TB research at UT-Houston--a review of cord factor: new approaches to drugs, vaccines and the pathogenesis of tuberculosis.

Tuberculosis remains a major threat as drug resistance continues to increase. Pulmonary tuberculosis in adults is responsible for 80% of clinical cases and nearly 100% of transmission of infection. Unfortunately, since we have no animal models of adult type pulmonary tuberculosis, the most important type of disease remains largely out of reach of modern science and many fundamental questions remain unanswered. This paper reviews research dating back to the 1950's providing compelling evidence that cord factor (trehalose 6,6 dimycolate [TDM]) is essential for understanding tuberculosis. However, the original papers by Bloch and Noll were too far ahead of their time to have immediate impact. We can now recognize that the physical and biologic properties of cord factor are unprecedented in science, especially its ability to switch between two sets of biologic activities with changes in conformation. While TDM remains on organisms, it protects them from killing within macrophages, reduces antibiotic effectiveness and inhibits the stimulation of protective immune responses. If it comes off organisms and associates with lipid, TDM becomes a driver of tissue damage and necrosis. Studies emanating from cord factor research have produced (1) a rationale for improving vaccines, (2) an approach to new drugs that overcome natural resistance to antibiotics, (3) models of caseating granulomas that reproduce multiple manifestations of human tuberculosis. (4) evidence that TDM is a key T cell antigen in destructive lesions of tuberculosis, and (5) a new understanding of the pathology and pathogenesis of postprimary tuberculosis that can guide more informative studies of long standing mysteries of tuberculosis.

Molecular evolution of primate immunodeficiency viruses and hepatitis delta virus

Primate immunodeficiency viruses, or lentiviruses (HIV-1, HIV-2, and SIV), and hepatitis delta virus (HDV) are RNA viruses characterized by rapid evolution. Infection by primate immunodeficiency viruses usually results in the development of acquired immunodeficiency syndrome (AIDS) in humans and AIDS-like illnesses in Asian macaques. Similarly, hepatitis delta virus infection causes hepatitis and liver cancer in humans. These viruses are heterogeneous within an infected patient and among individuals. Substitution rates in the virus genomes are high and vary in different lineages and among sites. Methods of phylogenetic analysis were applied to study the evolution of primate lentiviruses and the hepatitis delta virus. The following results have been obtained: (1) The substitution rate varies among sites of primate lentivirus genes according to the two parameter gamma distribution, with the shape parameter $\alpha$ being close to 1. (2) Primate immunodeficiency viruses fall into species-specific lineages. Therefore, viral transmissions across primate species are not as frequent as suggested by previous authors. (3) Primate lentiviruses have acquired or lost their pathogenicity several times in the course of evolution. (4) Evidence was provided for multiple infections of a North American patient by distinct HIV-1 strains of the B subtype. (5) Computer simulations indicate that the probability of committing an error in testing HIV transmission depends on the number of virus sequences and their length, the divergence times among sequences, and the model of nucleotide substitution. (6) For future investigations of HIV-1 transmissions, using longer virus sequences and avoiding the use of distant outgroups is recommended. (7) Hepatitis delta virus strains are usually related according to the geographic region of isolation. (8) Evolution of HDV is characterized by the rate of synonymous substitution being lower than the nonsynonymous substitution rate and the rate of evolution of the noncoding region. (9) There is a strong preference for G and C nucleotides at the third codon positions of the HDV coding region. ^

Client Home or Agency Office? How Do We Decide Where to See Our Clients?

Decisions about location of services sometimes appear to be made more on the basis of agency preference than assessment of need. Today the profession has enough experience with service locations that it is possible to develop more clear guidelines for the decision about where work with clients should take place, in the client’s home or nearby community or in the practitioner’s office. This study was conducted with two purposes; 1) to identify at a higher level of evidence the various reasons for seeing clients in their own homes and nearby community setting; and 2) to demonstrate how readily available information can be used to gradually increase the level of evidence by which practice decisions are made.

Assessing and applying evidence-based interventions at the community level in India as a model policy to reduce neonatal mortality rates in Nigeria

Background. The United Nations' Millennium Development Goal (MDG) 4 aims for a two-thirds reduction in death rates for children under the age of five by 2015. The greatest risk of death is in the first week of life, yet most of these deaths can be prevented by such simple interventions as improved hygiene, exclusive breastfeeding, and thermal care. The percentage of deaths in Nigeria that occur in the first month of life make up 28% of all deaths under five years, a statistic that has remained unchanged despite various child health policies. This paper will address the challenges of reducing the neonatal mortality rate in Nigeria by examining the literature regarding efficacy of home-based, newborn care interventions and policies that have been implemented successfully in India. ^ Methods. I compared similarities and differences between India and Nigeria using qualitative descriptions and available quantitative data of various health indicators. The analysis included identifying policy-related factors and community approaches contributing to India's newborn survival rates. Databases and reference lists of articles were searched for randomized controlled trials of community health worker interventions shown to reduce neonatal mortality rates. ^ Results. While it appears that Nigeria spends more money than India on health per capita ($136 vs. $132, respectively) and as percent GDP (5.8% vs. 4.2%, respectively), it still lags behind India in its neonatal, infant, and under five mortality rates (40 vs. 32 deaths/1000 live births, 88 vs. 48 deaths/1000 live births, 143 vs. 63 deaths/1000 live births, respectively). Both countries have comparably low numbers of healthcare providers. Unlike their counterparts in Nigeria, Indian community health workers receive training on how to deliver postnatal care in the home setting and are monetarily compensated. Gender-related power differences still play a role in the societal structure of both countries. A search of randomized controlled trials of home-based newborn care strategies yielded three relevant articles. Community health workers trained to educate mothers and provide a preventive package of interventions involving clean cord care, thermal care, breastfeeding promotion, and danger sign recognition during multiple postnatal visits in rural India, Bangladesh, and Pakistan reduced neonatal mortality rates by 54%, 34%, and 15–20%, respectively. ^ Conclusion. Access to advanced technology is not necessary to reduce neonatal mortality rates in resource-limited countries. To address the urgency of neonatal mortality, countries with weak health systems need to start at the community level and invest in cost-effective, evidence-based newborn care interventions that utilize available human resources. While more randomized controlled studies are urgently needed, the current available evidence of models of postnatal care provision demonstrates that home-based care and health education provided by community health workers can reduce neonatal mortality rates in the immediate future.^

Repeat length and RNA expression level are not primary determinants in CUG expansion toxicity in Drosophila models.

Evidence for an RNA gain-of-function toxicity has now been provided for an increasing number of human pathologies. Myotonic dystrophies (DM) belong to a class of RNA-dominant diseases that result from RNA repeat expansion toxicity. Specifically, DM of type 1 (DM1), is caused by an expansion of CUG repeats in the 3'UTR of the DMPK protein kinase mRNA, while DM of type 2 (DM2) is linked to an expansion of CCUG repeats in an intron of the ZNF9 transcript (ZNF9 encodes a zinc finger protein). In both pathologies the mutant RNA forms nuclear foci. The mechanisms that underlie the RNA pathogenicity seem to be rather complex and not yet completely understood. Here, we describe Drosophila models that might help unravelling the molecular mechanisms of DM1-associated CUG expansion toxicity. We generated transgenic flies that express inducible repeats of different type (CUG or CAG) and length (16, 240, 480 repeats) and then analyzed transgene localization, RNA expression and toxicity as assessed by induced lethality and eye neurodegeneration. The only line that expressed a toxic RNA has a (CTG)(240) insertion. Moreover our analysis shows that its level of expression cannot account for its toxicity. In this line, (CTG)(240.4), the expansion inserted in the first intron of CG9650, a zinc finger protein encoding gene. Interestingly, CG9650 and (CUG)(240.4) expansion RNAs were found in the same nuclear foci. In conclusion, we suggest that the insertion context is the primary determinant for expansion toxicity in Drosophila models. This finding should contribute to the still open debate on the role of the expansions per se in Drosophila and in human pathogenesis of RNA-dominant diseases.

The evidence behind the level of a random urine protein:creatinine in the diagnosis of preeclampsia: A systematic review

Objective. To determine the accuracy of the urine protein:creatinine ratio (pr:cr) in predicting 300 mg of protein in 24-hour urine collection in pregnant patients with suspected preeclampsia. ^ Methods. A systematic review was performed. Articles were identified through electronic databases and the relevant citations were hand searching of textbooks and review articles. Included studies evaluated patients for suspected preeclampsia with a 24-hour urine sample and a pr:cr. Only English language articles were included. The studies that had patients with chronic illness such as chronic hypertension, diabetes mellitus or renal impairment were excluded from the review. Two researchers extracted accuracy data for pr:cr relative to a gold standard of 300 mg of protein in 24-hour sample as well as population and study characteristics. The data was analyzed and summarized in tabular and graphical form. ^ Results. Sixteen studies were identified and only three studies met our inclusion criteria with 510 total patients. The studies evaluated different cut-points for positivity of pr:cr from 130 mg/g to 700 mg/g. Sensitivities and specificities for pr:cr of 130mg/g -150 mg/g were 90-93% and 33-65%, respectively; for a pr:cr of 300 mg/g were 81-95% and 52-80%, respectively; for a pr:cr of 600-700mg/g were 85-87% and 96-97%, respectively. ^ Conclusion. The value of a random pr:cr to exclude pre-eclampsia is limited because even low levels of pr:cr (130-150 mg/g) may miss up to 10% of patients with significant proteinuria. A pr:cr of more than 600 mg/g may obviate a 24-hour collection.^

A project to improve the information seeking skills and increase the use of evidence-based research in public health practice

The ability of public health practitioners (PHPs) to work efficiently and effectively is negatively impacted by their lack of knowledge of the broad range of evidence-based practice information resources and tools that can be utilized to guide them in their development of health policies and programs. This project, a three-hour continuing education hands-on workshop with supporting resources, was designed to increase knowledge and skills of these resources. The workshop was presented as a pre-conference continuing education program for the Texas Public Health Association (TPHA) 2008 Annual Conference. Topics included: identification of evidence-based practice resources to aid in the development of policies and programs; identification of sources of publicly available data; utilization of data for community assessments; and accessing and searching the literature through a collection of databases available to all citizens of Texas. Supplemental resources included a blog that served as a gateway to the resources explored during the presentation, a community assessment workbook that incorporates both Healthy People 2010 objectives and links to reliable sources of data, and handouts providing additional instruction on the use of the resources covered during the workshop.^ Before- and after-workshop surveys based on Kirkpatrick's 4-level model of evaluation and the Theory of Planned Behavior were administered. Of the questions related to the trainer, the workshop, and the usefulness of the workshop, participants gave "Good" to "Excellent" responses to all one question. Confidence levels overall increased a statistically significant amount; measurements of attitude, social norms, and control showed no significant differences before and after the workshop. Lastly, participants indicated they were likely to use resources shown during the workshop within a one to three month time period on average. ^ The workshop and creation of supplemental resources served as a pilot for a funded project that will be continued with the development and delivery of four 4-week long webinar-based training sessions to be completed by December 2008. ^