PTDM by 12-hour FPG levels drawn for clinic visits. In contrast, we describe the diagnosis of PTDM by home glucometer monitoring METHODS: We screened 89 consecutive nondiabetic renal transplant recipients for PTDM by ADA criteria and home glucometer monitoring during the first 3 months posttransplant RESULTS: Of 23 patients with impaired fasting glucose levels of 111-126 mg/dl, 14 (61%) met ADA criteria for diabetes mellitus of based on home glucometer monitoring. The incidence of de novo PTDM was 31% during this period. Predictors of PTDM in a Cox proportional hazards model were race and acute rejection, with a trend towards BMI. Clinic visit FPG levels did not differ between PTDM and non-PTDM patients. All diagnoses were made based on prelunch or supper FPG >200 mg/dl. CONCLUSIONS: Overnight FPG are inadequate for diagnosis of PTDM. All renal transplant recipients with impaired FPG should, at minimum, have home FPG testing.     

Photodynamic therapy of head and neck basal cell carcinoma according to different clinicopathologic features

BACKGROUND AND OBJECTIVES: We aimed to treat different pathologic types of basal cell carcinomas (BCCs) using photodynamic therapy (PDT). STUDY DESIGN/MATERIALS AND METHODS: Thirty lesions in six patients underwent PDT. The photosensitizer used was Photoheme, a hematoporphyrin derivative IX. It was injected intravenously at the dose of 2-3.25 mg/kg. After 24 hours, the lesions were illuminated by laser light (lambda = 632 nm, light exposure dose = 100-200 J/cm2). Lesions were evaluated pre and post-operatively and at follow-up sessions (of up to 6 months). RESULTS: After a single session of PDT, the average response rate in different histopathologic kinds of basal cell carcinoma (e.g., ulcerative, superficial, nodular, and pigmented forms) were 100%, 62%, 90%, and 14%, respectively. In patients who responded completely, the cosmetic results were excellent and there were no recurrence at 6th month of follow-up. CONCLUSION: Although PDT seems to be an effective treatment modality for superficial, ulcerative, and nodular BCCs, it is not recommended for pigmented lesions.     

The influence of the polymerization approach on the catalytic performance of novel porous poly (ionic liquid)s for green synthesis of pharmaceutical spiro-4-thiazolidinones

Although poly (ionic liquids) (PILs) have attracted great research interest owing to their various applications, the performance of nanoporous PILs has been rarely developed in the catalysis field. To this end, a micro–mesoporous PIL with acid–base bifunctional active sites was designed and fabricated by two different polymerization protocols including hydrothermal and classical precipitation polymerization in this paper. Based on our observations, hydrothermal conditions (high temperature and pressure) enabled the proposed sonocatalyst to possess a great porous structure with a high specific surface area (S_BET: 315 m² g⁻¹) and thermal stability (around 450 °C for 45% weight loss) through strengthening cross-linking. In a comparative study, the preferred nanoporous PIL was selected and utilized as the sonocatalyst in a multicomponent reaction of isatins, primary amines, and thioglycolic acid. In the following, a variety of new and known pharmaceutical spiro-4-thiazolidinone derivatives were synthesized at room temperature and obtained excellent yields (>90%) within short reaction times (4–12 min) owing to the substantial synergistic effect between ultrasound irradiation and magnetically separable catalyst.

Sustainable synthesize of a new mesoporous poly (ionic liquid) as acid–base bifunctional catalyst for environmental being preparation of monospiro derivatives has been developed.     

The Incidence of Primary vs Secondary Focal Segmental Glomerulosclerosis: A Clinicopathologic Study

Objectives

To describe the change in the incidence rates of primary and secondary focal segmental glomerulosclerosis (FSGS) from 1994 through 2013 in Olmsted County, Minnesota, and to identify the clinical and biopsy characteristics that distinguish primary from secondary FSGS.

Cartilage engineering from ovine umbilical cord blood mesenchymal progenitor cells

We aimed to determine whether three-dimensional (3D) cartilage could be engineered from umbilical cord blood (CB) cells and compare it with both engineered fetal cartilage and native tissue. Ovine mesenchymal progenitor cells were isolated from CB samples (n=4) harvested at 80-120 days of gestation by low-density fractionation, expanded, and seeded onto polyglycolic acid scaffolds. Constructs (n=28) were maintained in a rotating bioreactor with serum-free medium supplemented with transforming growth factor-beta1 for 4-12 weeks. Similar constructs seeded with fetal chondrocytes (n=13) were cultured in parallel for 8 weeks. All specimens were analyzed and compared with native fetal cartilage samples (n=10). Statistical analysis was by analysis of variance and Student's t-test (p<.01). At 12 weeks, CB constructs exhibited chondrogenic differentiation by both standard and matrix-specific staining. In the CB constructs, there was a significant time-dependent increase in extracellular matrix levels of glycosaminoglycans (GAGs) and type-II collagen (C-II) but not of elastin (EL). Fetal chondrocyte and CB constructs had similar GAG and C-II contents, but CB constructs had less EL. Compared with both hyaline and elastic native fetal cartilage, C-II and EL levels were, respectively, similar and lower in the CB constructs, which had correspondingly lower and similar GAG levels than native hyaline and elastic fetal cartilage. We conclude that CB mesenchymal progenitor cells can be successfully used for the engineering of 3D cartilaginous tissue in vitro, displaying select histological and functional properties of both native and engineered fetal cartilage. Cartilage engineered from CB may prove useful for the treatment of select congenital anomalies.     

Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1‐related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non‐NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.