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Osteoarthritis (OA) is a debilitating condition characterized by inflammation, breakdown, and consequent loss of cartilage of the joints. Epidemiological studies indicate obesity is an important risk factor involved in OA initiation and progression. Traditional views propose OA to be a biomechanical consequence of excess weight on weight-bearing joints; however, emerging data demonstrates that systemic and local factors released from white adipose depots play a role. Hence, current views characterize OA as a condition exacerbated by a metabolic link related to adipose tissue, and not solely related to redistributed/altered weight load. Factors demonstrated to influence cartilage and bone homeostasis include adipocyte-derived hormones ("adipokines") and adipose depot released cytokines. Epidemiological studies demonstrate a positive relation between systemic circulating cytokines, leptin, and resistin with OA types, while the association with adiponectin is controversial. Local factors in joints have also been shown to play a role in OA. In particular, this includes the knee, a weight-bearing joint that encloses a relatively large adipose depot, the infrapatellar fat pad (IFP), which serves as a source of local inflammatory factors. This review summarizes the relation of obesity and OA as it specifically relates to the IFP and other integral supporting structures. Overall, studies support the concept that metabolic effects associated with systemic obesity also extend to the IFP, which promotes inflammation, pain, and cartilage destruction within the local knee joint environment, thus contributing to development and progression of OA.

Scope: Nonalcoholic fatty liver disease is an obesity-related disorder characterized by lipid infiltration of the liver. Management is limited to lifestyle modifications, highlighting the need for alternative therapeutic options. The objective of this study was to examine if fermented Fuzhuan tea prevents metabolic impairments associated with development of hepatic steatosis., Methods and Results: Rats consumed control (CON) or high saturated fat (SAT) diets with or without Fuzhuan tea for 8 weeks. Outcomes included enzymatic and gene expression measures of metabolic dysregulation in liver and adipose tissue. Pyrosequencing was used to assess intestinal microbiota adaptations. Fuzhuan tea prevented diet-induced inflammation in the liver. Liver triglycerides of ∼18 mg/g were observed in SAT-fed animals, but remained similar to CON diet levels (∼12 mg/g) when supplemented with Fuzhuan tea. In adipose tissue, tea treatment prevented SAT-induced inflammation and reduced plasma leptin approximately twofold. Fuzhuan tea also altered intestinal function and was associated with a threefold increase in two Lactobacillus spp., Conclusions: These data suggest that Fuzhuan tea protects against liver and adipose tissue stress induced by a high SAT diet and positively influences intestinal function. Further investigation of the molecular targets of Fuzhuan tea is warranted., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Adipose tissue is a complex endocrine organ with an intricate role in whole body homeostasis. Beyond storing energy, adipose tissue is fundamental in numerous processes including, but not limited to, metabolism, food intake and immune cell function. Adipokines and cytokines are the signaling factors from adipose tissue. These factors play a role in maintaining health, but are also candidates for pathologies associated with obesity. Indeed excessive adiposity causes dysregulation of these factors which negatively affect health and contribute to numerous obesity-induced co-morbidities. In particular, adipokines are fundamental in regulation of glucose homeostasis and insulin signaling, thus aberrant production of these adipose derived hormones correlates with the development and progression of type 2 diabetes. Therefore, elucidation of adipose regulation is crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. In the present review, we summarize current data on the relation between adipokines and adipose depot derived cytokines in the maintenance of glucose homeostasis. Specifically, physiological and molecular functions of several adipokines are defined with particular focus on interactions within the insulin-signaling pathway and subsequent regulation of glucose uptake in both standard and obesity-induced dysregulated conditions. This same relation will be discussed for cytokines and inflammation as well.

The increased risk for cardiometabolic disease with the onset of menopause is widely studied and likely precipitated by the decline in endogenous estradiol (E2), yet the precise mechanisms are unknown. The gut microbiome is involved in estrogen metabolism and has been linked to metabolic disease, suggesting its potential involvement in the postmenopausal phenotype. Furthermore, menopause-associated risk factors, as well as gut ecology, are altered with exercise. Therefore, we studied microbial changes in an ovariectomized (OVX vs. Sham) rat model of high (HCR) and low (LCR) intrinsic aerobic capacity (n = 8-10/group) in relation to changes in body weight/composition, glucose tolerance, and liver triglycerides (TG). Nine weeks after OVX, HCR rats were moderately protected against regional adipose tissue gain and liver TG accumulation (P < 0.05 for both). Microbial diversity and number of the Bacteroidetes phylum were significantly increased in LCR with OVX, but unchanged in HCR OVX relative to Sham. Plasma short-chain fatty acids (SCFA), produced by bacteria in the gut and recognized as metabolic signaling molecules, were significantly greater in HCR Sham relative to LCR Sham rats (P = 0.05) and were decreased with OVX in both groups. These results suggest that increased aerobic capacity may be protective against menopause-associated cardiometabolic risk and that gut ecology, and production of signaling molecules such as SCFA, may contribute to the mediation., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Aims: Endovascular treatment of calcified femoral-popliteal disease is challenging. We sought to evaluate the mechanism of lumen gain when using the JETSTREAM Atherectomy System to treat calcified peripheral artery lesions., Methods and Results: The JETSTREAM Calcium Study was a prospective, single-arm, multicentre study to evaluate the JETSTREAM Atherectomy System for severely calcified femoral-popliteal artery lesions, i.e., patients with claudication and lesions with superficial calcium >90° and >5 mm in length as determined by intravascular ultrasound (IVUS). The 2.1 mm catheter was used in this study without distal protection. Fifty-five patients underwent angiographic screening: 26 (45%) met IVUS inclusion criteria. Angiographic calcium was moderate in eight cases and severe in 14, with no available data for four cases. Visual diameter stenosis was 86±9% pre-treatment, 37±13% post atherectomy, and 10±6% post adjunctive treatment (adjunctive PTA+stenting in eight and adjunct PTA alone in 16). IVUS showed lumen area increased from 6.6±3.7 mm2 to 10.0±3.6 mm2 (p=0.001): calcium reduction was responsible for 86±23% of the lumen increase. Although the superficial calcium arc did not change (151±70° to 146±71°, p=0.83), the arc of reverberation increased (23±20° to 65±40°, p=0.006), indicating device-related modification of calcium. Adjunctive balloon angioplasty was performed in 62% of the lesions, and stent implantation in 31%. In 11 cases with adjunctive balloon dilation, the MLA increased from 7.1 (6.4, 7.8) mm2 post atherectomy to 11.9 (10.3, 13.5) mm2 post balloon (p<0.001) without flow-limiting dissection. No major adverse events occurred up to 30 days post procedure in either the study group or the patients who were excluded from the analysis., Conclusions: The JETSTREAM Atherectomy System increased lumen dimensions in moderately or severely calcified femoral-popliteal lesions by removing superficial calcium without major complications.

Objectives: The purpose of the prospective, multicenter, nonrandomized CABANA study was to evaluate periprocedural clinical outcomes in high surgical risk patients with carotid artery stenosis treated with the Carotid WALLSTENT plus FilterWire EZ Embolic Protection System by a diverse group of clinicians., Background: There is a need for additional evidence evaluating carotid artery stenting (CAS) performed by operators with various experience and training levels., Methods: The study enrolled symptomatic (≥50% carotid artery stenosis) and asymptomatic (≥80% carotid stenosis) patients at high risk for carotid endarterectomy. Study centers were grouped into three tiers based on previous CAS experience while individual operators were grouped by their CAS training. The primary endpoint was the 30-day composite of major adverse events [MAEs; including stroke, death, and myocardial infarction (MI)]. Individual event rates were evaluated across the overall study, and by center experience and physician training tier., Results: Of 1,097 enrolled patients, 1,025 were evaluable for 30-day MAE rate. The stroke rate (3.3%) was a major contributing factor in the overall MAE rate (4.6%). Mortality was 1.3% and the MI rate was 0.5%. There was no statistically significant association between MAE rates among the center experience tiers (P = 0.61) nor among the operator training categories (P = 0.26)., Conclusions: CAS with the Carotid WALLSTENT and FilterWire EZ yielded a low 30-day MAE rate that did not differ significantly across operator experience and training levels. Clinicaltrials.gov identifier: NCT00741091., (© 2014 The Authors. Catheterization and Cardiovascular Interventions. Published by Wiley Periodicals, Inc.)

Objectives: Numerous publications have shown strong association between CHD risk and either apolipoprotein B (Apo-B) or low density lipoprotein (LDL) particle number (LDL-P). It is however unknown if Apo-B or LDL-P has a stronger predictive ability for future CHD. This uncertainty may be due to the inability of current Apo-B assays to separate the contribution of very low-density lipoprotein particles from the total Apo-B concentration. As such we have performed a laboratory validation of the Maine Standards LDL Apo-B assay on the Roche Cobas 6000 analyzer., Design and Methods: Imprecision, linear range, and limit of quantitation studies were performed using quality control materials. Plasma samples collected for lipid profile analysis were analyzed via the LDL Apo-B assay and compared to the LDL cholesterol (LDL-C) concentration determined via direct LDL assay and Friedewald equation., Results: The LDL Apo-B within-run imprecision was 2.3% at 62 mg/dL and 2.2% at 109 mg/dL. The within-laboratory imprecision was 9.7% at 57 mg/dl and 6.1% at 104 mg/dL. Linear regression analysis of LDL Apo-B versus calculated and measured LDL-c resulted in equations of LDL Apo-B=0.620∗(LDL)+45.4, R=0.9063 and LDL-Apo-B=0.607∗(LDL)+38.8, R=0.9393, respectively. Bias plot analyses revealed that at low LDL-C concentration, there was a tendency for a higher than anticipated LDL Apo-B concentration., Conclusions: The Maine Standards LDL Apo-B assay is a precise automated assay and comparison of LDL Apo-B to LDL-c concentration demonstrates that low LDL-C concentrations may still carry residual risk of CHD due to increased concentration of small dense LDL particles., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Adipose tissue distribution is an important determinant of obesity-related comorbidities. It is well established that central obesity (visceral adipose tissue accumulation) is a risk factor for many adverse health consequences such as dyslipidemia, insulin resistance and type-2-diabetes. We hypothesize that the metabolic dysregulation that occurs following high fat diet-induced increases in adiposity are due to alterations in visceral adipose tissue function which influence lipid flux to the liver via the portal vein. This metabolic pathology is not exclusively due to increases in visceral adipose tissue mass but also driven by intrinsic characteristics of this particular depot. In Experiment 1, high fat diet (HFD)-induced obese control (abdominal incision, but no fat manipulation) or autologous (excision and subsequent relocation of adipose tissue) subcutaneous tissue transplantation to the visceral cavity. In Experiment 2 mice received control surgery, subcutaneous fat removal or hetero-transplantation (tissue from obese donor) to the visceral cavity. Body composition analysis and glucose tolerance tests were performed 4 weeks post-surgery. Adipose mass and portal adipokines, cytokines, lipids and insulin were measured from samples collected at 5 weeks post-surgery. Auto- and hetero- transplantation in obese mice improved glucose tolerance, decreased systemic insulin concentration and reduced portal lipids and hepatic triglycerides compared with HFD controls. Hetero-transplantation of subcutaneous adipose tissue to the visceral cavity in obese mice restored hepatic insulin sensitivity and reduced insulin and leptin concentrations to chow control levels. Fat removal, however, as an independent procedure exacerbated obesity-induced increases in leptin and insulin concentrations. Overall subcutaneous adipose tissue protects against aspects of metabolic dysregulation in obese mice. Transplantation-induced improvements do not occur via enhanced storage of lipid in adipose tissue, however altered hepatic lipid regulation may play a contributory role.

Increased visceral adiposity is a risk factor for metabolic disorders such as dyslipidemia, hypertension, insulin resistance and type 2 diabetes, whereas peripheral (subcutaneous) obesity is not. Though the specific mechanisms which contribute to these adipose depot differences are unknown, visceral fat accumulation is proposed to result in metabolic dysregulation because of increased effluent, e.g., fatty acids and/or adipokines/cytokines, to the liver via the hepatic portal vein. Pathological significance of visceral fat accumulation is also attributed to adipose depot/adipocyte-specific characteristics, specifically differences in structural, physiologic and metabolic characteristics compared with subcutaneous fat. Fat manipulations, such as removal or transplantation, have been utilized to identify location dependent or independent factors that play a role in metabolic dysregulation. Obesity-induced alterations in adipose tissue function/intrinsic characteristics, but not mass, appear to be responsible for obesity-induced metabolic dysregulation, thus "quality" is more important than "quantity." This review summarizes the implications of obesity-induced metabolic dysfunction as it relates to anatomic site and inherent adipocyte characteristics.

Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in reduced food intake, body weight gain, and adiposity. The decrease in body weight and adiposity occurred relative to both ad libitum- and pair-fed controls, implying that reduced food intake in and of itself does not underlie all of these effects. Consistent with this, rats administered Ang II had increased whole body heat production and oxygen consumption. Additionally, chronic icv Ang II increased uncoupling protein-1 and β(3)-adrenergic receptor expression in brown adipose tissue and β3-adrenergic receptor expression in white adipose tissue, which is suggestive of enhanced sympathetic activation and thermogenesis. Chronic icv Ang II also increased hypothalamic agouti-related peptide and decreased hypothalamic proopiomelanocortin expression, consistent with a state of energy deficit. Moreover, chronic icv Ang II increased the anorectic corticotrophin- and thyroid-releasing hormones within the hypothalamus. These results suggest that Ang II acts in the brain to promote negative energy balance and that contributing mechanisms include an alteration in the hypothalamic circuits regulating energy balance, a decrease in food intake, an increase in energy expenditure, and an increase in sympathetic activation of brown and white adipose tissue.

Aims/hypothesis: We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function., Methods: Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function., Results: Weight loss associated with chronic CB1 antagonism was accompanied by increased energy expenditure, enhanced insulin-stimulated glucose utilisation, and marked activation of BAT thermogenesis. Insulin-dependent glucose uptake was significantly increased in white adipose tissue and BAT, whereas glycogen synthesis was increased in liver, fat and muscle. Despite marked weight loss in the mice, SR141716 treatment did not improve insulin-mediated suppression of hepatic glucose production nor increase skeletal muscle glucose uptake. Denervation of iBAT blunted the effect of SR141716 on iBAT differentiation and insulin-mediated glucose uptake., Conclusions/interpretation: Chronic CB1 antagonism markedly enhances insulin-mediated glucose utilisation in DIO mice, independent of its anorectic and weight-reducing effects. The potent effect on insulin-stimulated BAT glucose uptake reveals a novel role for CB1 receptors as regulators of glucose metabolism.

Aims/hypothesis: Intra-abdominal transplantation of non-visceral adipose tissue in rodents, simulating increased abdominal fat in obesity, paradoxically improves glucose tolerance and insulin sensitivity. We hypothesised that this improvement is due to transplant-induced enhanced uptake of fatty acids by adipose tissue, thus reducing fatty acid flux into, and triacylglycerol storage in, the liver., Methods: In Experiment 1, mice were sham-operated or received heterologous epididymal white adipose tissue (WAT; EWAT) or visceral WAT (VWAT) transplantation to the portal and splanchnic circulation regions in the visceral cavity. In Experiment 2, inguinal WAT (IWAT) or EWAT was removed and subsequently transplanted to the visceral cavity of the same mouse (autotransplant). IWAT and EWAT autotransplants were repeated in Experiment 3 and compared with heterotransplants., Results: Heterotransplantation of VWAT did not alter glucose tolerance, whereas auto- or hetero-transplantation of EWAT or IWAT significantly improved glucose tolerance. Transplantation-induced improvements in glucose tolerance 4 weeks after surgery coincided with decreased liver triacylglycerol, decreased portal plasma lipids and increased hepatic insulin sensitivity. By 8 weeks, these changes were apparent only in mice with autotransplantation. Heterologous EWAT transplantation-induced glucose improvement persisted without altered liver metabolism., Conclusions/interpretation: Increases in visceral fat, via transplantation of visceral or non-visceral adipose tissue, is not a major risk factor for glucose intolerance. In fact, there are dynamic metabolic improvements following transplantation that include decreased portal lipids and improved liver metabolism, but these improvements are transient under certain circumstances.

Epidemiological studies have demonstrated a strong link between increased visceral fat and metabolic syndrome. In rodents, removal of intra-abdominal but non-visceral fat improves insulin sensitivity and glucose homeostasis, though previous studies make an imprecise comparison to human physiology because actual visceral fat was not removed. We hypothesize that nutrient release from visceral adipose tissue may have greater consequences on metabolic regulation than nutrient release from non-visceral adipose depots since the latter drains into systemic but not portal circulation. To assess this we surgically decreased visceral white adipose tissue (~0.5 g VWATx) and compared the effects to removal of non-visceral epididymal fat (~4 g; EWATx), combination removal of visceral and non-visceral fat (~4.5 g; EWATx/VWATx) and sham-operated controls, in chow-fed rats. At 8 weeks after surgery, only the groups with visceral fat removed had a significantly improved glucose tolerance, although 8 times more fat was removed in EWATx compared with VWATx. This suggests that mechanisms controlling glucose metabolism are relatively more sensitive to reductions in visceral adipose tissue mass. Groups with visceral fat removed also had significantly decreased hepatic lipoprotein lipase (LPL) and triglyceride content compared with controls, while carnitine palmitoyltransferase (CPT-1A) was decreased in all fat-removal groups. In a preliminary experiment, we assessed the opposite hypothesis; i.e., we transplanted excess visceral fat from a donor rat to the visceral cavity (omentum and mesentery), which drains into the hepatic portal vein, of a recipient rat but observed no major metabolic effect. Overall, our results indicate surgical removal of intra-abdominal fat improves glucose tolerance through mechanism that may be mediated by reductions in liver triglyceride., (Published by Elsevier Inc.)

Syrian hamsters, like many humans, increase food intake and body adiposity in response to stress. We hypothesized that glucocorticoids (cortisol and corticosterone) mediate these stress-induced effects on energy homeostasis. Because Syrian hamsters are dual secretors of cortisol and corticosterone, differential effects of each glucocorticoid on energy homeostasis were investigated. First, adrenal intact hamsters were injected with varying physiological concentrations of cortisol, corticosterone, or vehicle to emulate our previously published defeat regimens (i.e., 1 injection/day for 5 days). Neither food intake nor body weight was altered following glucocorticoid injections. Therefore, we investigated the effect of sustained glucocorticoid exposure on energy homeostasis. This was accomplished by implanting hamsters with supraphysiological steady-state pellets of cortisol, corticosterone, or cholesterol as a control. Cortisol, but not corticosterone, significantly decreased food intake, body mass, and lean and fat tissue compared with controls. Despite decreases in body mass and adiposity, cortisol significantly increased circulating free fatty acids, triglyceride, cholesterol, and hepatic triglyceride concentrations. Although corticosterone did not induce alterations in any of the aforementioned metabolic end points, Syrian hamsters were responsive to the effects of corticosterone since glucocorticoids both induced thymic involution and decreased adrenal mass. These findings indicate that cortisol is the more potent glucocorticoid in energy homeostasis in Syrian hamsters. However, the data suggest that cortisol alone does not mediate stress-induced increases in food intake or body mass in this species.

Increases in intra-abdominal fat, a common feature associated with aging, is an established risk factor for insulin resistance, diabetes and the metabolic syndrome. To examine the direct contribution of intra-abdominal fat in the pathophysiology of insulin resistance we altered fat volume via removal or transplantation in a naturally occurring age-induced moderate model of obesity and insulin resistance. This was accomplished by bilateral removal of epididymal white adipose tissue (Lipx) or transplantation of donor fat into the intra-abdominal side of the peritoneal cavity of 28-week old rats. Control animals received sham surgery. Glucose tolerance was evaluated at baseline and 4 and 8weeks post-surgery in all groups, and fasting insulin and leptin were additionally measured in 28-week old rats. In addition, fasted and fed triglyceride, cholesterol and fatty acid concentrations were measured. Before surgery 28-week old rats weighed more and were glucose intolerant compared with 8-week old controls. Both Lipx and transplantation significantly prevented age-induced decreases in glucose tolerance, with Lipx causing improvement at 4weeks which declined by 8weeks; and with a significant transplantation improvement at 8weeks only. Lipx significantly increased insulin secretion 15min after a bolus injection of 0.75mg/kg dextrose at 4 and 8weeks compared with controls, while transplantation caused a significant ( approximately 220%) increase in fasted leptin level at 4weeks only. Taken together, these data suggest that surgical removal or addition of intra-abdominal fat prevents age-induced insulin resistance by different mechanisms and is a suitable model to investigate naturally occurring obesity., (Copyright 2010 Elsevier Inc. All rights reserved.)

The sympathetic nervous system (SNS) innervation of white adipose tissue (WAT) is the principal initiator of lipolysis. Using pseudorabies virus, a transneuronal viral tract tracer, brain sites involved in the SNS outflow to WAT have been identified previously by us. One of these sites, the hypothalamic paraventricular nucleus (PVH) that shows predominantly unilateral sympathetic outflow from each half of the nucleus to ipsilaterally located WAT depots, was tested for laterality in lipid accumulation/mobilization in Siberian hamsters. First we tested whether unilateral PVH electrolytic lesions (PVHx) would increase lipid accumulation in WAT pads ipsilateral to the side of the PVHx. PVHx significantly increased body and WAT pad masses compared with sham PVHx; however, there was no laterality effect. In addition, bilateral PVHx increased body and WAT pad masses, as well as food intake, to a greater extent than did unilateral PVHx. We next tested for possible laterality effects on WAT lipid mobilization using food deprivation as the lipolytic stimulus in hamsters bearing unilateral or bilateral PVHx. Lipid mobilization was not prevented, as indicated indirectly by WAT mass and thus laterality of lipid mobilization could not be tested. We then tested whether removal of adrenal catecholamines via adrenal demedullation (ADMEDx) alone, or combined with bilateral PVHx, would block food deprivation-induced lipid mobilization, but neither did so. These results suggest that an intact PVH is not necessary for food deprivation-induced lipid mobilization and support the primacy of the SNS innervation of WAT, rather than adrenal medullary catecholamines, for lipid mobilization from WAT.

Behavioral therapies aimed at reducing excess body fat result in limited fat loss after dieting. To understand the causes for maintenance of adiposity, high-fat (HF) diet-induced obese (DIO) mice were switched to a low-fat chow diet, and the effects of chow on histological and molecular alterations of adipose tissue and metabolic parameters were examined. DIO mice reduced and stabilized their body weights after being switched to chow (HF-chow), but retained a greater amount of adiposity than chow-fed mice. Reduction in adipocyte volume, not number, caused a decrease in fat mass. HF-chow mice showed normalized circulating insulin and leptin levels, improved glucose tolerance, and reduced inflammatory status in white adipose tissue (WAT). Circulating leptin levels corrected for fat mass were lower in HF-chow mice. Leptin administration was used to test whether reduced leptin level of HF-chow mice inhibited further fat loss. Leptin treatment led to an additional reduction in adiposity. Finally, HF-HF mice had lower mRNA levels of beta(3) adrenergic receptor (beta(3)-AR) in epididymal WAT (EWAT) compared to chow-fed mice, and diet change led to an increase in the WAT beta(3)-AR mRNA levels that were similar to the levels of chow-fed mice, suggesting an elevation in sympathetic activation of WAT during diet switch relative to HF-HF mice leading to the reduced leptin level and proinflammatory cytokine content. In summary, HF-chow mice were resistant to further fat loss due to leptin insufficiency. Diet alteration from HF to low fat improved metabolic state of DIO mice, although their adiposity was defended at a higher level.

Previous studies have shown reduced hypothalamo-pituitary-adrenal responses to both acute and chronic restraint stressors in rats allowed to ingest highly palatable foods (32% sucrose +/- lard) prior to restraint. In this study we tested the effects of prior access (7 d) to chow-only, sucrose/chow, lard/chow, or sucrose/lard/chow diets on central corticotropin-releasing factor (CRF) expression in rats studied in two experiments, 15 and 240 min after onset of restraint. Fat depot, particularly intraabdominal fat, weights were increased by prior access to palatable food, and circulating leptin concentrations were elevated in all groups. Metabolite concentrations were appropriate for values obtained after stressors. For unknown reasons, the 15-min experiment did not replicate previous results. In the 240-min experiment, ACTH and corticosterone responses were inhibited, as previously, and CRF mRNA in the hypothalamus and oval nucleus of the bed nuclei of the stria terminalis were reduced by palatable foods, suggesting strongly that both neuroendocrine and autonomic outflows are decreased by increased caloric deposition and palatable food. In the central nucleus of the amygdala, CRF was increased in the sucrose-drinking group and decreased in the sucrose/lard group, suggesting that the consequence of ingestion of sucrose uses different neural networks from the ingestion of lard. The results suggest strongly that ingestion of highly palatable foods reduces activity in the central stress response network, perhaps reducing the feeling of stressors.

Objective: To evaluate the safety and efficacy of a new nitinol stent positioning system to assist in the placement of aorto-ostial coronary stents., Background: The stenting of aorto-ostial lesions is technically challenging., Methods: We report the first clinical series using the Ostial Pro to assist in the precise placement of stents in coronary aorto-ostial lesions. These results were compared to matched cases performed without the ostial positioning system., Results: The Ostial Pro is a simple nitinol device with self-expanding legs that are advanced just distal to the tip of the guiding catheter. The nitinol legs prevent the entry of the guiding catheter into the target vessel and align the tip of the guiding catheter. Using the Ostial Pro positioning device, angiographic and clinical success was achieved in 30/30 (100%) cases. Excellent stent positioning was confirmed by angiography (n = 30) and intravascular ultrasound (n = 28). The final true ostial dimension was larger than the stented segment minimum luminal diameter in 30/30 cases. In a matched consecutive cohort of 30 consecutive coronary aorto-ostial stent cases placed without the Ostial Pro, we observed an ostial stent malpositioning in 18/30 (60%) of cases (p < 0.0001 vs. cases performed with Ostial Pro)., Conclusions: 1) The Ostial Pro is a new FDA-cleared nitinol device that is simple to use and effective in allowing the precise placement of stent(s) at the aorto-ostial location; 2) this approach appears to provide an efficient means to assure accurate stent placement and minimal residual stenosis in these difficult-to-treat lesions.

Insulin and signalling through the vagus nerve act in concert to regulate metabolic homeostasis and ingestive behaviour. Our previous studies using streptozotocin (STZ)-diabetic rats have shown that hepatic branch vagotomy (HV), gastroduodenal branch vagotomy (GV) and capsaicin treatment of the common hepatic branch that selectively destroys afferent fibres (CapV), all promote lard, but not total, caloric intake to levels similar to those achieved with insulin treatment. Because hypothalamic and limbic mRNA expression of neuropeptides linked to energy balance is altered by STZ-diabetes and HV, we examined the role(s) of insulin and the common hepatic and gastroduodenal branches of the vagus nerve and hepatic afferent fibres in the regulation of these neuropeptides in rats with high, steady-state corticosterone levels. STZ-diabetic rats were prepared with osmotic minipumps containing either saline or insulin and were compared with nondiabetic counterparts: half of each group received a vagal manipulation, the other half were sham operated. Five days after surgery, rats were offered the choice of lard and chow to consume for another 5 days, when brains were collected and processed for in situ hybridisation. Paraventricular nucleus corticotrophin-releasing factor (CRF) mRNA was elevated by STZ treatment, an effect prevented by either insulin treatment or GV. By contrast, CRF mRNA expression in the central nucleus of the amygdala and bed nuclei of the stria terminalis was unaffected by STZ treatment, but HV and CapV manipulations elevated expression in the nondiabetic, but not STZ-diabetic groups. Arcuate nucleus neuropeptide Y, but not pro-opiomelanocortin, mRNA expression was elevated by STZ treatment and all vagal manipulations; however, exogenous insulin treatment failed to prevent this, in keeping with their previously documented elevated caloric intake. These results strongly suggest that the gastroduodenal branch and hepatic branch proper, which merge to form the common hepatic branch, differentially interact with prevailing insulin levels to regulate hypothalamic and limbic neuropeptide mRNA expression.

The common hepatic branch of the vagus nerve negatively regulates lard intake in rats with streptozotocin (STZ)-induced, insulin-dependent diabetes. However, this branch consists of two subbranches: the hepatic branch proper, which serves the liver, and the gastroduodenal branch, which serves the distal stomach, pancreas, and duodenum. The aim of this study was to determine whether the gastroduodenal branch specifically regulates voluntary lard intake. We performed a gastroduodenal branch vagotomy (GV) on nondiabetic, STZ-diabetic, and STZ-diabetic insulin-treated groups of rats and compared them with sham-operated counterparts. All rats had high steady-state corticosterone levels to maximize lard intake. Five days after surgery, all rats were provided with the choice of chow or lard to eat for another 5 days. STZ-diabetes resulted in a reduction in lard intake that was partially rescued by either GV or insulin treatment. Patterns of white adipose tissue (WAT) deposition differed after GV- and insulin-induced lard intake, with subcutaneous WAT increasing exclusively after the former and mesenteric WAT increasing exclusively in the latter. GV also prevented the insulin-induced reduction in the STZ-elevated plasma glucagon, triglycerides, free fatty acids, and total ketone bodies but did not alter the effect of insulin-induced reduction of plasma glucose levels. These data suggest that the gastroduodenal branch of the vagus inhibits lard intake and regulates WAT deposition and plasma metabolite levels in STZ-diabetic rats.

In addition to the inhibitory role of central insulin on food intake, insulin also acts to promote lard intake. We investigated the neural pathways involved in this facet of insulin action. Insulin or saline was infused into either the superior mesenteric or right external jugular veins of streptozotocin-diabetic rodents with elevated steady-state circulating corticosterone concentrations. After postsurgical recovery, rats were offered the choice of chow or lard to eat. Irrespective of the site of venous infusion, insulin increased lard and decreased chow intake. After 4 days, lard was removed for 8 h. On return for 1 h, only insulin infused into the superior mesenteric vein resulted in lard intake. This facilitated distinction between the effects of circulating insulin concentrations (similar in the two insulin-infused groups) and lard ingestion on the patterns of c-Fos(+) cells in the brain, termed insulin- and lard-associated patterns, respectively. Insulin-associated changes in c-Fos(+) cell numbers were evident in the arcuate nucleus, bed nucleus of the stria terminalis and substantia nigra pars compacta, concomitant with elevated leptin levels and reduced chow intake. Lard-associated changes in c-Fos(+) cell numbers were observed in the nucleus of the tractus solitarius, lateral parabrachial nucleus, central nucleus of the amygdala, ventral tegmental area, nucleus accumbens shell and the prefrontal cortex, and were associated with lower levels of triglycerides and free fatty acids. The anterior paraventricular thalamic nucleus exhibited both patterns. These data collectively fit into a framework for food intake and reward and provide targets for pharmacological manipulation to influence the choice of food intake.

Glucocorticoids act primarily in a feed-forward fashion on brain to activate CNS pathways that implement wanting appropriate to physiological needs. Thus, depending on the available conditions, elevated glucocorticoids may augment the behavioural want to run, fight or feed. Although glucocorticoids stimulate intake of chow, fat and sucrose, insulin appears to sculpt calorie-associated desires toward foods high in fat, acting through hepatic branch afferents of the vagus nerve. Both conditions of reduced food allowance and chronic stress excite glucocorticoid-augmented central neural networks that may lead toward ultimate abdominal obesity.

The common hepatic branch of the vagus nerve is a two-way highway of communication between the brain and the liver, duodenum, stomach and pancreas that regulates many aspects of food intake and metabolism. In this study, we utilized the afferent-specific neurotoxin capsaicin to examine if common hepatic vagal sensory afferents regulate lard intake. Rats implanted with a corticosterone pellet were made diabetic using streptozotocin (STZ) and a subset received steady-state exogenous insulin replacement into the superior mesenteric vein. These were compared with non-diabetic counterparts. Each group was then subdivided into those whose common hepatic branch of the vagus was treated with vehicle or capsaicin. Five days after surgery, the rats were offered the choice of chow and lard to consume for a further 5 days. The STZ-diabetic rats ate significantly less lard than the non-diabetic rats. Capsaicin treatment restored lard intake to that of the insulin-replaced, STZ-diabetic rats, but modified neither chow nor total caloric intake. This increased lard intake led to selective fat deposition into the mesenteric white adipose tissue depot, as opposed to an increase in all visceral fat pad depots evident after insulin replacement-induced lard intake. Capsaicin treatment also increased the levels of circulating glucose and triglycerides and negated the actions of insulin on these and free fatty acids and ketone bodies. Collectively, these data suggest that afferent signalling through the common hepatic branch of the vagus inhibits lard, but not chow, intake, directs fat deposition and regulates plasma metabolite levels.

Although high insulin concentrations reduce food intake, low insulin concentrations promote lard intake over chow, possibly via an insulin-derived, liver-mediated signal. To investigate the role of the hepatic vagus in voluntary lard intake, streptozotocin-diabetic rats with insulin or vehicle replaced into either the superior mesenteric or jugular veins received a hepatic branch vagotomy (HV) or a sham operation. All rats received a pellet of corticosterone that clamped the circulating steroid at moderately high concentrations to enhance lard intake. After 5 d of recovery, rats were offered the choice of lard and chow for 5 d. In streptozotocin-diabetic rats, HV, like insulin replacement, restored lard intake to nondiabetic levels. Consequently, this reduced chow intake without affecting total caloric intake, and insulin site-specifically increased white adipose tissue weight. HV also ablated the effects of insulin on reducing circulating glucose levels and attenuated the streptozotocin-induced weight loss in most groups. Collectively, these data suggest that the hepatic vagus normally inhibits lard intake and can influence glucose homeostasis and the pattern of white adipose tissue deposition. These actions may be modulated by insulin acting both centrally and peripherally.

In mammals, glucocorticoid actions appear to have evolved to maintain and enhance energy stores to be used for life-saving gluconeogenesis. They act on the brain to stimulate search behaviors, palatable feeding and emotionally relevant memories, and they act on the body to mobilize stored peripheral energy and direct it to central depots that serve the substrate needs of the liver. Our work in rats shows that searching and intake of palatable foods (sucrose, saccharin and lard) are stimulated by corticosterone in a dose-related fashion. Adrenalectomized rats gain weight poorly, have low fat content, increased sympathetic neural and hypothalamo-pituitary-adrenal outflow, and altered behaviors. Replacement with corticosterone reverses these effects. Surprisingly, when such rats are provided with 30% sucrose to drink, in addition to saline, all of the usual effects of adrenalectomy are corrected without corticosterone. We hypothesize that there is a metabolic feedback system that decreases stress-responsiveness. Although we have not yet identified the signal associated with sucrose drinking, the weight of mesenteric fat correlates inversely with hypothalamic corticotropin-releasing factor (CRF). When rats eat lard and sucrose ad libitum, fat stores increase and CRF, ACTH and corticosterone responses are reduced. During stress, chow intake decreases but intake of lard and sucrose does not. Our current working model suggests that palatability signals and neural signals from fat stores act on brain to reduce activity in the central stress response system. Correlative results from a clinical study support the powerful role of small changes in glucocorticoids in type 2 diabetes.

Obesity is a world-wide epidemic, and many factors, including stress, have been linked to this growing trend. After social stress (i.e., defeat), subordinate laboratory rats and most laboratory mice become hypophagic and, subsequently, lose body mass; the opposite is true of subordinate Syrian hamsters. After social defeat, Syrian hamsters become hyperphagic and gain body mass compared with nonstressed controls. It is unknown whether this increase in body mass and food intake is limited to subordinate hamsters. In experiment 1, we asked, do dominant hamsters increase food intake, body mass, and adiposity after an agonistic encounter? Subordinate hamsters increased food intake and body mass compared with nonstressed controls. Although there was no difference in food intake or absolute body mass between dominant and nonstressed control animals, cumulative body mass gain was significantly higher in dominant than in nonstressed control animals. Total carcass lipid and white adipose tissue (WAT) (i.e., retroperitoneal and epididymal WAT) masses were significantly increased in subordinate, but not dominant, hamsters compared with nonstressed controls. In experiment 2, we asked, does footshock stress increase food intake, body mass, and adiposity. Hamsters exposed to defeat, but not footshock stress, increased food intake relative to nonstressed controls. In animals exposed to defeat or footshock stress, body mass, as well as mesenteric WAT mass, increased compared with nonstressed controls. Collectively, these data demonstrate that social and nonsocial stressors increase body and lipid mass in male hamsters, suggesting that this species may prove useful for studying the physiology of stress-induced obesity in some humans.

White adipocyte proliferation is a hallmark of obesity, but it largely remains a mechanistic mystery. We and others previously demonstrated that surgical denervation of white adipose tissue (WAT) triggers increases in fat cell number, but it is unknown whether this was due to preadipocyte proliferation or maturation of existing preadipocytes that allowed them to be counted. In addition, surgical denervation severs not only sympathetic but also sensory innervation of WAT. Therefore, we tested whether sympathetic WAT denervation triggers adipocyte proliferation using 5-bromo-2'-deoxyuridine (BrdU) as a marker of proliferation and quantified BrdU-immunoreactive (ir) cells that were co-labeled with AD-3-ir, an adipocyte-specific membrane protein marker. The unilateral denervation model was used for all experiments where Siberian hamster inguinal WAT (IWAT) was unilaterally denervated, the contralateral pad was sham denervated serving as a within-animal control, and then BrdU was injected systemically for 6 days. When IWAT was surgically denervated, severing both sympathetic and sensory nerves, tyrosine hydroxylase (TH)-ir, a sympathetic nerve marker, and calcitonin gene-related peptide (CGRP)-ir, a sensory nerve marker, were significantly decreased, and BrdU+AD-3-ir adipocytes were increased approximately 300%. When IWAT was selectively sensory denervated via local microinjections of capsaicin, a sensory nerve-specific toxin, CGRP-ir, but not TH-ir, was decreased, and BrdU+AD-3-ir adipocytes were unchanged. When IWAT was selectively sympathetically denervated via local microinjections of 6-hydroxy-dopamine, a catecholaminergic-specific toxin, TH-ir, but not CGRP-ir, was significantly decreased, and BrdU+AD-3-ir adipocytes were increased approximately 400%. Collectively, these data provide the first direct evidence that sympathetic nerves inhibit white adipocyte proliferation in vivo.

Overeating and increases in body and fat mass are the most common responses to day-to-day stress in humans, whereas stressed laboratory rats and mice respond oppositely. Group housing of Syrian hamsters increases body mass, adiposity, and food intake, perhaps due to social confrontation-induced stress. In experiment 1 we asked, Does repeated social defeat increase food intake, body mass, and white adipose tissue (WAT) mass in Syrian hamsters? Male hamsters subjected to the resident-intruder social interaction model and defeated intermittently 15 times over 34 days for 7-min sessions significantly increased their food intake, body mass, and most WAT masses compared with nondefeated controls. Defeat significantly increased terminal adrenal norepinephrine, but not epinephrine, content. In experiment 2 we asked, Are 15 intermittent resident-intruder interactions necessary to increase body mass and food intake? Body mass and food intake of subordinate hamsters defeated only once were similar to those of nondefeated controls, but four or eight defeats similarly and significantly increased these responses. In experiment 3 we asked, Do intermittent defeats increase adiposity and food intake more than consecutive defeats? Four intermittent or consecutive defeats similarly and significantly increased food intake and body mass compared with nondefeated controls, but only intermittent defeats significantly increased all WAT masses. Consecutive defeats significantly increased mesenteric and inguinal WAT masses. Plasma leptin, but not insulin, concentrations were similarly and significantly increased compared with nondefeated controls. Collectively, social defeat, a natural stressor, significantly increased food intake, body mass, and adiposity in Syrian hamsters and may prove useful in determining mechanisms underlying human stress-induced obesity.

While investigating the reversible seasonal obesity of Siberian hamsters, direct sympathetic nervous system (SNS) postganglionic innervation of white adipose tissue (WAT) has been demonstrated using anterograde and retrograde tract tracers. The primary function of this innervation is lipid mobilization. The brain SNS outflow to WAT has been defined using the pseudorabies virus (PRV), a retrograde transneuronal tract tracer. These PRV-labelled SNS outflow neurons are extensively co-localized with melanocortin-4 receptor mRNA, which, combined with functional data, suggests their involvement in lipolysis. The SNS innervation of WAT also regulates fat cell number, as noradrenaline inhibits and WAT denervation stimulates fat cell proliferation in vitro and in vivo respectively. The sensory innervation of WAT has been demonstrated by retrograde tract tracing, electrophysiological recording and labelling of the sensory-associated neuropeptide calcitonin gene-related peptide in WAT. Local injections of the sensory nerve neurotoxin capsaicin into WAT selectively destroy this innervation. Just as surgical removal of WAT pads triggers compensatory increases in lipid accretion by non-excised WAT depots, capsaicin-induced sensory denervation triggers increases in lipid accretion of non-capsaicin-injected WAT depots, suggesting that these nerves convey information about body fat levels to the brain. Finally, parasympathetic nervous system innervation of WAT has been suggested, but the recent finding of no WAT immunoreactivity for the possible parasympathetic marker vesicular acetylcholine transporter (VAChT) argues against this claim. Collectively, these data suggest several roles for efferent and afferent neural innervation of WAT in body fat regulation.

Unlabelled: Stent design and deployment characteristics of balloon-expandable stents may play an important role in determining both early and late outcomes of stenting. The purpose of this study was to compare the percent residual stenosis (RS) of two new-generation stent delivery systems, DUET and NIR, in patients with CAD. From September 1998 1999, a total of 100 consecutive patients with CAD receiving either a DUET (18 or 23 mm length; n = 50) or NIR stent (16 or 25 mm length; n = 50) using a 3.0 or 3.5 mm stent delivery system were compared by quantitative coronary analysis. The ability of each balloon delivery system to fully expand the stent was assessed using a new scoring index entitled the stent delivery balloon expansion ratio (SDBR; %). A high SDBR correlates with the angiographic appearance of a "dogbone" that is sometimes seen during stent deployment. A stent "scalloping" score was developed to quantitatively assess the cobblestone appearance observed angiographically with plaque protrusion after stent implantation. Mean deployment pressures were 14 +/- 2 atm (DUET) and 13 +/- 2 atm (NIR) (p=NS). Extent of elastic recoil was similar (6 +/- 5% for DUET vs. 6 +/- 4% for NIR; (p=NS). "Scalloping" was more pronounced in the DUET stent (score, 0.66 +/- 0.6 for DUET vs. 0.24 +/- 0.4 for NIR; p < 0.001). SDBR and RS were higher with DUET than with NIR stent implantation (SDBR, 15 +/- 5% vs. 12 +/- 5%; RS, 14 +/- 5% vs. 11 +/- 6%; p < 0.01). Multivariate analysis showed that SDBR and stent recoil, but not "scalloping", were associated with increased RS after stent implantation (r = 0.45 and p < 0.001 for "dogbone" effect; r = 0.39 and p < 0.001 for stent recoil)., Conclusion: The second-generation DUET and NIR stents and their respective delivery systems show angiographically different acute performance characteristics. Insufficient deployment of stents visualized by the "dogbone" effect plays a role in the extent of RS after stenting. The introduced angiographic indexes require further validation.

The diagnosis of cystic adventitial degeneration (CAD) is difficult. We present the first case in which intravascular ultrasound (IVUS) correctly identified CAD of the popliteal artery when duplex sonography and angiography were inconclusive., (Copyright 2001 Wiley-Liss, Inc.)

Despite improvements in catheter-based revascularization outcomes, coronary interventionalists face difficult challenges in the treatment of the thrombus-laden coronary lesion. In this report, we describe the use of the Acolysis device, which utilizes high-frequency (41.9 kHz) ultrasonic energy to vibrate a small metal tip at the end of a 4.5 Fr catheter to treat two thrombotically occluded saphenous vein grafts in two patients. In both cases, the Acolysis device provided normalization of flow with angiographically evident dissolution of thrombus and excellent acute angiographic and clinical results. We conclude that in these two selected cases the Acolysis device was used safely and effectively for thrombus debulking as an adjunct to stenting in diseased saphenous vein bypass grafts.

Slow or no reflow is a serious problem complicating catheter-based revascularization of degenerated saphenous vein bypass grafts. We examined the efficacy of rapidly delivered, high-velocity injections of intracoronary adenosine to reverse 11 slow-flow events complicating stenting of diseased bypass grafts. Ten of 11 events were rapidly improved to TIMI 3 flow by this technique within 3.8+/-1.6 min of the initial adenosine injection. In an ex vivo model, 3-ml syringes created higher peak pressures and velocities than 10- and 20-ml syringes. We conclude that rapid and repeated high-velocity intragraft administration of adenosine is a promising new approach to promptly reverse no-reflow events complicating PTCA and stenting of diseased saphenous vein grafts. Ex vivo studies demonstrate a potentially important mechanical advantage with the use of small syringes for injection. Further randomized studies will be required to better define the mechanism(s) and efficacy of this approach for treating no reflow, including its use in native vessels.

This study describes the detailed histopathologic appearance of human coronary arteries at 3 weeks, and 3 and 7 months after stent implantation in a cardiac transplant recipient. There was modest arterial injury associated with stent implantation, and immunocytochemistry staining provided evidence that a proliferative response from the adventitia contributes to neointimal hyperplasia.

Antiarrhythmic drugs remain the first line of therapy in patients with sustained ventricular arrhythmias. Although success with class Ia antiarrhythmic medications has been limited, there is evidence that the addition of a class Ib agent may improve results. A total of 110 consecutive patients referred for electrophysiologic evaluation who had inducible sustained ventricular arrhythmias resistant to a class Ia agent underwent repeat electrophysiologic study after the addition of a class Ib drug. Patients with ejection fraction >40% and ventricular fibrillation inducible in the baseline study had an 80% response rate, whereas those with inducible ventricular tachycardia and ejection fraction < or = 40% responded 11% of the time. Responders demonstrated marked prolongation of ventricular refractoriness and slight shortening of the QRS, whereas nonresponders had QRS prolongation and a more modest increase in ventricular refractoriness. Thus, the efficacy of class Ia/Ib combination therapy in patients with inducible sustained ventricular arrhythmias refractory to a class Ia drugs alone can be predicted by baseline variables. Marked prolongation of ventricular refractoriness in the absence of QRS prolongation appears to be a key factor in the success of this combination.

The objective of this study was to evaluate the metabolic effects and opthalmologic effects of alpha-interferon therapy in diabetes mellitus patients with proliferative diabetic retinopathy (PDR). Three volunteer patients [insulin-dependent diabetes mellitus (IDDM), insulin requiring non-insulin-dependent diabetes mellitus (NIDDM), and maturity onset diabetes of the young (MODY)] threatened with blindness due to progressive PDR were treated with alpha interferon for 4 months and were evaluated at intervals of 1-2 weeks to monitor the drug effects on carbohydrate tolerance and possible beneficial therapeutic effects on the preexisting PDR. Metabolic studies included basal and postsustacal glucose, c-peptide and glucagon, fasting serum cortisol, free fatty acids, growth hormone, insulin-like growth factor-1, and urinary microalbumin excretion. Ophthalmologic studies included visual acuity, slit lamp examination, gonioscopy, fluorescein angiography, and standard colored fundus photographs. In all subjects, hyperglycemia worsened with duration of increasing dosage of interferon therapy, requiring progressively higher daily insulin requirements of 17%-68% above pretreatment values. Lowered levels of stimulated C-peptide were observed in the NIDDM and MODY subjects. The counterregulatory hormones (cortisol, growth hormone, and glucagon) were elevated during the 4 months of interferon therapy. In all subjects, visual acuity appeared to stabilize. No new retinal hemorrhages occurred during the 4 months of interferon administration, although all subjects experienced hemorrhage within 6 weeks of termination of the drug. Although only three subjects were investigated, the 1-2 week frequency of metabolic and opthalmologic studies permit some conclusions. The metabolic effects of alpha interferon in our diabetic subjects were consistent worsening of carbohydrate tolerance associated with impaired beta-cell secretion and increased insulin resistance. The extensive opthalmologic investigation suggested protection from retinal hemorrhage while receiving interferon, but further studies are indicated to validate these proposed and antiangiogenic properties.

The older drugs used to treat pneumonia may still be useful in self-limiting infections. Newer antibiotics--augmented penicillins, trimethoprim-sulfamethoxazole, third-generation cephalosporins, and others--are quite effective, but resistance can be a problem, and some patients cannot tolerate the adverse events associated with these agents. The fluoroquinolones are effective in treating pneumonia because of their broad spectra of activity against gram-negative and gram-positive organisms, including Streptococcus pneumoniae and Haemophilus influenzae. They are rapidly and nearly completely absorbed after oral administration; bioavailability ranges up to 100% for ofloxacin and lomefloxacin. Concentrations attained in lung tissues and sputum generally exceed the minimum inhibitory concentrations for the most common respiratory tract pathogens. The quinolones are also well tolerated; most adverse events are mild and do not lead to discontinuation of therapy. Ciprofloxacin and ofloxacin are available in parenteral as well as oral formulations. The high bioavailability of oral ofloxacin (> 95%) allows a patient to be started on the parenteral form in the hospital and continued taking the oral form at home with no loss of efficacy, but with reduced costs and improved quality of life.

Ceftriaxone is generally recognized as safe and effective when used as a single drug in the therapy of septicemia and other serious infections involving bacteremia in both adults and children. An advantage of ceftriaxone over other third-generation cephalosporins is its long serum half-life, which allows the drug to be given every 12 hours in children or less frequently in adults.

Periprosthetic infections due to Mycobacterium fortuitum and Mycobacterium chelonei occurred in 17 women over a 3.5-year period after implantation of prostheses for breast augmentation. The median incubation period for 16 of the women was 28 days (range, one week to over two years) after surgery; etiologic diagnosis was usually delayed for weeks to months. Odorless and serosanguineous or purulent material was found when the implants were removed, and acid-fast bacilli were often present when smears were examined. Wound infections were chronic and refractory to therapy with various antimicrobial agents. Persistent or recurrent mycobacterial infections complicated attempts to implant new prostheses. Whereas M. fortuitum isolates were susceptible to amikacin, multiple strains of M. fortuitum were distinguished by conventional antituberculous and broth microdilution susceptibility tests. Several clusters of infections were temporally and geographically related; however, sporadic cases were also reported, and no evidence of a contaminated common product or other single source of infection was found.

The relation of infection with Neisseria gonorrhoeae to the blood groups A, B, AB, and O was examined in 584 women attending a prenatal clinic. The occurrence of gonorrhea was significantly higher in black patients with blood group B than in those with blood groups A, AB, or O.

A comprehensive drug-use review (DUR) program based on established criteria for use of each drug is described. The DUR program was developed to promote cost-effective drug therapy and satisfy Joint Commission on Accreditation of Hospitals standards for drug-use evaluation. Antibiotic and ambulatory-care drug-use subcommittees composed of physicians, pharmacists, nurses, and clinical laboratory personnel were formed as advisory groups to the pharmacy and therapeutics (P&T) committee. The subcommittees review overall drug-use patterns in their respective areas monthly and investigate the use of specific problem drugs. Drug-use reviews have been facilitated by the implementation of a mandatory antibiotic order form and pharmacy computer systems. Nonformulary drug use is monitored. The procedure for adding drugs to the formulary was modified to require the submission of specific criteria for appropriate drug use; when a drug is added to the formulary, the criteria for use are also adopted. The program has been successful in curtailing inappropriate drug use, reducing drug expenditures, and integrating P&T committee decisions into daily pharmacy practice. The implementation of this DUR program has enabled the P&T committee to conduct ongoing, systematic, criteria-based drug-use evaluations.

We have reported a case of lymph node botryomycosis caused by Serratia marcescens, which has not been listed previously as an etiologic agent.