Robustness of reliable change indices to variability in Parkinson's disease with mild cognitive impairment.

Ability to identify change is crucial for measuring response to interventions and tracking disease progression. Beyond psychometrics, investigations of Parkinson's disease with mild cognitive impairment (PD-MCI) must consider fluctuating medication, motor, and mental status. One solution is to employ 90% reliable change indices (RCIs) from test manuals to account for account measurement error and practice effects. The current study examined robustness of 90% RCIs for 19 commonly used executive function tests in 14 PD-MCI subjects assigned to the placebo arm of a 10-week randomized controlled trial of atomoxetine in PD-MCI. Using 90% RCIs, the typical participant showed spurious improvement on one measure, and spurious decline on another. Reliability estimates from healthy adults standardization samples and PD-MCI were similar. In contrast to healthy adult samples, practice effects were minimal in this PD-MCI group. Separate 90% RCIs based on the PD-MCI sample did not further reduce error rate. In the present study, application of 90% RCIs based on healthy adults in standardization samples effectively reduced misidentification of change in a sample of PD-MCI. Our findings support continued application of 90% RCIs when using executive function tests to assess change in neurological populations with fluctuating status.

Fall frequency and risk assessment in early Parkinson's disease.

BACKGROUND: We sought to define the frequency of falls in early PD and assess potential risk factors for falls in this population. METHODS: We analyzed the data from two randomized, placebo controlled trials (NET-PD FS1 and FS-TOO) of 413 individuals with early PD over 18 months of follow-up in FS1 and 12 months in FS-TOO. Falls were defined as any report of falls on the UPDRS or the adverse event log. We assessed the frequency of falls overall and by age. The relationship between prespecified fall risk markers and the probability of falling was assessed using logistic and multiple logistic regression. A hurdle Poisson model was used to jointly model the probability of remaining fall-free and the number of falls. RESULTS: During the follow-up period, 23% of participants fell, and 11% were habitual fallers. In a multiple logistic regression model, age, baseline UPDRS Falling score, and baseline PDQ-39 scores were associated with subsequent fall risk (p < 0.001). Similarly, in a hurdle Poisson regression model, age, baseline UPDRS falling item, and baseline PDQ-39 were all significantly related to the probability of falling, but only UPDRS falling >0 was associated with the number of falls. CONCLUSION: Falls are frequent and are associated with impaired quality of life, even in early PD. Current standard rating scales do not sufficiently explain future fall risk in the absence of a prior fall history. New assessment methods for falls and postural instability are required to better evaluate this important problem in clinical trials and clinical practice.

The impact of depressive symptoms in early Parkinson disease.

BACKGROUND: Depressive disorders may affect up to 50% of patients with Parkinson disease (PD) and are associated with increased disability and reduced quality of life. No previous study has systematically examined the impact of depressive symptoms in early, untreated PD. METHODS: We administered the 15-item Geriatric Depression Scale (GDS-15) as part of two NIH-sponsored phase II clinical trials in PD, enrolling 413 early, untreated PD subjects. We used linear mixed models to examine the relationship of depressive symptoms, measured by the GDS-15, with motor function and activities of daily living (ADLs), as measured by the Unified PD Rating Scale (UPDRS). A time-dependent Cox model was used to examine the effect of demographic and clinical outcome measures as predictors of investigator-determined time to need for symptomatic therapy for PD. RESULTS: A total of 114 (27.6%) subjects screened positive for depression during the average 14.6 months of follow-up. Forty percent of these subjects were neither treated with antidepressants nor referred for further psychiatric evaluation. Depression, as assessed by the GDS-15, was a significant predictor of more impairment in ADLs (p < 0.0001) and increased need for symptomatic therapy of PD (hazard ratio = 1.86; 95% CI 1.29, 2.68). CONCLUSIONS: Clinically important depressive symptoms are common in early Parkinson disease (PD), but are often not treated. Depressive symptoms are an important contributor to disability and the decision to start symptomatic therapy for motor-related impairment in early PD, highlighting the broad importance of identifying and treating depression in this population.

Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs.

Many agents are being considered for treatment of Parkinson disease (PD). Given the large number of agents and the limited resources to evaluate new agents, it is essential to reduce the likelihood of advancing ineffective agents into large, long-term Phase III trials. Futility design methodology addresses this goal. The authors describe how a single-arm Phase II futility study uses a short-term outcome to compare a treatment group response to a predetermined hypothesized or historically based control response. The authors present advantages and limitations of futility designs along with examples derived from the data archive of a large Phase III efficacy study of treatments to delay PD progression, the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. Using the same control progression rate and treatment effect assumptions used to power the original DATATOP trial, the authors calculated the number of subjects needed to conduct two 12-month futility studies. DATATOP was designed to enroll 800 patients. Using data on 124 consecutive subjects randomized into each of the DATATOP treatment groups, the authors identified tocopherol as futile and deprenyl as worthy of further study. Using Phase II information, DATATOP could have been simplified from a 2 x 2 factorial design to a comparison of deprenyl vs placebo. While not testing efficacy, futility designs provide a strategy for discarding treatments unlikely to be effective in Phase III. A limitation is the dependence on historical data or hypothesized outcomes for untreated controls. Futility studies may decrease the time to identify treatments unworthy of further pursuit and reduce subjects' exposure to futile treatments.

Hepatitis C, diagnosis and management: a survey of practicing physicians in Hawaii.

We surveyed 652 Hawaii physicians who diagnosed hepatitis C (HCV) since 1997. Less than 20% of licensed physicians have diagnosed HCV and initial estimates suggest there are 12,000 to 18,000 undiagnosed HCV cases in Hawaii. Treatment is concentrated among twelve physicians and aggressive case finding may overwhelm present resources. More primary care physicians need to participate in the detection and management of HCV.

Evidence for widespread infection of wild rats with hepatitis E virus in the United States.

Hepatitis E is an important medical pathogen in many developing countries but is rarely reported from the United States, although antibody to hepatitis E virus (anti-HEV) is found in > 1% of U.S. citizens. Zoonotic spread of the virus is suspected. Sera obtained from 239 wild rats trapped in widely separated regions of the United States were tested for anti-HEV. Seventy-seven percent of rats from Maryland, 90% from Hawaii, and 44% from Louisiana were seropositive for anti-HEV. Rats from urban as well as rural areas were seropositive and the prevalence of anti-HEV IgG increased in parallel with the estimated age of the rats, leading to speculation that they might be involved in the puzzling high prevalence of anti-HEV among some U.S. city dwellers. The discovery of a in rats in the United States and the recently reported discovery that HEV is endemic in U.S. swine raise many questions about transmission, reservoirs, and strains of HEV in developed countries.

Serological cross-reactivities between the retroviruses HIV and HTLV-1 and the malaria parasite Plasmodium falciparum.

Serum samples from three populations of Papua New Guinea, where Plasmodium falciparum malaria and human T-lymphotropic virus type 1 (HTLV-1) are coendemic at high prevalence rates, showed statistically significant ELISA co-seropositivity and co-seronegativity. Cross-reactivity was further indicated by the presence of 10 bands ranging from 134 kDa to 18 kDa on immunoblots of electrophoresed whole lysate P. falciparum antigen against serum of HTLV-1 seropositive patients from an area where malaria is not present. Similarly, sera from patients positive for human immunodeficiency virus (HIV) from a non-malarious region produced immunoblot bands ranging from 134 kDa to 33 kDa to the P. falciparum antigen. The HTLV-1 and HIV serum samples yielded a number of immunoblot bands when reacted to an electrophoresed human O type red cell membrane antigen, but those bands had no identity to the cross-reactive bands on the P. falciparum antigen immunoblots. Malaria-positive sera from Papua New Guinean subjects presumed to be uninfected with HIV produced a variety of bands, some of intense prominence, to HIV antigen on diagnostic Western blots.

PIP: Serum samples from three populations of Papua New Guinea, where Plasmodium falciparum malaria and human T-lymphotropic virus type 1 (HTLV-1) are coendemic at high prevalence rates, showed statistically significant ELISA co-seropositivity and co-seronegativity. Cross-reactivity was further indicated by the presence of 10 bands ranging from 134 kDa to 18 kDa on immunoblots of electrophoresed whole lysate P. falciparum antigen against serum of HTLV-1 seropositive patients from an area where malaria is not present. Similarly, sera from patients positive for HIV from a nonmalarious region produced immunoblot bands ranging from 134 kDa to 33 kDa to the P. falciparum antigen. The HTLV-1 and HIV serum samples yielded a number of immunoblot bands when reacted to an electrophoresed human O type red cell membrane antigen, but those bands had no identity to the cross-reactive bands on the P. falciparum antigen immunoblots. Malaria-positive sera from Papua New Guinean subjects presumed to be uninfected with HIV produced a variety of bands, some of intense prominence, to HIV antigen on diagnostic Western blots.

Plasmodium falciparum-specific immunoglobulin G (IgG), IgM, and IgE antibodies in paired maternal-cord sera from east Sepik Province, Papua New Guinea.

Enzyme-linked immunosorbent assay (ELISA) and Western blot (immunoblot) serological analyses for immunoglobulin G (IgG), IgM, and IgE antibodies to Plasmodium falciparum were made from 46 maternal-cord serum pairs obtained from parturient East Sepik (Papua New Guinea) women and their newborn. Concurrent study of these women had shown that placental parasitemia rates were related to parity with the highest rate (41%) in the primiparous group and the lowest rate (3%) in the women who had given birth more than three times (> 3 parity group). Overall ELISA positivity rates for antimalarial IgG, IgM, and IgE antibodies in the maternal sera were 54.3, 28.2, and 8.3%, respectively, while those for the cord sera were 36.9, 0, and 16.6% respectively. Seropositivity rates were not related to maternal parity group, except for maternal IgE, in which there was a higher rate, of borderline significance, in the > 3 parity group than in the primiparous group. Cord IgE positivity was largely independent of maternal positivity and vice versa. Cord and maternal IgG immunoblot pairs showed near homology. IgG antibodies to the P. falciparum antigens of sizes < 36 kDa were either weak or absent in parity group 1 and 2 maternal-cord serum pairs. Neither ELISA or immunoblot revealed IgM antibody in the cord serum samples. Maternal IgM antibodies showed a heterogeneity of responses both between paired IgG immunoblots and between different serum samples. The IgE immunoblots exhibited a similar diversity, albeit of less complexity. The presence of P. falciparum-specific IgE in the cord sera would indicate that prenatal immune hypersensitization of the fetus to malaria had occurred.

Prenatal immune hypersensitization to malaria: Plasmodium falciparum-specific IgE antibody in paired maternal and cord sera from Papua New Guinea.

In a study of malaria and pregnancy in East Sepik Province of Papua New Guinea 45 maternal and cord serum pairs were tested for Plasmodium falciparum-specific IgE antibody. There were 17 positive sera: 6 cases of maternal serum alone, 5 cases of cord serum alone and 3 pairs of maternal and cord sera. IgE antibody positivity rates in the mothers increased with parity, whereas placental parasitaemia rates decreased. Cord serum positivity was not affected by parity. Immunoblots of the sera revealed a diversity of IgE antibodies to specific antigens of the P. falciparum lysate, but an IgE antibody to a 48kd antigen was present in all positive maternal and cord sera.

Synthetic peptides in HIV antibody screening and typing.

We have defined continuous native epitopes of HIV proteins by using a systematic epitope-scanning technology. We have demonstrated that there is a highly immunoreactive continuous native epitope region in the transmembrane protein gp41 of HIV-1 that is immunoreactive with all studied HIV-1 antibody-positive sera. The corresponding region in HIV-2 gp34 behaves similarly. There is a clear difference, however, between HIV type 1 and type 2 transmembrane proteins in the number of highly immunoreactive regions, when presented properly as synthetic antigens in solid-phase EIA, can provide tests unusually suitable for early and reliable diagnosis of HIV-1 and HIV-2 infections and for type-specific distinction of the two types of HIV infections.

PIP: This article reviews the basic method used to define native epitopes from transmembrane proteins and the function of synthetic peptides in HIV screening and typing. Identification of continuous native epitopes from structural protein sequences of HIV-1 and HIV-2 involves the use of systematic scanning epitope technology. Scanning profiles of these two types of HIV demonstrated that there is a highly immunoreactive continuous native epitope region in the transmembrane protein gp41 of HIV-1 as well as in the corresponding region in HV-2 gp34. However, the number of highly immunoreactive regions differs in the structural proteins of the two types of HIV infections. These highly immunoreactive regions, when presented accurately as synthetic antigens in solid-phase enzyme immunoassay, can provide tests that are remarkably appropriate for the early and reliable diagnosis and type-specification of HIV-1 and HIV-2 infections.

Treatment of intracranial dengue virus infections in mice with a lipophilic derivative of ribavirin.

Rimantadine, ribavirin, and 6-mercapto-9-(tetrahydro-2-furyl)purine, administered intraperitoneally every 8 h for 7 days starting minutes after virus challenge, had no effect on survival and mean survival time of BALB/c mice inoculated intracranially with dengue virus type 2. In contrast, intraperitoneal treatment with ribavirin 2',3',5'-triacetate, a lipophilic analog of ribavirin, effected significant increases in both mean survival time and survival rate, suggesting that ribavirin 2',3',5'-triacetate may be superior to rabavirin for treatment of viral diseases of the brain.

Antiviral effects if ribavirin and 6-mercapto-9-tetrahydro-2-furylpurine against dengue viruses in vitro.

The antiviral effects of ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) and 6-mercapto-9-tetrahydro-2-furylpurine (6-MPTF) against dengue viruses were examined in vitro. Ribavirin significantly reduced the growth of dengue virus types 1-4 in LLC-MK2 cells at concentrations well below cytotoxic levels (cell viability was determined by trypan blue dye exclusion) Addition of guanosine to ribavirin-treated dengue virus-infected cell cultures completely reversed the antiviral effect of the drug. In contrast, ribavirin had no effect on dengue virus replication in human peripheral blood leukocytes (PBL). 6-MPIF, a specific inhibitor of hypoxanthine-guanine phosphoribosyltransferase, did not significantly reduce the growth of dengue viruses in either LIC-MK2 cells or human PBL. However, synergistic effects of 6-MPTF and ribavirin were observed, as combined treatment of the drugs markedly suppressed the replication of dengue viruses in human PBL. The successful demonstration that dengue virus replication in mononuclear leukocytes is markedly suppressed by the combined treatment of ribavirin and 6-MPTF signals a need to evaluate the efficacy of this treatment against dengue virus infections in vivo.

Propagation of dengue viruses in murine cell cultures.

Dengue viruses were cultivated in Balb 3T12-3 cells, a continuous line of cells derived from mouse embryo cell cultures. Optimal serum concentrations were determined for maximal kinetics of virus replication. All four types of dengue viruses replicate in these cells, and peak virus titers were obtained by 72 hours post-infection. The successful growth of dengue viruses in a continuous line of mouse cells should allow for more extensive studies examining the cellular immune response to dengue virus infection in murine models.

Suppression of dengue virus replication in vitro by rimantadine hydrochloride.

The effects of rimantadine on dengue virus replication were examined in a variety of tissue culture systems. The growth of dengue virus type 2 in human peripheral blood leukocytes (PBL) was completely suppressed when rimantadine was included in the culture medium at a concentration of 25 microgram/ml. Similarly, rimantadine caused a significant inhibition of dengue virus replicaton in cultures of rhesus monkey PBL. Addition of drug into virus-infected LLC-MK2 cell cultures caused a decrease in the production of all four types of dengue virus. Maximal inhibition of dengue virus replication by rimantadine was observed when the drug was added immediately following the viral adsorption period. Rimantadine did not induce may cytopathic effects on either LLC-MK2 cells or PBL at concentrations less than 75 microgram/ml. These findings demonstrate that rimantadine is an effective inhibitor of dengue virus replication in vitro, and indicate a need for further examination of the efficacy of rimantadine against severe dengue virus disease.

In vitro virulence marker: growth of dengue-2 virus in human leukocyte suspension cultures.

We wished to find a simple, biologically relevant method to evaluate the virulence of dengue viruses for human beings. Since cells of mononuclear phagocyte lineage may be important sites of dengue infection in primates, we evaluated the permissiveness of these cells to dengue virus as a correlate of virus virulence. Two wild-type, large-plaque, monkey-virulent dengue-2 virus strains and two small-plaque, monkey-avirulent dengue-2 virus strains were evaluated for their ability to replicate in human peripheral blood leukocyte cultures supplemented with enhancing antibody. One of the small-plaque strains was demonstrated to have reduced virulence for man. Wild-type dengue-2 viruses replicated readily in peripheral blood leukocyte suspension cultures, whereas small-plaque dengue-2 strains did not. Differences between our data and results obtained by other workers employing adherent peripheral blood leukocytes are discussed. Antibody-enhanced growth of dengue virus in suspension cultures of human peripheral blood leukocytes gives promise of being a simple in vitro system for characterizing dengue virus virulence.

Inhibition of dengue virus replication by amantadine hydrochloride.

The effect of amantadine hydrochloride (1-adamantanamine hydrochloride) on dengue virus replication was examined in vitro. Amantadine decreased the titers of all four types of dengue viruses grown in LLC-MK2 cells by greater than 90% at concentrations of 50 micrograms/ml. There was no evidence for any cytopathic effect of the drug at concentrations less than 100 micrograms/ml. Studies of the time of addition showed that the antiviral effect was maximal when drug was added to virus cultures immediately after the viral adsorption period. In addition, amantadine caused a marked reduction in the growth of dengue virus type 2 in both human and rhesus peripheral blood leukocytes without affecting cell viabili ty. These findings demonstrate that amantadine significantly inhibits the replication of dengue viruses in vitro and indicate a need to determine the efficacy of this drug against dengue virus infections in vivo.

Transplacental transmission and neonatal infection with swine influenza virus (Hsw1N1) in swine.

To study the question of chronicity or latency of swine influenza virus (Hsw1N1) infections in swine, newborn pigs were exposed to the virus in two experiments, and pregnant gilts were exposed in another experiment. Of five pigs exposed at 5 days of age, virus was isolated from throat swab samples of all (up to 10 postexposure days (PED) in one pig) and from a blood sample from one pig on PED 1 and 3. Virus was not isolated from urine, tissues, or explants of organs from pigs euthanatized PED 20 to 67, and disease was not evident. Of 11 pigs exposed within 2 hours of birth (before consuming colostrum), virus was shed for longer periods (for 10 and 11 days in four pigs) and severe respiratory tract pathologic changes developed. However, there was no evidence of chronic or latent infections. There was evidence of transplacental transmission of virus in one of ten pigs born to pregnant gilts that were exposed 10, 24, and 39 days before parturition, respectively.