Epidemiological Approach to Identifying Genetic Predispositions for Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is caused by several susceptibility genes. A registry including analyses of susceptibility genes, familial occurrence and genotype-phenotype correlation should provide classification insights.
Registry data of 187 unrelated index patients included age at onset, gender, family history, relapse of aHUS and potentially triggering conditions. Mutation analyses were performed in the genes CFH , CD46 and CFI and in the six potential susceptibility genes, FHR1 to FHR5 and C4BP .
Germline mutations were identified in 17% of the index cases; 12% in CFH , 3% in CD46 and 2% in CFI . Twenty-nine patients had heterozygous mutations and one each had a homozygous and compound heterozygous mutation. Mutations were not found in the genes FHR1-5 and C4BP . In 40% of the patients with familial HUS a mutation was found. Penetrance by age 45 was 50% among carriers of any mutation including results of relatives of mutation-positive index cases. The only risk factor for a mutation was family history of HUS (p = 0.02).
P enetrance of aHUS in carriers of mutations is not complete. Occurrence of homo- and heterozygous mutations in the same gene suggests that the number of necessary DNA variants remains unclear. Among clinical information only familial occurrence predicts a mutation.     

CT‐guided aspiration cytology of advanced silicosis and confirmation of the deposited zeolite nano particles through X ray diffraction: A novel approach

Silicosis is a common occupational lung disease, resulting in fibrotic nodular lesions in the upper lobes of the lung parenchyma. Most of the pneumoconioses are diagnosed on the basis of relevant history and clinico‐radiological correlation. Image‐guided aspiration cytology appears to be poorly yielding and is not usually considered as a diagnostic modality. However, silicosis may sometimes offer a diagnostic challenge because of its radiological resemblance and clinical overlap with pulmonary tuberculosis and neoplastic lesions. We present a unique situation where image‐guided fine needle aspiration cytology (FNAC) has been advised on the basis of nodular upper lobe opacities. The cytology smears revealed hypocellular granular material, while phase contrast and polarized light microscopy highlighted crystalline particles. History of silica dust exposure long back was available after the cytological evaluation, suggesting the diagnosis of pulmonary silicosis. X ray diffraction (XRD) crystallography was also possible on cytology smears, confirming zeolite nano particles of size as small as 40 ? 50 nm as the concerned agent for the first time. Cytological evaluation by phase contrast and polarized light microscopy may be useful for the confirmation of silicosis, supplemented by clinical history and radiological evaluation. XRD on smears may help in determination of chemical nature and particle size. Diagn. Cytopathol. 2016;44:246–249. © 2015 Wiley Periodicals, Inc.     

Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11

In a large collaborative screening project, 370 men with idiopathic azoospermia or severe oligozoospermia were analysed for deletions of 76 DNA loci in Yq11. In 12 individuals, we observed de novo microdeletions involving several DNA loci, while an additional patient had an inherited deletion. They were mapped to three different subregions in Yq11. One subregion coincides to the AZF region defined recently in distal Yq11. The second and third subregion were mapped proximal to it, in proximal and middle Yq11, respectively. The different deletions observed were not overlapping but the extension of the deleted Y DNA in each subregion was similar in each patient analysed. In testis tissue sections, disruption of spermatogenesis was shown to be at the same phase when the microdeletion occurred in the same Yq11 subregion but at a different phase when the microdeletion occurred in a different Yq11 subregion. Therefore, we propose the presence of not one but three spermatogenesis loci in Yq11 and that each locus is active during a different phase of male germ cell development. As the most severe phenotype after deletion of each locus is azoospermia, we designated them as: AZFa, AZFb and AZFc. Their probable phase of function in human spermatogenesis and candidate genes involved will be discussed.      

Evaluation of a scoring system for predicting lymph node malignancy in ultrasound guided fine needle aspiration practice

Ultrasound‐guided fine needle aspiration (USG‐FNA) has enabled cytopathologists to accurately diagnose smaller or non‐palpable lymph nodes (LN) on a regular basis. Pre‐FNA clinical and ultrasonographic factors, such as a patient's age, ratio of short to long axis diameter (S/L ratio), internal echogenicity, and the vascular pattern of a LN, are reported to be able to predict the benign or malignant nature of a LN. This study is designed to test the formula “0.06 × (age) + 4.76 × (S/L ratio) + 2.15 × (internal echo) + 1.80 × (vascular pattern)” generated from the study of Liao et al. as a scoring system for predicting LN malignancy in a cytopathologist operated USG‐FNA practice. Eighty‐three reports of USG‐FNA of LNs issued between 7/1/2008 and 4/28/2010 were reviewed. Patient's age, S/L ratio, internal echo, and vascular pattern were used to generate scores based on the aforementioned formula. A score of seven was used as a cutoff for predicting benign (<7) and malignant (>7) LNs. FNA cytology diagnosis, flow cytometric analysis as well as subsequent surgical diagnosis in some cases served as gold standard for statistical analysis. Among 46 USG‐FNA of LNs with scores > 7, 38 were malignant and eight were benign. All 37 USG‐FNA of LNs with scores < 7 were proven to be benign. The scoring system achieved 100% sensitivity, 82% specificity, 83% positive predictive value, 100% negative predictive value, and 90% accuracy. Further study of the eight “false‐positive” cases revealed that three of them (37.5%) were found to be malignant in follow‐up FNA and/or surgical biopsy. This scoring system may serve as a complementary tool in determining how aggressive a FNA procedure should be performed, how a FNA sample of LN should be triaged for ancillary study, and how closely a patient with lymphadenopathy should be followed up. Diagn. Cytopathol. 2013;41:1100–1106. © 2011 Wiley Periodicals, Inc.     

Common bile duct calculi: updated experience with dissolution with methyl tertiary butyl ether

The authors describe their experience with methyl tertiary butyl ether (MTBE) in a larger series of patients than previously reported in order to acquaint physicians with both its effectiveness for dissolution of common bile duct calculi and the limitations of its use. Ten patients with 13 biliary calculi underwent percutaneous stone dissolution treatment with the experimental cholesterol solvent, MTBE. Three stones completely dissolved within 30 minutes, seven were reduced in size, and three were visibly unaffected. All stones not completely dissolved were easily extracted by means of a stone basket except for one in a patient taken to surgery. Although MTBE perfusion is an effective technique for management of biliary calculi, practitioners should be aware that its use is quite time consuming and its odor difficult to control.     

Expression of blood group antigens including HLA markers in human adult liver

The localisation of the principal blood group antigens has been studied in human liver. These blood group antigens included the erythrocyte antigens and the antigen of the major histocompatibility complex. This study was performed by the indirect immunofluorescence technique using polyclonal antibodies of human or animal origin and monoclonal antibodies from hybridomas. This study has shown that the normal hepatocyte is lacking in blood group antigens. On the contrary, the biliary cell was rich in antigenic markers: the main antigens expressed were Lewis, Pr, HLA-A and B antigens. In Kupffer cells, only i and HLA-DR antigens were clearly expressed. The endothelial cells of blood vessels mainly show A, B, H, HLA-A and B antigens; HLA-DR and Pr are slightly expressed. HLA-DR antigens were more strongly expressed on veins than on arteries. Dendritic cells have been identified in the portal space of human liver. They bore i and HLA-DR antigens.     

Long-term follow-up patients with leukemia receiving platelet transfusions: identification of a large group of patients who do not become alloimmunized

Alloimmunization is the major complication of platelet transfusion therapy in patients with acute leukemia. To evaluate whether alloimmunization continues to be a long-term problem in patients surviving induction therapy, 114 patients with acute nonlymphocytic leukemia (ANLL) who survived more than 6 mo and who received multiple courses of chemotherapy and abundant platelet transfusions were studied. Clinical response to random donor platelets and lymphocytotoxic antibody (LCTAb) were measured pretreatment and serially throughout the study period. Fourteen patients (12%) were alloimmunized upon admission, 34 (30%) patients became alloimmunized during remission induction therapy, and 66 (58%) patients did not become alloimmunized during that period. Sixty-one of these 66 patients (92%) never became alloimmunized and responded to random donor platelets during their subsequent course despite the fact they received multiple further platelet transfusions, whereas the alloimmunized patients tended to remain alloimmunized for their entire clinical course. There was no difference in age or sex between groups, and prognostic factors predicting alloimmunization could not be detected. In greater than 90% of patients not alloimmunized at admission, the presence or absence of LCTAb after induction predicts later alloantibody production. This information can be used to plan the type of platelet transfusions (HLA-matched or random donor) needed for subsequent maintenance and induction therapy. It may also help to identify a group of patients to whom more aggressive maintenance chemotherapy may be more safely administered.     

Renal Kallikrein Excretion in Alcoholic Cirrhosis

Severe liver disease is often associated with renal hemodynamic changes, and these changes may involve vasoactive hormones. The vasodilatory renal kallikrein-kinin system has received little previous study in these patients. We measured urinary kallikrein in nine patients with alcoholic cirrhosis under rigid metabolic conditions and simultaneously evaluated renin, aldosterone and urinary prostaglandins. Plasma renin und aldosterone were generally increased as expected but urinary kallikrein was surprisingly diminished (13.3 ± 3.7 vs. 38.8 ± 11.1 SE, E.U./day. P < 0.05). despite adequate creatinine clearance (81 ± 9 ml./min.). Administration of prostaglandin inhibitors reduced urinary prostaglandin E by 72% and creatinine clearance by 56% but did not alter urinary kallikrein. Mineralocor-ticoid inhibition by spironolactone induced a natriuresis in four patients with ascites (from 1.4–140 mEq. Na⁺/day) but also failed to alter kallikrein. Thus, kallikrein excretion is paradoxically reduced and seemingly unresponsive to alterations in the prostaglandin and renin-aldosterone systems. If urinary kallikrein quantitatively reflects intrarenal kallikrein-kinin activity, the impairment in this vasodilatory system may mediate the altered renal hemodynamics of severe liver disease.