Towards canine rabies elimination: Economic comparisons of three project sites.

An appreciation of the costs of implementing canine rabies control in different settings is important for those planning new or expanded interventions. Here we compare the costs of three canine rabies control projects in South Africa, the Philippines and Tanzania to identify factors that influence the overall costs of rabies control efforts. There was considerable variation in the cost of vaccinating each dog, but across the sites these were lower where population density was higher, and later in the projects when dog vaccination coverage was increased. Transportation costs comprised a much higher proportion of total costs in rural areas and where house-to-house vaccination campaigns were necessary. The association between the cost of providing PEP and human population density was less clear. The presence of a pre-existing national rabies management programme had a marked effect on keeping infrastructure and equipment costs for the project low. Finally, the proportion of the total costs of the project provided by the external donor was found to be low for the projects in the Philippines and South Africa, but likely covered close to the complete costs of the project in Tanzania. The detailed economic evaluation of three recent large-scale rabies control pilot projects provides the opportunity to examine economic costs across these different settings and to identify factors influencing rabies control costs that could be applied to future projects.

Surveillance of Human Rabies by National Authorities--A Global Survey.

Effective prevention of deaths due to human rabies is currently hampered by a lack of understanding of the scale of the problem, and the distribution of both animal and human cases across countries, regions and continents. Unfortunately, despite the severity of the disease, accurate data on which to assess these questions and to prioritize and direct public health interventions are not available for many parts of the world. This survey sought to understand the current global situation regarding the surveillance of human rabies. Data were collected from 91 countries across all continents and all categories of human rabies risk, generating the most complete and representative global data set currently available. Respondents were asked key questions about whether human rabies was a notifiable disease, how the surveillance system for human rabies operated and whether the respondent considered that the surveillance system was working effectively. Across the 91 countries from which data were collated, human rabies was a notifiable disease in all but eight. Despite international guidance, surveillance systems were very varied. Even where rabies is a notifiable disease, many countries had surveillance system judged to be ineffective, almost all of these being high and moderate rabies risk countries in Africa and Asia. Overall, 41% of the population covered by this survey (around 2.5 billion people) live in countries where there is no or ineffective rabies surveillance. The lack of robust surveillance is hindering rabies control efforts. However, whilst worldwide rabies surveillance would be improved if rabies were notifiable in all countries, many other challenges to the implementation of effective global human rabies surveillance systems remain.

The angiotensin-converting enzyme gene insertion/deletion polymorphism in Indian patients with vitiligo: a case-control study and meta-analysis.

BACKGROUND: Vitiligo is a common, acquired, idiopathic depigmenting skin disorder. Although the exact pathogenesis remains unknown, genetic susceptibility and autoimmune responses play a role in vitiligo development. Previous studies have suggested that the D allele of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with vitiligo in Indians and Koreans. Furthermore, significantly higher serum ACE levels have been demonstrated in patients with some autoimmune and autoinflammatory disorders. OBJECTIVES: The objectives were to investigate any association between the ACE I/D polymorphism and vitiligo susceptibility in an Indian population, and to compare serum ACE levels in patients with vitiligo and healthy subjects. METHODS: The ACE I/D genotypes of 79 patients with vitiligo and 100 normal individuals were determined by polymerase chain reaction amplification. A meta-analysis was done to compare the distribution of the ACE I/D alleles and genotypes in the current and three previous studies. Serum ACE levels were evaluated by enzyme-linked immunosorbent assay. RESULTS: A significant increase in the frequency of the ACE I/D D allele was evident in patients with vitiligo in both the case-control study [P=0·005; odds ratio (OR) 1·87; 95% confidence intervals (CI) 1·22-2·85] and the meta-analysis (P=0·044; OR 1·44; 95% CI 1·01-2·06). Serum ACE levels were significantly increased in patients with vitiligo compared with healthy subjects (P<0·0001). CONCLUSIONS: In agreement with earlier reports, the ACE I/D D allele is associated with vitiligo susceptibility in the Indian population. The significantly elevated serum ACE levels in our cohort of patients with vitiligo concur with those previously found in patients with some other autoimmune diseases.

Genetic and phenotypic analysis of Tunisian Theileria annulata clones.

Many parasite species are known to show high levels of genetic diversity, yet the consequences of this diversity for host-parasite interactions are not well understood. Variation in phenotypic traits such as growth rates and the ability to form transmission stages are raw material for natural and artificial selection to act upon with consequences for the evolution of the parasite species and disease control. In order to study genetic and phenotypic diversity amongst Theileria annulata parasites, a collection of 52 parasite clones was generated from cattle isolates and tick material recently collected in Tunisia. Genetic diversity was assessed using PCR-RFLP and monoclonal antibody markers, and genetically distinct clones selected for further study. Clones varied significantly in their growth rates in culture at 37 degrees C, their viability after a period of culture at 41 degrees C and their differentiation rates into transmission stages after culturing at 41 degrees C. The viability of a clone after culturing at 41 degrees C could not be predicted from its growth rate at 37 degrees C, but across clones, differentiation rates were positively correlated with growth rates at 37 degrees C. All 3 in vitro measures are likely to have relevance to parasite-host interactions in animals with clinical theileriosis, and should be acted on by within-host and between-host selection.

Risk factors for human disease emergence.

A comprehensive literature review identifies 1415 species of infectious organism known to be pathogenic to humans, including 217 viruses and prions, 538 bacteria and rickettsia, 307 fungi, 66 protozoa and 287 helminths. Out of these, 868 (61%) are zoonotic, that is, they can be transmitted between humans and animals, and 175 pathogenic species are associated with diseases considered to be 'emerging'. We test the hypothesis that zoonotic pathogens are more likely to be associated with emerging diseases than non-emerging ones. Out of the emerging pathogens, 132 (75%) are zoonotic, and overall, zoonotic pathogens are twice as likely to be associated with emerging diseases than non-zoonotic pathogens. However, the result varies among taxa, with protozoa and viruses particularly likely to emerge, and helminths particularly unlikely to do so, irrespective of their zoonotic status. No association between transmission route and emergence was found. This study represents the first quantitative analysis identifying risk factors for human disease emergence.

Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence.

Pathogens that can be transmitted between different host species are of fundamental interest and importance from public health, conservation and economic perspectives, yet systematic quantification of these pathogens is lacking. Here, pathogen characteristics, host range and risk factors determining disease emergence were analysed by constructing a database of disease-causing pathogens of humans and domestic mammals. The database consisted of 1415 pathogens causing disease in humans, 616 in livestock and 374 in domestic carnivores. Multihost pathogens were very prevalent among human pathogens (61.6%) and even more so among domestic mammal pathogens (livestock 77.3%, carnivores 90.0%). Pathogens able to infect human, domestic and wildlife hosts contained a similar proportion of disease-causing pathogens for all three host groups. One hundred and ninety-six pathogens were associated with emerging diseases, 175 in humans, 29 in livestock and 12 in domestic carnivores. Across all these groups, helminths and fungi were relatively unlikely to emerge whereas viruses, particularly RNA viruses, were highly likely to emerge. The ability of a pathogen to infect multiple hosts, particularly hosts in other taxonomic orders or wildlife, were also risk factors for emergence in human and livestock pathogens. There is clearly a need to understand the dynamics of infectious diseases in complex multihost communities in order to mitigate disease threats to public health, livestock economies and wildlife.

The ecology of genetically diverse infections.

Microparasite infections often consist of genetically distinct clonal lineages. Ecological interactions between these lineages within hosts can influence disease severity, epidemiology, and evolution. Many medical and veterinary interventions have an impact on genetic diversity within infections, but there is little understanding of the long-term consequences of such interventions for public and animal health. Indeed, much of the theory in this area is based on assumptions contradicted by the available data.

Population biology of multihost pathogens.

The majority of pathogens, including many of medical and veterinary importance, can infect more than one species of host. Population biology has yet to explain why perceived evolutionary advantages of pathogen specialization are, in practice, outweighed by those of generalization. Factors that predispose pathogens to generalism include high levels of genetic diversity and abundant opportunities for cross-species transmission, and the taxonomic distributions of generalists and specialists appear to reflect these factors. Generalism also has consequences for the evolution of virulence and for pathogen epidemiology, making both much less predictable. The evolutionary advantages and disadvantages of generalism are so finely balanced that even closely related pathogens can have very different host range sizes.

Proinflammatory cytokine expression by Theileria annulata infected cell lines correlates with the pathology they cause in vivo.

Control of Theileria annulata is currently best achieved by the use of live attenuated cell line vaccines. However, the mechanisms underlying attenuation are unclear and there is a need to rapidly produce new cell line vaccines, which could safely and effectively vaccinate cattle against tropical theileriosis. There is increasing evidence to suggest that proinflammatory cytokines produced by T. annulata infected cells play a central role in both pathology and immune evasion. This study aimed to test this hypothesis and to evaluate cytokine expression as a marker of virulence. The pathogenicity and protective efficacy of cloned T. annulata cell lines that expressed different levels of proinflammatory cytokines were compared. In two independent trials using different stocks of T. annulata, cell lines that expressed higher levels of proinflammatory cytokines induced severe reactions, and in some cases death, when used to vaccinate groups of cattle. In contrast, low cytokine expressing lines induced low post-vaccinal reactions. The results clearly demonstrated that cytokine expression by T. annulata infected cells could be used as a marker of virulence and provided strong evidence to support a role for cytokines in the induction of pathology. Both high and low cytokine expressing cell lines protected cattle against heterologous challenge infection, offering the possibility of using cytokine expression to rapidly select new safe, potent vaccines against tropical theileriosis without the need for culture attenuation.

An open-label trial of St. John's Wort (Hypericum perforatum) in obsessive-compulsive disorder.

BACKGROUND: Recent interest in and evidence for the efficacy of St. John's wort (Hypericum perforatum) for the treatment of mild-to-moderate depression has led to speculation about its efficacy in other disorders. Hypericum's mechanism of action is postulated to be via inhibition of the synaptosomal uptake of serotonin. As such, there is a suggestion that Hypericum may be effective for obsessive-compulsive disorder (OCD). METHOD: Twelve subjects were evaluated with a primary DSM-IV diagnosis of OCD of at least 12 months' duration. Treatment lasted for 12 weeks, with a fixed dose of 450 mg of 0.3% hypericin (a psychoactive compound in Hypericum) twice daily (extended-release formulation). Weekly evaluations were conducted with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Patient Global Impressions of Improvement Scale, and the Clinical Global Impressions of Improvement scale (CGI) and monthly evaluation with the Hamilton Rating Scale for Depression. RESULTS: A significant change from baseline to endpoint was found, with a mean Y-BOCS change of 7.4 points (p = .001). Significant change occurred at 1 week (p = .020) and continued to increase throughout the trial. At endpoint, 5 (42%) of 12 were rated "much" or "very much improved" on the clinician-rated CGI, 6 (50%) were "minimally improved," and 1 (8%) had "no change." The most common side effects reported were diarrhea (N = 3) and restless sleep (N = 2). CONCLUSION: Significant improvement was found with Hypericum, with a drop-in Y-BOCS score similar to that found in clinical trials. The fact that a significant change was found as early as 1 week into treatment suggests a possible initial placebo response, although improvement grew larger over time. Results warrant a placebo-controlled study of Hypericum in OCD.

Randomized trial of a depression management program in high utilizers of medical care.

BACKGROUND: High utilizers of nonpsychiatric health care services have disproportionally high rates of undiagnosed or undertreated depression. OBJECTIVE: To determine the impact of offering a systematic primary care-based depression treatment program to depressed "high utilizers" not in active treatment. DESIGN: Randomized clinical trial. SETTING: One hundred sixty-three primary care practices in 3 health maintenance organizations located in different geographic regions of the United States. PATIENTS: A group of 1465 health maintenance organization members were identified as depressed high utilizers using a 2-stage telephone screening process. Eligibility criteria were met by 410 patients and 407 agreed to enroll: 218 in the depression management program (DMP) practices and 189 in the usual care (UC) group. INTERVENTION: The DMP included patient education materials, physician education programs, telephone-based treatment coordination, and antidepressant pharmacotherapy initiated and managed by patients' primary care physicians. MAIN OUTCOME MEASURES: Depression severity was measured using the Hamilton Depression Rating Scale (Ham-D) and functional status using the Medical Outcomes Study 20-item short form (SF-20) subscales. Outpatient visit and hospitalization rates were measured using the health plan's encounter data. RESULTS: Based on an intent-to-treat analysis, at least 3 antidepressant prescriptions were filled in the first 6 months by 151 (69.3%) of 218 of DMP patients vs 35 (18.5%) of 189 in UC (P < .001). Improvements in Ham-D scores were significantly greater in the intervention group at 6 weeks (P = .04), 3 months (P = .02), 6 months (P < .001), and 12 months (P < .001). At 12 months, DMP intervention patients were more improved than UC patients on the mental health, social functioning, and general health perceptions scales of the SF-20 (P < .05 for all). CONCLUSION: In depressed high utilizers not already in active treatment, a systematic primary care-based treatment program can substantially increase adequate antidepressant treatment, decrease depression severity, and improve general health status compared with usual care.

Development of dermal denticles in skates (Chondrichthyes, Batoidea): patterning and cellular differentiation.

Patterning, cellular differentiation, and developmental sequences of dermal denticles (denticles) are described for the skate Leucoraja erinacea. Development of denticles proceeds caudo-rostrally in the tail and trunk. Once three rows of denticles form in the tail and trunk, denticles begin to appear in the region of the pelvic girdle, medio-caudal to the eyes and on the pectoral fins. Although timing of cellular differentiation of denticles differs among different locations of the body, cellular development of a denticle is identical in all locations. Thickening of the epidermis as a denticle lamina marks initiation of development. A single lamina for each denticle forms, and a small group of mesenchymal cells aggregates underneath it. The lamina then invaginates caudo-rostrally to form the inner- and outer-denticle epithelia (IDE and ODE, respectively). Before nuclei of IDE cells are polarized, enameloid matrix appears between the basement membrane of the IDE and the apical surface of the pre-odontoblasts. Pre-dentin is then laid down along with collagenous materials. Von Kossa stain visualizes initial mineralization of dentin, but not enameloid. During the growth of a denticle, dense fibrous connective tissue of the dermis forms the deep dermal tissue over the dorsal musculature. Attachment fibers and tendons anchor denticles and dorsal musculature, respectively, on deep dermal tissue. Basal tissue of the denticles develops as the denticle crown grows. If the basal tissue is bone of attachment, then the cells along the basal tissue would be osteoblasts. However, these cells could not be distinguished from odontoblasts using immunolocalization of type I pro-collagen (Col I), alkaline phosphatase (APase), and neural cell adhesion molecule (N-CAM). Well-developed dentin, (not pre-dentin), the enameloid matrix (probably when it begins to mineralize), and deep dermal tissue are Verhoeff stain-positive, suggesting that these tissues contain elastin and/or elastin-like molecules. Our study demonstrates that the cellular development of denticles resembles tooth development in elasmobranchs, but that dermal denticles differ from teeth in forming from a single denticle lamina. Whether the basal tissue of denticles is bone of attachment remains undetermined. Confirmation and function of Verhoeff-positive proteins in enameloid, dentin, and deep dermal tissue remain to be determined. We discuss these issues along with an analysis of recent findings of enamel and enameloid matrices.

Infection rates in, and the number of Plasmodium falciparum genotypes carried by Anopheles mosquitoes in Tanzania.

Naturally fed mosquitoes were collected from houses in a rural village in northern Tanzania. The number of Plasmodium falciparum oocysts which developed in each was counted, and the number of parasite genotypes carried by a subset was determined by PCR-based techniques. A higher proportion of Anopheles gambiae s.l. mosquitoes developed oocysts than of An. funestus but, on average, both species carried similar numbers of parasite genotypes. Overall, 68% of the sampled mosquitoes carried more than one genotype.

Determinants of transmission success of individual clones from mixed-clone infections of the rodent malaria parasite, Plasmodium chabaudi.

Interactions between malaria parasite clones within mixed infections can have a profound effect on transmission and therefore the epidemiology of the disease. However, factors which determine the relative transmission success of individual clones from mixed infections are unknown. We have used two clones of the rodent malaria Plasmodium chabaudi to investigate changes in the clonal composition of asexual parasites over the course of mixed-clone infections in mice and how these relate to the clonal composition of transmission (oocyst) populations in mosquitoes. Clonal composition was determined using monoclonal antibody analyses for the asexual blood stage populations and PCR analysis of single oocysts for the transmission populations in mosquitoes. The relative frequency of the two clones changed dramatically during the course of the infection in mice, depending on their ratio in the inoculum. The clonal composition of parasites within mosquitoes most closely resembled that in the asexual infection at the time of transmission rather than that at any point earlier in the infection. These results provide no evidence that clones increase rates of gametocytogenesis in response to competitive suppression. Most likely, transmission success follows from asexual success in the later parts of the infection. The clone which dominated the earlier part of the infection, when most parasites are produced, did not necessarily dominate the transmission from the infection. The two clones differed in competitive ability and the data suggest that interactions with the host immune system may be a major factor in determining transmission success from mixed-clone infections.

A computer-administered telephone interview to identify mental disorders.

CONTEXT: Common mental disorders are often not identified in primary care settings. OBJECTIVE: To evaluate the validity and clinical utility of a telephone-assisted computer-administered version of Primary Care Evaluation of Mental Disorders (PRIME-MD), a brief questionnaire and interview instrument designed to identify psychiatric disorders in primary care patients. DESIGN: Comparison of diagnoses obtained by computer over the telephone using interactive voice response (IVR) technology vs those obtained by a trained clinician over the telephone using the Structured Clinical Interview for DSM-IV [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition] Diagnosis (SCID). A subsample also received the clinician-administered version of PRIME-MD. PATIENTS: Outpatients (N=200) from 4 primary care clinics, an eating disorders clinic, an alcohol treatment facility, psychiatric outpatients, and community controls. SETTING: Interviews conducted by telephone, except for face-to-face administration of PRIME-MD, which was conducted at either the primary care clinic or a research clinic. MEASUREMENTS AND MAIN RESULTS: Prevalence rates for any psychiatric disorder were similar between diagnoses made by the computer and those made by a mental health professional using the SCID (60.0% vs 58.5%). Prevalence rates for individual diagnoses were generally similar across versions. However, primary care patients reported twice as much alcohol abuse on the computer (15.0%) as on either the SCID (7.5%) or the clinician-administered PRIME-MD (7.5%). Using the SCID as the criterion, both the computer- and clinician-administered versions of PRIME-MD demonstrated high and roughly equivalent levels of sensitivity and specificity. Overall agreement (K) for any diagnosis was 0.67 for the computer-administered PRIME-MD and 0.70 for the clinician-administered PRIME-MD. CONCLUSIONS: The computer-administered PRIME-MD appears to be a valid instrument for assessing psychopathology in primary care patients. Interactive voice response technology allows for increased availability, and provides primary care physicians with information that will increase the quality of patient care without additional physician time and at minimal expense.

Computerized screening for psychiatric disorders in an outpatient community mental health clinic.

OBJECTIVE: This study examined the validity and utility of two types of computer-administered versions of a screening interview, PRIME-MD (Primary Care Evaluation of Mental Disorders), in a mental health setting: one administered by desktop computer and one by computer using a touch-tone telephone and interactive voice response (IVR) technology. METHODS: Fifty-one outpatients at a community mental health clinic were given both IVR and desktop PRIME-MD and the Structured Clinical Interview for DSM-IV (SCID-IV), which was administered by a clinician, in a counterbalanced order. Diagnoses were also obtained from charts. RESULTS: Prevalence rates found by both computer interviews were similar to those obtained by the SCID-IV for the presence of any diagnosis, any affective disorder, and any anxiety disorder. Prevalence rates for specific diagnoses were also similar to those found by the SCID-IV except for dysthymia, obsessive-compulsive disorder, and panic disorder; the first two conditions were found to be more prevalent by the computer, and panic disorder was more prevalent by the SCID. Compared with the prevalence rates in the charts, the rates found by the computer were higher for anxiety disorders, particularly for obsessive-compulsive disorder and social phobia. Using the SCID-IV as the criterion, both computer-administered versions of PRIME-MD had high sensitivity, specificity, and positive predictive value for most diagnoses. No significant difference was found in how well patients liked each form of interview. CONCLUSIONS: Results support the validity and utility of both desktop and IVR PRIME-MD for gathering information from mental health patients about certain diagnoses.

Mixed-genotype infections of the rodent malaria Plasmodium chabaudi are more infectious to mosquitoes than single-genotype infections.

Interactions between parasite genotypes sharing a host are poorly understood, but have important consequences for the epidemiology and evolution of the parasite. In mixed-genotype malaria infections, patterns of asexual replication and transmission favoured by natural selection may be different from those in single-genotype infections. The infectivity to mosquitoes of mixed-genotype and single-genotype infections were compared using 2 clones of Plasmodium chabaudi inoculated into mice either together or alone. Mice given mixed-clone infections received the sum of the inocula given to the single-clone controls. Mosquitoes were fed on the mice and the numbers of oocysts which developed were counted to assess transmission intensity. For 3 combinations of starting inocula and feed days, mixed-clone infections produced more oocysts per mosquito than the sum of the 2 single-clone infections. This effect was correlated with an increase in gametocyte density, but was less clearly related to asexual infection parameters. The results show that interactions between clones in mixed-clone infections can profoundly affect transmission.

Mixed-genotype infections of malaria parasites: within-host dynamics and transmission success of competing clones.

Mixed-genotype infections of microparasites are common, but almost nothing is known about how competitive interactions within hosts affect the subsequent transmission success of individual genotypes. We investigated changes in the composition of mixed-genotype infections of the rodent malaria Plasmodium chabaudi clones CR and ER by monoclonal antibody analysis of the asexual infection in mice, and by PCR amplification of clone-specific alleles in oocysts sampled from mosquitoes which had fed on these mice. Mixed-clone infections were initiated with a 9:1 ratio of the two clones, with ER as the minority in the first experiment and CR as the minority in the second experiment. When beginning as the majority, clones achieved parasite densities in mice comparable to those achieved in control (single-clone) infections. When they began as the minority, clones were suppressed to less than 10% of control parasitaemias during the early part of the infections. However, in mosquitoes, the frequency of the initially rare clone was substantially greater than it was in mice at the start of the infection or four days prior to the feed. In both experiments, the minority clone in the inocula produced as many, or more, oocysts than it did as a single-clone infection. These experiments show that asexual dominance during most of the infection is poorly correlated to transmission probability, and therefore that the assumption that within-host population size correlates to transmission probability may not be warranted. They also raise the fundamental question of why transmission rates of individual genotypes are often higher from mixed than single-clone infections.

Adaptive changes in Plasmodium transmission strategies following chloroquine chemotherapy.

Both theory and data suggest that malaria parasites divert resources from within-host replication to the production of transmission stages (gametocytes) when conditions deteriorate. Increased investment into transmission stages should therefore follow subcurative treatment with antimalarial drugs, but relevant clinical studies necessarily lack adequate control groups. We therefore carried out controlled experiments to test this hypothesis, using a rodent malaria (Plasmodium chabaudi) model. Infections treated with a subcurative dose of the antimalarial chloroquine showed an earlier peak and a greater rate of gametocyte production relative to untreated controls. These alterations led to correlated changes in infectivity to mosquitoes, with the consequence that chloroquine treatment had no effect on the proportion of mosquitoes infected. Treatment of human malaria commonly does not result in complete parasite clearance. If surviving parasites produce compensatory increases in their rate of gametocyte production similar to those reported here, such treatment may have minimal effect on decreasing, and may actually increase, transmission. Importantly, if increased investment in transmission is a generalized stress response, the effect might be observed following a variety of antimalarial treatments, including other drugs and potential vaccines. Similar parasite life history counter-adaptations to intervention strategies are likely to occur in many disease-causing organisms.

Why so few transmission stages? Reproductive restraint by malaria parasites.

Vast numbers of malaria parasites exist in a population: perhaps 10(10) in just one vertebrate host. Yet gametocytes, the only stage capable of transmission, usually constitute just a few percent or even less of the circulating parasites. Why? Parasite fitness should be intimately linked with transmission probability and infectiousness rises with gametocyte density. Here, Louise Taylor and Andrew Read propose several testable hypotheses that might explain why natural selection has not favoured variants producing more transmission stages.