Reuniting overnutrition and undernutrition, macronutrients, and micronutrients.

Over-nutrition and its late consequences are a dominant theme in medicine today. In addition to the health hazards brought on by over-nutrition, the medical community has recently accumulated a roster of health benefits with obesity, grouped under "obesity paradox." Throughout the world and throughout history until the 20th century, under-nutrition was a dominant evolutionary force. Under-nutrition brings with it a mix of benefits and detriments that are opposite to and continuous with those of over-nutrition. This continuum yields J-shaped or U-shaped curves relating body mass index to mortality. The overweight have an elevated risk of dying in middle age of degenerative diseases while the underweight are at increased risk of premature death from infectious conditions. Micronutrient deficiencies, major concerns of nutritional science in the 20th century, are being neglected. This "hidden hunger" is now surprisingly prevalent in all weight groups, even among the overweight. Because micronutrient replacement is safe, inexpensive, and predictably effective, it is now an exceptionally attractive target for therapy across the spectrum of weight and age. Nutrition-related conditions worthy of special attention from caregivers include excess vitamin A, excess vitamin D, and deficiency of magnesium.

Is metformin poised for a second career as an antimicrobial?

Metformin, a widely used antihyperglycaemic, has a good safety profile, reasonably manageable side-effects, is inexpensive, and causes a desirable amount of weight loss. In 4 studies of patients with tuberculosis (1 prospective and 3 retrospective), metformin administration resulted in better outcomes. In mice with several models of endotoxemia, metformin diminished levels of proinflammatory cytokines and improved survival. Laboratory studies showed effectiveness of the drug on multiple pathogens, including Trichinella spiralis, Staphylococcus aureus, Pseudomonas aeruginosa, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Metformin administration in humans and mice produced major changes in the composition of the gut microbiota. These recently discovered microbe-modulating properties of the drug have led investigators to predict wide therapeutic utility for metformin. The recent easing in United States Food and Drug Administration (FDA) guidelines regarding administration of metformin to patients with kidney disease, and reduced anxiety about patient safety in terms of lactic acidosis, increase the probability of broadening of metformin's usage as a treatment of infectious agents. In this text we review articles pertinent to metformin's effects on microorganisms, both pathogens and commensals. We highlight the possible role of metformin in a wide range of infectious diseases and a possible expansion of its therapeutic profile in this field. A systematic review was done of PubMed indexed articles that examined the effects of metformin on a wide range of pathogens. Metformin was found to have efficacy as an antimicrobial agent in patients with tuberculosis. Mice infected with Trypanosomiasis cruzi had higher survival when also treated with metformin. The drug in vitro was active against T. spiralis, S. aureus, P. aeruginosa, and hepatitis B virus. In addition there is emerging literature on its role in sepsis. We conclude that metformin may have a potential role in the therapy for multiple infectious diseases. Metformin, in addition to its traditional effects on glucose metabolism, provides anti-microbial benefits in patients with tuberculosis and in a very wide range of other infections encounters in vitro and in vivo.

Obesity paradox, obesity orthodox, and the metabolic syndrome: An approach to unity.

Obesity and the accompanying metabolic syndrome are strongly associated with heightened morbidity and mortality in older adults. In our review of more than 20 epidemiologic studies of major infectious diseases, including leaders such as tuberculosis, community-acquired pneumonia, and sepsis, obesity was associated with better outcomes. A cause-and-effect relationship between over-nutrition and survival with infection is suggested by results of two preliminary studies of infections in mice, where high fat feeding for 8-10 weeks provided much better outcomes. The better outcomes of infections with obesity are reminiscent of many recent studies of "sterile" non-infectious medical and surgical conditions where outcomes for obese patients are better than for their thinner counterparts --- and given the tag "obesity paradox". Turning to the history of medicine and biological evolution, we hypothesize that the metabolic syndrome has very ancient origins and is part of a lifelong metabolic program. While part of that program (the metabolic syndrome) promotes morbidity and mortality with aging, it helps infants and children as well as adults in their fight against infections and recovery from injuries, key roles in the hundreds of centuries before the public health advances of the 20th century. We conclude with speculation on how understanding the biological elements that protect obese patients with infections or injuries might be applied advantageously to thin patients with the same medical challenges.

The brighter (and evolutionarily older) face of the metabolic syndrome: evidence from Trypanosoma cruzi infection in CD-1 mice.

BACKGROUND: Infection with Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, results in chronic infection that leads to cardiomyopathy with increased mortality and morbidity in endemic regions. In a companion study, our group found that a high-fat diet (HFD) protected mice from T. cruzi-induced myocardial damage and significantly reduced post-infection mortality during acute T. cruzi infection. METHODS: In the present study metabolic syndrome was induced prior to T. cruzi infection by feeding a high fat diet. Also, mice were treated with anti-diabetic drug metformin. RESULTS: In the present study, the lethality of T. cruzi (Brazil strain) infection in CD-1 mice was reduced from 55% to 20% by an 8-week pre-feeding of an HFD to induce obesity and metabolic syndrome. The addition of metformin reduced mortality to 3%. CONCLUSIONS: It is an interesting observation that both the high fat diet and the metformin, which are known to differentially attenuate host metabolism, effectively modified mortality in T. cruzi-infected mice. In humans, the metabolic syndrome, as presently construed, produces immune activation and metabolic alterations that promote complications of obesity and diseases of later life, such as myocardial infarction, stroke, diabetes, Alzheimer's disease and cancer. Using an evolutionary approach, we hypothesized that for millions of years, the channeling of host resources into immune defences starting early in life ameliorated the effects of infectious diseases, especially chronic infections, such as tuberculosis and Chagas disease. In economically developed countries in recent times, with control of the common devastating infections, epidemic obesity and lengthening of lifespan, the dwindling benefits of the immune activation in the first half of life have been overshadowed by the explosion of the syndrome's negative effects in later life.

Prediction of preeclampsia-bench to bedside.

Hypertensive disorders of pregnancy (HDP) constitute the most common medical condition seen during gestation, effecting 1 in 10 pregnancies in the USA. Traditionally, preeclampsia (PE) is defined as a new onset of hypertension and either proteinuria or end-organ dysfunction after 20 weeks of gestation in a previously normotensive woman. Preeclampsia is a potentially life-threatening condition with widespread underlying endothelial dysfunction, and accompanying inflammation, vasoconstriction, and platelet activation. Women with preeclampsia are at an increased risk for life-threatening complications and progression to eclampsia. Worldwide, 10 to 15 % of maternal deaths are from preeclampsia and related complications. Traditionally, diagnosis of preeclampsia is made based upon presence of risk factors and clinical criteria. Diagnosis is challenging in asymptomatic women early in pregnancy as well as in nulliparous women as they lack obstetric history; however, it is well known that women with previous preeclampsia have a 14.7 % risk of the condition in the second pregnancy. Prediction of those at risk and early diagnosis is crucial to enable close surveillance of high-risk women in order to improve maternal and fetal outcomes. There has been much advance in our understanding of the pathogenesis of PE and in the field of angiogenic markers. However, no one test meets the criteria for a good biomarker. A multiparametric approach appears to be optimal as we await newer systems biology approaches to give us better insight into the pathogenesis of the disease.

The protective effects of erythropoietin on rat glomerular podocytes in culture are modulated by extracellular matrix proteins.

BACKGROUND/AIMS: Podocytes are typically cultured on collagen I; however, collagen I is absent from healthy glomerular basement membranes. Erythropoietin (EPO) is thought to protect podocytes in vivo. Here, we studied how various types of extracellular matrix (ECM) proteins and EPO affect podocytes in culture. METHODS: Primary rat podocytes were replated on collagen I, collagen IV, whole ECM extract, laminin, or bare plastic. Cellular adhesion (8 hours after plating), proliferation (5 days, 10 % serum), and resistance to serum deprivation (3 days, 0.5 % serum) were assessed. BrdU incorporation and expression of podocyte-specific markers were employed as measures of cellular proliferation and differentiation, respectively. qPCR was used to verify expression of EPO receptor in cultured podocytes. RESULTS: Cellular adhesion was similar on all ECM proteins and unaffected by EPO. Proliferation was accelerated by laminin and the ECM extract, but the final cell density was similar on all ECM surfaces. Collagen IV supported the serum-deprived cells better than the other ECM proteins. EPO (2-20 ng/ml) improved viability of serum-deprived podocytes on collagen I, collagen IV, and ECM, but not on laminin or bare plastic. The cells expressed mRNA for EPO receptor. CONCLUSION: The physiological ECM proteins are more supportive of primary podocytic cultures compared with collagen I. The protective effects of EPO during serum deprivation are modulated by the cultivation surface.

Systemic Inflammatory Response Syndrome from Nitrofurantoin: A Case Report.

BACKGROUND Nitrofurantoin is an antibiotic that is commonly used and preferred to treat lower urinary tract infections due to its relatively safe adverse effects profile. However, with the increased emphasis on antibiotic stewardship, it is important to recognize the rare, yet serious adverse effects profile of this medication. One of the rare adverse reactions is the development of systemic inflammatory response syndrome from nitrofurantoin. CASE REPORT We present a case of a 66-year-old woman who developed a classic systemic inflammatory response syndrome, including leukocytosis and fevers, after 2 repeated exposures to nitrofurantoin after a urological procedure. The patient had an initial infectious workup which was negative. A suspected adverse reaction to nitrofurantoin was suspected and the patient was found to have complete resolution of symptoms with discontinuation of the drug and with supportive treatment. CONCLUSIONS This case demonstrates that although nitrofurantoin is known to be relatively well tolerated, clinicians should still be aware of the adverse reactions, including a potential systemic inflammatory response, from nitrofurantoin use. This information should be used to educate patients going forward on potential adverse effects to be aware of.

Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines.

Preeclampsia is becoming an increasingly common diagnosis in the developed world and remains a high cause of maternal and fetal morbidity and mortality in the developing world. Delay in childbearing in the developed world feeds into the risk factors associated with preeclampsia, which include older maternal age, obesity, and/or vascular diseases. Inadequate prenatal care partially explains the persistent high prevalence in the developing world. In this review, we begin by presenting the most recent concepts in the pathogenesis of preeclampsia. Upstream triggers of the well described angiogenic pathways, such as the heme oxygenase and hydrogen sulfide pathways, as well as the roles of autoantibodies, misfolded proteins, nitric oxide, and oxidative stress will be described. We also detail updated definitions, classification schema, and treatment targets of hypertensive disorders of pregnancy put forth by obstetric and hypertensive societies throughout the world. The shift has been made to view preeclampsia as a systemic disease with widespread endothelial damage and the potential to affect future cardiovascular diseases rather than a self-limited occurrence. At the very least, we now know that preeclampsia does not end with delivery of the placenta. We conclude by summarizing the latest strategies for prevention and treatment of preeclampsia. A better understanding of this entity will help in the care of at-risk women before delivery and for decades after.