Myeloproliferative neoplasms cause glomerulopathy

Myeloproliferative neoplasms are clonal hematopoietic stem cell disorders that can produce an undefined glomerulopathy. To better characterize the glomerular disease associated with myeloproliferative neoplasms, we evaluated features of 11 patients with myeloproliferative neoplasm-related glomerulopathy that included 8 patients with primary myelofibrosis, and 1 each with chronic myelogenous leukemia, polycythemia vera, and essential thrombocythemia. Indications for biopsy were nephrotic-range proteinuria (nephrotic syndrome in four) and chronic renal insufficiency. The mean time from diagnosis of the neoplasms to biopsy was 7.2 years. Histologically, mesangial sclerosis and hypercellularity were seen in all 11 cases, segmental sclerosis in 8, features of chronic thrombotic microangiopathy in 9, and intracapillary hematopoietic cells in 4. On follow-up, seven patients had persistent renal dysfunction and four progressed to end-stage renal disease (ESRD). Thus, glomerulopathy appears to be a late complication of myeloproliferative neoplasms, particularly primary myelofibrosis, with guarded prognosis. Greater awareness of this entity and larger studies are needed to define possible therapies.     

Dense Deposit Disease: Clinicopathologic Study of 32 Pediatric and Adult Patients

Background and objectives: Dense deposit disease (DDD) is a rare disorder that most commonly affects children. This study reports the largest North American series addressing clinicopathologic and outcome differences in children and adults.Design, setting, participants, & measurements: Thirty-two patients with DDD were analyzed from the archives of Columbia University between 1977 and 2007. Characteristic intramembranous electron-dense deposits defined all diagnoses.Results: The cohort included 14 children (<16 yr) and 18 adults, with 39% of adults >60 yr. The female/male ratio was 1.9. At presentation, the mean 24-h urine protein was 4.6 g, nephrotic syndrome was present in 33%, renal insufficiency in 59%, and hematuria in 87% of patients. Compared with adults, children had lower incidence of renal insufficiency and were more likely to have reduced C3. Histologic pattern included membranoproliferative, mesangial, endocapillary, and crescentic glomerulonephritis. Treatment included immunosuppression (IS) alone in seven, renin angiotensin system (RAS) blockade alone in six, and combined IS/RAS blockade in 11. On follow-up (mean 63 mo) available in 27 patients, 26% had complete response, 48% had persistent renal dysfunction, and 26% had ESRD. Correlates of ESRD were older age and higher creatinine at biopsy, the absence of combined IS/RAS blockade therapy and the presence of subepithelial humps, but not histologic pattern. On multivariate analysis, age and creatinine emerged as the only independent predictors of ESRD.Conclusions: DDD is clinically and pathologically heterogeneous. Adults have worse outcome than children, despite similar treatment. Combined IS/RAS blockade appears superior to either agent alone.Dense deposit disease (DDD) is a glomerular disease defined at the electron microscopic level by a transformation of the lamina densa of the glomerular basement membrane by ribbon-like, highly electron-dense material, which by immunofluorescence stains predominantly for C3. The disease was first recognized in France in 1963 by Galle (1). For many years, DDD was also called membranoproliferative GN (MPGN) type II. Because recent studies have indicated that the light microscopic pattern in most patients is not membranoproliferative, the modern trend is to consider DDD a distinct entity, rather than a variant of MPGN (2,3). The rarity of DDD, which afflicts only two to three individuals per million population (4), has impeded studies into its clinical course and optimal treatment. The disease has a Caucasian racial predominance and is most commonly seen in children and adolescents (5,6). Its natural history is variable, but approximately 50% of patients progress to ESRD within 8 to 10 yr (6,7). Animal and human studies indicate that the pathophysiologic basis of DDD is an uncontrolled systemic activation of the alternative complement pathway because of the presence of an autoantibody to C3 convertase, mutations in the factor H gene, or the presence of an autoantibody to factor H (4). Why the glomerulus is preferentially affected is unknown, although the physical stresses of glomerular filtration are likely to play a role in local complement activation.Although several studies of DDD were performed before 1990 (5–14), there has been only a single study in recent years evaluating the clinical characteristics and course of the disease (15). Particularly little is known about the course in adults, and only one study published in 1983 compared the features of DDD in children and adults (6). Herein, we report the largest North American series addressing the clinicopathologic characteristics and outcome in patients with DDD. Thirty-two patients, including 14 children and 18 adults, were studied with particular emphasis on identifying clinical, pathologic, and outcome differences between these age groups.     

Human platelet antigen 1, 2 and 5 gene polymorphisms in Egyptians and their potential association with susceptibility to immune thrombocytopenic purpura in Egyptian patients

Objectives: This study determined the incidence of HPA1, HPA2 and HPA5 polymorphisms in 120 Egyptian immune thrombocytopenic purpura (ITP) patients and 120 healthy Egyptian subjects.

Methods: Human platelet antigen (HPA) genotyping was done using the polymerase chain reaction-restriction fragment length polymorphism.

Results: The frequency of HPA1 allele a and b was 78.75 and 21.25% in controls, 80.8 and 19.2% in ITP, respectively. HPA2 allele a and b frequency was 86.25 and 13.75% in controls and of 74.6 and 25.4% in patients, respectively. HPA5 allele a and b frequency was 87.5 and 12.5% in controls, in patients it was 85 and 15%, respectively. With the exception of HPA2, no other significant difference was encountered in HPA allele frequency between controls and ITP patients.

Discussion: Egyptian HPA profile is closely linked to Middle East and neighboring Arabs. The current study noted that in all the studied HPA systems 1, 2 and 5, the ‘a’ allele is more prevalent than the b allele; the most frequent genotype was the homozygous a/a genotype. HPA2b frequency, homo- and hetero-zygous HPA2b genotype frequencies were significantly higher in ITP patients compared to controls.

Conclusion: HPA 2b are 2.37 times more likely to develop ITP compared to those without this allele. The relatively high allele frequency of the HPA-1b in the Egyptian population suggests that this ethnic group has a higher risk of alloimmunization.     

Safety of Carotid Canal during Transtympanic Dilatation of the Eustachian Tube: A Cadaver Pilot Study

To assess the safety of Transtympanic balloon dilatation of the cartilaginous proximal Eustachian tube under endoscopic guidance as it relates to the integrity of the carotid canal in cadaver model. Endoscopic guided Transtympanic dilatations of the cartilaginous proximal end of the Eustachian tube were performed in 15 ears of 8 fresh frozen cadaver heads. CT scans were done before and after dilatation. Images were reviewed by two otologists and one radiologist. Balloon catheter placement and dilatation of the proximal Eustachian tube was feasible in all specimens. Endoscopic examination post dilatation showed a consistent increase in the aperture of the proximal cartilaginous tube in all ears. Review of CT images after dilatation showed no evidence of trauma to the carotid canal in all ears instrumented. Endoscopically guided Transtympanic dilatation of the proximal Eustachian tube is not associated with damage to the carotid canal in cadaver model. Level of Evidence: 4.     

IgA-dominant postinfectious glomerulonephritis: a new twist on an old disease

IgA-dominant acute postinfectious glomerulonephritis (APIGN) is an increasingly recognized morphologic variant of APIGN, particularly in the elderly. In contrast to classic APIGN, in which there is typically glomerular deposition of IgG and C3 or C3 only, IgA is the sole or dominant immunoglobulin in IgA-dominant APIGN. Because the vast majority of reported cases occur in association with staphylococcal infections, the alternative designation 'IgA-dominant acute poststaphylococcal glomerulonephritis' has been applied. Diabetes is a major risk factor, likely reflecting the high prevalence of staphylococcal infection in diabetics, particularly involving skin. Patients typically present with severe renal failure, proteinuria and hematuria. Prognosis is guarded with less than a fifth of patients fully recovering renal function. This variant of APIGN must be distinguished from IgA nephropathy. Features that favor IgA-dominant APIGN over IgA nephropathy include initial presentation in older age or in a diabetic patient, acute renal failure, intercurrent culture-documented staphylococcal infection, hypocomplementemia, diffuse glomerular endocapillary hypercellularity with prominent neutrophil infiltration on light microscopy, stronger immunofluorescence staining for C3 than IgA, and the presence of subepithelial humps on electron microscopy. The pathogenetic mechanism of selective IgA deposition in patients with poststaphylococcal glomerulonephritis likely involves specific host responses to the inciting pathogen.     

Endoscopic transcanal middle ear surgery

The advantages and limitations of the microscope have defined postauricular access as the surgical intervention of choice for the treatment of diseases of the middle ear. The wide-angle view provided by the endoscope enables transcanal access to the tympanic cavity, and its otherwise difficult-to-reach extensions: The attic, sinus tympani, facial recess, and hypotympanum. These areas are the primary sites of disease and surgical failure to cure. The endoscope also allows an all encompassing view of the three main elements in tympanoplasty surgery: The ear canal, tympanic membrane, and the tympanic ring. This report is a summary of the author’s two 17 years of experience with the use of transcanal operative endoscopy as the primary approach to the management of middle ear disease.     

A Polynomial Chaos Expansion Trust Region Method for Robust Optimization

Robust optimization is an approach for the design of a mechanical structure which takes into account the uncertainties of the design variables. It requires at each iteration the evaluation of some robust measures of the objective function and the constraints. In a previous work, the authors have proposed a method which efficiently generates a design of experiments with respect to the design variable uncertainties to compute the robust measures using the polynomial chaos expansion. This paper extends the proposed method to the case of the robust optimization. The generated design of experiments is used to build a surrogate model for the robust measures over a certain trust region. This leads to a trust region optimization method which only requires one evaluation of the design of experiments per iteration (single loop method). Unlike other single loop methods which are only based on a first order approximation of robust measure of the constraints and which does not handle a robust measure for the objective function, the proposed method can handle any approximation order and any choice for the robust measures. Some numerical experiments based on finite element functions are performed to show the efficiency of the method.