Faculty Bibliography

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 20^th 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 20^th 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.

The role of high-density lipoprotein (HDL) function and advanced glycation end products (AGEs) in HIV-related atherosclerotic cardiovascular disease (CVD) is unclear. Both glycation and oxidation (HDLox) are major modifications of HDL that can alter its composition and function. Therefore, we explored the longitudinal association of HDLox with progression of glycation, as evaluated by measurement of circulating forms of receptor for AGE that predict morbidity (soluble Receptors for Advanced Glycation Endproducts [sRAGE], endogenous secretory Receptors for Advanced Glycation Endproducts [esRAGE]), in people with HIV-1 (PWH; HIV-1) and uninfected (HIV-1) individuals.We retrospectively assessed if levels of plasma sRAGE and esRAGE and HDL function (reduced antioxidant function is associated with increased HDL lipid hydroperoxide content; HDLox) in a subset of participants (n = 80) from a prospective 3-year study (AIDS Clinical Trials Group A5078). Primary outcomes were baseline and yearly rates of change over 96 of 144 weeks (Δ) in HDLox in HIV-1 versus uninfected HIV-1 controls (noted as HIV-1).Higher baseline levels of sRAGE in PWH on effective anti-retroviral therapy and with low CVD risk, but not in HIV-1 persons, were independently associated with higher HDLox. EsRAGE, but not sRAGE, had consistent inverse relationships with ΔHDLox in both HIV-1 and HIV-1 persons at baseline. In HIV-1 but not in HIV-1 persons, ΔHDLox had positive and inverse relationships with ΔRAGE and ΔesRAGE, respectively.Glycation and oxidation of HDL may contribute to impaired HDL function present in PWH.

UNLABELLED:The risk for diabetes risk is significantly elevated in persons who are older, overweight and have serious mental illness. However, primary care practitioners (PCP) tend to underestimate this risk. Although there are few opportunities for early detection of diabetes, blood exuded during routine oral exams in dental settings can be used to assess glycated hemoglobin (HbA1c) levels. The current study sought to understand how primary care practitioners would react to patients who screened positive for elevated HbA1c, how they estimated risk, and whether they provided treatment recommendations or counseling. METHOD/UNASSIGNED:Semi-structured telephone interviews were conducted on 61 subjects three months after demonstrating elevated HbA1c levels from dental screenings. Data were transcribed and analyzed using content analysis. RESULTS/UNASSIGNED:Qualitative analyses revealed four themes according to patients: (1) "Being told I needed to make lifestyle changes" (41%); (2) Realizing I needed a new health care provider or medication change" (10%); (3) "Being told of the need for monitoring but no counseling/treatment change" (16%); and (4) "Being told everything is fine and there is nothing to worry about" (31%). CONCLUSIONS/UNASSIGNED:Only half of the 61 cases reporting elevated HbA1C levels at screening experienced their PCP's as responding with counseling or medication changes. Almost a third of cases perceived that their PCP's dismissed the results, making no recommendations, and the rest perceived no counseling or interventions being proposed. Based on subjects' perceptions of their PCP's responses to their elevated HbA1c values, the impact of this intervention is substantially reduced over expectations.

Identification of biomarkers and/or mediators of cardiovascular disease (CVD) associated with HIV infection would be of diagnostic and therapeutic value. As soluble receptor for advanced glycation endproducts (sRAGE) and endogenous secretory (esRAGE) have been implicated in vascular complications in other settings, we investigated whether either soluble form of RAGE was associated with changes in carotid intima-media thickness (CIMT) in HIV-infected patients and HIV-uninfected controls. We found no differences in sRAGE, esRAGE, or CIMT among groups at study entry, or in yearly rates of change in sRAGE, esRAGE, or CIMT by HIV-serostatus (all p > 0.10). However, yearly rates of change in sRAGE (p = 0.07) and esRAGE (p < 0.001) were higher in those taking protease inhibitors, and lower baseline esRAGE levels (p = 0.06) were associated with increased odds of CIMT progression in HIV-infected individuals. Although esRAGE was not altered by HIV-serostatus (p = 0.17), its inverse relationship with CIMT progression in HIV-infected patients suggests a possible role as a mediator of CVD in HIV-infected persons.

BACKGROUND: Diabetes mellitus (DM) and metabolic syndrome are important targets for secondary prevention in cardiovascular disease. However, the prevalence in patients undergoing elective percutaneous coronary intervention (PCI) is not well defined. We aimed to analyze the prevalence and characteristics of patients undergoing PCI with previously unrecognized prediabetes, diabetes and metabolic syndrome. METHODS: Data were collected from 740 patients undergoing elective PCI between November 2010 and March 2013 at a tertiary referral center. Prevalence of DM and prediabetes was evaluated using Hemoglobin A1c (A1c >/= 6.5% for DM, A1c 5.7-6.4% for prediabetes). A modified definition was used for metabolic syndrome [3 or more of the following criteria: body mass index (BMI) >/=30 kg/m2; triglycerides >/= 150 mg/dL; high density lipoprotein <40 mg/dL in men and <50 mg/dL in women; systolic blood pressure >/= 130 mmHg and/or diastolic >/= 85 mmHg; A1c >/= 5.7% or on therapy]. RESULTS: Mean age was 67 years, median BMI was 28.2 kg/m2 , and 39% had known DM. Of those without known DM, 8.3% and 58.5% met A1c criteria for DM and for prediabetes at time of PCI. Overall, 54.9% met criteria for metabolic syndrome (69.2% of patients with DM and 45.8% of patients without DM). CONCLUSION: Among patients undergoing elective PCI, a substantial number were identified with new DM, prediabetes, and/or metabolic syndrome. Routine screening for an abnormal glucometabolic state at the time of revascularization may be useful for identifying patients who may benefit from additional targeting of modifiable risk factors

Objectives. We examined the potential for glycemic control monitoring and screening for diabetes in a dental setting among adults (n = 408) with or at risk for diabetes. Methods. In 2013 and 2014, we performed hemoglobin A1c (HbA1c) tests on dried blood samples of gingival crevicular blood and compared these with paired "gold-standard" HbA1c tests with dried finger-stick blood samples in New York City dental clinic patients. We examined differences in sociodemographics and diabetes-related risk and health care characteristics for 3 groups of at-risk patients. Results. About half of the study sample had elevated HbA1c values in the combined prediabetes and diabetes ranges, with approximately one fourth of those in the diabetes range. With a correlation of 0.991 between gingival crevicular and finger-stick blood HbA1c, measures of concurrence between the tests were extremely high for both elevated HbA1c and diabetes-range HbA1c levels. Persons already diagnosed with diabetes and undiagnosed persons aged 45 years or older could especially benefit from HbA1c testing at dental visits. Conclusions. Gingival crevicular blood collected at the dental visit can be used to screen for diabetes and monitor glycemic control for many at-risk patients. (Am J Public Health. Published online ahead of print February 25, 2015: e1-e6. doi:10.2105/AJPH.2014.302357).

With millions of at-risk people undiagnosed with pre-diabetes and diabetes, there is a need to identify alternate screening sites for out-of-range glucose values. We examined practical issues and accuracy (relative to High Performance Liquid Chromatography testing in a laboratory) in the use of the A1cNow point of care device for this screening in general practice dental clinics at a large University-based Dental College. Health care professionals obtained evaluable readings for only 70% of the subjects, even after two attempts, and its use according to manufacturer's instructions was often challenging in the busy environment of the dental clinic. At thresholds for pre-diabetes and diabetes established by the American Diabetes Association, sensitivities of the A1cNow kit relative to the HPLC method were 91.9% and 100%, respectively. However, specificities for pre-diabetes and diabetes were 66.7% and 82.4%, respectively, indicating many false positive results. A better strategy for diabetes screening may involve a laboratory-based analysis approach that is patient- and provider-friendly, with minimal burden to the dental team.

IntroductionEstrogen inhibition is effective in preventing breast cancer in only up to 50% of women with precancerous lesions and many experience side effects that are poorly tolerated. As insulin-like growth factor I (IGF-I) underlies both estrogen and progesterone actions and has other direct effects on mammary development and carcinogenesis, we hypothesized that IGF-I inhibition might provide a novel approach for breast cancer chemoprevention.MethodsIn total, 13 women with core breast biopsies diagnostic of atypical hyperplasia (AH) were treated for 10 days with pasireotide, a somatostatin analog which uniquely inhibits IGF-I action in the mammary gland. They then had excision biopsies. 12 patients also had proliferative lesions and one a ductal carcinoma in situ (DCIS). Primary outcomes were changes in cell proliferation and apoptosis after treatment. Expression of estrogen receptor (ER), progesterone receptor (PR), and phosphorylated Insulin-like growth factor I receptor (IGF-1R), protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2) were also assessed. Core and excision biopsies from 14 untreated patients served as non-blinded controls. Hyperglycemia and other side effects were carefully monitored.ResultsPasireotide decreased proliferation and increased apoptosis in all AH (from 3.6 inverted question mark+/- inverted question mark2.6% to 1.3 inverted question mark+/- inverted question mark1.2% and from 0.3 inverted question mark+/- inverted question mark0.2% to 1.5 inverted question mark+/- inverted question mark1.6%, respectively) and proliferative lesions (from 3.8 inverted question mark+/- inverted question mark2.5% to 1.8 inverted question mark+/- inverted question mark1.8% and from 0.3 inverted question mark+/- inverted question mark0.2% to 1.3 inverted question mark+/- inverted question mark0.6%, respectively). The DCIS responded similarly. ER and PR were not affected by pasireotide, while IGF-1R, ERK1/2 and AKT phosphorylation decreased significantly. In contrast, tissue from untreated controls showed no change in cell proliferation or phosphorylation of IGF-1R, AKT or ERK 1/2. Mild to moderate hyperglycemia associated with reduced insulin levels was found. Glucose fell into the normal range after discontinuing treatment. Pasireotide was well tolerated and did not cause symptoms of estrogen deprivation.ConclusionsIGF-I inhibition by pasireotide, acting through the IGF-1R, was associated with decreased proliferation and increased apoptosis in pre-malignant breast lesions and one DCIS. Assuming hyperglycemia can be controlled, these data suggest that inhibiting the IGF-I pathway may prove an effective alternative for breast cancer chemoprevention.Trial registration NCT01372644 Trial date: July 1, 2007.