Physiological determinants of residual cerebral arterial pulsatility on best medical treatment after TIA or minor stroke

Cerebral arterial pulsatility is strongly associated with cerebral small vessel disease and lacunar stroke yet its dependence on central versus local haemodynamic processes is unclear. In a population-based study of patients on best medical managment, 4–6 weeks after a TIA or non-disabling stroke, arterial stiffness and aortic systolic, diastolic and pulse pressures were measured (Sphygmocor). Middle cerebral artery peak and trough flow velocities and Gosling’s pulsatility index were measured by transcranial ultrasound. In 981 participants, aortic and cerebral pulsatility rose strongly with age in both sexes, but aortic diastolic pressure fell more with age in men whilst cerebral trough velocity fell more in women. There was no significant association between aortic systolic or diastolic blood pressure with cerebral peak or trough flow velocity but aortic pulse pressure explained 37% of the variance in cerebral arterial pulsatility, before adjustment, whilst 49% of the variance was explained by aortic pulse pressure, arterial stiffness, age, gender and cardiovascular risk factors. Furthermore, arterial stiffness partially mediated the relationship between aortic and cerebral pulsatility. Overall, absolute aortic pressures and cerebral blood flow velocity were poorly correlated but aortic and cerebral pulsatility were strongly related, suggesting a key role for transmission of aortic pulsatility to the brain.     

Oral ulceration in HIV infection: Investigation and pathogenesis

Oral ulcerations associated with HIV infection include recurrent aphthous ulcers (RAU). Whereas RAU prevalence is not increased, lesion severity is: among a group of HIV⁺ patients, 66% had the more severe herpetiform or major RAU. This increased severity suggests that HIV disease-related changes in the immune system may exacerbate RAU. In the peripheral blood of healthy subjects with RAU, CD4:CD8 cell ratios may be reversed and the proportion of T cell receptor-γδ⁺ cells increased. HIV disease-related immune system changes are characterized by reversed CD4:CD8, lowered CD4 cell counts and an inverse correlation between CD4 cell counts and per cent activated γδ lymphocytes. Adhesion molecules and cytokines involved in lymphocyte homing may be important in RAU pathogenesis: ICAM-I and ELAM are strongly expressed, and TNFα production is increased in peripheral blood lymphocytes of healthy patients with RAU. In patients with active HIV disease/AIDS, serum TNFα levels are increased. Thalidomide, which inhibits TNFα production, is effective treatment for RAU. Some RAU patients have vitamin B12 or folate deficiencies, levels of which are commonly low in HIV⁺/AIDS patients. However, in a case control study of HIV⁺ patients, vitamin B12- or folate-deficiencies were not found to be significant risk factors for RAU.     

Epstein-Barr virus BMRF-2 and BDLF-3 expression in hairy leukoplakia

Hairy leukoplakia (HL) is a lesion found on the side of the tongue of immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection. The lesion has unique histopathologic features and is characterised by high-level Epstein-Barr virus (EBV) replication, multiple EBV strains, and extensive inter-and intra-strain recombination. Expression of EBV genes spanning the entire viral life cycle from latency-associated genes to late, replicative genes has been detected in the lesion. HL thus provides a unique opportunity to study EBV expression in oral epithelium, and to study expression of novel EBV genes. We therefore constructed a cDNA library from an HL biopsy and detected expression of two genes not previously described in vivo: BMRF-2 and BDLF-3. Sequence analysis of the cDNAs revealed few amino acid changes from the B95-8 sequence. Expression of both genes was localized to the lower prickle cell layer of the tongue epithelium. BMRF-2 protein expression was primarily detected in the cell nuclei of the upper prickle cell layer. BDLF-3 protein expression was observed in the perinuclear space and Golgi compartment. The function of these proteins is currently under investigation.     

Bromodeoxyuridine incorporation and Ki 67 expression in oral hairy leukoplakia

OBJECTIVES: Oral hairy leukoplakia (HL) is an acan-thotic, hyperparakeratotic lesion characterised by the presence of a replicative Epstein-Barr virus (EBV) infection in the superficial and adjoining layers of the epithelium. EBV or its gene products are capable of modifying epithelial differentiation. The aim of this study was to establish whether the presence of EBV was associated with an alteration in cell turnover by assessing bromodeoxyuridine (BrdU) incorporation and Ki 67 expression in lesional tissue and control mucosa.
METHODS: Biopsies of HL together with age, site and sex matched controls ( n = 7 and 8 respectively) were incubated in 200 μM BrdU in vitro , fixed in methacarn and processed to paraffin wax. Following acid hydrolysis, incorporated BrdU and Ki 67 were identified in serial 5 fim sections using a three-stage immunoperoxidase technique and cell density expressed as the number of positive cells per mm basement membrane length.
RESULTS: Overall, there was no difference in the number of BrdU positive cells per mm basement membrane length between control and HL tissue. However, within HL alone, the presence'of focal EBV replication was associated with a significant reduction in the number of basal cells incorporating BrdU compared to adjacent EBV free areas (P < 0.05). There was no significant difference between Ki 67 positive cells in control and HL tissue and no evidence of a reduction of Ki 67 positive cells in areas associated with EBV replication.
CONCLUSIONS: These results suggest that there is no evidence of a generalised alteration of the proliferative capacity of basal cells in HL, although the focal reduction in BrdU incorporation may reflect subtle changes on cell turnover by EBV infection.     

Gestational diabetes identifies women at risk for permanent type 1 and type 2 diabetes in fertile age: predictive role of autoantibodies

OBJECTIVE: Our aim was to evaluate the predictive value of gestational diabetes mellitus (GDM), diabetes-associated autoantibodies, and other factors for development of clinical diabetes later in life. RESEARCH DESIGN AND METHODS: In this case-control study the presence of autoantibodies was studied in 435 women with GDM and in healthy matched control subjects. The need for exogenous insulin during GDM was recorded. In the GDM group, the mean follow-up period was 5.7 years and in the control group 6.1 years. RESULTS: Among the subjects with GDM, 20 (4.6%) developed type 1 diabetes and 23 (5.3%) developed type 2 diabetes, whereas none of the control subjects became diabetic. Two-thirds of those who developed type 1 diabetes tested positive initially for islet cell antibodies (ICAs), whereas 56% of them had autoantibodies to GAD (GADAs) and 38% to the protein tyrosine phosphatase-related IA-2 molecule. Only 2 of the 23 women who presented later with type 2 diabetes tested positive for autoantibodies. According to multivariate analysis, initial age < or =30 years, the need for insulin treatment for GDM, and antibody positivity for ICAs and GADAs were associated with increased risk for clinical type 1 diabetes. CONCLUSIONS: Pregnancy seems to identify women who are at risk of developing diabetes later in life. About 10% of Finnish women with GDM will develop diabetes over the next 6 years; nearly half of them develop type 1 diabetes and the other half type 2 diabetes. Age < or =30 years, the need for insulin treatment during pregnancy, and positivity for ICAs and GADAs confer a high risk of subsequent progression to type 1 diabetes in women affected by GDM.     

Extended Family History of Diabetes and Autoimmune Diseases in Children With and Without Type 1 Diabetes

OBJECTIVE

To determine the extended family history of diabetes or autoimmune diseases in families with and without children having type 1 diabetes.

RESEARCH DESIGN AND METHODS

Three hundred case families and 381 control families were interviewed using structured questionnaires.

RESULTS

The proportion of case children having at least one relative with type 1 diabetes outside the nuclear family was higher than that of control children (50.3 vs. 31.8%, P < 0.001). The proportions of case and control children having relatives with type 2 diabetes or gestational diabetes were similar. Other autoimmune diseases occurred more frequently among the case children (9.7 vs. 1.1%, P < 0.001), in the case nuclear families (22.0 vs. 12.9%, P = 0.002) and in relatives outside the case nuclear family (72.0 vs. 62.2%, P = 0.007).

CONCLUSIONS

Type 1 diabetes and autoimmune diseases not only cluster in the nuclear families of children with type 1 diabetes but are also overrepresented in their extended families.First degree relatives of patients with type 1 diabetes clearly have an increased disease risk (1–5), but little information is available about the occurrence of type 1 diabetes outside the nuclear family (6). It is also unclear whether type 2 diabetes and gestational diabetes are more frequently present in the families of children with type 1 diabetes (7–9). Type 1 diabetes is known to be associated with other autoimmune diseases, but there is a scarcity of data on the frequency of autoimmune diseases among other family members (10).     

Establishment of a system to standardize acceptability criteria for alanine aminotransferase activity in donated blood

A multilaboratory study was conducted to develop a system for standardizing alanine aminotransferase (ALT) acceptability criteria ("cutoffs") for donated blood. Without standardized cutoffs, each laboratory must develop its own cutoff, and this may not make optimal use of ALT testing to reduce transmission of non-A, non-B hepatitis (NANB). Defining an ALT acceptability criterion in absolute terms is necessary because relative cutoffs based on local donor populations may be affected by the prevalence of NANB in each community. This study involved 16 laboratories using 23 different analytic systems. The ALT results of the analysis of a plasma reference sample could be used to translate mathematically a single, absolute cutoff to units applicable to each analytic system. The distribution of ALT results in 1.4 million donations from across the country was established; basing the cutoff on this sample avoids the problems inherent in using a local donor base to establish a cutoff. We propose the implementation of a system to standardize ALT acceptability criteria to an activity level defined by analysis of a nationwide donor sample.