Jacob A. Wegelin

Viral Suppression and Immune Restoration in the Gastrointestinal Mucosa of Human Immunodeficiency Virus Type 1-Infected Patients Initiating Therapy during Primary or Chronic Infection

ABSTRACT Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11α, αEβ7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.

Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation

Until recently, individuals with premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene were believed to be psychologically unaffected. However, the recent documentation of abnormal elevation of FMR1 mRNA, discovery of fragile X‐associated tremor/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene–brain–behavior mechanism. In a large collaborative study, 68 men and 144 women with the FMR1 premutation completed a psychological symptoms checklist and FMR1 genetic testing, including determination of CGG repeat size, percentage of FMR1 protein (FMRP)‐positive lymphocytes, and FMR1 mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive‐compulsive symptoms. Elevated FMR1 mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive‐compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size, FMR1 mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X‐activation ratio toward >50% active premutation alleles. The results of this study support the hypothesis that FMR1 function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain‐of‐function model in a neuropsychiatric phenotype.

The Western States 100-Mile Endurance Run: Participation and Performance Trends

PURPOSE Examine changes in demographics of participants and performance trends at the Western States 100-Mile Endurance Run (WSER) since its inception in 1974. METHODS Name, age, sex, and finish information was obtained on runners in the WSER from 1974 to 2007. Linear regression analyses, ANOVA, and t-tests were used to examine participation and performance trends. RESULTS The mean age of participants increased (P < 0.001) to around 45 yr, with men being an average of 3 yr older (P < 0.001) than women. The increase in average age of starters was accounted for by the growth in participation among women >or=40 yr and men >or=50 yr, and by the decreasing participation among men <50 yr. Between 1986 and 2007, there was an increasing participation among women to around 20% of all starters. With this came improved (P < 0.01) finish times for the top 5 overall women and the top 5 women in the 30-39 and 40-49 yr age groups, whereas performances among the men did not improve over this time span. Average ages of the top performers increased (P <or= 0.002) since 1990 to the upper 30s for both sexes, but the fastest times among men were comparable across the 30-39 and 40-49 yr age groups. CONCLUSIONS Participation in the WSER has increased among women and older athletes, and the ages of the fastest runners at the WSER have gradually risen to the extent that these runners are older than the ages at which the fastest marathons are run. In contrast to what has been observed for men, finish times have improved for the top women across the last two decades at the WSER.

Evaluation of Short-term and Long-term Complications after Emergent Internal Iliac Artery Embolization in Patients with Pelvic Trauma

PURPOSE To assess the incidence of long- and short-term complications following internal iliac artery (IIA) embolization after blunt pelvic trauma. MATERIALS AND METHODS One hundred trauma patients with pelvic fractures underwent pelvic angiography from 1994 through 2006. Sixty-seven patients underwent IIA embolization. These patients were retrospectively identified for medical record review. Short- and long-term complications were defined as those occurring at less than or greater than 30 days, respectively. Complications and outcomes were assessed through chart review and, when possible, a standardized questionnaire. Patients who underwent IIA embolization were compared with matched control patients with blunt pelvic trauma who did not undergo pelvic arteriography. Individuals were matched by age, sex, year of admission, and injury scores. RESULTS There were no significant differences in skin necrosis, sloughing, pelvic perineal infection, or nerve injury between embolized and nonembolized patients within 30 days. There was no significant difference in claudication, skin ulceration, or regional pain at a mean of 18.4 months follow-up. In the long term, buttock, thigh, and perineal paresthesia occur at a significantly higher rate in embolized patients. Skin sloughing in the embolized patient group is an important but rare complication. CONCLUSIONS IIA embolization is an important means of controlling pelvic arterial hemorrhage. There is no significant increase in the risk of most evaluated long- and short-term complications in trauma patients who underwent IIA embolization versus those who did not. However, IIA embolization is associated with a marginally significantly increased rate of buttock, thigh, or perineal paresthesia.

Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid.

Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis.

Similar progression of fibrosis between HIV/HCV-infected and HCV-infected patients: Analysis of paired liver biopsy samples.

BACKGROUND & AIMS Fibrosis progression might be accelerated in patients who are coinfected with human immunodeficiency virus (HIV) and HCV (HIV/HCV). However, no studies have directly compared fibrosis progression by paired liver biopsy between patients infected with HIV and HCV versus those infected with only HCV. METHODS Liver biopsy samples were collected from patients with HIV/HCV (n = 306) and those with HCV; biopsies from 59 without a sustained virologic response (SVR) or cirrhosis were matched with those from patients with only HCV (controls) for initial fibrosis stage, demographics, and HCV treatment. For HIV/HCV patients, categorical variables at baseline and the area under the curve of continuous variables per unit time were analyzed for associations with fibrosis progression. RESULTS Liver biopsies from HIV/HCV patients had more piecemeal necrosis than controls (P = .001) and increased lobular inflammation (P = .002); HIV/HCV patients also had shorter intervals between liver biopsies (4.7 vs 5.9 years, P < .0001). Between the first and second biopsies, fibrosis remained unchanged or progressed 1 or 2 units in 55%, 18%, and 18% of HIV/HCV patients, respectively, compared with 45%, 30%, and 9% of controls. The fibrosis progression rate was similar between HIV/HCV and control patients (0.12 ± 0.40 vs 0.091 ± 0.29 units/y; P = .72). In paired biopsies from 66 patients, including those with SVR, there were no associations between fibrosis progression and demographics; numbers of CD4+ T cells; levels of aspartate aminotransferase or alanine aminotransferase; use of highly active antiretroviral therapy; response to HCV therapy (no treatment, SVR, or non-response); baseline levels of FIB-4; or histologic features including inflammation, fibrosis, or steatosis. CONCLUSIONS On the basis of analysis of liver biopsy samples, fibrosis progression was similar between HIV/HCV-infected and HCV-infected patients; no clinical or laboratory parameters predicted disease progression.

The utility of the model for end‐stage liver disease score: A reliable guide for liver transplant candidacy and, for select patients, simultaneous hospice referral

Patients with chronic liver disease are referred late to hospice or never referred. There are several barriers to timely referral. First, liver transplantation (LT) and hospice care have always been perceived as mutually exclusive. Yet the criteria for hospice referral and for LT are more similar than different (for example, advanced liver disease and imminent death). Second, physicians, patients, and families have not had a reliable metric to guide referral. However, many patients wait for transplantation but never receive an organ. We hypothesized that the Model for End‐Stage Liver Disease (MELD) score already in use to prioritize LT could be used in selected patients for concurrent hospice referral. Furthermore, we hypothesized that patients awaiting LT can receive hospice care and remain eligible for transplantation. Patients with advanced or end‐stage liver disease were referred to the University of California Davis Health System hospice program. We correlated the MELD score at admission to length of stay (LOS) in hospice. A total of 157 end‐stage liver disease patients were admitted to the hospice service. At the time of hospice admission the mean MELD score was 21 (range, 6‐45). The mean length of hospice stay was 38 days (range, 1‐329 days). A significant correlation was observed between hospice LOS and MELD score at hospice admission (P < 0.01). Six patients were offered a liver graft while on the combined (LT and hospice) program. MELD can be used to guide clinician recommendation to families about hospice care, achieving one of the national benchmark goals of increasing hospice care duration beyond the current median of 2‐3 weeks. A higher MELD score might augment physician judgment as to hospice referral. Hospice care for selected patients may be an effective strategy to improve the care of end‐stage liver disease patients waiting for LT. Liver Transpl 14:1100–1106, 2008.

Early acceleration of head circumference in children with fragile x syndrome and autism.

Objective: Head circumference (HC) growth has been shown in several studies to be accelerated early in life in both fragile X syndrome (FXS) and autism spectrum disorders (ASDs), but the rates of growth have not been compared between those with only FXS and those with FXS and ASD (FXS + ASD). Methods: We hypothesized that individuals with FXS + ASD would have significantly larger HCs from individuals with only FXS and that there would be an early acceleration of HC in both the FXS-only and FXS + ASD groups. HC measurements were available retrospectively for 44 males, five and younger, with FXS, of whom 22 also had ASD. Measurements over time were available for 24 of the 44 children. HC percentiles were compared between the groups in two ways: by focusing on cross-sectional subsamples and by fitting hierarchical linear models to the full sample. Results: Neither group differed significantly from the norm in the first year of life (p > 0.2). At 30 months, the FXS + ASD group was 27 percentile points above the norm (p = .0125), whereas the FXS-only group did not differ from the norm. At 60 months, the FXS-only group was 21 percentile points above the norm (p = .029), whereas the FXS + ASD group did not differ from the norm. Conclusion: The group difference in HC growth rate may differentiate brain development in individuals with FXS-only versus those with FXS + ASD.

Phonetic structures of Aleut

Abstract A detailed analysis of the phonetic structures of Aleut, a moribund language spoken in Alaska, shows how much general phonetic information can be gathered from the investigation of an endangered language. Aleut has an unusual distribution of consonants, with varying functional loads. There are no bilabial stops. Among alveolar, velar and uvular stops, VOT is shorter for alveolar than for velar or uvular stops, but, despite current general phonetic theories, there is no difference in VOT between velar and uvular stops. VOT is also longer before long vowels than before short vowels. Uvular consonants have a significant effect on the formants of following high vowels. There are three vowels and a vowel length contrast. Again, despite previous general phonetic predictions concerning languages with vowel-length contrasts, length plays a role in characterizing stress. Contrastive ratios are maintained between short and long vowels and stressed syllables are longer. Analyses of intonation show that each content word has a peak at its beginning and a trough at its end. Word contours combine with sentence downtrends to form sentence contours of cascading F 0, each word a step in the cascade. But, unlike the situation in other languages, yes/no questions have the same intonation contours as declarative sentences. Phonetic descriptions and measurements of general theoretical interest include C and V inventories, VOT measurements for coronal, velar and uvular stops, vowel-quality plots, vowel-duration measurements, question and declarative pitch tracks, pitch-track smoothing, and question vs. declarative sentence pitch medians.

Vestibular Dysfunction in DFNB1 deafness

Mutations of GJB2 and GJB6 (connexin‐26 and 30) at the DFNB1 locus are the most common cause of autosomal recessive, nonsyndromic deafness. Despite their widespread expression throughout the vestibular system, vestibular dysfunction has not been widely recognized as a commonly associated clinical feature. The observations of vertigo accompanying DFNB1 deafness in several large families prompted our hypothesis that vestibular dysfunction may be an integral, but often overlooked, component of DFNB1 deafness. Our aim was to define the prevalence of vestibular dysfunction in Cases of DFNB1 deafness and Controls with other forms of deafness. We developed and used a survey to assess symptoms of vestibular dysfunction, medical, and family history was distributed to Cases with deafness due to pathogenic GJB2 and/or GJB6 mutations and deaf Controls without DFNB1 deafness. Our results showed: Surveys were returned by 235/515 Cases (46%) with DFNB1 mutations and 121/321 Controls (38%) without these mutations. The mean age of Cases (41) was younger than Controls (51; P < 0.001). Vestibular dysfunction was reported by 127 (54%) of Cases and was present at significantly higher rates in Cases than in deaf Controls without DFNB1 deafness (P < 0.03). Most (63%) had to lie down in order for vertigo to subside, and 48% reported that vertigo interfered with activities of daily living. Vertigo was reported by significantly more Cases with truncating than non‐truncating mutations and was also associated with a family history of dizziness. We conclude that vestibular dysfunction appears to be more common in DFNB1 deafness than previously recognized and affects activities of daily living in many patients.