Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

Phase I trial of intravesical Suramin in recurrent superficial transitional cell bladder carcinoma

Suramin is an antitrypanosomal agent with antineoplastic activity, but with serious systemic side effects. We administered Suramin intravesically to determine a concentration with low toxicity but with evidence of a pharmacodynamic effect, to recommend a dose level for phase II trials. This was an open-labelled, nonrandomised dose-escalation phase I study. In all, 12 patients with a history of recurrent superficial bladder cancer were grouped into four dose levels (10–150 mg ml−1 in 60 ml saline). Six catheter instillations at weekly intervals were used. Cystoscopy and biopsy were performed before and 3 months after the start of treatment. Suramin was assayed using high-performance liquid chromatography, vascular endothelial growth factor (VEGF) using ELISA (enzyme-linked immunosorbent assay), and urinary protein profile using surface-enhanced laser desorption ionisation mass spectroscopy (SELDI). Minimal systemic absorption of Suramin was found at the highest dose of 150 mg ml−1. Urinary VEGF was affected by Suramin at doses above 50 mg ml−1, corresponding to the estimated threshold of saturation of Suramin binding to urine albumin. SELDI showed a specific disappearance of urinary protein peaks during treatment. Intravesical Suramin shows lack of toxicity and low systemic absorption. The results of this phase I trial support expanded clinical trials of efficacy at a dose of 100 mg ml−1 intravesically

Transcultural Diabetes Nutrition Therapy Algorithm: The Asian Indian Application

India and other countries in Asia are experiencing rapidly escalating epidemics of type 2 diabetes (T2D) and cardiovascular disease. The dramatic rise in the prevalence of these illnesses has been attributed to rapid changes in demographic, socioeconomic, and nutritional factors. The rapid transition in dietary patterns in India—coupled with a sedentary lifestyle and specific socioeconomic pressures—has led to an increase in obesity and other diet-related noncommunicable diseases. Studies have shown that nutritional interventions significantly enhance metabolic control and weight loss. Current clinical practice guidelines (CPGs) are not portable to diverse cultures, constraining the applicability of this type of practical educational instrument. Therefore, a transcultural Diabetes Nutrition Algorithm (tDNA) was developed and then customized per regional variations in India. The resultant India-specific tDNA reflects differences in epidemiologic, physiologic, and nutritional aspects of disease, anthropometric cutoff points, and lifestyle interventions unique to this region of the world. Specific features of this transculturalization process for India include characteristics of a transitional economy with a persistently high poverty rate in a majority of people; higher percentage of body fat and lower muscle mass for a given body mass index; higher rate of sedentary lifestyle; elements of the thrifty phenotype; impact of festivals and holidays on adherence with clinic appointments; and the role of a systems or holistic approach to the problem that must involve politics, policy, and government. This Asian Indian tDNA promises to help guide physicians in the management of prediabetes and T2D in India in a more structured, systematic, and effective way compared with previous methods and currently available CPGs

Climate Change, Coral Reef Ecosystems, and Management Options for Marine Protected Areas

Marine protected areas (MPAs) provide place-based management of marine ecosystems through various degrees and types of protective actions. Habitats such as coral reefs are especially susceptible to degradation resulting from climate change, as evidenced by mass bleaching events over the past two decades. Marine ecosystems are being altered by direct effects of climate change including ocean warming, ocean acidification, rising sea level, changing circulation patterns, increasing severity of storms, and changing freshwater influxes. As impacts of climate change strengthen they may exacerbate effects of existing stressors and require new or modified management approaches; MPA networks are generally accepted as an improvement over individual MPAs to address multiple threats to the marine environment. While MPA networks are considered a potentially effective management approach for conserving marine biodiversity, they should be established in conjunction with other management strategies, such as fisheries regulations and reductions of nutrients and other forms of land-based pollution. Information about interactions between climate change and more “traditional” stressors is limited. MPA managers are faced with high levels of uncertainty about likely outcomes of management actions because climate change impacts have strong interactions with existing stressors, such as land-based sources of pollution, overfishing and destructive fishing practices, invasive species, and diseases. Management options include ameliorating existing stressors, protecting potentially resilient areas, developing networks of MPAs, and integrating climate change into MPA planning, management, and evaluation

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

CARDIAC TOXICITY AND ANTITUMOR-ACTIVITY OF 4'-DEOXY-4'-IODO-DOXORUBICINOL

The acute and chronic cardiotoxicity as well as the cytotoxicity of 4'-deoxy-4'-iodo-doxorubicinol (I-DXRol), the major metabolite of the doxorubicin (DXR) derivative 4'-deoxy-4'-iodo-DXR (I-DXR), were compared with those of I-DXR and DXR. In the acute study, anesthetized rats received i.v. DXR (10 mg/kg), I-DXR (4 mg/kg), or I-DXRol (4 mg/kg) and were monitored for ECG (S alpha T segment and T wave), systolic (SBP) and diastolic (DBP) blood pressure, the first derivative of the systemic arterial pressure (SA dP/dtmax), and heart rate. Treatments induced a significant widening of the S alpha T segment, but I-DXRol was significantly less toxic than I-DXR or DXR. As compared with control values, DXR induced a marked increase in SBP and DBP and a decrease in SA dP/dtmax, whereas I-DXR and I-DXRol induced modest changes in hemodynamic parameters. In the chronic study, 3 mg/kg DXR given to rats by i.v. bolus once a week for 3 weeks resulted in severe chronic cardiotoxicity that lasted 6 weeks and was characterized by S alpha T-segment widening, T-wave flattening, and severe cardiac histological damage. Doses of 1.2 mg/kg I-DXR and 1.2 and 2.4 mg/kg I-DXRol, given i.v. once a week for 3 weeks, and 3.6 mg/kg I-DXRol given as a single dose were associated with a significant T-wave voltage reduction; I-DXR and 2.4 mg/kg I-DXRol induced significant histological alterations of cardiac tissue as compared with control values, whereas modest alterations of heart tissue were observed after injections of 1.2 and 3.6 mg/kg I-DXRol in three doses and in a single dose, respectively. The cytotoxicity of the three anthracyclines against one glioblastoma cell line and two human small-cell lung cancer lines was similar. Results indicate that the acute cardiotoxicity of I-DXRol is lower than that of I-DXR and DXR, whereas the chronic heart damage is similar to that induced by I-DXR and significantly lower compared than that caused by DXR. Moreover, the cytotoxicity of the metabolite appears to be similar to that of I-DXR and DXR. The lack of additional cardiac toxicity due to I-DXRol further supports the lower overall cardiac toxicity of I-DXR, which retains a cytotoxic activity similar to that of the parent drug