[Association of Deployment and Tobacco Dependence among Soldiers]. / Zusammenhang von Auslandseinsätzen und Tabakabhängigkeit bei Soldaten.

OBJECTIVE: Smoking is a highly preventable risk factor. The present study investigates whether military operations abroad, as compared to deployment preparation, increase the risk of starting to smoke, enhance tobacco dependence and moderator variables can be identified on smoking behavior. METHOD: The study was conducted at 2 mechanized infantry battalions with N=264 soldiers. The task force completed a deployment in Afghanistan, the control group performed a deployment training. Assessments of tobacco dependence, posttraumatic symptoms, depression and stress were done before (t1) and after (t3) deployment. In addition, one assessment was done at mid-point (t2) during deployment and during the pre-deployment training, respectively. RESULTS: The prevalence rate of smoking soldiers was 56,4%. 51,1% (n=135) of all examined soldiers smoked more than 20 cigarettes per day. The results show a significant increase of tobacco dependence in the task force from t1 to t3 (p=0,040) as compared to the control group. For both groups, there was no increase in starting to smoke during the period of investigation (χ²<1; n. s.). Moderator variables on smoking were not found, but there was a significant increase in posttraumatic stress symptoms in the deployed group (p=0,006). CONCLUSIONS: Perhaps the increase in tobacco dependence in the experimental group can be attributed to the specific burdens of deployment. If high smoking rates were to be found also in other branches of the armed services, effective smoking cessation programs should be offered more widely.

[TULC - total umbilical laparoscopic cholecystectomy]. / TULC - Total Umbilikale Laparoskopische Cholezystektomie.

BACKGROUND: Except for some few cases only symptomatic cholecystolithiasis constitutes an indication for operative treatment. The gold standard meanwhile has been the laparoscopic cholecystectomy, because the method shows good results with short hospital stay. Recently there has been an intensive discussion about combination of laparoscopic techniques with natural body orifice using surgery (NOTES). These techniques permit further reduction of surgical trauma and enhancing of cosmetic results. However, the technical effort is significant and most of the times a combination (hybrid procedure) of NOTES with standard laparoscopic procedure is performed, so that we concentrated on performing a laparoscopic cholecystectomy using a single incision through the umbilicus. METHODS: A 5-mm incision left deep in the umbilicus and a 10-mm incision directly below were used for creating a pneumoperitoneum and for inserting the ports for the optic and the dissector. Exposition of the gallbladder was carried out by sutures, that were penetrated from outside through the abdominal wall into the abdominal cavity and transfixed through the gallbladder in order to hang up the gallbladder like a puppet by penetrating the abdominal wall again to the outside. Removal occurred through the umbilical incision. RESULTS: We successfully operated on 90  patients in a 12-month period. Mean operating time was 48 (39-71) min whereby no conversion to open surgery was necessary. No intra- or postoperative complications occurred in any patient. Average hospital stay was 2.5 (2-4) days, postoperative examination showed no differences to the usual laparoscopic cholecystectomy with a good cosmetic result and no visible scars. CONCLUSION: The purpose of our study was to further improve the cosmetic results of minimally invasive surgery of the gallbladder by operating totally through the umbilicus, using 2  ports deep in the umbilicus. We thereby avoid further surgical trauma due to creating an access through another organ as is done in the NOTES technique. For this operation no special equipment like flexible endoscopes was needed as common laparoscopic instruments were used.

[Scintigraphically "hot" thyroid nodules mainly go hand in hand with a normal TSH]. / Szintigraphisch mehranreichernde Schilddrüsenknoten gehen überwiegend mit normwertigem TSH einher.

AIM: In recent years, various professional societies published guidelines for diagnostic evaluation of thyroid nodules, in which the indication for scintigraphy is restricted to patients with subnormal TSH values. It is seen controversial whether such recommendations should be transferred to Germany, partly because of lower iodine intake in this country and the consequent higher percentage of autonomous thyroid nodules, which are not accompanied by a measurable dysfunction. Since reliable data to this topic are scarce, we analyzed multicentrically the spectrum of scintigraphically "hot" and "warm" nodules under the current epidemiological conditions. PATIENTS, METHODS: In 10 German nuclear medicine out-patient institutions we evaluated the diagnostic data from a total of 514 patients, in whom unequivocally hyperfunctional nodules (focal increased uptake in comparison to perinodular tissue with a sonographically nodular correlative ≥1 cm) could be detected by (99m)Tc-pertechnetate scintigraphy. To minimize selection bias, the surveys were not carried out in hospitals.The recorded parameters included the thyroid hormone levels, the global (99m)Tc-uptake (TcTU), the size of each nodule and the total autonomous nodular volume (V(aut)). RESULTS: Only 20% of the patients with "hot" nodules had subnormal TSH levels (<0.1 to 0.33 mU / l), the remaining patients had TSH levels from 0.34 to 3.5 mU /l (in one third of the patients TSH levels even exceeded 1.0 mU/l). Moreover, we found no relevant correlation between TSH and TcTU or V(aut). CONCLUSIONS: In Germany, in at far the largest proportion of patients with autonomous thyroid nodules objectified by means of scintigraphy, TSH levels are within the normal range. Since such nodules with maximum safety can be classified as benign, a corresponding scintigraphic finding has a high priority for the patient. These current data support that it is not reasonable to restrict scintigraphy to patients with subnormal TSH values in this country.

Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer--a multi-centre randomised phase II study.

BACKGROUND: No standard treatment for locally advanced pancreatic cancer (LAPC) is defined. PATIENTS AND METHODS: Within a multi-centre, randomised phase II trial, 95 patients with LAPC were assigned to three different chemoradiotherapy (CRT) regimens: patients received conventionally fractionated radiotherapy of 50 Gy and were randomised to concurrent 5-fluorouracil (350 mg m(-2) per day on each day of radiotherapy, RT-5-FU arm), concurrent gemcitabine (300 mg m(-2)), and cisplatin (30 mg m(-2)) on days 1, 8, 22, and 29 (RT-GC arm), or the same concurrent treatment followed by sequential full-dose gemcitabine (1000 mg m(-2)) and cisplatin (50 mg m(-2)) every 2 weeks (RT-GC+GC arm). Primary end point was the overall survival (OS) rate after 9 months. RESULTS: The 9-month OS rate was 58% in the RT-5-FU arm, 52% in the RT-GC arm, and 45% in the RT-GC+GC arm. Corresponding median survival times were 9.6, 9.3, and 7.3 months (P=0.61) respectively. The intent-to-treat response rate was 19, 22, and 13% respectively. Median progression-free survival was estimated with 4.0, 5.6, and 6.0 months (P=0.21). Grade 3/4 haematological toxicities were more frequent in the two GC-containing arms, no grade 3/4 febrile neutropaenia was observed. CONCLUSION: None of the three CRT regimens tested met the investigators' definition for efficacy; the median OS was similar to those previously reported with gemcitabine alone in LAPC.

Naturally occurring amino acid substitutions at Arg1174 in the human insulin receptor result in differential effects on receptor biosynthesis and hybrid formation, leading to discordant clinical phenotypes.

Missense mutations in the tyrosine kinase domain of the human insulin receptor frequently result in a dominantly inherited form of insulin resistance. We noted a marked disparity in the clinical phenotypes of our study subjects with different missense mutations at the same residue (Arg1174) of the insulin receptor. Subjects with a tryptophan substitution (W) were only moderately hyperinsulinemic, whereas those with a glutamine substitution (Q) had severe clinical and biochemical insulin resistance. Studies were undertaken to explore the molecular mechanisms underlying these differences. Both W and Q mutant receptors bound insulin normally but were kinase inactive. The W mutation resulted in more rapid degradation of newly synthesized mutant receptor, which contrasted with the near-normal biosynthesis of the Q receptor. The propensity of the W receptor to form hybrids with the cotransfected wild-type (WT) receptor was also markedly impaired compared with the Q receptor, to an extent greater than could be explained by lower steady-state expression. Thus, the more clinically benign consequences of the heterozygous W mutant receptor are likely to relate to its impaired biosynthesis and/or reduced capacity to form hybrids with WT receptors. In addition to providing an explanation for the milder phenotype of 1174W versus 1174Q carriers, these studies provide further support for the notion that the dominant-negative effect of insulin receptor tyrosine kinase mutations involves the competition between inactive mutant homodimers and WT/mutant hybrids with active WT homodimers for both ligands and intracellular substrates.

Reduced pain during baroreceptor stimulation in patients with symptomatic and silent myocardial ischaemia.

OBJECTIVE: Baroreceptor activation has been shown to reduce pain, and the accumulation of such pain reduction has been implicated in the operant learning (under certain circumstances) of hypertension. The current study is an examination of differences in the pain dampening effects of baroreceptor activity in patients with symptomatic and asymptomatic myocardial ischaemia. The objective was to determine whether there are differences between patients with symptomatic and silent myocardial ischaemia with respect to their antinociceptive response to baroreceptor stimulation, and, if so, whether these differences could be related to the absence of angina pectoris pain in patients with silent myocardial ischaemia. METHODS: Sensory detection and electrical pain thresholds were compared in nine symptomatic and 10 asymptomatic patients with replicable myocardial ischaemia during PRES (phase related external suction) carotid baroreceptor manipulation in which the pressure inside a neck cuff was phase locked in time to the R wave of the ECG and negative pressure was applied during either systole or diastole. Tourniquet pain thresholds were also determined. RESULTS: It was found that (1) external baroreceptor manipulation had no effect on detection thresholds; (2) painful stimuli were judged by both symptomatic and asymptomatic patients as less intense when delivered during maximum baroreceptor activity; (3) symptomatic and asymptomatic patients did not differ in their sensory detection thresholds; and (4) asymptomatic patients had significantly higher ischaemic (tourniquet) pain thresholds than symptomatic patients. CONCLUSIONS: The results indicate that baroreceptor activity can modify the intensity of painful stimuli. The degree to which baroreceptor manipulation affects pain does not appear to differ between patients with painful and silent myocardial ischaemia. Thus the baroreceptor dependent pain inhibition effects seems not to be responsible for the higher ischaemic pain threshold found in the silent myocardial ischaemia group.

Truncated human leptin (delta133) associated with extreme obesity undergoes proteasomal degradation after defective intracellular transport.

We recently described a homozygous frameshift mutation in the human leptin (ob) gene associated with undetectable serum leptin and extreme obesity in two individuals. This represented the first identified genetic cause of morbid obesity in humans. Preliminary data suggested a defect in the secretion of this truncated (delta133) mutant leptin. In the present investigation, we have examined the mechanisms underlying the defective secretion of the delta133 leptin in transient transfection studies in Chinese hamster ovary and monkey kidney epithelium cells. Consistent with our previous observations, only immunoreactive wild-type (wt) leptin was secreted. In pulse chase experiments, intracellular wt leptin levels decreased, concomitant with secretion into the medium. In contrast, though immunoreactive delta133 leptin disappeared from cell lysates with kinetics similar to those of wt leptin (half-life, 45 min), it was not detected in the medium. Inhibition of the proteasome, using the inhibitor clastolactacystin beta-lactone, led to a significant increase in the intracellular levels of delta133 leptin, indicating a role for the proteasome in the degradation pathway. Although intracellular immunoprecipitated wt and delta133 leptin levels were comparable, analysis of total cell lysates revealed a 7-fold increase in total intracellular delta133 leptin, compared with wt leptin. Size-exclusion membrane filtration demonstrated that intracellular delta133 leptin accumulated in an aggregated form, presumably as a result of misfolding in the endoplasmic reticulum. Consistent with this, an endoplasmic reticulum-like localization for delta133 leptin was detected by immunofluorescence microscopy. In conclusion, the delta133 mutant leptin is not secreted but accumulates intracellularly, as a consequence of misfolding/aggregation, and is subsequently degraded by the proteasome. These studies further define the genotype/phenotype correlation in this paradigmatic case of human leptin deficiency.

The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus.

Several studies have demonstrated an association of CTLA4 (IDDM12) alanine-17 with type 1 diabetes, but CTLA4 variants have not yet been investigated in type 2 diabetes. The CTLA4 exon 1 polymorphism (49 A/G) was analyzed in 300 Caucasian patients with type 2 diabetes and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism, and restriction length fragment polymorphism analysis using BBV:I. The distribution of alleles as well as the genotypic and phenotypic frequencies were similar among patients and controls [AA, 42 vs. 39%; AG, 47 vs. 46%; GG, 11 vs. 15%, P = not significant (n.s.); A/G, 65/35% vs. 62/38%, P = n.s.; alanine/threonine 92/58% vs. 85/61%, P = n.s.]. However, detailed analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation (46.8 +/- 0.8 vs. 49.5 +/- 0.8 yr, mean +/- SEM), lower body mass index (21.4 +/- 0.5 vs. 24.4 +/- 0.5 kg/m(2), P = 0.042), and basal C-peptide level (0.33 +/- 0.07 vs. 0.53 +/- 0.07nmol/L), as well as earlier start of insulin treatment (5.8 +/- 1.2 vs. 8.7 +/- 0.6 yr) and higher portion of patients on insulin (71 vs. 61%). Patients with the AA genotype were significantly less likely to develop microangiopathic lesions (P < 0.0005). No differences were found for hypertension or family history of type 2 diabetes. In conclusion, CTLA4 alanine-17 does not represent a major risk factor for type 2 diabetes. Additional studies on larger groups and different ethnic groups are warranted to clarify the association of the GG genotype with faster ss-cell failure and the lower rate of microvascular complications in AA carriers.

Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease.

Because particular human leukocyte antigen (HLA) DQ alleles are the major predisposing factors for type 1 diabetes mellitus (IDDM), we investigated whether they are shared by other endocrine autoimmune diseases. We, therefore, analyzed the HLA DQ genotypes of 171 patients with IDDM, 271 with Graves' disease (GD), 65 with Hashimoto's thyroiditis, 51 with postpartum thyroiditis, 53 with Addison's disease (AD), and 271 healthy controls. HLA DQA1 and DQB1 alleles were defined by polymerase chain reaction and sequence-specific oligonucleotide hybridization as well as by single strand conformational polymorphism analysis. HLA DQA1*0501 was significantly more frequent in IDDM (60%), GD (65%), and AD (70%) than in controls (43%); DQA1*0301 was significantly more frequent only in IDDM (67% vs. 30% controls). The heterozygous state DQA1*0301/*0501 was found in 9% of controls and 35% of IDDM (relative risk, 5.6). An arginine at position 52 on either DQA1 allele was significantly more frequent in patients with IDDM (94%), GD (80%), and AD (89%) compared with controls (66%). HLA DQB1*0201 and DQB1*0302 were more frequent in IDDM patients (*0201, 62% vs. 36% in controls, *0302, 59% vs. 19% controls), whereas DQB1*0602 was less frequent in IDDM (4%) and GD (18% vs. 31% of controls). In conclusion, endocrine autoimmunity has a common immunogenetic background; susceptibility is conferred by DQA1*0501 as well as an arginine at position 52 of DQA1 alleles, and protection against IDDM and GD is conferred by DQB1*0602.

CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus.

The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.

Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease.

Endocrine autoimmune disorders share susceptibility and resistance factors of the human leukocyte antigen system on the short arm of chromosome 6, but other gene loci also contribute to predisposition and protection. Because the cytotoxic T lymphocyte antigen 4 (CTLA4) alanine-17 encoded by the CTLA4 gene on chromosome 2q33 confers susceptibility to Graves' disease, as well as to type 1 (insulin-dependent) diabetes mellitus, we investigated this dimorphism in the other endocrine autoimmune disorders: Hashimoto's thyroiditis and Addison's disease. We analyzed the CTLA4 exon 1 polymorphism (49 A/G) in 73 patients with Hashimoto's thyroiditis, 76 with Addison's disease, and 466 healthy controls. This dimorphism corresponds to an aminoacid exchange (Thr/Ala) in the leader peptide of the expressed protein. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism analysis, and restriction fragment length polymorphism analysis using BbvI. Patients with Hashimoto's thyroiditis had significantly more Ala alleles than controls, both as homozygotes (22% vs. 15%) and heterozygotes (53% vs. 46%), and less Thr than controls as homozygotes (25% vs. 39%), P < 0.04. The phenotypic frequency for Ala was significantly higher in patients (75%), compared with controls (61%), P < 0.03. Patients with Addison's disease did not differ significantly from controls, but those carrying the suceptibility marker, human leukocyte antigen DQA1*0501, were significantly more CTLA4 Ala17 positive than controls with the same DQA1 allele (P < 0.05). In conclusion, an alanine at codon 17 of CTLA4 confers genetic susceptibility to Hashimoto's thyroiditis, whereas this applies only to the subgroup of DQA1*0501+ patients with Addison's disease.

Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study.

Hypertension is often associated with insulin resistance, dyslipidemia and obesity, which indicate a prediabetic state and increased risk of cardiovascular disease. Pioglitazone treatment of patients with type 2 diabetes reduces insulin resistance and improves lipid profiles. The present double-blind placebo-controlled study is the first study to report effects of pioglitazone in non-diabetic patients with arterial hypertension. Following a one week run-in, 60 patients were randomized to receive either pioglitazone (45 mg/day) or placebo for 16 weeks. Insulin sensitivity (M-value) increased by 1.2 +/- 1.7 mg/min/kg with pioglitazone compared with 0.4 +/- 1.4 mg/min/kg (P = 0.022) with placebo. HOMA index was decreased (-22.5 +/- 45.8) by pioglitazone but not by placebo (+0.8 +/- 26.5; P < 0.001). Decreases in fasting insulin and glucose were significantly (P = 0.002 and P = 0.004, respectively) greater with pioglitazone than placebo. Body weight did not change significantly with either treatment. HDL-cholesterol was increased and apolipoprotein B was decreased to a significantly greater extent with pioglitazone. There was a significantly (P = 0.016) greater decrease from baseline in diastolic blood pressure with pioglitazone. These changes would suggest improved glucose metabolism and a possible reduction in risk of cardiovascular disease with pioglitazone treatment of non-diabetic patients with arterial hypertension.

Endogenous retroviral long terminal repeats of the HLA-DQ region are associated with susceptibility to insulin-dependent diabetes mellitus.

HLA-DQ genes are the main inherited factors predisposing to IDDM. This gene region harbors long terminal repeat (DQ LTR) elements of the human endogenous retrovirus HER V-K, which we analyzed for a possible association with disease. We first investigated whether LTR segregate with DQ alleles in families. Members (n = 110) of 29 families with at least one diabetic child, unrelated patients with IDDM (n = 159), and healthy controls (n = 173) were analyzed. Genomic DNA was amplified for DQ LTR3 by a nested primer approach as well as for DQA1 and DQB1 second exons, to assign DQA1 and DQB1 alleles. DQ LTR segregated in 24 families along with DQ alleles. Of the 29 families, 20 index patients were positive for DQ LTR. The DQ LTR was in all patients on the haplotype carrying the DQA1 *0301 and DQB1 *0302 alleles. A majority of patients had DQ LTR (62%) compared with controls (38%) (p < 1.3 x 10(-5)), even after matching for the high-risk alleles DQA1 *0501, DQB1 *0201-DQA1 *0301, and DQB1 *0302 (79% of patients and 48% of controls; p < 0.02). Subtyping for DRB1 *04 alleles in all DQB1 *0302+ individuals showed 56% DRB1 *0401, DQB1 *0302 [LTR' patients vs. 29% controls with the same haplotype (p < 0.002)]. In conclusion, these data demonstrate the segregation of DQ LTR with DQA1, DQB1 alleles on HLA haplotypes. Furthermore their presence on DRB1 *0401-, DQA1 *0301-, and DQB1 *0302-positive haplotypes suggest that they contribute to DQ-related susceptibility for IDDM.

Cardiovascular autonomic dysregulation in users of MDMA ("Ecstasy").

The present study examined resting heart rate variability (HRV; an index of parasympathetic tone) and heart rate response to the Valsalva maneuver (Valsalva ratio; an index of overall autonomic responsiveness) in 12 repeat users of 3.4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), and a matched comparison group of presumed nonusers. HRV and Valsalva ratio were smaller in users than in controls. Three out of 12 MDMA users but no controls had Valsalva ratios below 1.50, the cut-off for autonomic dysfunction. In several users, there was a total absence of post-Valsalva release bradycardia. All MDMA users were polydrug users. Parasympathetic cardiovascular tone appears impaired in repeat MDMA users, although the ubiquitous problems in such epidemiologic designs (including lack of testing before the first use of the drug and confounding with use of other drugs) preclude definitive causal interpretations.

Effects of smoking on thermal pain threshold in deprived and minimally-deprived habitual smokers.

This study examined the antinociceptive effects of smoking in nine habitual smokers under deprived (12 h) and minimally-deprived (< 30 min) conditions. Pain threshold for thermal stimuli, heart rate, blood pressure and ratings of mood, arousal, dominance and well-being were assessed before and after smoking a cigarette. Over-all, smoking affected all measured variables in the expected direction, leading to increased physiological activity, elevated pain threshold and improved mood. However, most of these effects depended on the deprivation status of the subjects, such that smoking after deprivation increased pain threshold whereas smoking after minimal deprivation did not. Pain threshold before smoking was the same for both groups. Deprived subjects had lower pre-smoke diastolic blood pressure, heart rate, and arousal levels, which rose to equal minimally-deprived subjects' scores after smoking.

Cigarette smoking, blood lipids, and baroreceptor-modulated nociception.

Activation of arterial blood pressure has been shown to influence higher central nervous activity. In animals, induction of sleep-like states and increases of seizure and pain thresholds in response to baroreceptor stimulation have been reported. In certain human groups, mechanical stimulation of the carotid baroreceptors also increases pain thresholds. The present paper examines the hypothesis that smokers show baroreceptor dependent antinociception as compared to non-smokers. It is speculated that one effect which rewards smoking is the nicotine induced phasic blood pressure increase which leads to baroreceptor stimulation and dampens pain perception. One hundred and twenty subjects were investigated using a recently developed mechanical baroreceptor stimulation technique and an electrical pain stimulus. The group of heavy smokers showed the predicted effect: their pain thresholds were enhanced during conditions of increased baroreceptor activity as compared to the control condition. The group of medium, light and non-smokers, however, did not show this effect. Neither blood lipid levels nor diastolic or systolic blood pressure paralleled the group differences on baroreceptor dependent antinociception. In heavy smokers, the nicotine induced phasic blood pressure increases might have baroreceptor dependent pain dampening effects, which might be among the reinforcing qualities of smoking.

Brain potentials during mental arithmetic: effects of extensive practice and problem difficulty.

Recent behavioral investigations indicate that the processes underlying mental arithmetic change systematically with practice from deliberate, conscious calculation to automatic, direct retrieval of answers from memory [Bourne, L.E.Jr. and Rickard, T.C., Mental calculation: The development of a cognitive skill, Paper presented at the Interamerican Congress of Psychology, San Jose, Costa Rica, 1991: Psychol. Rev., 95 (1988) 492-527]. Results reviewed by Moscovitch and Winocur [In: The handbook of aging and cognition, Erlbaum, Hillsdale, NJ, 1992, pp. 315-372] suggest that consciously controlled processes are more dependent on frontal lobe function than are automatic processes. It is appropriate, therefore to determine whether transitions in the locus of primary brain activity occur with practice on mental calculation. In this experiment, we examine the relationship between characteristics of event-related brain potentials (ERPs) and mental arithmetic. Single-digit mental multiplication problems varying in difficulty (problem size) were used, and subjects were trained on these problems for four sessions. Problem-size and practice effects were reliably found in behavioral measures (RT). The ERP was characterized by a pronounced late positivity after task presentation followed by a slow wave, and a negativity during response indication. These components responded differentially to the practice and problem-size manipulations. Practice mainly affected topography of the amplitude of positivity and offset latency of slow wave, and problem-size mainly offset latency of slow wave and pre-response negativity. Fronto-central positivity diminished from session to session, and the focus of positivity centered finally at centro-parietal regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Alteration of digital representations in somatosensory cortex in focal hand dystonia.

Focal hand dystonia involves a loss of motor control of one or more digits; it is associated with the repetitive, synchronous movements of the digits made by musicians over periods of many years. Magnetic source imaging revealed that there is a smaller distance (fusion) between the representations of the digits in somatosensory cortex for the affected hand of dystonic musicians than for the hands of non-musician control subjects. The data suggest that use-dependent susceptibility to digital representation fusion in cortex may be involved in the etiology of focal dystonia. A successful therapy for the condition has been developed based on this consideration.

Fully integrated biocatalytic electrodes based on bioaffinity interactions.

Integrated bioelectrocatalytically active electrodes are assembled by the deposition of enzymes onto respective electrically contacted affinity matrices and further cross-linking of the enzyme monolayers. A catalyst-NAD(+)-dyad for the binding of the NAD(+)-dependent enzymes and cytochrome-like molecules for the binding of the heme-protein-dependent enzymes are used to construct integrated electrically contacted biocatalytic systems. NAD(+)-dependent lactate dehydrogenase (LDH) is assembled onto a pyrroloquinoline quinone-NAD+ monolayer. The redox-active monolayer is organized via covalent attachment of pyrroloquinoline quinone (PQQ) to a cystamine monolayer associated with a Au-electrode, followed by covalent linkage of N6-(2-aminoethyl)-NAD+ to the monolayer. The interface modified with the PQQ-NAD(+)-dyad provides temporary affinity binding for LDH and allows cross-linking of the enzyme monolayer. The cross-linked LDH is bioelectrocatalytically active towards oxidation of lactate. The bioelectrocatalyzed process involves the PQQ-mediated oxidation of the immobilized NADH. Integrated, electrically contacted bioelectrodes are produced by the affinity binding and further cross-linking of nitrate reductase (NR) (cytochrome-dependent, E.C. 1.9.6.1 from E. coli) or CoII-protoporphyrin IX reconstituted myoglobin (CoII-Mb) atop the microperoxidase-11 (MP-11) monolayer associated with a Au-electrode. The MP-11 monolayer provides an affinity interface for the temporary binding of the enzymes, that allows the cross-linkage of the enzyme molecules. The MP-11 assembly acts as electron transfer mediator for the reduction of the secondary enzyme layer. The integrated bioelectrodes consisting of NR and CoII-Mb show catalytic activities for NO3- reduction and acetylene-dicarboxylic acid hydrogenation, respectively. Two FeIII-protoporphyrin IX units are reconstituted into a four alpha-helix bundle de novo protein assembled as a monolayer on a Au-electrode. Vectorial electron transfer proceeds in the synthetic heme-protein monolayer. Cross-linking of an affinity complex generated between the FeIII-protoporphyrin IX reconstituted de novo protein monolayer and NR yields an integrated, electrically contacted enzyme electrode that stimulates the bioelectrocatalyzed reduction of nitrate.

Resection of a branchiomeric paraganglioma at a rare extrapulmonary location.

Thoracic paragangliomas are a rare cause of hypertension. We report the occurrence of a sporadic benign norepinephrine-producing branchiomeric paraganglioma in a 32-year-old man with paroxysms of hypertension. After localization by iodine 123-metaiodobenzyl-guanidine scintigraphy and magnetic resonance imaging, the paraganglioma was resected successfully below the right pulmonary artery through a right-sided posterolateral thoracotomy. The particular location was consistent with a branchiomeric paraganglioma in an extremely rare extrapulmonary location.