California Health and Human Services Agency

The development of an effective human immunodeficiency virus type 1 (HIV-1) vaccine is likely to depend on knowledge of circulating variants of genes other than the commonly sequenced gag and env genes. In addition, full-genome data are particularly limited for HIV-1 subtype C, currently the most commonly transmitted subtype in India and worldwide. Likewise, little is known about sequence variation of HIV-1 in India, the country facing the largest burden of HIV worldwide. Therefore, the objective of this study was to clone and characterize the complete genome of HIV-1 from seroconverters infected with subtype C variants in India. Cocultured HIV-1 isolates were obtained from six seroincident individuals from Pune, India, and virtually full-length HIV-1 genomes were amplified, cloned, and sequenced from each. Sequence analysis revealed that five of the six genomes were of subtype C, while one was a mosaic of subtypes A and C, with multiple breakpoints in env, nef, and the 3' long terminal repeat as determined by both maximal chi2 analysis and phylogenetic bootstrapping. Sequences were compared for preservation of known cytotoxic T lymphocyte (CTL) epitopes. Compared with those of the HIV-1LAI sequence, 38% of well-defined CTL epitopes were identical. The proportion of nonconservative substitutions for Env, at 61%, was higher (P < 0.001) than those for Gag (24%), Pol (18%), and Nef (32%). Therefore, characterized CTL epitopes demonstrated substantial differences from subtype B laboratory strains, which were most pronounced in Env. Because these clones were obtained from Indian seroconverters, they are likely to facilitate vaccine-related efforts in India by providing potential antigens for vaccine candidates as well as for assays of vaccine responsiveness.

OBJECTIVE: The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if botulinum toxin is used as a biological weapon against a civilian population. PARTICIPANTS: The working group included 23 representatives from academic, government, and private institutions with expertise in public health, emergency management, and clinical medicine. EVIDENCE: The primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE (1960-March 1999) and their professional collections for literature concerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opinions were sought from the working group and other experts on diagnosis and management of botulism. Additional MEDLINE searches were conducted through April 2000 during the review and revisions of the consensus statement. CONSENSUS PROCESS: The first draft of the working group's consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group convened to review the first draft in May 1999. Working group members reviewed subsequent drafts and suggested additional revisions. The final statement incorporates all relevant evidence obtained in the literature search in conjunction with final consensus recommendations supported by all working group members. CONCLUSIONS: An aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.

OBJECTIVE: The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals following the use of plague as a biological weapon against a civilian population. PARTICIPANTS: The working group included 25 representatives from major academic medical centers and research, government, military, public health, and emergency management institutions and agencies. EVIDENCE: MEDLINE databases were searched from January 1966 to June 1998 for the Medical Subject Headings plague, Yersinia pestis, biological weapon, biological terrorism, biological warfare, and biowarfare. Review of the bibliographies of the references identified by this search led to subsequent identification of relevant references published prior to 1966. In addition, participants identified other unpublished references and sources. Additional MEDLINE searches were conducted through January 2000. CONSENSUS PROCESS: The first draft of the consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group was convened to review drafts of the document in October 1998 and May 1999. The final statement incorporates all relevant evidence obtained by the literature search in conjunction with final consensus recommendations supported by all working group members. CONCLUSIONS: An aerosolized plague weapon could cause fever, cough, chest pain, and hemoptysis with signs consistent with severe pneumonia 1 to 6 days after exposure. Rapid evolution of disease would occur in the 2 to 4 days after symptom onset and would lead to septic shock with high mortality without early treatment. Early treatment and prophylaxis with streptomycin or gentamicin or the tetracycline or fluoroquinolone classes of antimicrobials would be advised.

Infectious retroviruses have been detected in 22 of 45 randomly selected patients with acquired immune deficiency syndrome (AIDS) and in other individuals from San Francisco. The AIDS-associated retroviruses (ARV) studied in detail had a type D morphology, Mg2+-dependent reverse transcriptase, and cytopathic effects on lymphocytes. The viruses can be propagated in an established adult human T cell line, HUT-78. They cross-react with antiserum to the lymphadenopathy-associated retrovirus isolated from AIDS patients in France. Antibodies to ARV were found in all 86 AIDS patients and in a high percentage of 88 other homosexual men in San Francisco. This observation indicates the widespread presence of these lymphocytopathic retroviruses and their close association with AIDS.

OBJECTIVE: The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if tularemia is used as a biological weapon against a civilian population. PARTICIPANTS: The working group included 25 representatives from academic medical centers, civilian and military governmental agencies, and other public health and emergency management institutions and agencies. EVIDENCE: MEDLINE databases were searched from January 1966 to October 2000, using the Medical Subject Headings Francisella tularensis, Pasteurella tularensis, biological weapon, biological terrorism, bioterrorism, biological warfare, and biowarfare. Review of these references led to identification of relevant materials published prior to 1966. In addition, participants identified other references and sources. CONSENSUS PROCESS: Three formal drafts of the statement that synthesized information obtained in the formal evidence-gathering process were reviewed by members of the working group. Consensus was achieved on the final draft. CONCLUSIONS: A weapon using airborne tularemia would likely result 3 to 5 days later in an outbreak of acute, undifferentiated febrile illness with incipient pneumonia, pleuritis, and hilar lymphadenopathy. Specific epidemiological, clinical, and microbiological findings should lead to early suspicion of intentional tularemia in an alert health system; laboratory confirmation of agent could be delayed. Without treatment, the clinical course could progress to respiratory failure, shock, and death. Prompt treatment with streptomycin, gentamicin, doxycycline, or ciprofloxacin is recommended. Prophylactic use of doxycycline or ciprofloxacin may be useful in the early postexposure period.

Abstract Objective : To examine the relation between health outcomes and the equality with which income is distributed in the United States. Design : The degree of income inequality, defined as the percentage of total household income received by the less well off 50% of households, and changes in income inequality were calculated for the 50 states in 1980 and 1990. These measures were then examined in relation to all cause mortality adjusted for age for each state, age specific deaths, changes in mortalities, and other health outcomes and potential pathways for 1980, 1990, and 1989-91. Main outcome measure : Age adjusted mortality from all causes. Results : There was a significant correlation (r=0.62, P&lt;0.001) between the percentage of total household income received by the less well off 50% in each state and all cause mortality, unaffected by adjustment for state median incomes. Income inequality was also significantly associated with age specific mortalities and rates of low birth weight, homicide, violent crime, work disability, expenditures on medical care and police protection, smoking, and sedentary activity. Rates of unemployment, imprisonment, recipients of income assistance and food stamps, lack of medical insurance, and educational outcomes were also worse as income inequality increased. Income inequality was also associated with mortality trends, and there was a suggestion of an impact of inequality trends on mortality trends. Conclusions : Variations between states in the inequality of the distribution of income are significantly associated with variations between states in a large number of health outcomes and social indicators and with mortality trends. These differences parallel relative investments in human and social capital. Economic policies that influence income and wealth inequality may have an important impact on the health of countries. Key messages There was a significant correlation (r=0.62) between the proportion of total household income received by the less well off 50% of households and variation between states in death rates for the United States Income inequality was also significantly related to changes in mortality with smaller declines between 1980-90 in those states with greater income inequality Income inequality was associated with a large number of other health outcomes and with measures related to investments in human and social capital Economic policies that increase income inequality may also have a deleterious effect on population health

Autism spectrum disorders (ASDs) are complex, lifelong, neurodevelopmental conditions of largely unknown cause. They are much more common than previously believed, second in frequency only to mental retardation among the serious developmental disorders. Although a heritable component has been demonstrated in ASD etiology, putative risk genes have yet to be identified. Environmental risk factors may also play a role, perhaps via complex gene-environment interactions, but no specific exposures with significant population effects are known. A number of endogenous biomarkers associated with autism risk have been investigated, and these may help identify significant biologic pathways that, in turn, will aid in the discovery of specific genes and exposures. Future epidemiologic research should focus on expanding population-based descriptive data on ASDs, exploring candidate risk factors in large well-designed studies incorporating both genetic and environmental exposure data and addressing possible etiologic heterogeneity in studies that can stratify case groups and consider alternate endophenotypes.

Among the many genera of free-living amoebae that exist in nature, members of only four genera have an association with human disease: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri and Sappinia diploidea. Acanthamoeba spp. and B. mandrillaris are opportunistic pathogens causing infections of the central nervous system, lungs, sinuses and skin, mostly in immunocompromised humans. Balamuthia is also associated with disease in immunocompetent children, and Acanthamoeba spp. cause a sight-threatening infection, Acanthamoeba keratitis, mostly in contact-lens wearers. Of more than 30 species of Naegleria, only one species, N. fowleri, causes an acute and fulminating meningoencephalitis in immunocompetent children and young adults. In addition to human infections, Acanthamoeba, Balamuthia and Naegleria can cause central nervous system infections in animals. Because only one human case of encephalitis caused by Sappinia diploidea is known, generalizations about the organism as an agent of disease are premature. In this review we summarize what is known of these free-living amoebae, focusing on their biology, ecology, types of disease and diagnostic methods. We also discuss the clinical profiles, mechanisms of pathogenesis, pathophysiology, immunology, antimicrobial sensitivity and molecular characteristics of these amoebae.

Guidelines for the diagnosis and treatment of patients with encephalitis were prepared by an Expert Panel of the Infectious Diseases Society of America. The guidelines are intended for use by health care providers who care for patients with encephalitis. The guideline includes data on the epidemiology, clinical features, diagnosis, and treatment of many viral, bacterial, fungal, protozoal, and helminthic etiologies of encephalitis and provides information on when specific etiologic agents should be considered in individual patients with encephalitis.

The ability of antibodies to neutralize diverse primary isolates of human immunodeficiency virus-type 1 in vitro has been questioned, with implications for the likely efficacy of vaccines. A recombinant human antibody to envelope glycoprotein gp120 was generated and used to show that primary isolates are not refractory to antibody neutralization. The recombinant antibody neutralized more than 75 percent of the primary isolates tested at concentrations that could be achieved by passive immunization, for example, to interrupt maternal-fetal transmission of virus. The broad specificity and efficacy of the antibody implies the conservation of a structural feature on gp120, which could be important in vaccine design.

OBJECTIVE: To develop consensus-based recommendations for measures to be taken by medical and public health professionals following the use of anthrax as a biological weapon against a civilian population. PARTICIPANTS: The working group included 21 representatives from staff of major academic medical centers and research, government, military, public health, and emergency management institutions and agencies. EVIDENCE: MEDLINE databases were searched from January 1966 to April 1998, using the Medical Subject Headings anthrax, Bacillus anthracis, biological weapon, biological terrorism, biological warfare, and biowarfare. Review of references identified by this search led to identification of relevant references published prior to 1966. In addition, participants identified other unpublished references and sources. CONSENSUS PROCESS: The first draft of the consensus statement was a synthesis of information obtained in the formal evidence-gathering process. Members of the working group provided formal written comments which were incorporated into the second draft of the statement. The working group reviewed the second draft on June 12, 1998. No significant disagreements existed and comments were incorporated into a third draft. The fourth and final statement incorporates all relevant evidence obtained by the literature search in conjunction with final consensus recommendations supported by all working group members. CONCLUSIONS: Specific consensus recommendations are made regarding the diagnosis of anthrax, indications for vaccination, therapy for those exposed, postexposure prophylaxis, decontamination of the environment, and additional research needs.

Abstract This article reviews the emissions, environmental fate and transport, analytical chemistry, uptake and metabolism, toxicology, and human epidemiology of chromium. Chromium is unique among regulated toxic elements in the environment in that different species of chromium, specifically chromium (III) and chromium (VI), are regulated in different ways, in contrast to other toxic elements where the oxidation state is not distinguished. In both industrial and environmental situations chromium (III) and chromium (VI) can inter-convert, with reduction of chromium (VI) to chromium (III) generally being favored in most environmental situations. Chromium released into the air, water, and soil can be transported among the various environmental media through various intermedia transport processes. Once in the environment, chromium can be taken up by human and other ecological receptors. Chromium (III) is generally absorbed through cell membranes albeit to a significantly lesser degree than chromium (VI). Because most of the biosphere is reducing for chromium (VI) and chromium (III) is relatively immobile, there is little bioconcentration or biomagnification of chromium (VI). Chromium appears to be a nutrient for at least some plants and animals, including humans, although chromium (VI) species have been reported to be toxic to bacteria, plants, and animals. Human toxicity includes lung cancer, liver, kidney and gastric damage, and epidermal irritation and sensiti-zation. However, it is noted that medical, toxicological, and epidemiological evidence suggests that not all compounds containing chromium (VI) species (e.g., chromate salts) are carcinogenic. Keywords: chromium (III)chromium (VI)intermedia transport and transformationsexposuretoxicology.

CONTEXT: Exposure to maternal or placental infection is related to risk of preterm birth and, in premature infants, of brain lesions predictive of cerebral palsy (CP). Few studies have investigated whether maternal infection is associated with risk of CP in children of normal birth weight. OBJECTIVE: To investigate maternal infection during the admission for delivery as a possible risk factor for CP in infants born weighing 2500 g or more. DESIGN: Population-based case-control study. SETTING: All hospitals in 4 northern California counties, 1983 through 1985. PARTICIPANTS: A total of 46 children with disabling spastic CP who had no recognized prenatal brain lesions and 378 randomly selected control children weighing 2500 g or more at birth and surviving to age 3 years. MAIN OUTCOME MEASURES: Disabling spastic CP and signs of neonatal morbidity. RESULTS: Maternal fever exceeding 38 degrees C in labor was associated with increased risk of unexplained CP (odds ratio [OR], 9.3; 95% confidence interval [CI], 2.7-31.0), as was a clinical diagnosis of chorioamnionitis. One or more indicators of maternal infection were present in 2.9% of control children, 22% of children with CP (OR, 9.3; 95% CI, 3.7-23.0), and 37% of those with the spastic quadriplegic subtype of CP (OR, 19.0; 95% CI, 6.5-56.0). Newborns exposed to maternal infection, both cases and controls, had 5-minute Apgar scores below 6 more often than those unexposed. Among children with CP, those born to infected women were more often hypotensive, needed intubation, had neonatal seizures, and received a clinical diagnosis of hypoxic-ischemic encephalopathy. CONCLUSION: Intrauterine exposure to maternal infection was associated with a marked increase in risk of CP in infants of normal birth weight. Maternal infection was also linked with low Apgar scores, other evidence of hypotension [corrected] and need for resuscitation, and neonatal seizures-signs commonly attributed to birth asphyxia.

Precision medicine is making an impact on patients, health care delivery systems, and research participants in ways that were only imagined fifteen years ago when the human genome was first sequenced. Discovery of disease-causing and drug-response genetic variants has accelerated, while adoption into clinical medicine has lagged. We define precision medicine and the stakeholder community required to enable its integration into research and health care. We explore the intersection of data science, analytics, and precision medicine in the formation of health systems that carry out research in the context of clinical care and that optimize the tools and information used to deliver improved patient outcomes. We provide examples of real-world impact and conclude with a policy and economic agenda necessary for the adoption of this new paradigm of health care both in the United States and globally.

It has been almost 10 years since a major review on the association of Aeromonas with human disease has been published. During that period the number of valid species in the genus has grown to 14, with a new family (Aeromonadaceae) established to house this genus. Despite this explosion in the number of new genomospecies, only five (Aeromonas hydrophila, A. caviae, A. veronii, A. jandaei, and A. schubertii) are currently recognized as human pathogens. New syndromes attributed to this genus include hemolytic uremic syndrome, burn-associated sepsis, and a variety of respiratory tract infections, including epiglottitis. Convincing evidence suggests that some aeromonads do cause gastroenteritis, but it is presently unclear whether many of the strains isolated from feces are involved in diarrheal disease. Many questions regarding this genus remain unanswered.

BACKGROUND: Encephalitis is a complex syndrome, and its etiology is often not identified. The California Encephalitis Project was initiated in 1998 to identify the causes and further describe the clinical and epidemiologic characteristics of encephalitis. METHODS: A standardized report form was used to collect demographic and clinical data. Serum, cerebrospinal fluid, and respiratory specimens were obtained prospectively and were tested for the presence of herpesviruses, arboviruses, enteroviruses, measles, respiratory viruses, Chlamydia species, and Mycoplasma pneumoniae. The association between an identified infection and encephalitis was defined using predetermined, organism-specific criteria for confirmed, probable, or possible causes. RESULTS: From 1998 through 2005, a total of 1570 patients were enrolled. Given the large number of patients, subgroups of patients with similar clinical characteristics and laboratory findings were identified. Ten clinical profiles were described. A confirmed or probable etiologic agent was identified for 16% of cases of encephalitis: 69% of these agents were viral; 20%, bacterial; 7%, prion; 3%, parasitic; and 1%, fungal. An additional 13% of cases had a possible etiology identified. Many of the agents classified as possible causes are suspected but have not yet been definitively demonstrated to cause encephalitis; these agents include M. pneumoniae (n=96), influenza virus (n=22), adenovirus (n=14), Chlamydia species (n=10), and human metapneumovirus (n=4). A noninfectious etiology was identified for 8% of cases, and no etiology was found for 63% of cases. CONCLUSIONS: Although the etiology of encephalitis remains unknown in most cases, the recognition of discrete clinical profiles among patients with encephalitis should help focus our efforts toward understanding the etiology, pathogenesis, course, and management of this complex syndrome.

The relation between level of physical activity and risk of subsequent depression was examined using three waves of data from the Alameda County Study. Among subjects who were not depressed at baseline, those who reported a low activity level were at significantly greater risk for depression at the 1974 follow-up than were those who reported high levels of activity at baseline. Adjustments for physical health, socioeconomic status, life events, social supports, and other health habits did not affect the association appreciably. Associations between 1965-1974 changes in activity level and depression in the 1983 follow-up suggest that the risk of depression can be altered by changes in exercise habits, although these associations were not statistically significant after adjustment for covariates. These results provide somewhat stronger evidence for an activity-depression link than do previous studies, and they argue for the inclusion of exercise programs as part of community mental health programs, as well as for further studies that focus on the relation between life-style and mental health.

This paper reviews the process of elimination of creatinine (CRE), and the limitations presented when using it to express urine concentrations. This literature review leads to three conclusions: (1) CRE excretion is subject to wide fluctuations due to specific internal and external factors; (2) the use of CRE to correct chemical concentrations in urine will not necessarily improve the correlation to the exposure dose for all chemicals (it may, in fact, worsen the result); and (3) other means of expressing urine concentration may offer greater accuracy towards estimating individually absorbed dose.

Although official efforts to control air pollution have traditionally focused on outdoor air, it is now apparent that elevated contaminant concentrations are common inside some private and public buildings. Concerns about potential public health problems due to indoor air pollution are based on evidence that urban residents typically spend more than 90 percent of their time indoors, concentrations of some contaminants are higher indoors than outdoors, and for some pollutants personal exposures are not characterized adequately by outdoor measurements. Among the more important indoor contaminants associated with health or irritation effects are passive tobacco smoke, radon decay products, carbon monoxide, nitrogen dioxide, formaldehyde, asbestos fibers, microorganisms, and aeroallergens. Efforts to assess health risks associated with indoor air pollution are limited by insufficient information about the number of people exposed, the pattern and severity of exposures, and the health consequences of exposures. An overall strategy should be developed to investigate indoor exposures, health effects, control options, and public policy alternatives.

We examined the relationship among low, moderate, and high levels of hopelessness, all-cause and cause-specific mortality, and incidence of myocardial infarction (MI) and cancer in a population-based sample of middle-aged men. Participants were 2428 men, ages 42 to 60, from the Kuopio Ischemic Heart Disease study, an ongoing longitudinal study of unestablished psychosocial risk factors for ischemic heart disease and other outcomes. In 6 years of follow-up, 174 deaths (87 cardiovascular and 87 noncardiovascular, including 40 cancer deaths and 29 deaths due to violence or injury), 73 incident cancer cases, and 95 incident MI had occurred. Men were rated low, moderate, or high in hopelessness if they scored in the lower, middle, or upper one-third of scores on a 2-item hopelessness scale. Age-adjusted Cox proportional hazards models identified a dose-response relationship such that moderately and highly hopeless men were at significantly increased risk of all-cause and cause-specific mortality relative to men with low hopelessness scores. Indeed, highly hopeless men were at more than three-fold increased risk of death from violence or injury compared with the reference group. These relationships were maintained after adjusting for biological, socioeconomic, or behavioral risk factors, perceived health, depression, prevalent disease, or social support. High hopelessness also predicted incident MI, and moderate hopelessness was associated with incident cancer. Our findings indicate that hopelessness is a strong predictor of adverse health outcomes, independent of depression and traditional risk factors. Additional research is needed to examine phenomena that lead to hopelessness.