Longitudinal study of urinary albumin excretion in young diabetic patients--Wessex Diabetic Nephropathy Project.

AIMS: This study was established to follow changes in albumin/creatinine ratio (ACR) and to determine the prevalence and degree of progression of microalbuminuria (MA) or of clinical proteinuria (CP) in children with Type 1 diabetes. The study has investigated subjects for up to 12 years in establishing the correlation between MA and gender, age, duration of diabetes and glycated haemoglobin (HbA1c). The study has defined clinical cut-offs for MA in daytime clinic urine samples in young diabetic subjects. METHODS: Three hundred and sixty-one patients were involved in the study, with 221 (61.2%) having over six sets of data. Urine samples were collected at routine annual clinic visits and analysed without prior freezing for ACR. Blood samples were taken for HbA1c measurement. Data including sex, age and duration of diabetes were recorded. RESULTS: A random clinic ACR of < 4.5 mg/mmol (males) and 5.2 mg/mmol (females) creatinine was used as the 'clinical cut-off' to define the presence of MA. The presence of MA was independent of HbA1c and duration of diabetes but appeared be associated with the adolescent years (> 10 years). There was little evidence of progression from normoalbuminuria to MA, or from MA to CP. Of patients aged 10-18 years, 30.9% of males and 40.4% of females had one or more episodes of MA. CONCLUSIONS: Persistent MA and random episodes of MA or CP may be associated with the adolescent years but not with duration of diabetes. Further study will reveal if the substantial increases in ACR sometimes seen during adolescence are predictive of diabetic nephropathy. Clinical cut-offs of < 4.5 and < 5.2 mg/mmol creatinine for males and females, respectively, are suggested for the interpretation of changes in ACR in random urine samples in young people with Type 1 diabetes.     

Diclofenac-induced hepatotoxicity

Two patients developed clinical, biochemical and histopathological signs of a liver hypersensitivity reaction following treatment with diclofenac. Hepatic side effects of this drug are very rare. The relevant literature is reviewed.     

Obesity and body fat distribution and breast cancer prognosis

This study addresses the effect of obesity and body fat distribution on axillary lymph node involvement, tumor size, and estrogen receptor (ER) level in breast cancer patients. Anthropometric measurements were prospectively obtained on 248 consecutively and newly diagnosed women with invasive breast cancer. The anthropometric measurements evaluated were abdomen, thigh, subscapular, and midaxillary skinfolds; weight; and height. Weight and Quetelet Index (kg/m2) were significantly (P = 0.001) associated with lymph node involvement in postmenopausal patients. The abdomen:thigh skinfold ratio was significantly higher in premenopausal patients (P = 0.004) and postmenopausal (P = 0.03) without axillary node involvement compared with women with 4+ axillary node involvement. The abdomen:thigh skinfold was higher (P = 0.05) in women with smaller breast cancers (less than 2.0 cm) and higher ER levels. Weight and Quetelet Index did not affect tumor size or ER level. This study demonstrated that obese postmenopausal women who developed breast cancer tend to have more axillary node involvement than their leaner counterparts. Generalized obesity did not affect tumor size or ER level. Premenopausal and postmenopausal women with upper body fat distribution appear to be a subset of women who have a more favorable prognosis as measured by less lymph node involvement, smaller tumors, and higher levels of ER in their tumors.     

Protein kinase and adenylate cyclase of erythrocyte membrane from patients with duchenne muscular dystrophy

In freshly prepared erythrocyte membranes from normal individuals and from patients with Duchenne progressive muscular dystrophy the endogenous protein kinase and the cAMP stimulated phosphorylation was identical for the three main ³²P proteins including spectrin (protein band II). Another enzyme, adenylate cyclase, was found unchanged. Altered protein kinase and adenylate cyclase has been reported in this disorder. We have no explanation for these discrepancies.     

Friedreich's ataxia impact scale: A new measure striving to provide the flexibility required by today's studies

To develop, using modern techniques of rating scale construction, a new patient reported rating scale for clinical studies of Friedreich's ataxia (FA) that strives to meet the measurement needs of different types of study. Qualitative research methods were used to generate a conceptual framework of the impact of FA, and a pool of items necessary to construct a subscale for each area identified. This item pool was then administered to 492 people with FA. Rasch measurement methods guided scale construction. Eight areas for measurement were identified (speech, upper limb functioning, lower limb functioning, body movement, complex tasks, isolation, mood, self perceptions), and a 126‐item scale constructed (FA Impact Scale; FAIS). In addition, three shorter versions were developed to illustrate how the FAIS can be adapted for observational studies, more disabled, and less disabled samples of people with FA. The FAIS is a psychometrically sound 126‐item measure from which subsets of items can be selected to meet the needs of different studies. Importantly, all versions can be referred back to the original scale. This study shows one of the many clinical advantages of using Rasch measurement methods to construct rating scales. © 2009 Movement Disorder Society     

Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion

We studied six unrelated children with depletion of mitochondrial DNA (mtDNA). They presented with Leigh syndrome, infantile hepatocerebral mtDNA depletion syndrome, or Alpers-Huttenlocher syndrome. Several genes have been implicated in mtDNA depletion. Screening of candidate genes indicated that all six patients were compound heterozygous for missense mutations in the gene for the catalytic subunit of DNA polymerase gamma (POLG). Three of the identified mutations, c.3328C>T (p.H1110Y), c.3401A>G (p.H1134R), and c.3406G>A (p.E1136K), have not been reported earlier. To investigate the functional consequences of the mutations, we carried out a series of biochemical assays in cultured fibroblasts. These studies revealed that fibroblast cultures from the patients with infantile hepatocerebral mtDNA depletion syndrome progressively lost their mtDNA during culturing, whereas fibroblast cultures from patients presenting with Leigh syndrome or Alpers-Huttenlocher syndrome had reduced but stable levels of mtDNA. DNA polymerase gamma activity was below the normal range in all patient cultures, except for one; however, this culture showed low levels of the heterodimeric enzyme and poor DNA polymerase gamma processivity. Parental fibroblast cultures had normal catalytic efficiency of DNA polymerase gamma, consistent with the observation that all carriers are asymptomatic. Thus, we report the first patient with Leigh syndrome caused by POLG mutations. The cell culture experiments established the pathogenicity of the identified POLG mutations and helped to define the molecular mechanisms responsible for mtDNA depletion in the patients' tissues. The assays may facilitate the identification of those patients in whom screening for POLG mutations would be most appropriate.     

Associations of serum EBV DNA and gammopathy with post-transplant lymphoproliferative disease

Abstract: Background: Post‐transplant lymphoproliferative disease (PTLD) is a life‐threatening complication of immunosuppression following transplantation. Epstein–Barr virus (EBV) and gammopathy in serum are associated with PTLD, but these two parameters have not been evaluated in parallel for their association with PTLD. Methods: We evaluated the incidence of EBV load positivity, gammopathy, and protein expression in sera from all PTLD patients diagnosed at our hospital during the past seven yr. Results were compared with those of a control group including matched transplanted patients who did not develop PTLD. Results: Seven of 10 PTLD patients presented EBV⁺ PTLD, for which five patients had detectable serum EBV DNA levels compared with none of 38 controls (RR between two groups =121, p < 0.0001). Five out of 10 patients had gammopathy at PTLD diagnosis compared with 5/38 controls (RR between two groups = 6.6, p = 0.022). Additionally, protein serum analysis by high‐resolution two‐dimensional gel electrophoresis and image examination failed to evidence specific abnormality in patients with PTLD compared with controls. Conclusions: Our results confirm an association between EBV in sera and gammopathy with PTLD, and highlight the high specificity of the former analysis. Whether a combination of both analyses will improve the clinical detection of PTLD remains to be evaluated in a larger prospective cohort study.     

Characterization of a novel TYMP splice site mutation associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive disorder caused by loss-of-function mutations in the thymidine phosphorylase gene (TYMP). We report here a patient compound heterozygous for two TYMP mutations: a novel g.4009G>A transition affecting the consensus splice donor site of intron 9, and a previously reported g.675G>C splice site mutation. The novel mutation causes exon 9 skipping but leaves the reading frame intact; however, TYMP protein was not detected by immunoblot analysis, suggesting that neither mutant allele is expressed as protein. The patient’s fibroblasts showed gradual loss of the mitochondrial DNA-encoded subunit I of cytochrome-c oxidase, suggesting a progressive mitochondrial DNA defect in culture.