Scott V. Monte

Reduction in endotoxemia, oxidative and inflammatory stress, and insulin resistance after Roux-en-Y gastric bypass surgery in patients with morbid obesity and type 2 diabetes mellitus.

BACKGROUND Roux-en-Y gastric bypass (RYGB) results in profound weight loss and resolution of type 2 diabetes mellitus (T2DM). The mechanism of this remarkable transition remains poorly defined. It has been proposed that endotoxin (lipopolysaccharide [LPS]) sets inflammatory tone, triggers weight gain, and initiates T2DM. Because RYGB may diminish LPS from endogenous and exogenous sources, we hypothesized that LPS and the associated cascade of oxidative and inflammatory stress would diminish after RYGB. METHODS Fifteen adults with morbid obesity and T2DM undergoing RYGB were studied. After an overnight fast, a baseline blood sample was collected the morning of surgery and at 180 days to assess changes in glycemia, insulin resistance, LPS, mononuclear cell nuclear factor (NF)-κB binding and mRNA expression of CD14, TLR-2, TLR-4, and markers of inflammatory stress. RESULTS At 180 days after RYGB, subjects had a significant decrease in body mass index (52.1 ± 13.0 to 40.4 ± 11.1), plasma glucose (148 ± 8 to 101 ± 4 mg/dL), insulin (18.5 ± 2.2 mμU/mL to 8.6 ± 1.0 mμU/mL) and HOMA-IR (7.1 ± 1.1 to 2.1 ± 0.3). Plasma LPS significantly reduced by 20 ± 5% (0.567 ± 0.033 U/mL to 0.443 ± 0.022 E U/mL). NF-κB DNA binding decreased significantly by 21 ± 8%, whereas TLR-4, TLR-2, and CD-14 expression decreased significantly by 25 ± 9%, 42 ± 8%, and 27 ± 10%, respectively. Inflammatory mediators CRP, MMP-9, and MCP-1 decreased significantly by 47 ± 7% (10.7 ± 1.6 mg/L to 5.8 ± 1.0 mg/L), 15 ± 6% (492 ± 42 ng/mL to 356 ± 26 ng/mL) and 11 ± 4% (522 ± 35 ng/mL to 466 ± 35 ng/mL), respectively. CONCLUSION LPS, NF-κB DNA binding, TLR-4, TLR-2, and CD14 expression, CRP, MMP-9, and MCP-1 decreased significantly after RYGB. The mechanism underlying resolution of insulin resistance and T2DM after RYGB may be attributable, at least in part, to the reduction of endotoxemia and associated proinflammatory mediators.

Safety of ceftriaxone sodium at extremes of age

Background: Isolated reports of neonatal and infant deaths associated with ceftriaxone–calcium precipitation in the lungs and kidneys have prompted a recommendation from the US FDA in June 2007 advising that in patients of all ages, calcium-containing solutions should not be administered simultaneously or within 48 h of the last ceftriaxone dose. Objective: To provide a comprehensive review of the literature surrounding the safety of ceftriaxone in the neonatal (≤ 28 days) and geriatric populations (≥ 65 years). Methods: Multi-database literature search for original research articles, review articles and case reports pertaining to safety of ceftriaxone in the neonatal and geriatric populations. Results/conclusions: Ceftriaxone should be avoided or significantly minimized in neonates (especially those treated concomitantly with intravenous calcium solutions and those with hyperbilirubinemia), and potentially restricted in the geriatric population treated concomitantly with intravenous calcium.

Clinical and economic impact of a diabetes clinical pharmacy service program in a university and primary care–based collaboration model

OBJECTIVE To provide program methodology and outcomes data identifying the impact of clinical pharmacy services (CPSs) in patients with type 2 diabetes. DESIGN Longitudinal pre-post cohort study. SETTING Regional primary care group in Buffalo, NY, during 2006-2007. PATIENTS Patients with type 2 diabetes identified by their primary care providers were referred to the MedSense program; a pharmacist-led, patient-centered pharmacotherapy management program developed through university collaboration with a regional primary care physician group. INTERVENTIONS Education, clinical assessments, provider recommendations, and longitudinal follow-up of treatment goals provided by MedSense pharmacists. MAIN OUTCOME MEASURES Clinical outcomes were followed for 1 year from the index date for primary diabetes endpoints (glycosylated hemoglobin and fasting plasma glucose) and accompanying metabolic parameters (body mass index, blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides). Economic endpoints from the payer perspective were also followed for 1 year from the index date for medical and prescription-related costs. RESULTS Primary diabetes endpoints were significantly reduced versus baseline at the 6-month (-1.1%; P < 0.0001, -39 mg/dL; P = 0.003) and 12-month (-1.1%; P < 0.0001, -35 mg/dL; P = 0.005) assessments. Improvement rates were observed for all accompanying metabolic parameters at each assessment (range 40-64%). Geometric mean costs tended to decrease versus baseline at 6-month (-

Reduction in Inflammation and the Expression of Amyloid Precursor Protein and Other Proteins Related to Alzheimer's Disease following Gastric Bypass Surgery

84; P = 0.785) and 12-month (-

Increase in the mediators of asthma in obesity and obesity with type 2 diabetes: reduction with weight loss.

216; P = 0.414) assessments, despite nominal increases in diabetes and total medication costs. CONCLUSION In this CPS model, there were initial and sustained reductions in the primary diabetes endpoints and a high rate of improvement for accompanying metabolic parameters. Concurrent with clinical improvements, total direct medical costs were reduced despite an increase in antidiabetic medication and total medication costs.

Impact of pharmacist intervention on clinical outcomes in the palliative care setting.

OBJECTIVE Obesity and type 2 diabetes are associated with an increase in the incidence and prevalence of Alzheimers disease (AD) and an impaired cognitive function. Because peripheral blood mononuclear cells (MNC) express amyloid precursor protein (APP), the precursor of β-amyloid, which forms the pathognomonic plaques in the brain, we hypothesized that APP expression diminishes after the marked caloric restriction and weight loss associated with Roux-en-Y gastric bypass (RYGB) surgery. RESEARCH DESIGN AND METHODS Fifteen type 2 diabetic patients with morbid obesity (body mass index, 52.1 ± 13 kg/m(2)) underwent RYGB, and the expression of inflammatory and AD-related genes was examined before and after 6 months in plasma and in MNC. RESULTS Body mass index fell to 40.4 ± 11.1 kg/m(2) at 6 months after RYGB. There was a significant fall in plasma concentrations of glucose and insulin and in homeostasis model of assessment for insulin resistance. The expression of APP mRNA fell by 31 ± 9%, and that of protein fell by 36 ± 14%. In addition, there was a reduction in the expression of other AD-related genes including presinilin-2, ADAM-9, GSK-3β, PICALM, SORL-1, and clusterin (P < 0.05 for all). Additionally, the expression of c-Fos, a subunit of the proinflammatory transcription factor AP-1, was also suppressed after RYGB. These changes occurred in parallel with reductions in other proinflammatory mediators including C-reactive protein and monocyte chemoattractant protein-1. CONCLUSIONS Thus, the reversal of the proinflammatory state of obesity is associated with a concomitant reduction in the expression of APP and other AD-related genes in MNC. We conclude that obesity and caloric intake modulate the expression of APP in MNC. If indeed, this effect also occurs in the brain, this may have implications for the pathogenesis and the treatment of AD. It is relevant that cognitive function has been shown to improve with weight loss following bariatric surgery.

A disease model descriptive of progression between chronic obstructive pulmonary disease exacerbations and community-acquired pneumonia: roles for underlying lung disease and the pharmacokinetics/pharmacodynamics of the antibiotic

To determine whether the expression of key asthma related genes, IL‐4, LIGHT, LTBR, MMP‐9, CCR‐2, and ADAM‐33 in mononuclear cells and the plasma concentration of nitric oxide metabolites (NOM) and MMP‐9 are increased in the obese, obese type 2 diabetics (T2DM) and in morbidly obese patients prior to and after gastric bypass surgery (RYGB).

Distal small bowel bypass for weight regain after gastric bypass: safety and efficacy threshold occurs at<70% bypass

Background: Although accepted as an integral part of the interdisciplinary team, pharmacist value in palliative care has predominantly been evaluated by subjective methods. This study was conducted to identify factors that impact physician acceptance of the pharmacist’s recommendation and to determine whether acceptance is a significant predictor of clinical outcome. Methods: As a mandated in-house quality assurance project at Niagara Hospice, Inc, 2 clinical pharmacists tracked each request for pharmacotherapeutic intervention over a 4-month period (April-July 2009). Through retrospective examination of clinical notes, each intervention was reviewed to determine age, gender, death date, presenting symptom, recommending pharmacist, recommendation type, recommendation status (accepted vs declined), and clinical outcome (achieved vs not achieved). Results: Overall, 89.4% of recommendations were accepted, and 79.9% of patients achieved the desired clinical outcome. With the exception of delirium as a presenting symptom (75% accepted vs 90.8% all other symptoms accepted; P = .02), no significant associations were identified between any variable and recommendation acceptance. Multivariate analysis revealed acceptance of the pharmacist’s recommendation (OR, 19.0; 95% CI, 7.10-50.93; P < .001), the recommending pharmacist (resident, OR, 2.46; 95% CI, 1.18-5.12; P = .02), and closer proximity to death (day 0-30, OR, 2.79; 95% CI, 1.16-6.70; P = .02) to be significant predictors of achieving the desired clinical outcome. Conclusion: None of the included variables significantly influenced the physician’s decision to accept or decline the pharmacist’s recommendation. Acceptance of the pharmacist’s recommendation was significantly associated with the strongest predictor of the patient achieving the desired clinical outcome.

Glucose supply and insulin demand dynamics of antidiabetic agents.

Patients with chronic obstructive pulmonary disease (COPD) may progress to community-acquired pneumonia (CAP), but there has been no formal study of the factors responsible. We studied the influence of severity of underlying lung disease, pathogen characteristics and the ratio of the area under the concentration-time curve from 0-24h to minimum inhibitory concentration (AUC24/MIC), i.e. the area under the inhibitory curve (AUIC), during the progression from acute exacerbation of chronic bronchitis (AECB) in COPD to CAP. The model parameters were derived from a multinational database of 3885 patients with AECB or CAP (April 1996 to July 2006). Patients with underlying COPD were evaluated in two separate analyses: infection progression between COPD and CAP within Global Initiative for Chronic Obstructive Lung Disease (GOLD)-like grouping (GLG); and distribution of pathogen by GLG, CAP and AECB. Secondary analyses examined the impact of target AUIC attainment on progression to CAP for Streptococcus pneumoniae. The relative impact of GLG and AUIC were modelled in multivariate logistic regression for S. pneumoniae. Progression to CAP linked directly with GLG I/II, III and IV (18.3%, 31.7% and 48.9%, respectively; P < 0.001). Progression to CAP was strongly associated with S. pneumoniae (57.3%), whilst other pathogens were predominant in AECB that did not progress to CAP (61.7%) (P = 0.002). AUIC > or = 100 was associated with AECB (65.1%) and AUIC < 100 with CAP (91.7%) (P < 0.001). In conclusion, the frequency of progression to CAP increases directly with GLG. For S. pneumoniae, achieving an AUIC > or =100 can attenuate progression, regardless of GLG. Thus, AUIC > or = 100 appears to be a viable antibiotic selection strategy to protect patients with S. pneumoniae from developing CAP.

Provider Perception of Pharmacy Services in the Patient-Centered Medical Home.

BACKGROUND For patients with poor weight loss (WL) after Roux-en-Y gastric bypass (RYGB) there are few well-tolerated and effective surgical options. Revision to distal bypass by shortening of the common channel (CC) induces significant WL but often produces protein calorie malnutrition (PCM) and severe diarrhea. OBJECTIVE The aim of this study was to identify a safe and effective threshold for distal small bowel bypass when done for revision of gastric bypass. SETTING Academic Institution, United States. METHODS We performed revision of RYGB for WL in 20 patients by shortening the CC to a new length of 120-300 cm. The Roux limb length was unchanged. WL and PCM were monitored. A threshold for percent of small bowel bypassed at which PCM was avoided was retrospectively determined. WL was then compared in patients above and below this threshold. Five patients completed a 250-kcal mixed meal challenge before and 3 months after revision to determine selected gut hormone responses. RESULTS Bypassing ≥70% small bowel resulted in PCM in 4 of 10 patients but in none of 10 patients below that threshold. PCM was observed as late as 2 years after revision and necessitated rerevision by lengthening of the CC in 3 patients. Additionally, nocturnal diarrhea was more common and more intractable when ≥70% bypass was done. Both groups had significant excess body WL over 2 years, but it was greater in patients with ≥70% bypass (47±19 versus 26±17; P<.05). A favorable gut hormone response was observed with 3-hour decrease in glucose-dependent insulinotropic peptide (GIP) by 25% and increase in glucagon-like peptide-1 (GLP-1) by 25%, whereas fasting peptide-YY (PYY) increased by 71% (P<.05 for all). CONCLUSIONS Revision of RYGB to distal bypass when it is <70% of a patients small bowel length results in an acceptable balance of WL and a positive safety profile. WL may be mediated through an enhanced gut hormone effect, an aversion to ingested fat, and possibly other mechanisms.