Utility of high-resolution ultrasound for the diagnosis of dialysis-related amyloidosis.

OBJECTIVE. To evaluate the utility of real-time, high-resolution ultrasound of the shoulder in the diagnosis of dialysis-related amyloidosis. METHODS. We performed a case series study of 2 groups of patients seen at a referral-based clinic in a tertiary care hospital. The shoulders of 13 patients with normal renal function and of 38 patients receiving long-term hemodialysis were studied by real-time, high-resolution ultrasound. All hemodialysis patients were evaluated clinically for the presence of dialysis-related amyloidosis. Surgical specimens of joints were available for all 13 patients with normal renal function and for 17 of the 38 hemodialysis patients. These specimens were evaluated for the presence of beta 2-microglobulin (beta 2m) amyloid by Congo red and immunohistochemical staining. RESULTS. Two ultrasonographic findings were selectively observed in the dialysis patients with clinical and histologic evidence of beta 2m amyloid in comparison with patients with normal renal function and no evidence of amyloid: rotator cuffs greater than 8 mm in thickness and echogenic pads between muscle groups of the rotator cuff. The presence of at least 1 of these 2 findings corresponded to the presence of clinically and histologically evident beta 2m amyloid with a sensitivity of 79% and a specificity of 100%. When additional patients without surgical specimens for histologic confirmation of amyloidosis were included, the sensitivity of these 2 sonographic findings was 72% and the specificity was 97%. CONCLUSION. Real-time, high-resolution ultrasound is a relatively sensitive and highly specific noninvasive adjunct to the clinical diagnosis of beta 2m amyloidosis in patients receiving long-term hemodialysis.     

The major histocompatibility complex region marked by HSP70-1 and HSP70- 2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat- shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.     

Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia

Allogeneic hematopoietic stem cell transplantation is the only curative therapy for myelodysplasia (MDS). To identify factors influencing transplantation outcome, we studied 452 recipients of HLA-identical sibling transplants for MDS from 1989 to 1997, reported to the International Bone Marrow Transplant Registry. Patients with treatment-related MDS or unclassified MDS were excluded. Median age was 38 years (range, 2-64 years). Sixty percent had refractory anemia with excess blasts (n = 136) or with excess blasts in transformation (n = 136). Conditioning regimens included total body irradiation in 199 (44%) cases. Marrow was T-cell depleted for 58 (13%) transplants. Cumulative incidences of neutrophil engraftment, grades II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were 91% (95% confidence interval [CI], 88%-93%), 36% (95% CI, 31%-40%), and 39% (95% CI, 33%-44%), respectively. Three-year transplantation-related mortality (TRM), relapse, disease-free survival, and overall survival rates were 37% (95% CI, 32%-42%), 23% (95% CI, 19%-27%), 40% (95% CI, 36%-45%), and 42% (95% CI, 37%-47%), respectively. Multivariate analyses showed that young age and platelet counts higher than 100 x 10(9)/L at transplantation were associated with lower TRM and higher disease-free and overall survival rates. Relapse incidence was higher in patients with high percentages of blasts in the marrow at transplantation or presentation, with high International Prognostic Scoring System scores at diagnosis, and with T-cell-depleted transplants. These findings indicate that transplantation from an HLA-identical sibling offers the possibility of long-term, disease-free survival to patients with MDS. Best candidates are younger patients with a low percentage of blasts and preserved platelet counts.     

Securing sustainable funding for viral hepatitis elimination plans

The majority of people infected with chronic hepatitis C virus (HCV) in the European Union (EU) remain undiagnosed and untreated. During recent years, immigration to EU has further increased HCV prevalence. It has been estimated that, out of the 4.2 million adults affected by HCV infection in the 31 EU/ European Economic Area (EEA) countries, as many as 580 000 are migrants. Additionally, HCV is highly prevalent and under addressed in Eastern Europe. In 2013, the introduction of highly effective treatments for HCV with direct‐acting antivirals created an unprecedented opportunity to cure almost all patients, reduce HCV transmission and eliminate the disease. However, in many settings, HCV elimination poses a serious challenge for countries’ health spending. On 6 June 2018, the Hepatitis B and C Public Policy Association held the 2nd EU HCV Policy summit. It was emphasized that key stakeholders should work collaboratively since only a few countries in the EU are on track to achieve HCV elimination by 2030. In particular, more effort is needed for universal screening. The micro‐elimination approach in specific populations is less complex and less costly than country‐wide elimination programmes and is an important first step in many settings. Preliminary data suggest that implementation of the World Health Organization (WHO) Global Health Sector Strategy on Viral Hepatitis can be cost saving. However, innovative financing mechanisms are needed to raise funds upfront for scaling up screening, treatment and harm reduction interventions that can lead to HCV elimination by 2030, the stated goal of the WHO.     

Timing of diagnosis of 47,XXY and 48,XXYY: A survey of parent experiences

47,XXY/Klinefelter syndrome is the most common sex chromosomal aneuploidy, yet 64% of males with this condition go undiagnosed. 48,XXYY is less common and there is less known about the diagnosis. The objective of this study is to describe the diagnosis experiences of parents of males with 47,XXY and 48,XXYY. Parents of 89 males with 47,XXY and 76 males with 48,XXYY completed a survey that gathered data about their experiences leading to a diagnosis, including the current age of the child, age at diagnosis, reasons for initial concern, and the specialists providing the diagnosis. In the 47,XXY cohort diagnosed postnatally, 59% presented with developmental delay, with a mean age at first parental concern of 5.2 years and mean age of diagnosis at 10.0 years. The remaining 41% presented with endocrinologic issues with a mean age at first concern of 19.1 years and mean age of diagnosis at 21.1 years. In the 48,XXYY group, 93% presented with developmental delay, with mean age at first parental concern of 2.4 years and mean age of diagnosis at 7.6 years. Hence, the average time from initial parental concern to diagnosis of 47,XXY or 48,XXYY ranges from 2 to 5 years, with those presenting with developmental issues having a longer lag to diagnosis compared to those presenting with endocrinologic issues. Increased awareness of the developmental, psychological, and medical features of 47,XXY and 48,XXYY is important to facilitate timely diagnosis and initiation of appropriate screenings and treatments that are important for optimal outcomes. © 2013 Wiley Periodicals, Inc.