CHF5074 Reduces Biomarkers of Neuroinflammation in Patients with Mild Cognitive Impairment: A 12-Week, Double-Blind, Placebo-Controlled Study.

As neuroinflammation is an early event in the pathogenesis of Alzheimer's disease, new selective anti-inflammatory drugs could lead to promising preventive strategies. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of CHF5074, a new microglial modulator, in a 12-week, double-blind, placebo-controlled, parallel groups, ascending dose study involving 96 MCI patients. Subjects were allocated into three successive study cohorts to receive ascending, titrated doses of CHF5074 (200, 400 or 600 mg/day) or placebo. Vital signs, cardiac safety, neuropsychological performance and safety clinical laboratory parameters were assessed on all subjects. Plasma samples were collected throughout the study for measuring drug concentrations, soluble CD40 ligand (sCD40L) and TNF-α. At the end of treatment, cerebrospinal fluid (CSF) samples were optionally collected after the last dose to measure drug levels, ß-amyloid1-42 (Aß42), tau, phospho-tau181, sCD40L and TNF-α. Ten patients did not complete the study: one in the placebo group (consent withdrawn), two in the 200-mg/day treatment group (consent withdrawn and unable to comply) and seven in the 400-mg/day treatment group (five AEs, one consent withdrawn and one unable to comply). The most frequent treatment-emergent adverse events were diarrhea, dizziness and back pain. There were no clinically significant treatment-related clinical laboratory, vital sign or ECG abnormalities. CHF5074 total body clearance depended by gender, age and glomerular filtration rate. CHF5074 CSF concentrations increased in a dose-dependent manner. At the end of treatment, mean sCD40L and TNF-α levels in CSF were found to be inversely related to the CHF5074 dose (p=0.037 and p=0.001, respectively). Plasma levels of sCD40L in the 600-mg/day group were significantly lower than those measured in the placebo group (p=0.010). No significant differences between treatment groups were found in neuropsychological tests but a positive dose-response trend was found on executive function in APOE4 carriers. This study shows that CHF5074 is well tolerated in MCI patients after a 12-week titrated treatment up to 600 mg/day and dose-dependently affects central nervous system biomarkers of neuroinflammation.

Mass vaccination of children with pertussis toxoid--decreased incidence in both vaccinated and nonvaccinated persons.

During 1979-1995, there was no vaccination against pertussis in Sweden. With the aim of studying the epidemiology and transmission of pertussis, mass vaccination with pertussis toxoid of children born during the 1990s was instituted in the Göteborg area (population, 778,597) in 1995. Infants were offered 3 doses of pertussis toxoid combined with diphtheria and tetanus toxoids. Children aged > or =1 year were offered 3 doses of pertussis toxoid alone. From June 1995 through February 1999, 167,810 doses of pertussis toxoid were given to 61,219 children born during the 1990s (56% received 3 doses). The number of Bordetella pertussis isolates per year declined from 1214 (1993-1995) to 64 (January 1997 through June 1999; P<.0001), and hospitalizations due to pertussis declined from 62 to 5 (P<.0001). Significant decreases in B. pertussis isolates and hospitalizations occurred in all age groups, including adults and nonvaccinated infants. Thus, mass vaccination of children with pertussis toxoid decreases spread of B. pertussis in the population.

Immunogenicity and reactogenicity of diphtheria, tetanus and pertussis toxoids combined with inactivated polio vaccine, when administered concomitantly with or as a diluent for a Hib conjugate vaccine.

In an open trial, 400 infants were randomized to vaccination with a combined diphtheria-tetanus-pertussis-inactivated polio vaccine (DTaP-IPV) either mixed with a Haemophilus influenzae type b (Hib) tetanus toxoid conjugate immediately before injection (DTaP-IPV/Hib (mix)) or given concurrently with the Hib conjugate at separate injection sites (DTaP-IPV+Hib (sep)). The pertussis component consisted of pertussis toxoid alone. The vaccines were given intramuscularly at 3, 5 and 12 months of age. No vaccine-related serious adverse events occurred. Local reactions were evaluated from diary cards completed by the parents. Infants who received DTaP-IPV/Hib (mix) experienced fewer local reactions. Sera were obtained 28-45 days after the second and third vaccinations. Total Hib capsular antibodies were similar in the two groups after the second injection but lower in the group receiving DTaP-IPV/Hib (mix) than in the group receiving DTaP-IPV+Hib (sep) after the third injection (geometric mean 6.1 vs 10.4 microg/ml). Mixing of the vaccines also led to somewhat lower diphtheria toxin antibodies (5.9 vs. 7.7 IU/ml after the third injection) while tetanus antibodies were higher (3.9 vs. 2.5 IU/ml after the third injection). Antibodies against pertussis toxin and the three polio virus types were similar in the two groups. The moderate impairment of the Hib antibody response caused by mixing of the Hib conjugate with aluminium adsorbed DTaP may be due to physicochemical interference but is probably of little clinical importance because of the ability of the Hib conjugates to induce an immunologic memory.

Population-based study of the adequacy of well-child care services: a rural county's report card.

OBJECTIVE: To determine the adequacy of well-child care services using a population-based study. DESIGN: The medical records of all county providers and the immunization records at the local health department were reviewed. A county birth cohort, identified using electronic birth certificates, was compared with those who migrated into the area (hereafter, in-migrants). SETTING: All primary care sites (private, network, etc) in a rural county. PATIENTS: Two-year-old children born between May 31, 1993, and May 30, 1994. MAIN OUTCOME MEASURES: Immunization rates and preventive screenings. RESULTS: A total of 674 medical records were reviewed. Of these, 377 (56%) belonged to a county birth cohort and 297 (44%) were in-migrants. Medical records of 64% of the birth cohort were reviewed. Among all 2-year-olds, 80% received 4 doses of diphtheria and tetanus toxoids and pertussis vaccine; 89%, 3 doses of Haemophilus influenzae type b (Hib); 75%, 4 doses of Hib; 77%, 3 doses of hepatitis B vaccine; 85%, measles-mumps-rubella vaccine; 85%, 3 doses of oral poliovirus vaccine; 17%, varicella live virus vaccine (Varivax). The 4:3:1 rate was 75% at age 2 years. Sixty-eight percent had had 1 hematocrit, 74% had 1 lead screening test, and 43% had 2 lead screening tests. A total of 64% had had 6 well-child visits and 30% had had 9. The mean number of weights and heights measured was 4.8 and 4.5, respectively, at age 1 year and 7.3 and 6.8, respectively, at age 2 years. The birth cohort had notably higher rates of documented immunization and preventive screening than in-migrants. CONCLUSIONS: This study demonstrated immunization coverage at or below the national average, and well-child care service provisions below American Academy of Pediatrics standards at a county level. This study enabled individual primary care sites to assess their well-child care provision and provided a useful baseline for targeting the improvement of well-child care services in the county.

Cryptosporidiosis in children during a massive waterborne outbreak in Milwaukee, Wisconsin: clinical, laboratory and epidemiologic findings.

During the spring of 1993 an estimated 403000 residents of the greater Milwaukee, Wisconsin area experienced gastrointestinal illness due to infection with the parasite Cryptosporidium parvum following contamination of the city's water supply. To define the clinical, laboratory and epidemiologic features of outbreak-associated cryptosporidiosis in children, medical and laboratory records for all children submitting stool samples to the microbiology laboratory of the Children's Hospital of Wisconsin between 7 April and 13 May 1993 were reviewed retrospectively. Interviews with parents were also conducted to obtain additional clinical history. Cryptosporidium, as the sole pathogen, was identified in stools from 49 (23%) of the 209 children enrolled in the study. Children with laboratory-confirmed cryptosporidiosis were more likely to live in areas of Milwaukee supplied with contaminated water (RR = 1.92, CI = 1.19-3.09), to be tested later in their illness (P < 0.05), to have submitted more than one stool specimen (P = 0.01), to have an underlying disease that altered their immune status (RR = 2.78, CI = 1.60-4.84), and to be older than 1 year of age (RR = 2.02, CI = 1.13-3.60). Clinical illness in these patients was more prolonged and associated with weight loss and abdominal cramps compared with Cryptosporidium-negative children. In the context of this massive waterborne outbreak relatively few children had documented infection with Cryptosporidium. If many children who tested negative for the parasite were truly infected, as the epidemiologic data suggest, existing laboratory tests for Cryptosporidium were insensitive, particularly early in the course of illness.

The impact of WIC and AFDC in screening and delivering childhood immunizations.

Two publicly funded programs, the Special Supplemental Food Program for Women, Infants and Children (WIC) and Aid to Families with Dependent Children (AFDC), serve large numbers of children who may be at risk for poor immunization status. A review of the literature as well as conference abstracts and program reports for studies of immunization initiatives carried out in these settings was conducted. Although the available literature is limited, it does indicate that children in these programs have low immunization levels and that interventions to improve their immunization status can be successful. Measures to improve immunization status should be implemented through WIC and AFDC.

Epidemiologic applications of novel molecular methods to detect and differentiate small round structured viruses (Norwalk-like viruses).

The molecular epidemiology of a large, multistate outbreak of oyster-associated gastroenteritis [Kohn et al. (1995): Journal of the American Medical Association 273:466-471. Dowell et al. (1995): Journal of Infectious Diseases 171:1497-1503.] was examined using new methods to detect small round structured viruses (SRSVs) by reverse transcription-polymerase chain reaction (RT-PCR) and to characterize strains by Southern hybridization and nucleotide sequencing of 81-bp of a PCR product amplified from the RNA polymerase gene. Of 37 stool specimens examined from patients in eight clusters of the multistate outbreak, 32 (86%) gave RT-PCR products specific for SRSVs of P1-A phylogenetic group. Nineteen PCR products from the eight clusters were confirmed to have the identical sequence, indicating that this large outbreak was attributed to a single strain of SRSV. In one of the eight clusters, five (63%) of eight patients had a mixed infection with a second SRSV strain that belonged to P2-B phylogenetic group. Of 12 specimens from patients in five other outbreaks and one sporadic case which occurred at the same time as the multistate outbreak, 10 (83%) gave products specific for SRSVs representing four phylogenetic groups (P1-A, P1-B, P2-A, and P2-B). The sequences of the P1-A products from two outbreaks and that of the P2-B product from another outbreak were identical to the P1-A sequence from the eight clusters and the P2-B sequence from the one cluster of the multistate outbreak, respectively. These results demonstrate the first application of these methods to enhance our understanding of the molecular epidemiology of SRSVs and provide answers of public health interest that could not have been obtained using classical epidemiologic methods alone.

A multistate outbreak of oyster-associated gastroenteritis: implications for interstate tracing of contaminated shellfish.

In November 1993, clusters of gastroenteritis in six states following oyster consumption were investigated to identify common features, and stool samples were obtained to identify a pathogen. Efforts were made to account for all potentially contaminated oysters using harvest tags and the interstate recall system. Consumption of oysters was associated with illness in 10 clusters; no other food was implicated. A Norwalk-like virus was detected by electron microscopy in 9 of 18 samples and by reverse transcription-polymerase chain reaction in 20 of 26 samples from 6 clusters. Nucleotide sequences of a 123-bp fragment from all specimens were identical, consistent with a common source outbreak. Implicated oysters were harvested from the Louisiana coast between 9 and 12 November. Although some were recalled and destroyed, most oysters harvested from the area during this time remain unaccounted for. Current regulations and commercial practices need to be revised to permit thorough tracing and recall of contaminated oysters and to improve control of future epidemics.

Comparison of four different methods for detection of Cryptosporidium species.

Newly available assays offer alternatives to conventional microscopic examination for Cryptosporidium spp. We compared two enzyme immunoassays, ProSpect Cryptosporidium microtiter assay (Alexon, Inc., Mountain View, Calif.) and Color Vue Cryptosporidium assay (Serady, Indianapolis, Ind.), and a direct immunofluorescent assay, Merifluor Cryptosporidium kit (Meridian Diagnostics, Cincinnati, Ohio), with acid-fast Kinyoun-staining for the detection of Cryptosporidium spp. Examinations were performed on 129 stool specimens received from patients during a recent waterborne outbreak. A specimen was considered positive when organisms could be identified visually by acid-fast and immunofluorescent stains or if organisms could be visualized by either acid-fast or immunofluorescent stain and detected by both enzyme immunoassays. The final number of positive specimens was 55. No single procedure detected all 55 positive specimens. Of these, ProSpect and Color Vue detected 52 (sensitivity, 94.5%), and the Kinyoun stain and Merifluor detected 53 (sensitivity, 96.4%). The final number of negative specimens was 74. One false-positive result was seen with both the Kinyoun stain and the ProSpect assay. The Color Vue and ProSpect assays required the most hands-on technologist time. The ProSpect assay and Merifluor kit were easiest to perform. The acid-fast stain was difficult to interpret. The Merifluor kit was easiest to read and was adaptable to both batch and single testing. Overall, the Kinyoun stain and the Merifluor test were preferable to both of the enzyme immunoassays because of the high reagent cost and hands-on time required for the enzyme immunoassays. The difficult interpretation of the Kinyoun stain smears made the Merifluor a more desirable test despite its higher cost. We conclude that all methods tested were equally sensitive and specific for the detection of Cryptosporidium spp. Ease of use, adaptability to batch testing, and cost are important criteria in determining the method of choice.

High prevalence of rotavirus infection among neonates born at hospitals in Delhi, India: predisposition of newborns for infection with unusual rotavirus.

Although rotavirus is the most common cause of diarrhea in children older than 3 months of age, neonatal infections, which are asymptomatic, have rarely been surveyed and have been identified in only a few discrete nosocomial outbreaks. After such a nosocomial outbreak of rotavirus infection among newborns at a hospital in Delhi, we screened infants born at five other nurseries in the immediate area to assess the prevalence of neonatal infections and to determine whether the unique neonatal rotavirus strain, 116E, previously identified in Delhi, was present in other settings. Infection was documented in 43 to 78% of hospitalized infants between 4 and 6 days of life born at five of the six hospitals. Infection with strains related to 116E were the most common, but other unusual strains and no strains common in the community were detected. In addition a shift in genotype was observed among specimens collected from two of these hospitals during a 2-year period. Our observation that neonatal rotavirus infections are more common than recognized previously would encourage the administration of rotavirus vaccines during the newborn period and suggests that the low efficacy of vaccines observed during trials in developing countries may be caused by early natural exposure of infants before immunization. The extraordinary predisposition of neonates for unusual rotavirus strains not commonly found in the community should encourage others to screen neonates for this infection, characterize the strains more fully and attempt to understand at a molecular level the unique relationship between the infecting strain type and the age of the host.

Characterization of rotavirus strains from newborns in New Delhi, India.

Between 1986 and 1993, 72% of rotavirus strains isolated from newborns at five hospitals in New Delhi, India, had long electropherotypes, subgroup II VP6 antigens, and G and P genotypes (G9P11) identical to those of prototype strain 116E. A novel strain with a G9P6 genotype, representing 13% of the isolates, was identified. These results demonstrate that G9P11 and G9P6 rotavirus strains are common in nurseries in New Delhi.

Differential recognition of a protective filarial antigen by antibodies from humans with bancroftian filariasis.

The objectives of this study were to identify filarial antigens which induce enhanced clearance of circulating microfilariae and to establish if human antibody reactivity with these molecules correlates with the apparent parasite burdens of residents of an endemic area of Bancroftian filariasis. Mice immunized with an extract of Brugia malayi microfilariae develop IgG antibodies to four major filarial antigens with an apparent molecular weight (Mr) of approximately 112,000, 60,000, 45,000, and 25,000. Animals immunized with gel slices containing the approximately 25,000-Mr antigen are resistant to intravenous challenge with live microfilariae (78-98% reduction in parasitemia vs. controls, P less than 0.01). A group of 22 amicrofilaremic humans had a significantly higher (P less than 0.025) mean antibody titer to the Mr 25,000-Mr antigen (1: 424) than 16 microfilaremic individuals (1:95). There were no significant differences between the two groups in antibody titers to filarial antigens of Mr approximately 112,000, 60,000, and 45,000 Mr. These data suggest that a high degree of reactivity to the 25,000-Mr antigen in humans with lymphatic filariasis correlates with a parasitologic status that is least conducive to transmission of infection.

Induction of protection against Brugia malayi infection in jirds by microfilarial antigens.

The development of immunologic methods to reduce transmission of human lymphatic filariasis depends on measures that will enhance the host's ability to eliminate infective larvae, adult worms, or blood-borne microfilariae (mf). The present study was designed to assess the capacity of a crude extract of Brugia malayi mf to decrease the level of microfilaremia and adult worm burden in jirds inoculated with infective larvae, and to identify the filarial antigens that elicit antibody responses in these animals. Thirty weeks after subcutaneous inoculation with 75 infective larvae, 100% of control jirds were patent (i.e., had microfilaremia) compared with 60% of the group immunized with 10 micrograms of crude microfilarial extract (p less than 0.05). In addition, microfilaremia was lower in patent immunized animals compared with controls (p less than 0.05). The mean total number of adult female B. malayi per jird recovered at necropsy in control animals was 16.0 vs 7.0 in immunized jirds (p less than 0.05). Serum of immunized jirds contained anti-mf antibodies with an end titer of 1:8000, a value similar to that of animals with chronic B. malayi infection. Microfilarial antigens of Mr approximately 150,000, 75,000, 42,000, and 25,000 were identified in immunoblotting studies by reactivity with antibodies in sera of immunized jirds. Antibodies induced by immunization with microfilarial extract were not specific for this stage of the parasite life cycle, as jird anti-mf antibodies reacted with a Mr approximately 150,000 and several Mr 50,000 to 110,000 antigens derived from immature and mature adult parasites of both sexes. These data indicate that immunization of jirds with a water soluble microfilarial extract enhances the host's ability to eliminate adult worms and blood-borne mf. The filarial antigens that induce antibodies in immunized jirds have been identified.