Investigation of susceptibility loci identified in the UK rheumatoid arthritis whole-genome scan in a further series of 217 UK affected sibling pairs

OBJECTIVE: A previous whole-genome scan (WGS) of 182 UK rheumatoid arthritis (RA) affected sibling pair (ASP) families suggested linkage to HLA and 11 other chromosome regions. Replication of such findings in an independent cohort can help to distinguish true linkages from false-positive linkages. Since RA is a heterogeneous disease, some loci may be linked only in subsets of patients. Thus, the aim of this study was to investigate in an additional set of RA ASP families linkage to regions showing deviation in expected allele-sharing ratios in the UK WGS and to perform subset analysis on the combined cohort. METHODS: Twenty loci were investigated for linkage in 217 Caucasian UK RA ASPs. Stratification analysis was performed on the combined cohort of 377 RA ASP families to account for sex, RA severity, and the shared epitope (SE). RESULTS: None of the regions of linkage identified in the initial WGS achieved statistical significance in the second cohort. In contrast, after stratification analysis, 14 regions showed nominal evidence of linkage (logarithm of odds score >0.8) in one or more subgroups. In particular, the strength of evidence for linkage to chromosome 16p was increased in subsets of ASPs with younger age at disease onset (LOD score 2.38) and for linkage to chromosome 6q in female-female ASPs (LOD score 2.31) and in ASPs in which both siblings had 2 copies of the SE (LOD score 3.03). CONCLUSION: These results support the evidence for heterogeneity of RA. This information will inform the future design of association-based investigations as the search for disease genes in the linked regions begins.     

A model of lytic, latent, and reactivating varicella-zoster virus infections in isolated enteric neurons

Because human primary afferent neurons are not readily obtained, we sought to develop a model in which the lytic, latent, and reactivating phases of varicella-zoster virus (VZV) infection were recapitulated in neurons from an animal source. Enteric neurons were obtained from the small intestine of adult guinea pigs and from the bowel of fetal mice. Latency was established when these neurons were infected by cell-free VZV in the absence of fibroblasts or other cells of mesodermal origin. In contrast, lytic infection ensued when fibroblasts were present or when the enteric neurons were infected by cell-associated VZV. Latency was associated with the expression of a limited subset of viral genes, the products of which were restricted to the cytoplasm. Lysis was associated with the expression of viral glycoproteins, nuclear translocation of latency-associated gene products, and rapid cell death. Reactivation was accomplished by expressing VZV open reading frame (ORF) 61p or herpes simplex virus ICP0 in latently infected neurons. Isolated enteric neurons from guinea pigs and mice recapitulate latent gene expression in human cranial nerve and dorsal root ganglia. Expression of latency-associated VZV gene products was detected in 88% of samples of adult human intestine, suggesting that VZV not only infects enteric neurons but also is latent in the human enteric nervous system. This in vitro model should facilitate further understanding of latency and reactivation of VZV.     

Maternal HLA class II compatibility in men with systemic lupus erythematosus

OBJECTIVE: Maternal-fetal cell transfer during pregnancy can lead to long-lasting microchimerism, which raises the question of whether microchimerism sometimes contributes to autoimmune disease later in life. In an experimental model, transfusion of parental lymphocytes homozygous for major histocompatibility complex alleles results in systemic lupus erythematosus (SLE). We identified male patients with SLE and healthy male subjects and their mothers in order to investigate the mother-son HLA relationship in SLE risk. Male subjects were selected in order to avoid confounding due to fetal microchimerism, which may occur in women. METHODS: HLA genotyping for DRB1, DQA1, and DQB1 was conducted for sons and their mothers. Thirty men with SLE and their mothers were compared with 76 healthy men and their mothers. RESULTS: Sons with SLE were HLA-identical with their mothers (bidirectionally compatible) for the basic HLA-DRB1 groups encoded by DRB1*01 through DRB1*14 more often than were healthy sons (odds ratio [OR] 5.0, P = 0.006). Each DRB1 group contains multiple allelic variants; male patients with SLE and their mothers often were identical for both DRB1 allelic variants (OR 3.2, P = 0.08). For DQA1 and DQB1, the ORs were 2.3 (P = 0.08) and 2.0 (P = 0.21), respectively. When analysis was limited to male subjects with SLE-associated HLA genes (encoding HLA-DR2 or HLA-DR3), the differences further increased for DRB1 basic groups (OR 7.2, P = 0.01), DRB1 alleles (OR 15.0, P = 0.018), DQA1 6.4 (P = 0.006), and DQB1 (OR 5.7, P = 0.027). No increase in (unidirectional) compatibility of the mother from the son's perspective was observed at any locus. CONCLUSION: We observed increased bidirectional HLA class II compatibility of male SLE patients and their mothers compared with healthy men and their mothers. This observation implies that maternal microchimerism could sometimes be involved in SLE and therefore merits further investigation.     

Hypertension and dementia

Hypertension is one of the principal risk factors for cerebrovascular diseases. Several epidemiologic studies have also indicated a positive correlation between cognitive decline or dementia and blood pressure level. Indeed, the results of most longitudinal studies show that cognitive functioning is often inversely proportional to blood pressure values measured 15 or 20 years previously. Cerebral infarcts, lacunae, and white matter changes are implicated in the pathogenesis of vascular dementia, but may also favor the development of Alzheimer’s disease. Microcirculation disorders and endothelial dysfunctions are also advanced to explain the deterioration in cognitive functions in hypertensive subjects. Data from recent therapeutic trials open the way to the prevention of dementia (vascular or Alzheimer’s type) by antihypertensive treatments and must be confirmed by other studies.     

3alpha-Hydroxysteroid dehydrogenase type III deficiency: a novel mechanism for hirsutism

CONTEXT: Dihydrotestosterone (DHT), the primary active androgen in peripheral target tissues, is metabolized by 3alpha-hydroxysteroid dehydrogenase type III (3alpha-HSD), encoded by the AKR1C2 gene, forming 5alpha-androstane-3alpha,17beta-diol (3alpha-diol). 3alpha-HSD may play a role in the pathogenesis of hirsutism. OBJECTIVES: Our objective was to evaluate the role of 3alpha-HSD in hirsutism by comparing 1) tissue levels of active androgens, 2) relative gene expression of AKR1C2, and 3) activity of 3alpha-HSD in genital skin from normal and hirsute women. DESIGN: Genital skin was obtained from normal and hirsute women. After homogenization, testosterone (T) and DHT levels were quantified by conventional RIA. From isolated RNA, relative expression of AKR1C2 was determined by real-time PCR. In addition, minced genital skin was incubated with [(3)H]DHT, and the product, [(3)H]3alpha-diol, was quantified by radio-HPLC. SETTING: The study took place at an inner-city hospital. Patients: Patients included women undergoing posterior colporrhaphy. MAIN OUTCOME MEASURES: We assessed 1) tissue levels of T, DHT, and 3alpha-diol; 2) relative expression of AKR1C2; and 3) conversion ratio of [(3)H]3alpha-diol to [(3)H]DHT. Results: In genital skin, tissue DHT and T concentrations in hirsute women were 1.90-fold and 1.84-fold higher than in normal women (P =0 .002 and 0.03), and relative expression of AKR1C2 mRNA was reduced approximately 7-fold (P = 0.04). Genital skin from hirsute women showed less metabolism of [(3)H]DHT to [(3)H]3alpha-diol (conversion ratio, 0.24 +/- 0.19 vs. 0.85 +/- 0.55, P = 0.01). CONCLUSIONS: In genital skin of hirsute women, reduced AKR1C2 gene expression and 3alpha-HSD activity results in decreased DHT metabolism and elevated tissue levels of DHT. Diminished DHT metabolism may play an important role in the pathogenesis of hirsutism.     

Acute sinusitis: Finnish clinical practice guidelines

These clinical practice guidelines aim at providing assistance mainly to primary health care physicians for the diagnosis and management of acute sinusitis. Despite the huge impact of upper respiratory infections, criteria for diagnoses are often vague, and physicians are often uncertain of their diagnoses. This is not surprising, as the sole definition of acute sinusitis is somewhat confusing, not to mention the existing discrepancies between treatments, even among specialists. The Finnish Society of Otorhinolaryngology has set up a committee to evaluate existing data on acute sinusitis and to formulate these guidelines. The committee comprised Finnish experts in adult and paediatric otorhinolaryngology, clinical microbiology, radiology, paediatrics, and epidemiology. Recommendations given are based on the principles of evidence-based medicine, with the level of evidence presented.     

Macrocystic pancreatic cystadenoma: The role of EUS and cyst fluid analysis in distinguishing mucinous and serous lesions

BACKGROUND: Benign pancreatic serous cystadenoma usually is morphologically distinguishable from mucinous cystadenomas, which require resection because of their malignant potential. A macrocystic variant of serous cystadenoma recently has been described, rendering this important distinction more difficult. The aim of this study was to determine the EUS and tumor marker characteristics of mucinous cystadenoma compared with macrocystic serous cystadenomas. METHODS: Medical records for consecutive patients seen between 1995 and 2002, with a histopathologic diagnosis of mucinous cystadenoma or macrocystic serous cystadenoma after surgery, who had undergone a detailed EUS examination, including EUS-guided FNA, were retrospectively reviewed. RESULTS: A resection specimen was available for 32 mucinous cystadenomas and 9 macrocystic serous cystadenomas. No significant differences were observed with regard to clinical data (age, gender, presence of symptoms), lesion size, and location within the pancreas. All mucinous cystadenomas had a discernible cyst wall (thickened, 66%; focal parietal nodules, 25%) compared with 56% of macrocystic serous cystadenomas (p<0.0001). A thick echo content also was more frequent in mucinous cystadenoma (56% vs. 11%; p=0.04; statistical significance removed by the Bonferroni correction). Microcysts were only observed in macrocystic serous cystadenomas (44%; p=0.0008). The combination of a cyst wall that is thickened and the absence of microcysts had a sensitivity of 100% and specificity of 78% for the diagnosis of mucinous cystadenoma compared with macrocystic serous cystadenoma. Although intracystic carbohydrate-associated antigen 72-4 and mucins M1 were non-discriminatory, low carcinoembryonic antigen (<5 ng/mL) and carbohydrate-associated antigen 19-9 (<50,000 U/mL) values were found in macrocystic serous lesions (respectively, 100% and 100%; p=0.0002 and p=0.0002). CONCLUSIONS: Although there is considerable overlap, helpful EUS characteristics that differentiate mucinous cystadenoma from macrocystic serous cystadenoma include a thick cyst wall and microcysts. These features, coupled with analysis of aspirated fluid for tumor markers (especially carcinoembryonic antigen), should help to confirm the diagnosis.     

A role for ASIC3 in the modulation of high-intensity pain stimuli

Acid-sensing ion channel 3 (ASIC3), a proton-gated ion channel of the degenerins/epithelial sodium channel (DEG/ENaC) receptor family is expressed predominantly in sensory neurons including nociceptive neurons responding to protons. To study the role of ASIC3 in pain signaling, we generated ASIC3 knockout mice. Mutant animals were healthy and responded normally to most sensory stimuli. However, in behavioral assays for pain responses, ASIC3 null mutant mice displayed a reduced latency to the onset of pain responses, or more pain-related behaviors, when stimuli of moderate to high intensity were used. This unexpected effect seemed independent of the modality of the stimulus and was observed in the acetic acid-induced writhing test (0.6 vs. 0.1-0.5%), in the hot-plate test (52.5 and 55 vs. 50 degrees C), and in tests for mechanically induced pain (tail-pinch vs. von Frey filaments). We postulate that ASIC3 is involved in modulating moderate- to high-intensity pain sensation.