[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.

Comparison of a single global item and an index of a multi-item health status measure among persons with and without diabetes in the US.

This study examined the hypothesis that a single global item can be substituted for an index of a multi-item assessment and lead to equivalent interpretative outcomes. Substitutability would be demonstrated if: (1) the two measures were strongly correlated, and regression analysis showed that the same variables accounted for variation in each measure, and (2) difference scores between multi-item and global scores were close to zero and remained so as socio-demographic and co-morbid conditions varied. A multi-item assessment was constructed by mapping items from the NHANES I Epidemiologic Follow-up Study (NHEFS), using available data for persons with and without diabetes, onto the health-status classification system of the Health Utilities Index Mark 1 (HUI), creating the NHEFS-HUI. NHEFS-HUI data, when correlated to the self-assessed health status (SAHS) item, revealed a coefficient of 0.55. Regression analyses identified 9 of 14 variables contributed to the variability of each health status index, but differences existed in which variables were significant for which measure. Five of the possible 14 difference scores for persons with diabetes and non-diabetics approached zero. Persons with diabetes had lower NHEFS-HUI scores than non-diabetics. These data were considered insufficient for demonstrating substitutability. Suggestions were made on how optimal substitutability could be achieved.

Monoclonal antibody purification by affinity chromatography with ligands derived from the screening of peptide combinatory libraries.

The peptide, Ala-Pro-Ala-Arg (APAR), was selected from the screening of a tetrapeptide combinatorial synthetic library as the ligand for affinity purification of an anti-Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) monoclonal antibody (Mab) developed in mouse ascitis. The affinity chromatographic matrix obtained by attachment of APAR to agarose, having a peptide density of 0.5 micromol ml(-1), showed a maximum capacity of 9.1 mg Mab ml(-1) and a dynamic capacity of 3.9 mg Mab ml(-1). A 95% yield of electrophoretically pure anti-GM-CSF was obtained in a single step.

[Transient neurologic symptoms after spinal anesthesia with 4% hyperbaric mepivacaine]. / Vorübergehende neurologische Symptome nach einer Spinalanästhesie mit 4%igem hyperbarem Scandicain (Mepivacain).

This is a case report of transient neurologic symptoms (TNS) after spinal anesthesia with 4% hyperbaric mepivacaine,which have not been reported before. The patient was a 44-year-old man with a meniscus lesion who received spinal anesthesia with 80 mg 4% mepivacaine while undergoing knee arthroscopy. A L3-L4 mid-line approach was used with a 26-gauge Quincke needle and a 21-gauge introducer. The local anaesthetic was injected over approximately 30 s with the aperture of the Quincke needle in a cephalad direction. A transient pain syndrome was observed 4 h after spinal anesthesia, which included symmetric pain and/or dysesthesia in the buttocks and posterior thighs appearing 4 h after recovery from the spinal anesthesia and had a duration of 2 days. The patient stated that the pain radiated through the hips, buttocks, and posterior thighs and extended past the buttocks and lower legs. The pain was described as strong and aching,occasionally decreasing when walking around. It responded well to NSAID and resolved spontaneously within 3 days. No other neurologic symptoms or signs were noted.

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.

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.

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.

N-Cadherin: structure, function and importance in the formation of new intercalated disc-like cell contacts in cardiomyocytes.

N-Cadherin belongs to a superfamily of calcium-dependent transmembrane adhesion proteins. It mediates adhesion in the intercalated discs at the termini of cardiomyocytes thereby serving as anchor for myofibrils at cell-cell contacts. A large body of data on the molecular structure and function of N-cadherin exists, however, little is known concerning spatial and temporal interactions between the different junctional structures during formation of the intercalated disc and its maturation in postnatal development. The progression of compensated left ventricular hypertrophy to congestive left heart failure is accompanied by intercalated disc remodeling and has been demonstrated in animal models and in patients. The long-term culture of adult rat cardiomyocytes allows to investigate the development of de novo intercalated disc-like structures. In order to analyze the dynamics of the cytoskeletal redifferentiation in living cells, we used the expression of chimeric proteins tagged with the green fluorescent protein reporter. This technique is becoming a routine method in basic research and complements video time-lapse and confocal microscopy. Cultured cardiomyocytes have been used for a variety of studies in cell biology and pharmacology. Their ability to form an electrically coupled beating tissue-like network in culture possibly allows reimplantation of such cells into injured myocardium, where they eventually will form new contacts with the healthy muscle tissue. Several groups have already shown that cardiomyocytes can be grafted successfully into sites of myocardial infarcts or cryoinjuries. Autologous adult cardiomyocyte implantation, might indeed contribute to cardiac repair after infarction, thanks to advances in tissue engineering.

Differences in morbidity measures and risk factor identification using multiple data sources: the case of stroke.

BACKGROUND: Epidemiologic studies utilise medical information from a variety of sources. These include subject or proxy interviews, medical records, death certificates and administrative records. Since the choice of data source may affect the validity of study results, it is important to understand the effect of different case-ascertainment methodologies on estimates of risk. METHODS: The NHANES I Epidemiologic Follow-up Study (NHEFS) contains several sources of information that can be used to define case status. In this report we investigate whether the use of seven different algorithms for case ascertainment, each based on different combinations of data sources, results in substantive differences in the estimates of incidence rates and relative risks associated with selected, documented, risk factors for stroke. RESULTS: The seven different models of case identification gave very different estimates of stroke incidence. However, the characteristics of the cases defined by the models, except for cases identified by death certificate only, were remarkably similar. There was also remarkable similarity in relative risks obtained from six of the seven models. The model using only death certificate information generally produced higher relative risk estimates. CONCLUSIONS: Despite wide variations in the estimates of incidence, characteristics of the cases using different case definition were remarkably similar, as were the risks associated with stroke incidence. The main difference occurred when cases were identified from the death certificate only. These results furnish some evidence that analyses based on self report can provide valid, useful information.

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.

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.

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.

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.

IGF-I and bFGF differentially influence atrial natriuretic factor and alpha-smooth muscle actin expression in cultured atrial compared to ventricular adult rat cardiomyocytes.

In the present study, we compare expression, storage and secretion of the atrial natriuretic factor (ANF) in atrial and ventricular adult rat cardiomyocytes (aARC and vARC) in long-term culture. The influence of insulin-like growth factor-I (IGF-I) and of basic fibroblast growth factor (bFGF) on ANF production and secretion, as well as on the expression of a structural component, alpha-smooth muscle actin (alpha-sm actin), was studied in the two cell types. Antibodies against alpha-ANF were used for immunocytochemical localization of ANF. aARC contained more ANF-granules than vARC, and they were distributed throughout the cell bodies. Quantitative determination of ANF storage and secretion was done by radioimmunoassay (RIA; 125I), and it was demonstrated that aARC stored and secreted ANF 18- and 16-times more, respectively, when compared to vARC. Immuno-electron microscopy confirmed that ANF storing secretory granules were present in both types of cardiomyocytes. Expression of ANF and alpha-sm actin in aARC and vARC responded differently to treatment with either IGF-I or bFGF. In aARC, neither IGF-I nor bFGF had an influence on expression of ANF. In vARC, expression of ANF was downregulated by IGF-I and upregulated by bFGF with regard to both immunoreactivity and message. In contrast to vARC, expression of alpha-sm actin was not affected by IGF-I in aARC, whereas bFGF produced a strong upregulation similar to that found in vARC. Mitogen-activated protein kinases (MAPK) 42 and 44, though, were equally activated by bFGF and IGF-I in both aARC and vARC.