Anatomical and physiological basis for the allometric scaling of cisplatin clearance in dogs.

Cisplatin is a platinum-containing cytotoxic drug indicated for the treatment of solid tumors in veterinary and human patients. Several of the algorithms used to standardize the doses of cytotoxic drugs utilize allometry, or the nonproportional relationships between anatomical and physiological variables, but the underlying basis for these relationships is poorly understood. The objective of this proof of concept study was to determine whether allometric equations explain the relationships between body weight, kidney weight, renal physiology, and clearance of a model, renally cleared anticancer agent in dogs. Postmortem body, kidney, and heart weights were collected from 364 dogs (127 juveniles and 237 adults, including 51 dogs ≥ 8 years of age). Renal physiological and cisplatin pharmacokinetic studies were conducted in ten intact male dogs including two juvenile and eight adult dogs (4-55 kg). Glomerular filtration rate (GFR), effective renal plasma flow, effective renal blood flow, renal cisplatin clearance, and total cisplatin clearance were allometrically related to body weight with powers of 0.75, 0.59, 0.61, 0.71, and 0.70, respectively. The similar values of these diverse mass exponents suggest a common underlying basis for the allometry of kidney size, renal physiology, and renal drug handling.

Reaction phenotyping of vinblastine metabolism in dogs.

Vinblastine is a vinca alkaloid used either as a single agent or in combination therapy for the treatment of canine mast cell tumours and lymphomas. The objective of this study was to determine which isoform of cytochrome P450 enzyme is responsible for the majority of vinblastine metabolism in dogs. A panel of eight recombinant canine cytochrome P450 enzymes (CYP1A1, CYP1A2, CYP3A12, CYP3A26, CYP2B11, CYP2C41, CYP2C21 and CYP2D15) were incubated in vitro with vinblastine. Findings were confirmed by the use of canine polyclonal antibodies of cytochrome P450 enzymes (CYP1A1, CYP3A12, CYP2B11 and CYP2C21) that were pre-incubated with individual and pooled hepatic microsomes that were purified from canine liver. Substrate depletion was observed in the presence of recombinant CYP3A12, whereas depletion did not substantially occur when microsomes were pre-incubated with polyclonal antibodies against CYP3A12. These findings confirmed that CYP3A12 is the major cytochrome P450 isoform responsible for the metabolism of vinblastine in dogs.

Extending tuberculosis notification to the private sector in India: programmatic challenges?

In May 2012, the Government of India declared tuberculosis a notifiable disease, requiring all public and private health sectors throughout the country to report all cases. Until then, TB disease was notifiable only by public authorities. In India, the private sector dominates anti-tuberculosis treatment, and poorly managed cases lead to severe forms of TB. Several challenges need to be addressed for effective implementation, including the creation of an electronic case-based web-based mechanism for TB notification. Stricter enforcement backed by regulation and punitive measures for non-compliance, along with vigilant mechanisms in place to monitor private health facilities, is required. Massive campaigns and advocacy programmes for a notification drive may be the way forward.

Sex, drugs and prisons: HIV prevention strategies for over 190 000 clients in Ukraine.

SETTING: One hundred and forty non-governmental organisations implementing human immunodeficiency virus (HIV) prevention programmes among clients, including people who inject drugs, prisoners, female sex workers, men who have sex with men and street children in Ukraine, 2010-2011. OBJECTIVE: Among enrolled clients, to assess factors associated with HIV testing, HIV retesting within a year of initial testing and HIV seroconversion. DESIGN: Retrospective cohort study involving record reviews. RESULTS: Of 192 487 clients, 42 109 (22%) underwent an initial HIV test (22% were positive). Among HIV-negative clients at baseline, 10 858 (27%) were retested within a year: 317 (3%) of these were HIV-positive. HIV testing and retesting rates were lower among prisoners (0.3%) and others (street children and partners of those in risk groups, 6%), and those who did not receive counselling or services such as condom and needle distribution. Individuals who were not counselled were more likely to seroconvert. CONCLUSIONS: In this large cohort of high-risk groups from Eastern Europe, HIV testing was low and HIV sero-conversion was high. This is of public health concern, bringing into question the overall quality of counselling and how well it is tailored to the specific needs of various risk groups. Qualitative studies to understand the reasons for non-testing are urgently required for designing client-specific interventions.

Contexte : Cent quarante organisations non gouvernementales impliquées dans la mise en œuvre de programmes de prévention du virus de l'immunodéficience humaine (VIH) pour des clients comprenant des utilisateurs de drogues injectables, des détenus, des travailleuses du sexe, des homosexuels masculins et des enfants des rues en Ukraine de 2010 à 2011.Objectif : Evaluer les facteurs associés au dépistage du VIH, à un second dépistage dans l'année qui suit et à une séroconversion parmi les clients enrôlés.Schéma : Etude rétrospective de cohorte par revue de dossiers.Résultats : Sur 192 487 clients, 42 109 (22%) ont eu un test VIH initial (22% étaient positifs). Parmi les clients négatifs au départ, 10 858 (27%) ont eu un deuxième test dans l'année, dont 317 (3%) se sont révélés VIH positifs. Les taux de dépistage initial et subséquent étaient plus faibles parmi les prisonniers (0,3%) et d'autres groupes comme les enfants des rues et les partenaires de groupes à risque (6%), ainsi que ceux qui n'avaient pas bénéficié de conseil ni de services comme la distribution de préservatifs et d'aiguilles. Les sujets qui n'avaient pas bénéficié de conseil étaient plus enclins à la séroconversion.Conclusions: Dans cette vaste cohorte de groupes à risque élevé d'Europe de l'Est, le taux de dépistage était faible et le taux de séroconversion élevé. Cette situation est préoccupante en termes de santé publique et met en doute la qualité d'ensemble du conseil et la manière dont il est adapté aux besoins spécifiques de divers groupes à risque. Il est urgent de réaliser des études qualitatives afin de comprendre les raisons du non dépistage et d'élaborer des interventions spécifiques des clients.

Marco de referencia: Las 140 organizaciones no gubernamentales que aplican programas de prevención de la infección por el virus de la inmunodeficiencia humana (VIH) a usuarios como los consumidores de drogas inyectables, los reclusos, las trabajadoras del sexo, los hombres que tienen relaciones sexuales con hombres y los niños de la calle en Ucrania entre el 2010 y el 2011.Objetivo: Evaluar los factores que se asocian con la práctica de la prueba diagnóstica del VIH, la repetición de la prueba un año después de la primera y la seroconversión en los usuarios inscritos.Método: Fue este un estudio retrospectivo de cohortes con análisis de las historias clínicas.Resultados: De los 192 487 usuarios del programa, 42 109 recibieron una primera prueba del VIH (22%); 22% fueron positivos. De las personas con un resultado negativo inicial, 10 858 repitieron la prueba un año después (27%) y 317 de ellas obtuvieron un resultado positivo (3%). Las tasas de práctica de la prueba del VIH y de repetición de la misma fueron inferiores en los reclusos (0,3%), en el grupo de otros (los niños de la calle y las parejas de personas de los grupos de riesgo, 6%) y en las personas que no recibieron asesoramiento ni servicios como la distribución de agujas o preservativos. La seroconversión fue más frecuente en las personas que no recibieron orientación.Conclusión: En este amplio estudio de cohortes de grupos de riesgo en Europa oriental, la tasa de pruebas diagnósticas del VIH fue baja y los índices de seroconversión fueron altos. Esta situación representa un problema de salud pública y pone en tela de juicio la calidad general de los programas de asesoramiento y la forma como estos se adaptan a las necesidades específicas de los diversos grupos de riesgo. Se precisan con urgencia estudios cualitativos que analicen las razones de la falta de la prueba diagnóstica, con el fin de elaborar intervenciones que sean específicas para determinados usuarios.

Retention and HIV seroconversion among drug users on methadone maintenance treatment in Yunnan, China.

SETTING: Thirteen methadone maintenance treatment (MMT) clinics across Yunnan, the province with the highest human immunodeficiency virus (HIV) burden in China. OBJECTIVES: To determine, among HIV-negative participants on MMT, the proportion lost to follow-up (defined as those who missed the 6-monthly follow-up examination), factors associated with loss to follow-up (LFU), HIV seroconversion rate and factors associated with seroconversion. DESIGN: Prospective cohort study from October 2008 to April 2011. All participants were administered a pre-tested structured questionnaire to capture associated factors and offered HIV testing every 6 months. χ(2) test and log-binomial regression were used for data analysis. RESULTS: Of 1146 participants, 541 (47%) were lost to follow-up in 2.5 years. Factors associated with higher LFU proportion include <6 months of previous MMT, inconvenient location of the MMT clinic and average methadone dose ⩽60 mg/day, with adjusted relative risks (RRs) of respectively 1.4 (95%CI 1.2-1.5), 1.2 (95%CI 1.0-1.4) and 1.1 (95%CI 1.0-1.3). The overall HIV seroconversion rate was 6.6 (95%CI 3.7-11.0) per 1000 person-years. Not living with a partner contributed to higher HIV rates, with an adjusted RR of 3.6 (95%CI 1.0-12.8). CONCLUSION: The retention rate of MMT participants in Yunnan was not satisfactory. Decentralising service delivery in the community and making directly observed treatment more convenient has the potential to improve retention.

Contexte : Treize centres de traitement par méthadone (MMT) dans le Yunnan, la province la plus touchée par le virus de l'immunodéficience humaine (VIH) en Chine.Objectifs : Déterminer, parmi les participants VIH négatifs, la proportion de perdus de vue (ceux qui ont manqué l'examen de suivi à 6 mois), les facteurs associés à cet abandon du suivi, le taux de séroconversion VIH et les facteurs associés.Schéma : Etude prospective de cohorte d'octobre 2008 à avril 2011. Tous les participants ont rempli un questionnaire structuré prétesté afin d'identifier ces facteurs et on leur a proposé un test VIH tous les 6 mois. L'analyse des données a été réalisée à l'aide du test χ2 et de la régression logarithmique binomiale.Résultats : Sur 1146 patients, 541 (47%) ont été perdus de vue en 2 ans et demi. Les facteurs associé à cet abandon comprenaient : <6 mois de séjour préalable dans un centre MMT, localisation peu pratique du centre et dose moyenne de méthadone ⩽60 mg/jour avec un risque relatif (RR) ajusté de 1,4 (IC95% 1,2­1,5), 1,2 (IC95% 1,0­1,4) et 1,1 (IC95% 1,0­1,3), respectivement. Le taux global de séroconversion était de 6,6% personnes-années (IC95% 3,7­11). Le fait de ne pas vivre avec un partenaire contribuait à un taux plus élevé de VIH avec un RR ajusté de 3,6 (IC95% 1,0­12,8).Conclusion : Le taux de rétention des participants à un traitement en centre MMT au Yunnan n'était pas satisfaisant. Une prestation de services décentralisée au niveau communautaire avec observation directe du traitement serait plus pratique et pourrait améliorer cette rétention.

Marco de referencia: Trece consultorios de tratamiento de mantenimiento con metadona en Yunnan, la provincia donde se observa la más alta carga de morbilidad por la infección causada por el virus de la inmunodeficiencia humana (VIH) en la China.Objetivos: Determinar la proporción de pérdidas durante el tratamiento de mantenimiento con metadona en los pacientes sin infección por el VIH (es decir, los pacientes que no acudieron al seguimiento mensual durante 6 meses), los factores que se asociaron con esta pérdida, la tasa de conversión de la serología frente al VIH y los factores relacionados con la seroconversión.Métodos: Se llevó a cabo un estudio prospectivo de cohortes entre octubre del 2008 y abril del 2011. Se administró a todos los participantes un cuestionario estructurado validado, destinado a captar los factores asociados y se les propuso la prueba diagnóstica del VIH cada 6 meses. En el análisis de los datos se aplicó la prueba de la χ2 y un análisis de regresión logarítmica binaria.Resultados: De los 1146 pacientes se perdieron durante el seguimiento 541 (47%) en 2,5 años. Los factores que se asociaron con una proporción más alta de pérdidas fueron los siguientes: una duración del tratamiento previo de mantenimiento con metadona <6 meses (riesgo relativo ajustado [RRa] 1,4; IC95% 1,2­1,5), una localización poco práctica del consultorio (RRa 1,2; IC95% 1,0­1,4) y una dosis promedio de metadona ⩽60 mg/día (RRa 1,1; IC95% 1,0­1,3). La tasa global de seroconversión frente al VIH fue 6,6 (IC95% 3,7­11,0) por 1000 años-persona. El hecho de no vivir en pareja contribuyó a una tasa más alta de serologías positivas, con un RRa de 3,6 (IC95% 1,0­12,8).Conclusión: En Yunnan, el índice de fidelización al tratamiento de mantenimiento con metadona de los participantes es deficiente. Se podría mejorar la retención de los pacientes mediante la descentralización de la prestación de los servicios hacia la comunidad y una mejor adaptación de la observación directa del tratamiento.

Characteristics of patients with diabetes screened for tuberculosis in a tertiary care hospital in South India.

SETTING: Tertiary care hospital for diabetes mellitus (DM) in Tamil Nadu, South India. OBJECTIVE: To compare the socio-demographic, clinical and biochemical characteristics in DM patients with and without tuberculosis (TB). DESIGN: A descriptive study involving a review of routinely maintained records to capture the results of screening of DM patients for TB between March and December 2012. DM patients were first asked whether they already had TB, and if not they were screened for TB symptoms, followed by investigations for and possible diagnosis of TB. RESULTS: Of 7083 DM patients, 38 already had TB. Of the remainder, 125 (1.8%) had TB symptoms; 71 were investigated and 12 were newly diagnosed with TB. Of the 50 TB patients, 64% had smear-positive pulmonary TB (PTB). DM-TB patients were older, and had lower education level and economic status, a higher frequency of alcohol use, lower body mass index, a longer duration of DM, a greater likelihood of receiving insulin and poorer glycaemic control. CONCLUSION: Screening of DM patients for TB was feasible in a tertiary care hospital. The yield of new TB cases was low and merits further investigation. Socio-demographic and clinical characteristics were different in patients with DM and TB compared to those with DM only.

Screening patients with tuberculosis for diabetes mellitus in Gujarat, India.

SETTING: Anklav Tuberculosis Unit, Anand, Gujarat, India. OBJECTIVE: To determine in a cohort of TB patients 1) the prevalence of diabetes (DM) and impaired fasting glucose (IFG), 2) the time taken for diagnosis, 3) demographic and clinical factors associated with DM and IFG, and 4) the number needed to screen (NNS) for diagnosing new cases of DM and IFG. DESIGN: Descriptive study. TB patients registered between January and September 2012 were asked whether they had a history of DM. Those with unknown DM were tested for random and fasting blood glucose (FBG). FBG of ≥126 mg/dl and 110-125 mg/dl were considered indicative of DM and IFG, respectively. RESULTS: Of 556 TB patients, 553 (99%) were assessed: 36 (6.5%) had diabetes (14 had been previously diagnosed DM and 22 were newly diagnosed), and 39 (7%) had IFG. The median (interquartile range) time to DM diagnosis was 5 (1-17) days. Age ≥35 years was associated with DM. The NNS was 25 and 14 for one new case of DM and IFG, respectively, with a lower NNS in males, those aged ≥35 years, those with smear-positive pulmonary TB, retreatment patients and smokers. CONCLUSION: This pilot project shows that it is feasible and valuable to screen patients with TB for DM in a routine setting, resulting in earlier identification of DM and opportunities for better management of comorbidity.

Epidemiology and interaction of diabetes mellitus and tuberculosis and challenges for care: a review.

The global burden of diabetes mellitus (DM) is immense, with numbers expected to rise to over 550 million by 2030. Countries in Asia, such as India and China, will bear the brunt of this unfolding epidemic. Persons with DM have a significantly increased risk of developing active tuberculosis (TB) that is two to three times higher than in persons without DM. This article reviews the epidemiology and interactions of these two diseases, discusses how the World Health Organization and International Union Against Tuberculosis and Lung Disease developed and launched the Collaborative Framework for the care and control of TB and DM, and examines three important challenges for care. These relate to 1) bi-directional screening of the two diseases, 2) treatment of patients with dual disease, and 3) prevention of TB in persons with DM. For each area, the gaps in knowledge and the priority research areas are highlighted. Undiagnosed, inadequately treated and poorly controlled DM appears to be a much greater threat to TB prevention and control than previously realised, and the problem needs to be addressed. Prevention of DM through attention to unhealthy diets, sedentary lifestyles and childhood and adult obesity must be included in broad non-communicable disease prevention strategies. This collaborative framework provides a template for action, and the recommendations now need to be implemented and evaluated in the field to lay down a firm foundation for the scaling up of interventions that work and are effective in tackling this dual burden of disease.

Le fardeau mondial du diabète sucré (DM) est immense et l'on s'attend à ce que le nombre de cas augmente d'ici 2030 jusqu'à plus de 550 millions. Les pays d'Asie, comme l'Inde et la Chine, devront supporter le poids principal de cette épidémie en expansion. Le risque de développer une tuberculose (TB) active est significativement accru chez les patients atteints de DM : il est de deux à trois fois supérieur à celui des personnes sans DM. Cet article fait la revue de l'épidémiologie et des interactions de ces deux maladies, discute la façon dont l'Organisation Mondiale de la Santé et l'Union Internationale Contre la Tuberculose et les Maladies Respiratoires ont élaboré et lancé le réseau de collaboration pour les soins et la lutte contre la TB et le DM et examine trois défis importants pour les soins de ces affections. Ceux-ci sont en relation avec 1) un dépistage bidirectionnel des deux maladies, 2) le traitement des patients atteints des deux maladies, et 3) la prévention de la TB chez les sujets atteints de DM. Pour chaque secteur, les déficiences en matière de connaissances et les zones prioritaires de recherche sont soulignées. Un diabète sucré non diagnostiqué, traité de manière inadéquate et médiocrement contrôlé semble une menace beaucoup plus importante pour la prévention et la lutte contre la TB qu'on ne l'avait pensé précédemment, et ce problème doit être abordé. La prévention du diabète grâce à une attention portée aux régimes inadéquats, au style de vie sédentaire et à l'obésité de l'enfant et de l'adulte doit être incluse dans de larges stratégies de prévention des maladies non transmissibles. Le réseau de collaboration fournit un modèle d'action et les recommandations doivent à présent être mises en œuvre et évaluées sur le terrain afin de donner un fondement solide à l'extension d'interventions qui fonctionnent et sont efficientes pour lutter contre le double fardeau de ces maladies.

La carga mundial de morbilidad por diabetes sacarina (DM) es considerable y se prevé que se sobrepasen los 550 millones de personas en el 2030. Países de Asia como la India y la China soportarán la mayor parte de la carga de esta epidemia en expansión. Las personas que padecen DM presentan un riesgo considerable de contraer tuberculosis (TB) activa, el cual es de dos a tres veces mayor que el riesgo de las personas que no sufren DM. En el presente artículo se consideran las características epidemiológicas de ambas enfermedades, se analizan la elaboración y la puesta en marcha del marco conjunto de atención y de lucha contra la TB y la DM de la Organización Mundial de la Salud y la Unión Internacional contra la Tuberculosis y las Enfermedades Respiratorias y se examinan además tres dificultades importantes que plantea la atención. Estos problemas hacen referencia a: 1) el cribado bidireccional de ambas enfermedades, 2) el tratamiento de pacientes aquejados de ambas enfermedades, y 3) la prevención de la TB en las personas diabéticas. Se destacaron las deficiencias en los conocimientos y los dominios prioritarios de investigación en cada aspecto. La DM no diagnosticada, tratada inadecuadamente o mal equilibrada constituye una amenaza a la prevención y la lucha contra la TB, que es más determinante de lo que se conside-raba y es preciso atenderla. La prevención de la DM mediante la corrección de los regímenes poco saludables, los estilos de vida sedenta-rios y la obesidad infantil se debe incorporar a las estrategias globales de prevención de las enfermedades no transmisibles. El marco conjunto de atención ofrece un modelo para la acción y es preciso poner en práctica sus recomendaciones y evaluarlas en el terreno, a fin de sentar unas bases firmes a la ampliación de escala de las intervenciones que dan resultados y abordan eficazmente esta carga de morbilidad doble.

Screening tuberculosis patients for diabetes in a tribal area in South India.

SETTING: Ten peripheral health institutions of a tribal tuberculosis unit, Saluru, Vizianagaram District, South India. OBJECTIVE: To assess among tuberculosis (TB) patients: 1) the feasibility of screening for diabetes mellitus (DM), 2) the prevalence of DM, 3) the demographic and clinical features associated with DM, and 4) the number needed to screen (NNS) to find one new case of DM. DESIGN: Cross-sectional study: all TB patients registered from January to September 2012 were screened for DM using a screening questionnaire and random blood glucose, followed by fasting blood glucose (FBG) measurements using a glucometer. DM was diagnosed if FBG was ≥126 mg/dl. RESULTS: Of 381 patients, 374 (98%) were assessed for DM, suggesting feasibility of screening, and 19 (5%) were found to have DM (12 were newly diagnosed and 7 had a previous diagnosis of DM). The only characteristic associated with DM was age ≥40 years. The NNS to detect a new case of DM among all TB patients was 31; among those aged ≥40 years, the NNS was 20, and among current smokers it was 21. CONCLUSION: Screening of TB patients for DM was feasible and effective, and this should inform national scale-up. Other key considerations include the continued provision of free TB-DM screening, with co-location and integration of services.