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Assistant Professor, Idaho College of Osteopathic Medicine

Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Increased adipose tissue expression of tumor necrosis factor- in human obesity and insulin resistance. The expression of tumor necrosis factor in human adipose tissue: regulation by obesity, weight loss and relationship to lipoprotein lipase. Expression pattern of tumour necrosis factor receptors in subcutaneous and omental human adipose tissue: role of obesity and non-insulin-dependent diabetes mellitus. Impairment of insulin signaling in human skeletal muscle by coculture with human adipocytes. Monocyte chemotactic protein-1 is a potential player in the negative crosstalk between adipose tissue and skeletal muscle. Autocrine action of adiponectin on human fat cells prevents the release of insulin resistance inducing factors. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. Loss-of-function mutation in Tolllike receptor 4 prevents diet-induced obesity and insulin resistance. Endoplasmatic reticulum stress links obesity, insulin action, and type 2 diabetes. Reduction of macrophage infiltration and chemoattractant gene expression in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Immunohistochemical and ultrastructural localization of leptin and leptin receptor in human white adipose tissue and differentiating human adipose cells in primary culture. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout and uric calculous disease. Impact of obesity on metabolism in men and women: importance of regional adipose tissue distribution. Management of the metabolic syndrome and type 2 diabetes through lifestyle modification. Beneficial effects of high fiber intake in patients with type 2 diabetes mellitus. Comparison of a high-carbohydrate diet with high-monounsaturated-fat diet in patients with non-insulin-dependent diabetes mellitus. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrate. Macrophages and adipocytes in human obesity: adipose tissue gene expression and insulin sensitivity during calorie restriction and weight stabilization. The effect of short periods of caloric restriction on weight loss and glycemic control in type 2 diabetes. The incretin system: glucagon-like-peptide-1 receptor agonists and dipeptidyl pepdidase-4 inhibitors in type 2 diabetes. Patients have dominantly inherited mild fasting hyperglycemia with only modest changes in glycated hemoglobin. High dose sulfonylurea treatment is often more effective than insulin where mutations affecting Kir6. In the absence of lipodystrophy an insulin receptor mutation is the most common cause. Introduction Monogenic diabetes results from inheritance of one or more mutations in a single gene and accounts for 1­2% of diabetes cases. Correct genetic diagnosis is important to predict clinical course, explain other associated clinical features, enable genetic counseling and diagnose family members, and most importantly guide appropriate treatment.

Limitations in the availability of self-management education and the lack of ongoing self-management support impair patient adherence to self-care. This refers to the situation where physicians fail to intensify therapy when faced with patients who are not meeting target goals for clinical variables. This inertia certainly has many components including 1070 Future Models of Diabetes Care Chapter 62 decreased provider visit time, lack of timely appropriate data, inadequate provider attention to patient adherence and financial barriers. More information is ultimately needed on the basic epidemiology of clinical inertia including a careful analysis of associated patient, physician and clinic characteristics. Compounding these challenges of self-management and clinical inertia is the plethora of new diabetes management data that is becoming available to the provider. The expanding use of continuous glucose monitoring, personal health records and shared web-based patient portals presents the risk of overwhelming diabetes care providers. Better management systems with appropriate filters and alerts are needed to analyze all these data and to present them in a usable format for providers. Therefore, any reorganization of care will need to focus on the primary care settings. Overall, the solutions to these issues will require reorganizing and reinventing diabetes care from a systems approach. Although variation existed among countries in terms of both provider and patient perspectives of diabetes care, all respondents (primary care physicians, nurses and specialists) noted lack of care coordination and implementation of chronic disease strategies as an area in need of improvement worldwide. By the same token, primary care physicians noted a lack of multidisciplinary care and a need for more coordination of care. This chapter focuses on the most promising models for diabetes care, provides current examples and attempts to project into the future how these systems will evolve. This provides a conceptual framework and roadmap for redesigning care from the typical acute reactive system to one transformed to population-based proactively planned care of individuals with chronic diseases such as diabetes. One of the most critical elements of transforming care relates to the systems for delivery of care. Planned visits are focused to meet the needs of the patient in terms of disease complexity, cognition, social needs, learning style and degree of support needed from providers and staff. Reorienting care towards team-based care delivery includes elements such as clinical case management for complex patients, defining and distributing roles amongst team members (nurses, physician assistants, diabetes educators, dietitians, pharmacists and non-medically trained office staff), ensuring follow-up care and identifying patients who "fall between the cracks. Self-management support is focused on providing the knowledge needed by the patient to manage their own disease successfully. Although diabetes education has long been recognized as a crucial part of diabetes management, there is increased recognition for the need for ongoing support. These systems leverage information technology to provide timely reminders to both providers and patients and to identify high-risk subpopulations for proactive care. Diabetes registries that provide searchable information on diabetes populations have proliferated in many health care settings [22]. Embedding evidence-based guidelines into daily clinical practice and sharing those guidelines and information with patients to encourage their participation are the keys to decision support. Guidelines are best integrated through reminder systems that can be embedded into daily care; periodic feedback and standing orders can be used to empower other pratice staff to ensure that evidence-based guidelines are implemented. Although much attention has been given to provider education, better models are needed to integrate specialist expertise and primary care. Innovative approaches that incorporate real-time specialist-based decision support are needed. Patients should be encouraged to participate in effective community programs, and this highlights the need of providers to partner with those within the community to fill gaps of care. Partnering becomes even more critical in limited resource environments where extending care beyond the confines of the clinic is essential. The diabetes care culture must promote effective improvement strategies and support optimal diabetes care. This can include better reimbursement models to encourage optimal care and leadership that stresses the importance of such care. Realistically, primary care providers have reached their limit in terms of additional tasks that they can undertake, and therefore it is inevitable that the care team needs to be expanded. In many ways, team management has been considered a central feature of superior diabetes care.

When sirolimus is given without calcineurin inhibitors, higher trough levels are needed; usually 12 to 20 ng/mL, but occasionally up to 20 to 30 ng/mL. Preferred therapeutic ranges may vary by transplant type, protocol, and comedications. Therapeutic ranges are based on specimens drawn at trough (ie, immediately before a scheduled dose). The assay is specific for sirolimus; it does not cross-react with cyclosporine, cyclosporine metabolites, tacrolimus, tacrolimus metabolites, or sirolimus metabolites. Results by liquid chromatography with detection by liquid chromatography/tandem mass spectrometry are approximately 30% less than by immunoassay. Useful For: Evaluating patients with signs and symptoms of a connective tissue disease in whom the test for antinuclear antibodies is positive Interpretation: A positive result for anti-Sm antibodies is consistent with a diagnosis of lupus erythematosus. In addition to its role as a membrane lipid, it is the precursor to numerous molecules that play an important role in cell growth and differentiation, protein glycosylation, and signaling pathways. The biosynthesis of cholesterol and its subsequent conversion to other essential compounds is complex, involving a number of intermediates and enzymes. In addition to an accumulation of specific intermediates, defects in this pathway may result in a deficiency of cholesterol. Clinical features include microcephaly, growth retardation, developmental delay, dysmorphic facial features, limb abnormalities (especially syndactyly and polydactyly of the toes), and heart and kidney malfunctions. Other disorders of cholesterol biosynthesis, including desmosterolosis (desmosterol reductase deficiency) and sitosterolemia, may present with similar manifestations. These disorders can be detected biochemically by performing a quantitative profile of plasma sterols (#82079 "Sterols, Plasma"). Mild elevations of these cholesterol precursors can be detected in patients with hypercholesterolemia and patients treated with haloperidol. Reference Values: Negative (reported as positive or negative) Quantitative results are provided when positive. Although the phenotype is variable, the syndrome can be suspected in patients with failure to thrive, brachycephaly (short head), prominent forehead, microcephaly (small head), flat and broad midface, broad nasal bridge, strabismus, myopia, malformed ears, high and cleft palate, prognathism (protruding mandible), short and broad hands and feet, scoliosis (laterally curved spine), and cryptorchidism (undescended testes). Unusual features of the syndrome include specific self-destructive behavior, including insertion of foreign objects into bodily orifices, pulling out fingernails and toenails, and sleep abnormalities (especially disturbed rapid eye movement sleep). Mental retardation is variable but usually severe with seizures and hyperactivity. Other diseases in this differential diagnosis group include primary biliary cirrhosis, chronic viral hepatitis, and alcoholic chronic hepatitis. Useful For: Evaluating patients with chronic liver disease in whom the diagnosis of chronic active autoimmune hepatitis is suspected Interpretation: Antibody titers in the range of 80 to 320 occur commonly in patients with active chronic hepatitis; lower titers (usually <80) may occur in the other conditions mentioned earlier. If the relationship between osmolality, potassium, and sodium (see equation above) indicates an osmotic gap, diarrhea may be osmotically induced by exogenous agents such as magnesium sulfate or saccharides. If there is no osmotic gap but sodium concentration or 24-hour excretion rate is 2 to 3 times normal, secretory diarrhea may be the cause, and agents such as phenolphthalein, bisacodyl, or cholera toxin should be suspected. Increased fecal sodium content or daily excretion rate with normal fecal potassium and no osmotic gap indicates secretory diarrhea. Normal fecal sodium and potassium in the presence of an osmotic gap (>30 mOsm/kg) suggests osmotic diarrhea. Normal or low fecal sodium in association with high fecal potassium suggests deterioration of the epithelial membrane or a bleeding lesion. Reference Values: 0-15 years: not established > or =16 years: 0-19 mEq/24 hour Clinical References: 1. If there is no osmotic gap but sodium concentration is 2 to 3 times normal, secretory diarrhea may be the cause, and agents such as phenolphthalein, bisacodyl, or cholera toxin should be suspected. Na+ is responsible for almost one half the osmolality of the plasma and, therefore, plays a central role in maintaining the normal distribution of water and the osmotic pressure in the extracellular fluid compartment. The amount of Na+ in the body is a reflection of the balance between Na+ intake and output. The normal daily diet contains 8 to 15 grams of sodium chloride (NaCl), which is nearly completely absorbed from the gastrointestinal tract.

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Suspected fetal macrosomia Cesarean delivery to avoid potential birth trauma should be limited to estimated fetal weights of at least 5,000 g in women without diabetes and at least 4,500 g in women with diabetes. The prevalence of birth weight of 5,000 g or more is rare, and patients should be counseled that estimates of fetal weight, particularly late in gestation, are imprecise. Twin gestations Perinatal outcomes for twin gestations in which the first twin is in cephalic presentation are not improved by cesarean delivery. Thus, women with either cephalic/cephalic-presenting twins or cephalic/noncephalic presenting twins should be counseled to attempt vaginal delivery. Other Individuals, organizations, and governing bodies should work to ensure that research is conducted to provide a better knowledge base to guide decisions regarding cesarean delivery and to encourage policy changes that safely lower the rate of primary cesarean delivery. Morbidity and Mortality the maternal mortality rate for elective repeat cesarean delivery is 13. In recent years, there has been a shift in the etiology of mortalities from hemorrhage and infection to thromboembolic events. For patients with complicating factors (eg, placenta previa or prior classical uterine incision), the risk of maintaining the pregnancy to 39 weeks may outweigh the risks to the mother and fetus if delivered before 39 weeks. Similarly, women with planned repeat cesarean deliveries may have obstetrical complications with indications for delivery before 39 weeks such as preeclampsia or intrauterine growth restriction with abnormal Doppler studies. If the mother is medically unstable and the fetus is nonviable, then it is recommended that the maternal condition be stabilized regardless of fetal consideration. If the fetus is of a gestational age consistent with viability, then the maternal condition should also be stabilized first and delivery considered only for obstetric indications. Anatomy and Physiology Many alterations in maternal cardiovascular physiology during pregnancy are relevant to cesarean delivery. These physiologic changes increase maternal blood volume and flow in the pelvic organs, rendering the woman more susceptible to serious hemorrhage during cesarean delivery. The surgical anatomy is described in this chapter with each aspect of the procedure. An understanding of pelvic blood supply is essential for physicians performing a cesarean delivery. Additionally, they showed that delivery before 39 weeks was associ- Uterine Artery the aorta bifurcates into bilateral common iliac arteries at the level of the fourth lumbar vertebra. Maternal-Fetal Failure to progress in labor: Arrest of descent Arrest of dilation Placental abruption Placenta previa Conjoined twins Perimortem Maternal Repeat cesarean delivery Contracted pelvis: Congenital Fracture Obstructive tumors Abdominal cerclage Reconstructive vaginal surgery Medical conditions (eg, cardiac, pulmonary, thrombocytopenia) 4 Chapter Q - Cesarean Delivery the common iliac divides into external and internal iliac arteries. The internal iliac or hypogastric artery drops medio-inferiorly along the border of the psoas muscle and divides into anterior and posterior divisions. The uterine artery, a main visceral branch of the anterior division of the hypogastric artery, descends for a short distance, enters the base of the broad ligament, and turns medially to the lateral aspect of the uterus. Approximately 2 cm lateral to the cervix, the uterine artery crosses over the ureter. The ureter can be injured in the process of clamping and ligating the uterine vessels in postpartum hemorrhage or during hysterectomy. A common way to remember this is that the uterine vessels form a bridge over running water. The inferior branch of the uterine artery supplies the upper vagina and the lower cervix, and the marginal branch traverses the lateral aspect of the uterus before dividing into three terminal branches: ovarian, tubal, and fundal. Near the upper lateral portion of the uterus, the ovarian artery anastomoses with the ovarian branch of the uterine artery. Throughout its length, the marginal branch is a convoluted vessel with numerous branches penetrating the body of the uterus, including one large branch that extends to the upper portion of the cervix. Vaginal Blood Supply the vagina receives blood from the inferior extension of the uterine artery along the lateral sulci of the vagina and from a vaginal branch of the hypogastric artery. Branches of these vessels also merge along the anterior and posterior vaginal walls. Physical Findings and Diagnosis History History should be obtained that is pertinent to impending surgery, including medical, surgical, obstetric, gynecologic, family, tobacco and drug habits, transfusion, medications, allergies, and thrombotic and anesthetic complications.