[Pain and analgesia : Mutations of voltage-gated sodium channels]. / Schmerz und Schmerzlosigkeit : Mutationen spannungsabhängiger Natriumkanäle.

Voltage-gated sodium channels (Navs) are crucial for the generation and propagation of action potentials in all excitable cells, and therefore for the function of sensory neurons as well. Preclinical research over the past 20 years identified three Nav-isoforms in sensory neurons, namely Nav1.7, Nav1.8 and Nav1.9. A specific role for the function of nociceptive neurons was postulated for each. Whereas no selective sodium channel inhibitors have been established in the clinic so far, the relevance of all three isoforms regarding the pain sensitivity in humans is currently undergoing a remarkable verification through the translation of preclinical data into clinically manifest pictures. For the last ten years, Nav1.7 has been the main focus of clinical interest, as a large number of hereditary mutants were identified. The so-called "gain-of-function" mutations of Nav1.7 cause the pain syndromes hereditary erythromelalgia and paroxysmal extreme pain disorder. In addition, several Nav1.7 mutants were shown to be associated with small-fiber neuropathies. On the contrary, "loss-of-function" Nav1.7 mutants lead to a congenital insensitivity to pain. Recently, several gain-of-function mutations in Nav1.8 and Nav1.9 have been identified in patients suffering from painful peripheral neuropathies. However, another gain-of-function Nav1.9 mutation is associated with congenital insensitivity to pain. This review offers an overview of published work on painful Nav mutations with clinical relevance, and proposes possible consequences for the therapy of different pain symptoms resulting from these findings.

Intra-phylum and inter-phyla associations among gastrointestinal parasites in two wild mammal species.

A growing body of literature reveals that the interactions among the parasite community may be strong and significant for parasite dynamics. There may be inter-specific antagonistic interactions as a result of competition and cross-effective immune response, or synergistic interactions where infection by one parasite is facilitated by another one, either by an impoverishment of the host's defenses, parasite-induced selective immunosuppression, or trade-offs within the immune system. The nature of these interactions may depend on how related are the parasite species involved. Here we explored the presence of associations among gastrointestinal parasites (coccidia and helminths) in natural populations of two wild mammal species, the capybara (Hydrochoerus hydrochaeris) and the guanaco (Lama guanicoe). The associations explored were between the oocyst outputs of a selected Eimeria species and the other coccidia of that parasite community, and between Eimeria spp. and the predominant nematodes. The statistical analysis included adjustment for potential confounders or effect modifiers. In guanacos, the prevailing interactions were synergistic among the coccidia and between coccidia and nematodes (Nematodirus spp.). However, in capybaras, the interaction between nematodes (Viannaiidae) and Eimeria spp. depended on environmental and host factors. The relationship was positive in some circumstances (depending on season, year, sex, or animal size), but it appeared to become antagonistic under different scenarios. These antagonist interactions did not follow a particular seasonal pattern (they occurred in autumn, spring, and summer), but they were predominantly found in females (when they depended on sex) or in 2010 and 2011 (when they depended on the sampling year). These results suggest that the relationship between coccidia and nematodes in capybaras may be context dependent. We propose that the context-dependent immune investment documented in capybaras may be the cause of these varying interactions.

Adult rat cardiomyocytes cultured in creatine-deficient medium display large mitochondria with paracrystalline inclusions, enriched for creatine kinase.

In adult regenerating cardiomyocytes in culture, in contrast to fetal cells, mitochondrial creatine kinase (Mi-CK) was expressed. In the same cell, two populations of mitochondria, differing in shape, in distribution within the cell and in content of Mi-CK, could be distinguished. Immunofluorescence studies using antibodies against Mi-CK revealed a characteristic staining pattern for the two types of mitochondria: giant, mostly cylindrically shaped, and, as shown by confocal laser light microscopy, randomly distributed mitochondria exhibited a strong signal for Mi-CK, whereas small, "normal" mitochondria, localized in rows between myofibrils, gave a much weaker signal. Transmission EM of the giant mitochondria demonstrated paracrystalline inclusions located between cristae membranes. Immunogold labeling with anti-Mi-CK antibodies revealed a specific decoration of these inclusions for Mi-CK. Addition of 20 mM creatine, the substrate of Mi-CK, to the essentially creatine-free culture medium caused the disappearance of the giant cylindrically shaped mitochondria as well as of the paracrystalline inclusions, accompanied by an increase of the intracellular level of total creatine. Replacement of creatine in the medium by the creatine analogue and competitor beta-guanidinopropionic acid caused the reappearance of the enlarged mitochondria. It is believed that the accumulation of Mi-CK within the paracrystalline inclusions, similar to those observed in certain myopathies, represents a compensatory effect of the cardiomyocytes to cope with a metabolic stress situation caused by low intracellular total creatine levels.

Formation of hydroxyl radicals and Co3+ in the reaction of Co(2+)-EDTA with hydrogen peroxide. Catalytic effect of Fe3+.

Co2+ ions (Co(NO3)2.6H2O) react with H2O2 only in presence of EDTA to yield OH radicals and Co3+. This reaction was carried out in unbuffered aqueous solutions (pH = 2.6). The formation of Co3+ was confirmed by spectroscopy. The Co(3+)-EDTA complex shows two typical absorptions at 382 nm and 532 nm. The Co(3+)-EDTA complex can be prepared by a number of oxidizing agents, like Fe3+, Fe(3+)-EDTA, Ag+, Ag2+, Ce4+, and hydroxyl radicals. Since Fe3+ oxidizes Co(2+)-EDTA to Co(3+)-EDTA and Fe2+ we initiate a chain reaction for .OH formation. Our results show that there are two modes for H2O2 decomposition: (1) One electron transfer to give OH radicals and (2) Decomposition of H2O2 to H2O and O2 without intermediate .OH formation. This reaction depends strongly on the pH of the buffer. The H2O2 decomposition increases with increasing pH and increasing Co2+ concentration.

Correlates of insulin antibodies in newly diagnosed children with insulin-dependent diabetes before insulin therapy.

Insulin antibodies, as measured by plasma radiolabeled insulin-binding capacity, were determined in 124 newly diagnosed insulin-dependent diabetic (IDDM) children before and after 1, 3, and 5 days of insulin therapy. Controls were 35 nondiabetic children with plasma insulin binding capacity of 1.0 +/- 0.7%. The patients were divided into three groups according to their plasma insulin-binding capacity. Group 1 (N = 79) had binding within two standard deviations (SD) of the control mean, group 2 (N = 20) had insulin binding 2-6 SD above controls, and group 3 (N = 25) showed insulin-binding capacity of more than 6 SD above the control mean. After exogenous insulin therapy, plasma 125I-insulin-binding capacity dropped significantly in both groups 2 and 3, concurrent with significant increases in plasma insulin levels. The three groups differed from each other in that patients in group 3 were significantly younger than in the other groups and clinically seemed to be more severely dehydrated, as reflected in their higher levels of serum urea nitrogen, plasma glucose, potassium, and elevated pulse rate. The three groups did not differ in respect to sex, HLA-DR antigens, Coxsackie-B antibody titers, islet cell cytoplasmic antibodies, immunoglobulin level, and C-peptide levels. Only two of 446 siblings of IDDM children showed elevated insulin binding, one of whom developed IDDM 6 wk later. The presence of an insulin-binding substance probably representing insulin antibodies in some cases of newly diagnosed IDDM suggests that autoimmunity in this disorder is not limited to the B-cell membrane and cytoplasm and lends further support to the heterogeneity of IDDM.

HLA heterogeneity of insulin-dependent diabetes mellitus at diagnosis. The Pittsburgh IDDM study.

Although some previous studies have suggested that insulin-dependent diabetes mellitus (IDDM) is a heterogeneous condition with variant forms being associated with HLA-DR types, the evidence, thus far, is conflicting. To address this issue, we have examined the presenting characteristics of a consecutive admission series of 200 newly diagnosed cases of IDDM from the Children's Hospital of Pittsburgh. Because HLA-DR frequencies vary by race, data are presented only for the 172 white cases with complete HLA-DR typing. HLA-DR3 was found more frequently among male cases and DR4 among female cases (P less than 0.005). Generally, patients with DR4 presented with a severer clinical picture, being more likely to have impaired consciousness and significant dehydration. In addition, patients with DR4 were more likely to be acidotic, ketotic, and to more frequently report a recent viral infection. This latter finding was supported by a greater frequency of antibodies to Coxsackie-B viruses in the DR4 cases at presentation. These results therefore suggest that there is considerable heterogeneity in IDDM, at least in presenting characteristics, according to HLA-DR type.

Glucose and palmitic acid induce degeneration of myofibrils and modulate apoptosis in rat adult cardiomyocytes.

Several studies support the concept of a diabetic cardiomyopathy in the absence of discernible coronary artery disease, although its mechanism remains poorly understood. We investigated the role of glucose and palmitic acid on cardiomyocyte apoptosis and on the organization of the contractile apparatus. Exposure of adult rat cardiomyocytes for 18 h to palmitic acid (0.25 and 0.5 mmol/l) resulted in a significant increase of apoptotic cells, whereas increasing glucose concentration to 33.3 mmol/l for up to 8 days had no influence on the apoptosis rate. However, both palmitic acid and elevated glucose concentration alone or in combination had a dramatic destructive effect on the myofibrillar apparatus. The membrane-permeable C2-ceramide but not the metabolically inactive C2-dihydroceramide enhanced apoptosis of cardiomyocytes by 50%, accompanied by detrimental effects on the myofibrils. The palmitic acid-induced effects were impaired by fumonisin B1, an inhibitor of ceramide synthase. Sphingomyelinase, which activates the catabolic pathway of ceramide by metabolizing sphingomyeline to ceramide, did not adversely affect cardiomyocytes. Palmitic acid-induced apoptosis was accompanied by release of cytochrome c from the mitochondria. Aminoguanidine did not prevent glucose-induced myofibrillar degeneration, suggesting that formation of nitric oxide and/or advanced glycation end products play no major role. Taken together, these results suggest that in adult rat cardiac cells, palmitic acid induces apoptosis via de novo ceramide formation and activation of the apoptotic mitochondrial pathway. Conversely, glucose has no influence on adult cardiomyocyte apoptosis. However, both cell nutrients promote degeneration of myofibrils. Thus, gluco- and lipotoxicity may play a central role in the development of diabetic cardiomyopathy.

Adult rat cardiomyocytes in culture A model system to study the plasticity of the differentiated cardiac phenotype at the molecular and cellular levels.

Adult rat cardiomyocytes (ARCs) in long-term culture, which show a distinct adaptive flexibility, are presented as a system to study cardiac cell hypertrophy in vitro. In the first 1-2 weeks after isolation, ARCs undergo a process of de- and redifferentiation during which the cell morphology is remodeled and the myofibrillar apparatus is restructured, accompanied by a cell enlargement. The growing cells spread and eventually establish new cell-cell contacts, which display newly formed intercalated discs; synchronous cell beating is resumed in the resulting tissuelike sheet. During myofibrillogenesis, the early fetal program of gene expression is reactivated for several genes, as is observed during hemodynamic overload hypertrophy. The cells resume hormonal activity and express atrial natriuretic factor (ANF); the expression pattern of ANF is also reminiscent of that seen in hypertrophy. In cells grown in a medium conditioned by 12-day ARCs, though, myofibrillogenesis is accelerated and accompanied by a downregulation of ANF. In a creatine-deficient medium, on the other hand, the ARCs display giant mitochondria with paracrystalline inclusions imitating a situation found, for example, in mitochondrial myopathies.

Frequency and determinants of screening for diabetes in the U.S.

OBJECTIVE: To determine the prevalence of risk factors for non-insulin-dependent diabetes mellitus (NIDDM) and the frequency of screening for NIDDM in U.S. adults. RESEARCH DESIGN AND METHODS: A detailed questionnaire was administered to a representative sample of 19,680 adults > or = 18 years of age who reported no medical history of diabetes in the 1989 National Health Interview Survey (NHIS). Information was obtained on risk factors for diabetes, complications related to diabetes, and whether the subjects had been screened for diabetes in the past year. Women reporting pregnancy in the past year were excluded from analysis. The prevalence of undiagnosed NIDDM according to the frequency of risk factors for NIDDM was determined based on oral glucose tolerance data from the National Health and Nutrition Examination Survey (NHANES) II and Hispanic Health and Nutrition Examination Survey (HHANES). RESULTS: Prevalence of undiagnosed NIDDM based on the NHANES II and HHANES increased with age, obesity, and family history of diabetes, reaching 11.7% in people with all three risk factors. Based on the NHIS, 77.5% of U.S. adults with no medical history of diabetes (131 million people) had at least one risk factor for NIDDM or complication related to NIDDM, and 22.9% (38 million people) had three or more risk factors or complications. Approximately 31% of adults reported being screened for diabetes in the past year. Screening rates increased with an increasing number of risk factors, but even among those with three risk factors, only 38.6% were screened for NIDDM. CONCLUSIONS: More than 7 million U.S. adults have undiagnosed NIDDM. Nevertheless, screening for diabetes in high-risk groups occurs substantially less frequently than necessary to detect undiagnosed NIDDM and institute appropriate hypoglycemic treatment.

Subclinical states of glucose intolerance and risk of death in the U.S.

OBJECTIVE: Although clinically evident type 2 diabetes is a well-established cause of mortality, less is known about subclinical states of glucose intolerance. RESEARCH DESIGN AND METHODS: Data from the Second National Health and Nutrition Examination Survey Mortality Study, a prospective study of adults, were analyzed. This analysis focused on a nationally representative sample of 3,174 adults aged 30-75 years who underwent an oral glucose tolerance test at baseline (1976-1980) and who were followed up for death through 1992. RESULTS: Using 1985 World Health Organization criteria, adults were classified as having previously diagnosed diabetes (n = 248), undiagnosed diabetes (n = 183), impaired glucose tolerance (IGT) (n = 480), or normal glucose tolerance (n = 2,263). For these groups, cumulative all-cause mortality through age 70 was 41, 34, 27, and 20%, respectively (P < 0.001). Compared with those with normal glucose tolerance, the multivariate adjusted RR of all-cause mortality was greatest for adults with diagnosed diabetes (RR 2.11, 95% CI 1.56-2.84), followed by those with undiagnosed diabetes (1.77, 1.13-2.75) and those with IGT (1.42, 1.08-1.87; P < 0.001). A similar pattern of risk was observed for cardiovascular disease mortality. CONCLUSIONS: In the U.S., there was a gradient of mortality associated with abnormal glucose tolerance ranging from a 40% greater risk in adults with IGT to a 110% greater risk in adults with clinically evident diabetes. These associations were independent of established cardiovascular disease risk factors.

Comparison of diabetes diagnostic categories in the U.S. population according to the 1997 American Diabetes Association and 1980-1985 World Health Organization diagnostic criteria.

OBJECTIVE: To compare the 1997 American Diabetes Association (ADA) and the 1980-1985 World Health Organization (WHO) diagnostic criteria in categorization of the diabetes diagnostic status of adults in the U.S. RESEARCH DESIGN AND METHODS: Analyses are based on a probability sample of the U.S. population age 40-74 years in the 1988-1994 Third National Health and Nutrition Examination Survey (NHANES III). People with diabetes diagnosed before the survey were identified by questionnaire. For 2,844 people without diagnosed diabetes, fasting plasma glucose was obtained after an overnight 9 to < 24-h fast, HbA1c was measured, and a 2-h oral glucose tolerance test was administered. RESULTS: Prevalence of diagnosed diabetes in this age-group is 7.9%. Prevalence of undiagnosed diabetes is 4.4% by ADA criteria and 6.4% by WHO criteria. The net change of -2.0% occurs because 1.0% are classified as having undiagnosed diabetes by ADA criteria but have impaired or normal glucose tolerance by WHO criteria, and 3.0% are classified as having impaired fasting glucose or normal fasting glucose by ADA criteria but have undiagnosed diabetes by WHO criteria. Prevalence of impaired fasting glucose is 10.1% (ADA), compared with 15.6% for impaired glucose tolerance (WHO). For those with undiagnosed diabetes by ADA criteria, 62.1% are above the normal range for HbA1c compared with 47.1% by WHO criteria. Mean HbA1c is 7.07% for undiagnosed diabetes by ADA criteria and 6.58% by WHO criteria. CONCLUSIONS: The number of people with undiagnosed diabetes by ADA criteria is lower than that by WHO criteria. However, those individuals classified by ADA criteria are more hyperglycemic, with higher HbA1c values and a greater proportion of values above the normal range. This fact, together with the simplicity of obtaining a fasting plasma glucose value, may result in the detection of a greater proportion of people with undiagnosed diabetes in clinical practice using the new ADA diagnostic criteria.

Racial and ethnic differences in glycemic control of adults with type 2 diabetes.

OBJECTIVE: To evaluate glycemic control in a representative sample of U.S. adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: The Third National Health and Nutrition Examination Survey included national samples of non-Hispanic whites, non-Hispanic blacks, and Mexican Americans aged > or = 20 years. Information on medical history and treatment of diabetes was obtained to determine those who had been diagnosed with type 2 diabetes by a physician before the survey (n = 1,480). Fasting plasma glucose and HbA1c were measured, and the frequencies of sociodemographic and clinical variables related to glycemic control were determined. RESULTS: A higher proportion of non-Hispanic blacks were treated with insulin and a higher proportion of Mexican Americans were treated with oral agents compared with non-Hispanic whites, but the majority of adults in each racial or ethnic group (71-83%) used pharmacologic treatment for diabetes. Use of multiple daily insulin injections was more common in whites. Blood glucose self-monitoring was less common in Mexican Americans, but most patients had never self-monitored. HbA1c values in the nondiabetic range were found in 26% of non-Hispanic whites, 17% of non-Hispanic blacks, and 20% of Mexican Americans. Poor glycemic control (HbA1c > 8%) was more common in non-Hispanic black women (50%) and Mexican-American men (45%) compared with the other groups (35-38%), but HbA1c for both sexes and for all racial and ethnic groups was substantially higher than normal levels. Those with HbA1c > 8% included 52% of insulin-treated patients and 42% of those taking oral agents. There was no relationship of glycemic control to socioeconomic status or access to medical care in any racial or ethnic group. CONCLUSIONS: These data indicate that many patients with type 2 diabetes in the U.S. have poor glycemic control, placing them at high risk of diabetic complications. Non-Hispanic black women, Mexican-American men, and patients treated with insulin and oral agents were disproportionately represented among those in poor glycemic control. Clinical, public health, and research efforts should focus on more effective methods to control blood glucose in patients with diabetes.

Use of GHb (HbA1c) in screening for undiagnosed diabetes in the U.S. population.

OBJECTIVE: To evaluate the use of GHb as a screening test for undiagnosed diabetes (fasting plasma glucose > or =7.0 mmol/l) in a representative sample of the U.S. population. RESEARCH DESIGN AND METHODS: The Third National Health and Nutrition Examination Survey included national samples of non-Hispanic whites, non-Hispanic blacks, and Mexican Americans aged > or =20 years. Of these subjects, 7,832 participated in a morning examination session, of which 1,273 were excluded because of a previous diagnosis of diabetes, missing data, or fasting time of <8 h before examination. Venous blood was obtained to measure fasting plasma glucose and GHb in the remaining 6,559 subjects. Receiver operating characteristic curve analysis was used to examine the sensitivity and specificity of GHb for detecting diabetes at increasing GHb cutoff levels. RESULTS: GHb demonstrated high sensitivity (83.4%) and specificity (84.4%) for detecting undiagnosed diabetes at a GHb cutoff of 1 SD above the normal mean. Moderate sensitivity (63.2%) and very high specificity (97.4%) were evident at a GHb cutoff of 2 SD above the normal mean. Sensitivity at this level ranged from 58.6% in the non-Hispanic white population to 83.6% in the Mexican-American population; specificity ranged from 93.0% in the nonHispanic black population to 98.3% in the non-Hispanic white population. CONCLUSIONS: GHb is a highly specific and convenient alternative to fasting plasma glucose for diabetes screening. A GHb value of 2 SD above the normal mean could identify a high proportion of individuals with undiagnosed diabetes who are at risk for developing diabetes complications.

Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994.

OBJECTIVE: To evaluate the prevalence and time trends for diagnosed and undiagnosed diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults by age, sex, and race or ethnic group, based on data from the Third National Health and Nutrition Examination Survey, 1988-1994 (NHANES III) and prior Health and Nutrition Examination Surveys (HANESs). RESEARCH DESIGN AND METHODS: NHANES III contained a probability sample of 18,825 U.S. adults > or = 20 years of age who were interviewed to ascertain a medical history of diagnosed diabetes, a subsample of 6,587 adults for whom fasting plasma glucose values were obtained, and a subsample of 2,844 adults between 40 and 74 years of age who received an oral glucose tolerance test. The Second National Health and Nutrition Examination Survey, 1976-1980, and Hispanic HANES used similar procedures to ascertain diabetes. Prevalence was calculated using the 1997 American Diabetes Association fasting plasma glucose criteria and the 1980-1985 World Health Organization (WHO) oral glucose tolerance test criteria. RESULTS: Prevalence of diagnosed diabetes in 1988-1994 was estimated to be 5.1% for U.S. adults > or = 20 years of age (10.2 million people when extrapolated to the 1997 U.S. population). Using American Diabetes Association criteria, the prevalence of undiagnosed diabetes (fasting plasma glucose > or = 126 mg/dl) was 2.7% (5.4 million), and the prevalence of impaired fasting glucose (110 to < 126 mg/dl) was 6.9% (13.4 million). There were similar rates of diabetes for men and women, but the rates for non-Hispanic blacks and Mexican-Americans were 1.6 and 1.9 times the rate for non-Hispanic whites. Based on American Diabetes Association criteria, prevalence of diabetes (diagnosed plus undiagnosed) in the total population of people who were 40-74 years of age increased from 8.9% in the period 1976-1980 to 12.3% by 1988-1994. A similar increase was found when WHO criteria were applied (11.4 and 14.3%). CONCLUSIONS: The high rates of abnormal fasting and postchallenge glucose found in NHANES III, together with the increasing frequency of obesity and sedentary lifestyles in the population, make it likely that diabetes will continue to be a major health problem in the U.S.

Report of the AAN Task Force on access to health care: the effect of no personal health insurance on health care for people with neurologic disorders. Task Force on Access to Health Care of the American Academy of Neurology.

Access to medical care is limited for people with no health insurance. In the United States, an estimated 31 to 41 million people under age 65 have no health insurance. Among the uninsured, an estimated 340,000 new cases of neurologic disorders occur annually. The Task Force on Access to Health Care of the Academy analyzed data from four nationwide health surveys to describe the national population of people with neurologic disorders (PWND) by insurance status and to examine access to care, utilization of services, and expenses for health care of PWND. Health insurance status significantly affected access to and utilization of health care services. Compared with insured PWND, the uninsured less often had a usual source of medical care, saw a particular doctor, or visited a neurologist. The uninsured had fewer doctor's office visits and fewer hospital admissions than privately insured PWND. In the doctor's office they got fewer tests, fewer referrals for therapies, but more medications. In the hospital they received more diagnostic and therapeutic procedures overall, but those with cerebrovascular disease received fewer angiograms and endarterectomies. National health care reform may improve access to care for PWND if they are equitably included in the new systems. However, neurologists should assertively advocate for the needs of PWND to have adequate insurance and appropriate access to neurologic consultations, neurologic tests, and treatments.

Serum creatinine levels in the US population: third National Health and Nutrition Examination Survey.

This report describes the distribution of serum creatinine levels by sex, age, and ethnic group in a representative sample of the US population. Serum creatinine level was evaluated in the third National Health and Nutrition Examination Survey (NHANES III) in 18,723 participants aged 12 years and older who were examined between 1988 and 1994. Differences in mean serum creatinine levels were compared for subgroups defined by sex, age, and ethnicity (non-Hispanic white, non-Hispanic black, and Mexican-American). The mean serum creatinine value was 0.96 mg/dL for women in the United States and 1.16 mg/dL for men. Overall mean creatinine levels were highest in non-Hispanic blacks (women, 1.01 mg/dL; men, 1.25 mg/dL), lower in non-Hispanic whites (women, 0.97 mg/dL; men, 1.16 mg/dL), and lowest in Mexican-Americans (women, 0.86 mg/dL; men, 1.07 mg/dL). Mean serum creatinine levels increased with age among both men and women in all three ethnic groups, with total US mean levels ranging from 0.88 to 1.10 mg/dL in women and 1.00 to 1.29 mg/dL in men. The highest mean creatinine level was seen in non-Hispanic black men aged 60+ years. In the total US population, creatinine levels of 1.5 mg/dL or greater were seen in 9.74% of men and 1.78% of women. Overall, among the US noninstitutionalized population, 10.9 million people are estimated to have creatinine values of 1.5 mg/dL or greater, 3.0 million have values of 1.7 mg/dL or greater, and 0.8 million have serum creatinine levels of 2.0 mg/dL or greater. Mean serum creatinine values are higher in men, non-Hispanic blacks, and older persons and are lower in Mexican-Americans. In the absence of information on glomerular filtration rate (GFR) or lean body mass, it is not clear to what extent the variability by sex, ethnicity, and age reflects normal physiological differences rather than the presence of kidney disease. Until this information is known, the use of a single cutpoint to define elevated serum creatinine values may be misleading.

Analyses on possible heterogeneity of IDDM based on presence of islet cell cytoplasmic antibody at diagnosis.

In a large, representative sample of newly-diagnosed IDDM patients, using a highly sensitive assay to detect islet cell cytoplasmic antibodies (ICA), no marked differences were found between ICA+ and ICA- patients on various clinical, genetic, immunologic, and epidemiologic characteristics. In particular, there was no evidence for associations between ICA status at diagnosis and either sex, race, family history of IDDM, HLA-DR phenotype, antibody titers to Coxsackie B viruses, immunoglobulin levels, C-peptide and glycosylated hemoglobin concentrations, or insulin requirements. The most significant relationship was between the presence of ICA and a young age at diagnosis; however, the large overlap between the distributions of the ages at onset for ICA+ and ICA- groups on this variable suggests that this association is of limited importance. These data suggest that the presence or absence of ICA at diagnosis may not be useful in defining possible subtypes of IDDM.

Is race related to glycemic control? An assessment of glycosylated hemoglobin in two South Carolina communities.

To consider the relationship between race and long-term glycemic control, as measured by glycosylated hemoglobin (GHb), we analyzed data from a community-based sample of 3175 adults in the South Carolina Cardiovascular Disease Prevention Project. A clinically meaningful difference for mean GHb levels (10.5 vs 8.4%, P < 0.001) was present between black people and white people reporting diabetes. Similarly, a significant association between race and GHb was present among people reporting "borderline diabetes" or no diabetes. Logistic regression confirmed this finding in all three diabetic categories, however, controlling for insulin use in the diabetic group reduced (P < 0.001) the association between GHb and race. These findings confirm that further improvements in glycemic control are necessary, especially for black patients and that black people not reporting diabetes have higher GHb levels compared to white people, possibly due to undiagnosed diabetes.

Medullary carcinoma of the thyroid--therapeutic strategy derived from fifteen years of experience.

BACKGROUND: The purpose of this investigation was to analyze our experience with patients treated for medullary carcinoma of the thyroid to identify prognostic factors and to develop a stage-related treatment strategy that might improve cure rates. METHODS: Between 1970 and 1985 a total of 40 patients with medullary thyroid carcinoma were treated (21 women, 19 men; mean age +/- SEM; 40 +/- 3 years; mean follow-up, 82 +/- 12 months). Initial operation involved total thyroidectomy (28 patients), subtotal resection (11 patients), and a lobectomy (1 patient). The initial lymph node dissection generally consisted of a selective removal of enlarged nodes. Unilateral neck dissection was performed in six cases. Secondary operation for recurrent disease was necessary in 26 patients. RESULTS: At the end of the follow-up period 10 patients were tumor free, 12 patients were scheduled for further treatment, six patients suffered from persistent but clinically occult disease, and 12 patients had died (mean survival time, 68 +/- 7 months). The paramount prognostic factor was the absence or presence of lymph node involvement at the time of primary operation (p = 0.011). Patients with distant metastases died within 2 years of diagnosis. Women, patients younger than 40 years of age, and those elicited by familial screening programs exhibited increased survival times. CONCLUSIONS: Because of the prognostic and therapeutic importance we recommend the total thyroidectomy with a complete dissection of the central lymph node compartment as primary treatment. Patients with lymph node involvement or elevated serum calcitonin levels should subsequently be treated by a modified radical neck dissection of the lateral compartments.

Familial and sporadic insulin-dependent diabetes: evidence for heterogeneous etiologies?

Heterogeneity within insulin-dependent diabetes mellitus (IDDM) has been hypothesized, but few studies have focused on differences which may exist between familial and sporadic IDDM cases. Presenting characteristics for 330 white, newly diagnosed IDDM cases were evaluated. Familial cases were older (10.2 +/- 5.1 years vs 7.9 +/- 4.2 years, P = 0.010) and had, on average, less severe metabolic disturbances at presentation, as demonstrated by lower mean hemoglobin A1 (12.6 +/- 2.4% vs 14.4 +/- 2.6%, P = 0.001) and mean insulin dose at discharge (0.62 +/- 0.35 U/kg/day vs 0.85 +/- 0.29 U/kg/day, P less than 0.001), and higher mean plasma bicarbonate concentrations (19.3 +/- 3.9 mmol/l vs 15.8 +/- 5.9 mmol/l, P = 0.023) and mean plasma C-peptide levels (0.35 +/- 0.36 pmol/ml vs 0.14 +/- 0.15 pmol/ml, P less than 0.001). Further analyses on a subset of IDDM cases (n = 100) indicated that initial differences in metabolic indices observed at diagnosis were no longer apparent at one-year post-diagnosis. These results suggest that the etiology of familial and sporadic IDDM is similar and that the less severe presentation observed at diagnosis in the familial cases may be due to earlier identification of the disease, reflecting increased parental knowledge of diabetic symptoms and/or frequent testing for diabetes.