Science that "knows" and science that "asks"

Clinician-researchers and experimental scientists do not speak the same language; they have different professional environments and different end-points in their research. This creates considerable problems of comprehension and communication, which constitute a major drawback in multidisciplinary work such as translational medicine. A stereotypic representation of both these worlds is presented as a starting point to encourage debate on this issue

The United States and global health: inseparable and synergistic? The Institute of Medicine's report on global health

In the wake of dynamic economic and political transitions worldwide, the Institute of Medicine recently released its report advocating investments in global health from the United States (US). The expert panel reinforces the ‘transnational and interdisciplinary’ nature of global health research and practice as an endeavor ‘to improve health and achieve greater equity for all people worldwide.’ This report was judiciously timed given the growing recognition of global health, and is also acknowledged for incorporating themes that are particularly pertinent to the twenty-first century. New paradigms are introduced, denouncing the dichotomous distinction between rich and poor countries with the rapidly transitioning countries emerging as global powers, and affirming the need for models of respectful partnership and wider translation of science into practice. Cultivating sustainable partnerships and investing in the understanding and combat of diseases worldwide will become increasingly important for the US to maintain its global competitiveness, and may offer lessons in innovation, efficiency, and organization of institutions and human resources

Thrombotic gene polymorphisms and postoperative outcome after coronary artery bypass graft surgery

<p>Abstract</p> <p>Background</p> <p>Emerging perioperative genomics may influence the direction of risk assessment and surgical strategies in cardiac surgery. The aim of this study was to investigate whether single nucleotide polymorphisms (SNP) affect the clinical presentation and predispose to increased risk for postoperative adverse events in patients undergoing coronary artery bypass grafting surgery (CABG).</p> <p>Methods</p> <p>A total of 220 patients undergoing first-time CABG between January 2005 and May 2008 were screened for factor V gene G1691A (FVL), prothrombin/factor II G20210A (PT G20210A), angiotensin I-converting enzyme insertion/deletion (ACE-ins/del) polymorphisms by PCR and Real Time PCR. End points were defined as death, myocardial infarction, stroke, postoperative bleeding, respiratory and renal insufficiency and event-free survival. Patients were compared to assess for any independent association between genotypes for thrombosis and postoperative phenotypes.</p> <p>Results</p> <p>Among 220 patients, the prevalence of the heterozygous FVL mutation was 10.9% (n = 24), and 3.6% (n = 8) were heterozygous carriers of the PT G20210A mutation. Genotype distribution of ACE-ins/del was 16.6%, 51.9%, and 31.5% in genotypes I/I, I/D, and D/D, respectively. FVL and PT G20210A mutations were associated with higher prevalence of totally occluded coronary arteries (p < 0.001). Furthermore the risk of left ventricular aneurysm formation was significantly higher in FVL heterozygote group compared to FVL G1691G (<it>p </it>= 0.002). ACE D/D genotype was associated with hypertension (<it>p </it>= 0.004), peripheral vascular disease (p = 0.006), and previous myocardial infarction (<it>p </it>= 0.007).</p> <p>Conclusions</p> <p>FVL and PT G20210A genotypes had a higher prevalence of totally occluded vessels potentially as a result of atherothrombotic events. However, none of the genotypes investigated were independently associated with mortality.</p

Research on health transition in Africa: time for action

With rapidly increasing globalization, trends towards unhealthy diets, obesity, sedentary lifestyles and unhealthy habits are resulting in an increased worldwide burden of chronic non-communicable diseases (NCDs). In Africa this means that health systems face the challenge of an increasing burden of NCDs and of continuing high morbidity and mortality from communicable diseases. This health transition represents an enormous challenge to Africa as the region with the least resources for an effective response. Whereas previous epidemics, including HIV, have caught Africa unprepared, the opportunity now arises to take the advancing wave of health transition in Africa seriously. Health research has a key role to play in meeting health and development goals, and must be responsive to changing disease patterns, such as health transition. There is an urgent need for research on health transition in Africa to enable countries to respond effectively to rapidly changing health needs

Is the HIV burden in India being overestimated?

BACKGROUND: The HIV burden estimate for India has a very wide plausibility range. A recent population-based study in a south Indian district demonstrated that the official method used in India to estimate HIV burden in the population, which directly extrapolates annual sentinel surveillance data from large public sector antenatal and sexually transmitted infection (STI) clinics, led to a 2–3 times higher estimate than that based on population-based data. METHODS: We assessed the generalisability of the reasons found in the Guntur study for overestimation of HIV by the official sentinel surveillance based method: addition of substantial unnecessary HIV estimates from STI clinics, the common practice of referral of HIV positive/suspect patients by private practitioners to public hospitals, and a preferential use of public hospitals by lower socioeconomic strata. We derived conservative correction factors for the sentinel surveillance data and titrated these to the four major HIV states in India (Andhra Pradesh, Maharashtra, Karnataka and Tamil Nadu), and examined the impact on the overall HIV estimate for India. RESULTS: HIV data from STI clinics are not used elsewhere in the world as a component of HIV burden estimation in generalised epidemics, and the Guntur study verified that this was unnecessary. The referral of HIV positive/suspect patients from the private to the public sector is a widespread phenomenon in India, which is likely causing an upward distortion in HIV estimates from sentinel surveillance in other parts of India as well. Analysis of data from the nationwide Reproductive and Child Health Survey revealed that lower socioeconomic strata were over-represented among women seeking antenatal care at public hospitals in all major south Indian states, similar to the trend seen in the Guntur study. Application of conservative correction factors derived from the Guntur study reduced the 2005 official sentinel surveillance based HIV estimate of 3.7 million 15–49 years old persons in the four major states to 1.5–2.0 million, which would drop the official total estimate of 5.2 million 15–49 years old persons with HIV in India to 3–3.5 million. CONCLUSION: Plausible and cautious extrapolation of the trends seen in a recent large and rigorous population-based study of HIV in a south Indian district suggests that India is likely grossly overestimating its HIV burden with the current official sentinel surveillance based method. This method needs revision

Long Term Stabilization of Expanding Aortic Aneurysms by a Short Course of Cyclosporine A through Transforming Growth Factor-Beta Induction

Abdominal aortic aneurysms (AAAs) expand as a consequence of extracellular matrix destruction, and vascular smooth muscle cell (VSMC) depletion. Transforming growth factor (TGF)-beta 1 overexpression stabilizes expanding AAAs in rat. Cyclosporine A (CsA) promotes tissue accumulation and induces TGF -beta1 and, could thereby exert beneficial effects on AAA remodelling and expansion. In this study, we assessed whether a short administration of CsA could durably stabilize AAAs through TGF-beta induction. We showed that CsA induced TGF-beta1 and decreased MMP-9 expression dose-dependently in fragments of human AAAs in vitro, and in animal models of AAA in vivo. CsA prevented AAA formation at 14 days in the rat elastase (diameter increase: CsA: 131.9±44.2%; vehicle: 225.9±57.0%, P = 0.003) and calcium chloride mouse models (diameters: CsA: 0.72±0.14 mm; vehicle: 1.10±0.11 mm, P = .008), preserved elastic fiber network and VSMC content, and decreased inflammation. A seven day administration of CsA stabilized formed AAAs in rats seven weeks after drug withdrawal (diameter increase: CsA: 14.2±15.1%; vehicle: 45.2±13.7%, P = .017), down-regulated wall inflammation, and increased αSMA-positive cell content. Co-administration of a blocking anti-TGF-beta antibody abrogated CsA impact on inflammation, αSMA-positive cell accumulation and diameter control in expanding AAAs. Our study demonstrates that pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the degradation/repair balance towards healing

Effects of cognac on coronary flow reserve and plasma antioxidant status in healthy young men

<p>Abstract</p> <p>Background</p> <p>The cardioprotective effects of certain alcoholic beverages are partly related to their polyphenol content, which may improve the vasodilatory reactivity of arteries. Effect of cognac on coronary circulation, however, remains unknown. The purpose of this randomized controlled cross-over study was to determine whether moderate doses of cognac improve coronary reactivity as assessed with cold pressor testing (CPT) and coronary flow reserve (CFR) measument.</p> <p>Methods</p> <p>Study group consisted of 23 subjects. Coronary flow velocity and epicardial diameter was assessed using transthoracic echocardiography at rest, during CPT and adenosine infusion-derived CFR measurements before drinking, after a moderate (1.2 ± 0.1 dl) and an escalating high dose (total amount 2.4 ± 0.3 dl) of cognac. To explore the bioavailability of antioxidants, the antioxidant contents of cognac was measured and the absorption from the digestive tract was verified by plasma antioxidant capacity determination.</p> <p>Results</p> <p>Serum alcohol levels increased to 1.2 ± 0.2‰ and plasma antioxidant capacity from 301 ± 43.9 μmol/l to 320 ± 25.0 μmol/l by 7.6 ± 11.8%, (p = 0.01) after high doses of cognac. There was no significant change in flow velocity during CPT after cognac ingestion compared to control day. CFR was 4.4 ± 0.8, 4.1 ± 0.9 (p = NS), and 4.5 ± 1.2 (p = NS) before drinking and after moderate and high doses on cognac day, and 4.5 ± 1.4, and 4.0 ± 1.2 (p = NS) on control day.</p> <p>Conclusion</p> <p>Cognac increased plasma antioxidant capacity, but it had no effect on coronary circulation in healthy young men.</p> <p>Trial Registration</p> <p>NCT00330213</p

STK35L1 Associates with Nuclear Actin and Regulates Cell Cycle and Migration of Endothelial Cells

BACKGROUND: Migration and proliferation of vascular endothelial cells are essential for repair of injured endothelium and angiogenesis. Cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors play an important role in vascular tissue injury and wound healing. Previous studies suggest a link between the cell cycle and cell migration: cells present in the G(1) phase have the highest potential to migrate. The molecular mechanism linking these two processes is not understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we explored the function of STK35L1, a novel Ser/Thr kinase, localized in the nucleus and nucleolus of endothelial cells. Molecular biological analysis identified a bipartite nuclear localization signal, and nucleolar localization sequences in the N-terminal part of STK35L1. Nuclear actin was identified as a novel binding partner of STK35L1. A class III PDZ binding domains motif was identified in STK35L1 that mediated its interaction with actin. Depletion of STK35L1 by siRNA lead to an accelerated G(1) to S phase transition after serum-stimulation of endothelial cells indicating an inhibitory role of the kinase in G(1) to S phase progression. Cell cycle specific genes array analysis revealed that one gene was prominently downregulated (8.8 fold) in STK35L1 silenced cells: CDKN2A alpha transcript, which codes for p16(INK4a) leading to G(1) arrest by inhibition of CDK4/6. Moreover in endothelial cells seeded on Matrigel, STK35L1 expression was rapidly upregulated, and silencing of STK35L1 drastically inhibited endothelial sprouting that is required for angiogenesis. Furthermore, STK35L1 depletion profoundly impaired endothelial cell migration in two wound healing assays. CONCLUSION/SIGNIFICANCE: The results indicate that by regulating CDKN2A and inhibiting G1- to S-phase transition STK35L1 may act as a central kinase linking the cell cycle and migration of endothelial cells. The interaction of STK35L1 with nuclear actin might be critical in the regulation of these fundamental endothelial functions