Cognition and eating behavior in amyotrophic lateral sclerosis: effect on survival.

It is increasingly recognized that metabolic factors influenced by eating behavior, may affect disease progression in neurodegeneration. In frontotemporal dementia (FTD), which shares a significant overlap with Amyotrophic lateral sclerosis (ALS), patients are well known to develop changes in eating behavior. Whether patients with pure ALS and those with cognitive and behavioral changes associated with ALS also develop similar changes is not known. The current study aimed to examine caloric intake, eating behavioral changes, body mass index, and using cox regression analyses survival across the spectrum of 118 ALS-FTD patients (29 pure ALS, 12 ALS-plus and 21 ALS-FTD, 56 behavioral variant FTD), compared with 25 control subjects. The current study found contrary to previous assumptions eating changes are not restricted to FTD, but a spectrum of eating behavioral changes occur in ALS, present in those with pure ALS and worsening as patients develop cognitive changes. ALS patients with cognitive impairment exhibited changes in food preference, with caloric intake and BMI increasing with the development of cognitive/behavioral changes. Both pure ALS and those with cognitive impairment demonstrated increased saturated fat intake. Survival analyses over the mean patient follow-up period of 6.9 years indicated that increasing eating behavioral changes were associated with an improved survival (threefold decrease risk of dying). Changes in eating behavior and metabolism occur in ALS in association with increasing cognitive impairment, perhaps exerting a protective survival influence. These changes provide insights into the common neural networks controlling eating and metabolism in FTD and ALS and provide potential targets to modify disease prognosis and progression.

Body mass index delineates ALS from FTD: implications for metabolic health.

Weight loss and catabolic changes are increasingly recognized as factors that influence outcomes in patients with amyotrophic lateral sclerosis (ALS). An association between disease progression and low BMI has been reported in ALS; however, it remains unknown whether low BMI occurs across all forms of ALS and whether BMI changes with the development of cognitive impairment across the spectrum between ALS and frontotemporal dementia (FTD). One hundred and three ALS patients (56 limb predominant, 18 bulbar predominant, 13 ALS plus, 16 ALSFTD) were recruited and compared to 19 behavioral variant FTD (bvFTD) patients and a group of age-matched healthy controls. BMI was measured at the initial clinical visit. Patients were characterized as underweight, normal, overweight or obese, based on the current World Health Organization (WHO) guidelines. Limb and bulbar ALS patients had significantly lower BMI than ALS plus, ALSFTD, and bvFTD patient groups. When BMI was categorized using WHO guidelines the majority of the limb and bulbar ALS patients were either underweight or normal weight, whilst the majority of the ALS plus, ALSFTD and bvFTD patients were either overweight or obese. On follow-up BMI assessment the limb and bulbar groups tended to decline whilst ALS plus, ALSFTD and bvFTD groups remained stable or increased. BMI is significantly higher in ALS individuals with cognitive deficits. The present findings have prognostic implications for disease progression and may help delineate the metabolic profile across the ALSFTD spectrum.

Gender difference in HIV-1 RNA viral loads.

OBJECTIVES: To test and characterize the dependence of viral load on gender in different countries and racial groups as a function of CD4 T-cell count. METHODS: Plasma viral load data were analysed for > 30,000 HIV-infected patients attending clinics in the USA [HIV Insight (Cerner Corporation, Vienna, VA, USA) and Plum Data Mining LLC (East Meadow, NY, USA) databases] and the Netherlands (Athena database; HIV Monitoring Foundation, Amsterdam, Netherlands). Log-normal regression models were used to test for an effect of gender on viral load while adjusting for covariates and allowing the effect to depend on CD4 T-cell count. Sensitivity analyses were performed to test the robustness of conclusions to assumptions regarding viral loads below the lower limit of quantification (LLOQ). RESULTS: After adjusting for covariates, women had (nonsignificantly) lower viral loads than men (HIV Insight: -0.053 log(10) HIV-1 RNA copies/mL, P = 0.202; Athena: -0.005 log(10) copies/mL, P = 0.667; Plum: -0.072 log(10) copies/mL, P = 0.273). However, further investigation revealed that the gender effect depended on CD4 T-cell count. Women had consistently higher viral loads than men when CD4 T-cell counts were at most 50 cells/microL, and consistently lower viral loads than men when CD4 T-cell counts were greater than 350 cells/microL. These effects were remarkably consistent when estimated independently for the racial groups with sufficient data available in the HIV Insight and Plum databases. CONCLUSIONS: The consistent relationship between gender-related differences in viral load and CD4 T-cell count demonstrated here explains the diverse findings previously published.

Adherence to antiretroviral therapy and its impact on clinical outcome in HIV-infected patients.

We analyse data on patient adherence to prescribed regimens and surrogate markers of clinical outcome for 168 human immunodeficiency virus infected patients treated with antiretroviral therapy. Data on patient adherence consisted of dose-timing measurements collected for an average of 12 months per patient via electronic monitoring of bottle opening events. We first discuss how such data can be presented to highlight suboptimal adherence patterns and between-patient differences, before introducing two novel methods by which such data can be statistically modelled. Correlations between adherence and subsequent measures of viral load and CD4+T-cell counts are then evaluated. We show that summary measures of short-term adherence, which incorporate pharmacokinetic and pharmacodynamic data on the monitored regimen, predict suboptimal trends in viral load and CD4+T-cell counts better than measures based on adherence data alone.

The seasonal pattern of dengue in endemic areas: mathematical models of mechanisms.

In dengue-endemic areas such as Thailand, there is clear seasonality in the number of reported cases of dengue virus disease. However, the roles of different entomological and biological variables in determining this pattern have not been ascertained. To investigate this, seasonally-varying parameters were introduced in a step-wise fashion into a mathematical model of the transmission dynamics of dengue viruses. The predicted prevalence of infection was then compared to observed seasonal patterns of disease. The strongest influences on the pattern of infection and its seasonal variation were duration of infectiousness of the host, vector mortality, and biting rate. However, seasonally-varying parameters such as the latent period of infection in the vector had to be incorporated into the model to generate the correct timing of peak infection prevalence. A few limiting variables usually control the prevalence of an infectious disease because small changes in their values can carry the infection beyond the threshold at which its basic reproductive number is one. It was changes in such parameters (vector biting and mortality rate) which caused seasonal prevalence, but the timing of peak prevalence was a result of time delays within the system.

Assessment of the factors associated with flavivirus seroprevalence in a population in Southern Vietnam.

Dengue and Japanese encephalitis flaviviruses cause severe disease and are hyperendemic in southern Vietnam. This study assesses associations between sociodemographic factors and flavivirus seroprevalence in this region. Sera were collected from 308 community and hospital-based subjects between April 1996 and August 1997 and tested with an indirect ELISA. The factors associated with seroprevalence were assessed using multivariate logistic regression. In this first report of adjusted prevalence odds ratios (POR) for flavivirus infection in Vietnam, seropositivity was associated with increasing age in children (multiple regression coefficients for a child compared to an adult = -4.975 and for age in children = 0.354) and residence in the city compared to surrounding rural districts. The association with age indicates that subjects were most likely to have acquired infection in early childhood. This is key to the design of Vietnamese health education and immunization programmes.

A single-molecule study of RNA catalysis and folding.

Using fluorescence microscopy, we studied the catalysis by and folding of individual Tetrahymena thermophila ribozyme molecules. The dye-labeled and surface-immobilized ribozymes used were shown to be functionally indistinguishable from the unmodified free ribozyme in solution. A reversible local folding step in which a duplex docks and undocks from the ribozyme core was observed directly in single-molecule time trajectories, allowing the determination of the rate constants and characterization of the transition state. A rarely populated docked state, not measurable by ensemble methods, was observed. In the overall folding process, intermediate folding states and multiple folding pathways were observed. In addition to observing previously established folding pathways, a pathway with an observed folding rate constant of 1 per second was discovered. These results establish single-molecule fluorescence as a powerful tool for examining RNA folding.

Use of duplex rigidity for stability and specificity in RNA tertiary structure.

The Tetrahymena group I ribozyme's oligonucleotide substrate, CCCUCUA(5), forms six base pairs with the ribozyme's internal guide sequence (IGS, 5'GGAGGG) to give the P1 duplex, and this duplex then docks into the active site via tertiary interactions. Shortening the substrate by three residues to give UCUA(5) reduces the equilibrium constant for P1 docking by approximately 200-fold even though UCUA(5) retains all the functional groups known to be involved in tertiary interactions [Narlikar, G. J., Bartley, L. E., Khosla, M., and Herschlag, D. (1999) Biochemistry 38, 14192-14204]. Here we show that the P1 duplex formed with UCUA(5) engages in all of the major tertiary interactions made by the standard P1 duplex. This suggests that the destabilization is not due to disruption of specific tertiary interactions. It therefore appears that the weaker docking of UCUA(5) arises from the increased conformational freedom of the undocked P1 duplex, which has three unpaired IGS residues and thus a larger entropic cost for docking. Further, a 2'-methoxy substitution at an IGS residue that is base-paired in the standard P1 duplex with CCCUCUA(5) but unpaired in the P1 duplex with UCUA(5) destabilizes docking of the standard P1 duplex approximately 300-fold more than it destabilizes docking of the P1 duplex formed with UCUA(5). These results suggest that fixation of groups in the context of a rigid duplex may be a general strategy used by RNA to substantially increase interaction specificity, both by aiding binding of the desired functional groups and by increasing the energetic cost of forming alternative interactions.

Characterization of a local folding event of the Tetrahymena group I ribozyme: effects of oligonucleotide substrate length, pH, and temperature on the two substrate binding steps.

Binding of the Tetrahymena group I ribozyme's oligonucleotide substrate occurs in two steps: P1 duplex formation with the ribozyme's internal guide sequence which forms an "open complex" is followed by docking of the P1 duplex into tertiary interactions within the catalytic core which forms a "closed complex". By systematically varying substrate length, pH, and temperature, we have identified conditions under which P1 duplex formation, P1 docking, or the chemical cleavage step limits the rate of the ribozyme reaction. This has enabled characterization of the individual steps as a function of substrate length, pH, and temperature, leading to several conclusions. (1) The rate constant for formation of the open complex is largely independent of substrate length, pH, and temperature, analogous to that of duplex formation in solution. This extends previous results suggesting that open complex formation entails mainly secondary structure formation and strengthens the view that the second binding step, P1 docking, represents a simple transition from secondary to tertiary structure in the context of an otherwise folded RNA. (2) The temperature dependence of the rate constant for P1 docking yields a negative activation entropy, in contrast to the positive entropy change previously observed for the docking equilibrium. This suggests a model in which tertiary interactions are not substantially formed in the transition state for P1 docking. (3) Shortening the substrate by three residues decreases the equilibrium constant for P1 docking by 200-fold, suggesting that the rigidity imposed by full-length duplex formation facilitates formation of tertiary interactions. (4) Once docked, shortened substrates are cleaved at rates within 3-fold of that for the full-length substrate. Thus, all the active site interactions required to accelerate the chemical cleavage event are maintained with shorter substrates. (5) The rate constant of approximately 10(3) min(-1) obtained for P1 docking is significantly faster than the other steps previously identified in the tertiary folding of this RNA. Nevertheless, P1 docking presumably follows other tertiary folding steps because the P1 duplex docks into a core that is formed only upon folding of the rest of the ribozyme.

Multiple recurrences of cervical intraepithelial neoplasia in women with the human immunodeficiency virus.

OBJECTIVE: To evaluate the long-term outcomes after treatment of cervical intraepithelial neoplasia (CIN) in women infected with the human immunodeficiency virus (HIV). METHODS: Human immunodeficiency virus-infected and HIV-negative women treated for CIN by ablation or excision were followed-up prospectively by cytology and colposcopy for periods of up to 73 months. RESULTS: Among 127 HIV-infected CIN patients, 62% developed recurrent CIN by 36 months after treatment, compared with 18% of the 193 HIV-negative CIN patients. Recurrence rates reached 87% in 41 HIV-infected women with CD4 counts less than 200 cells/mm3. Progression to higher-grade neoplasia, including one invasive cancer, occurred by 36 months in 25% of HIV-infected and 2% of HIV-negative women. After adjusting for age, CIN severity, and treatment type, predictors of recurrence included HIV infection (rate ratio 4.4), and, in HIV-positive women, low CD4 count (rate ratio 2.2). In patients treated by excision, predictors of recurrence included HIV infection (rate ratio 2.0) and residual CIN after treatment (rate ratio 2.7). After a second treatment,a second CIN recurrence developed in 14 of 33 HIV-infected and in one of 17 HIV-negative women. After a third treatment, three of six HIV-infected women developed a third recurrence. With long-term follow-up, 45% of treated HIV-infected CIN patients had chronic condylomatous changes in the cervix compared with 5% of HIV-negative women. CONCLUSION: In HIV-infected women, CIN may recur despite multiple treatments, and chronic condylomatous changes are common. Innovative therapies for controlling CIN in HIV-infected women are needed.

Newborn minor physical anomalies and problem behavior at age three.

The authors followed up 136 three-year-olds who had high or low scores for minor physical anomalies of face, head, hands, and feet at birth. Interviews with parents revealed that high-anomaly infants were somewhat more likely to have problem behaviors at age three; this was particularly true for hyperactive-impulsive behavior for boys. Preschool teachers' ratings of hyperactivity, however, did not show a significant relationship to anomaly score. The results suggest some congenital contributors to behavior disorders of childhood, but the relationship between anomalies and problem behavior is weak and limits clinical usefulness of this measure when used alone for identifying a high-risk population.