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Louise H Taylor,1 Louis H Nel1,21Global Alliance for Rabies Control, Manhattan, KS, USA; 2Department of Microbiology and Plant Pathology, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria, South Africa Abstract: The rabies virus, a public health scourge from ancient times, is currently responsible for an estimated 59,000 human deaths a year, almost all transmitted via dog bites. It causes considerable economic impacts on developing countries, primarily in Africa and Asia, which can least afford these losses. However, despite its almost 100% case fatality rate, canine rabies is a completely preventable disease, and historic examples of canine rabies elimination in the developed world attest to this. Over the last decade, programs based on eliminating the source of the disease from dogs have shown success in reducing the public health burden of canine rabies in developing countries, notably across Latin America, and this has contributed to the growing evidence base necessary to change attitudes toward the feasibility of global canine rabies elimination. More recently, assessments of the current economic burden of canine rabies and the potential cost savings achievable through mass dog vaccinations have been added to this evidence base. Tools and support are available from the international community to help countries move progressively toward canine rabies elimination, and there is optimism that global freedom from canine rabies can be achieved within the next few decades. Keywords: canine rabies, epidemiology, elimination, zoonosis, rabies virus

Background: Little is known about the effects of a mild SARS-CoV-2 infection on health-related quality of life., Methods: This prospective observational study of symptomatic adults (18-87 years) who sought outpatient care for an acute respiratory illness, was conducted from 3/30/2020 to 4/30/2021. Participants completed the Short Form Health Survey (SF-12) at enrollment and 6-8 weeks later, to report their physical and mental health function levels as measured by the physical health and mental health composite scores (PHC and MHC, respectively). PHC and MHC scores for COVID-19 cases and non-COVID cases were compared using t-tests. Multivariable regression modeling was used to determine predictors of physical and mental health function at follow-up., Results: Of 2301 enrollees, 426 COVID-19 cases and 547 non-COVID cases completed both surveys. PHC improved significantly from enrollment to follow-up for both COVID-19 cases (5.4 ± 0.41; P  < 0.001) and non-COVID cases (3.3 ± 0.32; P  < 0.001); whereas MHC improved significantly for COVID-19 cases (1.4 ± 0.51; P  < 0.001) and decreased significantly for non-COVID cases (-0.8 ± 0.37; P < 0.05). Adjusting for enrollment PHC, the most important predictors of PHC at follow-up included male sex (β = 1.17; SE = 0.5; P  = 0.021), having COVID-19 (β = 1.99; SE = 0.54; P  < 0.001); and non-white race (β = -2.01; SE = 0.70; P  = 0.004). Adjusting for enrollment MHC, the most important predictors of MHC at follow-up included male sex (β = 1.92; SE = 0.63; P = 0.002) and having COVID-19 (β = 2.42; SE = 0.67; P  < 0.001)., Conclusion: Both COVID-19 cases and non-COVID cases reported improved physical health function at 6-8 weeks' convalescence; whereas mental health function improved among COVID-19 cases but declined among non-COVID cases. Both physical and mental health functioning were significantly better among males with COVID-19 than females., Competing Interests: Drs. Nowalk and Balasubramani have grant funding from 10.13039/100004334Merck & Co., Inc. for an unrelated project. Drs. Zimmerman, Nowalk and Balasubramani have grant funding from 10.13039/100014588Sanofi on an unrelated project. Mr. Clarke, Ms. Clarke, Mr. Susick, Ms. Dauer, Ms. Sax, Dr. Taylor, Dr. Moehling Geffel have no conflicts to report., (© 2023 The Authors.)

Women in recovery from substance use disorders often have difficulty establishing recovery-supportive networks. This exploratory study uses qualitative thematic analysis to examine how 88 women in recovery describe the actions they take to manage their personal social networks 12 months after intake into residential substance use treatment. Participants describe disconnecting or limiting contact with recovery-endangering people and adding recovery-supportive people to their networks as primary relationship actions for maintaining recovery. Their actions to build recovery-supportive networks can provide a focus for clinical work to help them become integrated into their communities.

As part of a province wide rabies elimination program, rabies specific information was integrated into the curriculum of all public elementary schools in Ilocos Norte, Philippines using a specifically developed teachers' manual. The rabies educational messages included rabies, animal bite prevention, bite management and responsible pet ownership and were integrated into lessons in several subjects. Four elementary schools were randomly selected and an assessment of the change in student's rabies knowledge and animal bite incidence were conducted. The study tested all students in grades 1-5 before the curriculum integration was implemented and retested these cohorts 1 year later, after implementation. Awareness of rabies was high before the implementation, likely due to the province-wide elimination campaign. However, awareness still increased significantly across all schools, and detailed knowledge of rabies increased significantly in all but one school and age cohort. Bite incidence in the 6 months prior to each survey was also recorded and the percentage of students suffering animal bites fell significantly between the two tests. The data suggested that knowledge increase correlated with decreased bite incidence in some groups but not all, suggesting a more complex relationship between knowledge acquisition and behavioral change which warrants further investigation.

Background: The Philippines has built an extensive decentralised network of Animal Bite Treatment Centers (ABTCs) to help bite victims receive timely rabies post-exposure prophylaxis (PEP) at little cost. This study surveyed patients in the community and at ABTCs of three provinces to assess animal bite/scratch incidence, health-seeking behaviour and PEP-related out-of pocket expenses (OOPE)., Methodology and Principal Findings: During community surveys in 90 barangays (neighbourhoods), 53% of households reported at least one animal bite /scratch injury over the past 3 years, similar across urban and rural barangays. Overall bite/scratch incidences in 2016-17 were 67.3, 41.9 and 48.8 per 1,000 population per year for Nueva Vizcaya, Palawan and Tarlac respectively. Incidences were around 50% higher amongst those under 15 years of age, compared to -those older than 15. Household awareness of the nearest ABTCs was generally over 80%, but only 44.9% sought proper medical treatment and traditional remedies were still frequently used. The proportion of patients seeking PEP was not related to the distance or travel time to the nearest ABTC. For those that did not seek medical treatment, most cited a lack of awareness or insufficient funds and almost a third visited a traditional healer. No deaths from bite/scratch injuries were reported. A cohort of 1,105 patients were interviewed at six ABTCs in early 2017. OOPE varied across the ABTCs, from 5.53 USD to 37.83 USD per patient, primarily dependent on the need to pay for immunization if government supplies had run out. Overall, 78% of patients completed the recommended course, and the main reason for non-completion was a lack of time, followed by insufficient funds. Dog observation data revealed that 85% of patients were not truly exposed to rabies, and education in bite prevention might reduce provoked bites and demand for PEP. An accompanying paper details the ABTC network from the health provider's perspective., Competing Interests: Funding for this investigator-sponsored study was provided by GlaxoSmithKline Biologicals SA. ACBA, SIJ, MLLM, MPZDC, DAL, MCR, MCLQ, and LHT were funded proportionate to their time spent on the study. GlaxoSmithKline Biologicals SA reviewed and approved the protocol, but did not influence the project implementation, data collection, analysis or interpretation. They were also provided with an opportunity to review a preliminary version of this report for factual accuracy but the authors are solely responsible for final content and interpretation. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The Philippine government has an extensive network of 513 Animal Bite Treatment Centers (ABTCs) to supply rabies post exposure prophylaxis (PEP), reaching over 1 million bite victims in 2016. The network was evaluated using a review of existing national and provincial data, key informant interviews and surveys in sample ABTCs to determine the cost-effectiveness of this network in preventing human rabies deaths., Methodology and Principal Findings: One urban and one rural ABTC in each of three selected provinces were studied in more detail. PEP delivery generally followed national guidance based on best practices, but there was evidence of operational challenges in supplying all ABTCs with adequate biologics and recently trained staff. Funding was contributed by different levels of government and in some clinics, patients paid for a significant fraction of the total cost. From a health provider perspective including both fixed and variable costs, the average PEP course delivered cost USD 32.91 /patient across urban ABTCs (with higher patient throughput) and USD 57.21 /patient across rural ABTCs. These costs suggests that PEP provision in the Philippines cost USD 37.6 million in 2016, with a cost per life saved of USD 8,290. An analysis of the 2,239 suspected rabies deaths from 2008 to 2016 showed no significant decline, and from 2014-16 an average of 8,534 years of life were lost annually. The incidence of rabies deaths from 2014-16 was not clearly related to the provision of ABTCs (per 100,000 population) or human population density, but deaths were more common in higher income provinces., Conclusions/significance: In the context of comprehensive rabies control (including dog vaccination and public awareness) ways to reduce this high expenditure on PEP should be explored, to most cost-effectively reach the elimination of human rabies deaths. This paper is accompanied by another containing data on the operation of ABTCs network from a patient perspective., Competing Interests: Funding for this investigator-sponsored study was provided by GlaxoSmithKline Biologicals SA. ACBA, SIJ, LHT, MCR, and MCLQ were funded proportionate to their time spent on the study. GlaxoSmithKline Biologicals SA reviewed and approved the protocol, but did not influence the project implementation, data collection, analysis or interpretation. They were also provided with an opportunity to review a preliminary version of this report for factual accuracy but the authors are solely responsible for final content and interpretation. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

Free-roaming dogs and rabies transmission are integrally linked across many low-income countries, and large unmanaged dog populations can be daunting to rabies control program planners. Dog population management (DPM) is a multifaceted concept that aims to improve the health and well-being of free-roaming dogs, reduce problems they may cause, and may also aim to reduce dog population size. In theory, DPM can facilitate more effective rabies control. Community engagement focused on promoting responsible dog ownership and better veterinary care could improve the health of individual animals and dog vaccination coverage, thus reducing rabies transmission. Humane DPM tools, such as sterilization, could theoretically reduce dog population turnover and size, allowing rabies vaccination coverage to be maintained more easily. However, it is important to understand local dog populations and community attitudes toward them in order to determine whether and how DPM might contribute to rabies control and which DPM tools would be most successful. In practice, there is very limited evidence of DPM tools achieving reductions in the size or turnover of dog populations in canine rabies-endemic areas. Different DPM tools are frequently used together and combined with rabies vaccinations, but full impact assessments of DPM programs are not usually available, and therefore, evaluation of tools is difficult. Surgical sterilization is the most frequently documented tool and has successfully reduced dog population size and turnover in a few low-income settings. However, DPM programs are mostly conducted in urban settings and are usually not government funded, raising concerns about their applicability in rural settings and sustainability over time. Technical demands, costs, and the time necessary to achieve population-level impacts are major barriers. Given their potential value, we urgently need more evidence of the effectiveness of DPM tools in the context of canine rabies control. Cheaper, less labor-intensive tools for dog sterilization will be extremely valuable in realizing the potential benefits of reduced population turnover and size. No one DPM tool will fit all situations, but if DPM objectives are achieved dog populations may be stabilized or even reduced, facilitating higher dog vaccination coverages that will benefit rabies elimination efforts.

Rabies, a vaccine preventable neglected tropical disease, still claims an estimated 35,000-60,000 human lives annually. The international community, with more than 100 endemic countries, has set a global target of 0 human deaths from dog-transmitted rabies by 2030. While it has been proven in several countries and regions that elimination of rabies as a public health problem is feasible and tools are available, rabies deaths globally have not yet been prevented effectively. While there has been extensive rabies research, specific areas of implementation for control and elimination have not been sufficiently addressed. This article highlights some of the commonest perceived barriers for countries to implementing rabies control and elimination programs and discusses possible solutions for sociopolitical, organizational, technical, and resource-linked requirements, following the pillars of the global framework for the elimination of dog-mediated human rabies adopted at the global rabies meeting in December 2015.

As canine rabies control in Africa and Asia transitions from research-led proof-of-concept studies to government-led programs for elimination, experience and evidence of their impact and costs must be shared for the benefit of future programs. The Ilocos Norte Communities against Rabies Exposure project was implemented in April 2012 by the provincial veterinary and health offices and supported by many other partners. It delivered a comprehensive dog vaccination program and increased awareness of the need for postexposure prophylaxis (PEP), aiming to eliminate human and animal rabies cases from Ilocos Norte by 2015. Prior to the intervention, confirmed rabies cases in dogs were between 19 and 50 per year (2008-2011). The primary outcome of the project was a reduction in rabies cases in both dogs and humans to 0 in 2014 and 2015, which has subsequently been maintained. Animal bite consultations increased significantly during the project. Economic data for the dog vaccination and PEP components of the project were collated for two sites: Laoag City (an urban setting) and Dingras Municipality (a rural setting) between 2012 and 2014. The average programmatic cost of vaccinating each dog was $4.54 in Laoag City and $8.65 in Dingras, and costs fell as the project reached more dogs. The average costs of providing PEP were $69.72 per patient and $49.02 per patient for the two sites, respectively, again falling as the project reached more people. External donor contributions contributed less than 20% of dog vaccination costs and less than 1% of PEP costs. The project demonstrated that rabies elimination can be achieved in a short period of time, with concerted effort across multiple sectors. A lack of clear dog population estimates hampered interpretation of some aspects of the programme. From 2016, the provincial government has assumed complete responsibility for the programme and must now continue the vaccination and surveillance efforts. Although safeguards are in place, reintroduction from surrounding areas remains a threat, and vigilance must be maintained.

There is a need for innovation to improve control of all Neglected Zoonotic Diseases (NZDs). The Global Alliance for Rabies Control was formed to prevent human deaths from rabies and relieve the burden of rabies in other animal populations, especially dogs. It aims to identify reasons for the neglect of rabies in developing countries and to develop strategies to improve rabies control. Through initiatives such as World Rabies Day and the Partners for Rabies Prevention, progress has been made towards increased awareness of the burden of rabies transmitted by dogs at scales from local to international. An evidence base of the feasibility of canine rabies elimination has been built up and now easier access to information and tools enables countries to design and implement rabies elimination strategies in a logical way, utilizing the structures of regional networks for rabies control. The body of evidence has built consensus amongst international stakeholders in rabies control and is now being used to encourage international policy change, attract investment and increase delivery of effective rabies control programmes in canine rabies endemic countries., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Current passive surveillance data for canine rabies, particularly for the regions where the burden is highest, are inadequate for appropriate decision making on control efforts. Poor enforcement of existing legislation and poor implementation of international guidance reduce the effectiveness of surveillance systems, but another set of problems relates to the fact that canine rabies is an untreatable condition which affects very poor sectors of society. This results in an unknown, but potentially large proportion of rabies victims dying outside the health system, deaths that are unlikely to be recorded by surveillance systems based on health center records. This article critically evaluates the potential sources of information on the number of human deaths attributable to canine rabies, and how we might improve the estimates required to move towards the goal of global canine rabies elimination., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

World Rabies Day was set up in 2007 to raise global awareness about rabies, to provide information on how to prevent the disease in at-risk communities and support advocacy for increased efforts in rabies control. It is held annually on September 28th, with events, media outreach and other initiatives carried out by individuals, professionals, organisations and governments from the local to the international level. The Global Alliance for Rabies Control coordinates World Rabies Day, amplifying the campaign's reach through the provision of a central event platform and resources to support events across the world, the promotion of messages through key rabies stakeholders, and the implementation of specific activities to highlight particular issues. Over the last decade, more than 1,700 registered events have been held across the world and shared with others in the global rabies community. Events in canine rabies endemic countries, particularly in Africa and Asia, have increased over time. Beyond the individual events, World Rabies Day has gained the support of governments and international agencies that recognise its value in supporting existing rabies control initiatives and advocating for improvements. As the rabies landscape has changed, World Rabies Day remains a general day of awareness but has also become an integral part of national, regional and global rabies elimination strategies. The global adoption of 2030 as the goal for the elimination of rabies as a public health threat has led to even greater opportunities for World Rabies Day to make a sustainable impact on rabies, by bringing the attention of policy makers and donors to the ongoing situation and elimination efforts in rabies-endemic countries.

Objectives: Suspected seizures are a common reason for emergency calls to ambulance services. Prehospital management of these patients is an important element of good quality care. The aim of this study, conducted in a regional ambulance service in the UK, was to quantify the number of emergency telephone calls for suspected seizures in adults, the associated costs, and to describe the patients' characteristics, their prehospital management and their immediate outcomes., Design: Quantitative cross-sectional study using routinely collected data and a detailed review of the clinical records of a consecutive series of adult patients (≥ 16 years)., Setting: A regional ambulance service within the National Health Service in England., Participants: Cross-sectional data from all 605,481 adult emergency incidents managed by the ambulance service from 1 April 2012 to 31 March 2013. We selected a consecutive series of 178 individual incidents from May 2012 for more detailed analysis (132 after exclusions and removal of non-seizure cases)., Results: Suspected seizures made up 3.3% of all emergency incidents. True medical emergencies were uncommon but 3.3% had partially occluded airways, 6.8% had ongoing seizure activity and 59.1% had clinical problems in addition to the seizure (29.1% involving injury). Emergency vehicles were dispatched for 97.2% of suspected seizures, the seizure had terminated on arrival in 93.2% of incidents, 75% of these patients were transported to hospital. The estimated emergency management cost per annum of suspected seizures in the English ambulance services is £45.2 million (€64.0 million, $68.6 million)., Conclusions: Many patients with suspected seizures could potentially be treated more effectively and at lower cost by modifying ambulance call handling protocols. The development of innovative care pathways could give call handlers and paramedics alternatives to hospital transportation. Increased adoption of care plans could reduce 999 calls and could increase the rates of successful home or community treatment., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

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., (© 2015 Blackwell Verlag GmbH.)

The aquaporin family of integral membrane proteins is composed of channels that mediate cellular water flow. Aquaporin 4 (AQP4) is highly expressed in the glial cells of the central nervous system and facilitates the osmotically driven pathological brain swelling associated with stroke and traumatic brain injury. Here we show that AQP4 cell surface expression can be rapidly and reversibly regulated in response to changes of tonicity in primary cortical rat astrocytes and in transfected HEK293 cells. The translocation mechanism involves PKA activation, influx of extracellular calcium, and activation of calmodulin. We identify five putative PKA phosphorylation sites and use site-directed mutagenesis to show that only phosphorylation at one of these sites, serine 276, is necessary for the translocation response. We discuss our findings in the context of the identification of new therapeutic approaches to treating brain edema., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Introduction: Increased progesterone levels during pregnancy may cause decidualisation of endometriomas mimicking malignancies on radiology and causing management dilemmas., Case: An ovarian cyst was detected in a 33-year-old woman at her routine 12-week gestation ultrasound scan. By 18 weeks, the unilocular mass was increasing in size with features suggestive of early ovarian malignancy. The cyst was monitored throughout pregnancy and caesarean section at 38 weeks delivered a healthy male. Histology confirmed a decidualised endometrioma and benign dermoid cyst with no evidence of malignancy., Literature Review: The evidence for decidualised ovarian endometriomas in pregnancy was explored; 14 papers were identified, which reported 26 cases, excluding our index case. Of the 27 cases, 19 (70%) were managed surgically, 4 of which were delayed till caesarean section with concomitant cyst excision; 8 cases were managed conservatively through serial monitoring of the cyst, which spontaneously regressed following delivery., Conclusion: Surgical management of the cyst provides histological diagnosis but may introduce risks to mother and fetus; a conservative approach may cause anxiety but limits interventions. Elective caesarean section following monitoring throughout pregnancy may bridge the gap between surgical and purely conservative approaches if appropriate. Limited available evidence makes a definitive decision regarding management difficult. Decidualisation should be considered as a differential for suspicious ovarian lesions in pregnancy.

Objective: To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking, PTPN22 R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA)., Methods: Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage., Results: Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28-1.90, p = 8.5 × 10(-6)), carriage of at least 1 of the PTPN22 risk alleles (OR 1.50, 95% CI 1.13-2.00, p = 5.5 × 10(-3)) and both ever smoking and carriage of at least 1 of the PTPN22 risk alleles (OR 2.22, 95% CI 1.69-2.91, p = 8.3 × 10(-9)). There was no evidence of an association between presence of erosive damage and smoking status or carriage of PTPN22 risk alleles when analyzed overall or separately by ACPA status., Conclusion: This metaanalysis indicates that both smoking and the PTPN22 risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction between PTPN22 and smoking with erosive damage, despite evidence that ACPA positivity is associated with erosive damage.

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., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

The control of cellular water flow is mediated by the aquaporin (AQP) family of membrane proteins. The structural features of the family and the mechanism of selective water passage through the AQP pore are established, but there remains a gap in our knowledge of how water transport is regulated. Two broad possibilities exist. One is controlling the passage of water through the AQP pore, but this only has been observed as a phenomenon in some plant and microbial AQPs. An alternative is controlling the number of AQPs in the cell membrane. Here, we describe a novel pathway in mammalian cells whereby a hypotonic stimulus directly induces intracellular calcium elevations through transient receptor potential channels, which trigger AQP1 translocation. This translocation, which has a direct role in cell volume regulation, occurs within 30 s and is dependent on calmodulin activation and phosphorylation of AQP1 at two threonine residues by protein kinase C. This direct mechanism provides a rationale for the changes in water transport that are required in response to constantly changing local cellular water availability. Moreover, because calcium is a pluripotent and ubiquitous second messenger in biological systems, the discovery of its role in the regulation of AQP translocation has ramifications for diverse physiological and pathophysiological processes, as well as providing an explanation for the rapid regulation of water flow that is necessary for cell homeostasis.

Objective: Whether accumulating short intermittent bouts of light-to-moderate physical activity (LMPA) can elicit significant improvements in the fitness of sedentary adults, compared to one longer continuous bout., Methods: Fifty sedentary 35- to 60-year-old adults in Hong Kong were randomly appointed to one of two gender-balanced intervention programs: Exercise Prescription Model (EPM) of 30-minute continuous activity, 3-4 days per week, or a Lifestyle group (LIFE) of 6-minute activity, 5 times per day, 4-5 days per week. Aerobic fitness (VO(2)max), mass, body composition, blood pressure, waist-to-hip ratio, and body mass index (BMI) were assessed at baseline (December 1995) and after 8 weeks., Results: Nearly half of bouts by the LIFE group were < or =6 min, while 85% of the EPM bouts were > or =30 min, with no differences in additional energy expenditure between groups (EPM: 163.0+/-89.6 MET h vs LIFE: 148.2+/-71.6 MET h). Both groups significantly improved their VO(2)max, 7.4% (ES=0.36) and 5.3% (ES=0.24) for the EPM and Lifestyle groups respectively (F((1,43))=34.0, p<0.0001)., Conclusions: Accumulating multiple short bouts of LMPA, of which approximately 50% were < or =6 min, can provide significant improvements in the fitness of sedentary adults that is not dissimilar as one continuous bout of similar total duration.

Mixed-genotype infections occur frequently in natural populations. Parasite genotypes are expected to interact within a host: competing for shared nutrients and being affected by the host's immune response to each other. Theoretically, competing parasites can be expected to exhibit increased rates of replication. Here, we investigate whether interactions between clones of Theileria annulata, a protozoan parasite of cattle, affect clones' replication rates in mixed cultures in vitro. Intrinsic replication rates and carrying capacities estimated from single-clone control cultures were used to predict replication rates of mixed cultures under different competitive assumptions. Mixed-culture dynamics deviated significantly from expectations in five out of six different clone combinations tested. Contrary to expectation, mixed cultures often replicated more slowly than predicted from single-clone control cultures. Competition coefficients were calculated from the mixed-culture data and a competitive hierarchy of clones determined. The results suggest that inherent competitive ability may be greater in clones with lower carrying capacities-those clones which would otherwise be excluded in a genetically diverse environment. Moreover, significant negative deviations from expected replication rates corresponded with successful out-competing of a higher carrying capacity clone by a lower carrying capacity clone.

Preorganised urea groups moderate the anion-exchange properties of cationic receptor 2, favouring halide extraction and promoting anion transport through a bulk liquid membrane.

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.

Many infectious agents, especially those that cause emerging diseases, infect more than one host species. Managing reservoirs of multihost pathogens often plays a crucial role in effective disease control. However, reservoirs remain variously and loosely defined. We propose that reservoirs can only be understood with reference to defined target populations. Therefore, we define a reservoir as one or more epidemiologically connected populations or environments in which the pathogen can be permanently maintained and from which infection is transmitted to the defined target population. Existence of a reservoir is confirmed when infection within the target population cannot be sustained after all transmission between target and nontarget populations has been eliminated. When disease can be controlled solely by interventions within target populations, little knowledge of potentially complex reservoir infection dynamics is necessary for effective control. We discuss the practical value of different approaches that may be used to identify reservoirs in the field.

Theoretically, parasite virulence should be higher for faster growing parasites, and higher in mixed infections compared to single-clone infections. Virulence should also be positively correlated to transmission rates. Theileria annulata provides a good model system for studying such hypotheses, as parasite replication causes harm to the host, and there is evidence suggesting that the genetic complexity of an infection might affect its virulence. Two clones of T. annulata were chosen, one fast growing and one slow growing in vitro and these were used to establish cattle infections, either alone, or in a mixed infection. Virulence was measured using lymph node expansion, temperature, and blood parameters as correlates. As predicted, the faster growing clone was found to produce higher virulence. Mixed infections did not show higher virulence than single-clone infections, but interactions within mixed infections resulted in more transmission stage production than seen in either of the single-clone infections. Index Descriptors and Abbreviations. Theileria annulata, Apicomplexa, mixed infections, virulence, growth rates, red blood cell, RBC; packed cell volume, PCV.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Most evolutionary models treat virulence as an unavoidable consequence of microparasite replication and have predicted that in mixed-genotype infections, natural selection should favor higher levels of virulence than is optimal in genetically uniform infections. Increased virulence may evolve as a genetically fixed strategy, appropriate for the frequency of mixed infections in the population, or may occur as a conditional response to mixed infection, that is, a facultative strategy. Here we test whether facultative alterations in replication rates in the presence of competing genotypes occur and generate greater virulence. An important alternative, not currently incorporated in models of the evolution of virulence, is that host responses mounted against genetically diverse parasites may be more costly or less effective than those against genetically uniform parasites. If so, mixed clone infections will be more virulent for a given parasite replication rate. Two groups of mice were infected with one of two clones of Plasmodium chabaudi parasites, and three groups of mice were infected with 1:9, 5:5, or 9:1 mixtures of the same two clones. Virulence was assessed by monitoring mouse body weight and red blood cell density. Transmission stage densities were significantly higher in mixed- than in single-clone infections. Within treatment groups, transmission stage production increased with the virulence of the infection, a phenotypic correlation consistent with the genetic correlation assumed by much of the theoretical work on the evolution of virulence. Consistent with theoretical predictions of facultative alterations in virulence, we found that mice infected with both parasite clones lost more weight and had on average lower blood counts than those infected with single-clone infections. However, there was no consistent evidence of the mechanism invoked by evolutionary models that predict this effect. Replication rates and parasite densities were not always higher in ∗∗∗mixed-clone infections, and for a given replication rate or parasite density, mixed-clone infections were still more virulent. Instead, prolonged anemia and increased transmission may have occured because genetically diverse infections are less rapidly cleared by hosts. Differences in maximum weight loss occured even when there were comparable parasite densities in mixed- and single-clone infections. We suggest that mounting an immune response against more that one parasite genotype is more costly for hosts, which therefore suffer higher virulence., (© 1998 The Society for the Study of Evolution.)

Recrudescent Plasmodium falciparum parasites were sampled from 108 children taking part in a drug efficacy trial in Gabon. A finger-prick blood sample was taken from each child before treatment, and a post-treatment sample taken of the recrudescent parasites. Sample deoxyribonucleic acid was amplified by the polymerase chain reaction using primers specific to the P. falciparum antigen genes MSP-1, MSP-2 and GLURP. Seventy-seven children had identical parasites in their pre- and post-treatment samples, indicating genuine recrudescences of resistant parasites. Fourteen children had completely different parasites in their pre- and post-treatment samples, indicating either a fresh infection from a mosquito or growth of a population of parasites not detected in the pre-treatment sample, perhaps due to sequestration. The remaining 17 children had a mixture of pre-treatment and new parasites in their post-treatment samples. This study demonstrated the use of polymorphic markers to confirm whether parasites in patients with clinical recrudescences after drug treatment are genuinely resistant.

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.

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.

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 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.

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.

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.