Clinical characteristics of chronic kidney disease patients with and without diabetes: a subanalysis of the PAERI study.

AIMS: Diabetes is the leading cause of chronic kidney disease (CKD) in the United States, and cardiac disease is the primary cause of death in patients with CKD and diabetes. The Prevalence of Anemia in Early Renal Insufficiency (PAERI) study evaluated the prevalence of anemia and associated comorbidities in a community-based sample of patients with CKD. The purpose of this post hoc analysis was to identify differences, if any, in the prevalence and severity of anemia (hemoglobin < or = 12 g/dl (120 g/l)) and other clinical characteristics between CKD patients with diabetes and patients with CKD who did not have diabetes. MATERIALS AND METHODS: The PAERI study was a prospective, cross-sectional, multicenter survey. Eligible patients were > or = 18 years old with CKD, defined as serum creatinine 1.5 - 6.0 mg/dl (132.6 - 530.4 micromol/l) in females and 2.0 - 6.0 mg/dl (176.8 530.4 micromol/l) in males within 12 months before enrollment. Study duration for each patient was a single site visit. RESULTS: Of the original 5,222 patients enrolled, 3,361 had diabetes and 1,861 did not. A family history of diabetes was present in 72.7% of diabetic patients vs. 27.2% of nondiabetic patients (p < 0.0001). Patients with diabetes had a significantly higher prevalence of anemia (52.7 vs. 39.4%, p < 0.0001) and cardiac disease (55.7 vs. 42.9%, p < 0.0001). The prevalence of hypertension was high in both groups (91.5 and 89.3%). Significantly more diabetic patients than nondiabetic patients received angiotensin-converting enzyme inhibitors (60.4 vs. 43.8%, p < 0.0001). Hyperlipidemia was more common in patients with diabetes (73.9 vs. 55.4%, p < 0.0001). Patients with diabetes were slightly younger and had a significantly higher mean body mass index and lower transferrin saturation compared with nondiabetic patients. In diabetic and nondiabetic patients, more than 97% had glomerular filtration rate < 60 ml/min/1.73 m2 and more than 70% had serum creatinine < 2.5 mg/dl (221.0 micromol/l). CONCLUSIONS: These findings underscore the extent and severity of concurrent illnesses in patients with both diabetes and CKD. In those patients, diabetes was associated with a greater prevalence of serious cardiac-related comorbidities than observed in nondiabetic patients.

Effect of immediate hemoglobin A1c results on treatment decisions in office practice.

OBJECTIVE: To assess the effect of an immediately available hemoglobin A1c (HbA1c) result on glycemic control and physician decisions about pharmacologic therapy in an office practice. METHODS: In a 1-year retrospective review of medical records, HbA1c results were analyzed in 115 patients beyond the age of 65 years, who had type 2 diabetes and were referred for the first time to a private endocrinology practice between April 1, 1997, and March 31, 1998. These patients were classified into two groups: group A (N = 93, insured by standard Medicare) had immediate HbA1c results (during the patient encounter) and group B (N = 22, insured by Medicare health maintenance organization [HMO]) had commercial laboratory HbA1c results available within 2 to 3 days. We reviewed the changes in the HbA1c level during the 12-month period and the presence or absence of a change in therapy at each visit. HbA1c levels were measured by ion-exchange low-pressure liquid chromatography in group A and by one of three capitated commercial laboratories (depending on HMO contracts) in group B. RESULTS: At the end of the 12 months, the mean HbA1c decrease was 1.03 +/- 0.33% in group A and 0.33 +/- 0.83% in group B. During the first visit, 52% of the patients in group A had pharmacologic treatment interventions, whereas only 27% in group B had such interventions. CONCLUSION: Rapid availability of the HbA1c results during the clinical encounter improves the ability of the physician to make appropriate therapeutic decisions and results in improved glycemic control.

Propylthiouracil-induced perinuclear-staining antineutrophil cytoplasmic autoantibody-positive vasculitis in conjunction with pericarditis.

OBJECTIVE: To describe a case of propylthiouracil-induced vasculitis manifesting with pericarditis. METHODS: We present the first case report of a woman with hyperthyroidism treated with propylthiouracil in whom a syndrome of pericarditis, fever, and glomerulonephritis developed. Serologic testing and immunologic studies were done, and a pericardial biopsy was performed. RESULTS: A 25-year-old woman with Graves' disease had a febrile illness and evidence of pericarditis, which was confirmed by biopsy. Serologic evaluation revealed the presence of perinuclear-staining antineutrophil cytoplasmic autoantibodies (pANCA) against myeloperoxidase (MPO). Propylthiouracil therapy was withdrawn, and she was treated with a 1-month course of prednisone, which alleviated her symptoms. A literature review revealed no prior reports of pericarditis in anti-MPO pANCA-positive vasculitis associated with propylthio- uracil therapy. CONCLUSION: Pericarditis may be the initial manifestation of drug-induced vasculitis attributable to propylthio- uracil therapy.

Docking molecules by families to increase the diversity of hits in database screens: computational strategy and experimental evaluation.

Molecular docking programs screen chemical databases for novel ligands that fit protein binding sites. When one compound fits the site well, close analogs typically do the same. Therefore, many of the compounds that are found in such screens resemble one another. This reduces the variety and novelty of the compounds suggested. In an attempt to increase the diversity of docking hit lists, the Available Chemicals Directory was grouped into families of related structures. All members of every family were docked and scored, but only the best scoring molecule of a high-ranking family was allowed in the hit list. The identity and scores of the other members of these families were recorded as annotations to the best family member, but they were not independently ranked. This family-based docking method was compared with molecule-by-molecule docking in screens against the structures of thymidylate synthase, dihydrofolate reductase (DHFR), and the cavity site of the mutant T4 lysozyme Leu99 --> Ala (L99A). In each case, the diversity of the hit list increased, and more families of known ligands were found. To investigate whether the newly identified hits were sensible, we tested representative examples experimentally for binding to L99A and DHFR. Of the six compounds tested against L99A, five bound to the internal cavity. Of the seven compounds tested against DHFR, six inhibited the enzyme with apparent K(i) values between 0.26 and 100 microM. The segregation of potential ligands into families of related molecules is a simple technique to increase the diversity of candidates suggested by database screens. The general approach should be applicable to most docking methods. Proteins 2001;42:279-293.

What works? The Diabetes Care and Information Center.

This report focuses on the contribution of a referral practice that offers specialist diabetes care to a multi-ethnic population in New York, and describes the process and outcome of an intensive management policy that is particularly strong on communication. The Diabetes Care and Information Center (DCIC), which practices shared care with local primary care physicians, has developed a programme of intensive management for Type 1 and Type 2 diabetes based on a detailed initial patient assessment by a physician, nurse-educator and dietician team. The assessment is followed by an individualized programme of patient education that includes a combination of individual and group education, and counselling. Patients are followed up primarily by an educator or a physician, with frequent interdisciplinary communication to optimize self-care procedures. Medication programmes for patients with Type 2 diabetes include monotherapy and combination therapy with oral agents and single or multiple doses of insulin. Metabolic improvement has been demonstrated by significant changes in mean HbA1c. In addition to initial assessment and routine metabolic follow up, the DCIC provides routine screening and treatment for micro- and macrovascular complications of diabetes, which results in early referral to podiatrists, vascular surgeons and ophthalmologists for appropriate preventive care.

Flexible ligand docking using conformational ensembles.

Molecular docking algorithms suggest possible structures for molecular complexes. They are used to model biological function and to discover potential ligands. A present challenge for docking algorithms is the treatment of molecular flexibility. Here, the rigid body program, DOCK, is modified to allow it to rapidly fit multiple conformations of ligands. Conformations of a given molecule are pre-calculated in the same frame of reference, so that each conformer shares a common rigid fragment with all other conformations. The ligand conformers are then docked together, as an ensemble, into a receptor binding site. This takes advantage of the redundancy present in differing conformers of the same molecule. The algorithm was tested using three organic ligand protein systems and two protein-protein systems. Both the bound and unbound conformations of the receptors were used. The ligand ensemble method found conformations that resembled those determined in X-ray crystal structures (RMS values typically less than 1.5 A). To test the method's usefulness for inhibitor discovery, multi-compound and multi-conformer databases were screened for compounds known to bind to dihydrofolate reductase and compounds known to bind to thymidylate synthase. In both cases, known inhibitors and substrates were identified in conformations resembling those observed experimentally. The ligand ensemble method was 100-fold faster than docking a single conformation at a time and was able to screen a database of over 34 million conformations from 117,000 molecules in one to four CPU days on a workstation.

Phenformin-associated lactic acidosis due to imported phenformin.

OBJECTIVE: To emphasize the continued incidence of phenformin-associated lactic acidosis. CASE REPORT: We report a case of phenformin-associated lactic acidosis in a Chinese man who received phenformin while in China. Diagnosis was made; the patient was treated appropriately and survived. COMMENTS: Phenformin-associated lactic acidosis may still occur in the U.S.

Nonketotic hypertonicity in diabetes mellitus.

Nonketotic hypertonicity (NKH) is one of the most common endocrine emergencies. It is more common in the elderly patient with noninsulin-dependent diabetes mellitus but may occur in insulin-dependent diabetes as well. Although there are many possible precipitating causes, the final common pathway is usually decreased access to water. Treatment consists of vigorous hydration, electrolyte replacement, and small amounts of insulin. Most deaths from NKH occur in the first 2 days of hospitalization; therefore, a significant decrease in morbidity and mortality can be expected by education of patients and their caregivers in the prevention of NKH.

Postprandial hypoglycemia in islet beta cell hyperplasia with adenomatosis of the pancreas.

Organic hyperinsulinism causing hypoglycemia in adults is caused by insulinoma, islet hyperplasia, or a combination of adenomata and hyperplasia. We present a patient with long-standing symptoms of postprandial hypoglycemia occurring within 15 minutes of meals in the absence of fasting hypoglycemic symptoms. An intravenous glucagon stimulation test resulted in a rise of plasma insulin from 194 to 21,883 pmol/L at 7.5 minutes. Blood glucose simultaneously rose from 4.9 to 5.9 mmol/L. A glucose tolerance test revealed an exuberant insulin response. A euglycemic hyperinsulinemic clamp demonstrated incomplete suppression of plasma C-peptide. At surgery, three nodules were found and a 50-60% distal pancreatectomy was performed. The pancreas revealed a combination of multiple beta-cell islet adenomata and islet hyperplasia with no evidence of nesidioblastosis. The coexistence of islet adenomata with hyperplasia must be considered in the differential diagnosis of postprandial hypoglycemia.

Diabetic ketoacidosis and insulin resistance with subcutaneous terbutaline infusion: a case report.

Diabetic ketoacidosis may occur in women treated with intravenous beta-sympathomimetic agents for tocolysis. We describe diabetic ketoacidosis and transient severe insulin resistance in a woman with diabetes who was treated with subcutaneous terbutaline infusion. Subcutaneous terbutaline infusion may precipitate transient insulin resistance and diabetic ketoacidosis in women with diabetes.

Adrenocortical micronodular dysplasia, cardiac myxomas, lentigines, and spindle cell tumors. Report of a kindred.

In a family encompassing three generations, six of 11 evaluated members have two or three elements of a triad comprising adrenocortical micronodular dysplasia, mucocutaneous lentigines, and cardiac myxomas. Evaluation of the adrenals in affected members revealed characteristic pathologic lesions of micronodular adrenal hyperplasia and corticotropin-independent steroidogenesis that correlated with age, suggesting a progressive lesion that begins in early childhood. Since all subjects with micronodular hyperplasia and/or cardiac myxomas also had mucocutaneous lentigines, the skin lesions were markers for affected subjects. This family is one of the larger reported with this syndrome. Of special note was the finding of rare visceral tumors in affected family members, including melanocytic schwannomas and a fibrolamellar hepatoma, signaling another feature of the syndrome. Since 60% of this family encompassing three contiguous generations were affected, the syndrome appears to be inherited as an autosomal or X-linked dominant gene.

Evaluation of provocative tests in suspected medullary carcinoma of the thyroid:heterogeneity of calcitonin responses to calcium and pentagastrin.

Abnormal calcitonin secretion provides a reliable marker for the presence of medullary carcinoma of the thyroid (MCT) and its precursor form, C-cell hyperplasia (CCH). Since this tumor may be transmitted by a dominant autosomal gene, the coincidence of a sensitive marker and an easily identified "at risk" population affords an unusual opportunity for cancer prophylaxis. To evaluate the specificity and sensitivity of provocative tests used for detection of C-cell disease, we have compared the calcitonin (hCT) responses to calcium (3 mg/kg body weight over 10 minutes intravenously), pentagastrin (0.5 microgram/kg body weight), and injection of calcium (1.0 mg/kg body weight) plus pentagastrin (0.25 microgram/kg body weight) over 60 seconds in 13 patients with subsequently proven MCT or CCH and in 31 normal volunteers. The ranges of hCT observed in normals after injection of pentagastrin and combined calcium and pentagastrin were lower than those seen in all nine patients with MCT. One subject, the only MCT patient with normal basal hCT values, had a normal response to calcium whereas all others achieved supranormal levels. Basal hCT levels were normal in the four patients with CCH but the hCT response to calcium was to a value in excess of 300 pg/mL, a level exceeded by only 3 of 31 normal subjects; the hCT response to pentagastrin in CCH and in normal subjects was indistinguishable. Combined calcium and pentagastrin administration was associated with abnormal hCT responses in two of the CCH patients and in the MCT patient with a normal response to calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

The endocrine manifestations of hemochromatosis.

We have evaluated the endocrine changes in 10 male subjects with hemochromatosis. Two subjects initially had aplastic anemia, and the remainder had idiopathic hemochromatosis. Four of the ten patients had diabetes mellitus. Sexual dysfunction (impotence and/or decreased libido) was observed in 8 subjects. Six patients had subnormal testosterone levels; FSH levels were almost uniformly low, but LH concentrations were more variable. Only three patients had normal testosterone responses to hCG. Hypothyroidism, free T4 less than 0.9 ng/dl, was present in 4 subjects, and the etiology was heterogeneous. Basal prolactin levels were elevated in 2 patients and failed to respond adequately to TRH in 2 other patients. Growth hormone reserve was normal in all but 1 patient, and pituitary-adrenal reserve was normal in all but 1 patient. We conclude that disturbances in both pituitary and end-organ function are observed in hemochromatosis. These central and end-organ defects may exist alone or simultaneously. Hypogonadism is almost universal, and is a consequence of defective function of the hypothalamic-pituitary axis and/or primary Leydig cell disturbance. Other evidence of pituitary disturbance are observed but are rather uncommon.

Dissociation of LH and FSH Responses to LHRH during estrogen therapy of patients with ovarian failure.

This study examines the effect of oral estrogen treatment on gonadotropin secretion in three young women with gonadal failure. Each subject was treated with 0.1 mg BID of ethinyl estradiol for four weeks, and the LH and FSH responses to 200 microgram of intravenously administered LHRH were measured basally and weekly during therapy. Significant reduction of basal levels of FSH occurred within one week of treatment, with obliteration of LHRH-mediated FSH responsiveness within two weeks. By contrast, basal levels of LH were significantly reduced by the end of the second week of treatment, and LHRH-mediated LH levels were sustained for three weeks. In one subject an LHRH test was performed every other day for two weeks after cessation of therapy. Return of FSH responsiveness was delayed one week beyond that of LH, which occurred within three days of discontinuation of estrogen. These results indicate that during the early phase of oral estrogen replacement therapy, FSH secretion may be selectively blunted; after discontinuation of treatment, recovery of FSH secretion lags behind recovery of LH.

Testicular activity in Cushing's disease.

Plasma testosterone levels were suppressed in 6 of 8 mature male patients with Cushing's disease, all of whom complained of loss of libido and decreased sexual potency. Gonadotrophin levels, both under basal conditions and in response to LH-RH, were generally normal. The testicular response to stimulation with hCG was brisk in the 2 patients examined. Oestradiol levels were slightly elevated in 2 patients and prolactin levels were normal in all patients. Thus, male patients with Cushing's disease demonstrated normal gonadotrophin levels in the presence of suppressed testosterone, or, viewed from a slightly different prospect, low testosterone levels despite normal gonadotrophins. Neither oestradiol nor prolactin excess appeared to account for the observations. Possible explanations for these findings include (a) a combination of impaired hypothalamic and testicular function, and (b) a resetting downwards of the level of testosterone that is seen as appropriate by the disordered bypothalamic-pituitary unit. Following correction of cortisol excess in Cushing's disease, testosterone levels rose into the normal range.

Responses to isoproterenol in a general population sample.

The response of forced expiratory flow to inhalation of isoproterenol was evaluated in a general population sample of 1,063 subjects. Percentage changes in the forced expiratory volume in 1 sec and in the maximal flow measured at 50 percent of the initial expired forced vital capacity appeared to be the best indicators of responsiveness to bronchodilator. Subjects with a history of asthma more often showed responsiveness than did the remainder of the population, even when their initial function was within normal limits. Over-all, a high proportion of subjects with abnormalities in baseline forced expiratory volume in 1 sec or maximal flow after exhalation of 50 per cent of the forced vital capacity showed sufficient improvement after bronchodilator to cause their values after isoproterenol to fall within the normal range. The data suggest that responsiveness to bronchodilator aerosol may be a useful guide to the presence of bronchial reactivity in epidemiologic studies of obstructive airway diseases.