Cross-sectional analysis of the dermoscopic patterns and structures of melanocytic naevi on the back and legs of adolescents.

BACKGROUND: Junctional (flat) naevi predominate on the extremities, whereas dermal (raised) naevi are found primarily on the head, neck and trunk. Few studies have investigated the anatomical site prevalence of melanocytic naevi categorized using dermoscopy. OBJECTIVES: To identify the prevalence of dermoscopic patterns and structures of naevi from the back and legs of adolescents. METHODS: Dermoscopic images of acquired melanocytic naevi were obtained from the back and legs of students from a population-based cohort in Framingham, Massachusetts. Naevi were classified into reticular, globular, homogeneous or complex dermoscopic patterns. Multinomial logistic regression modelling assessed the associations between dermoscopic pattern and anatomical location. RESULTS: In total 509 participants (mean age 14 years) contributed 2320 back naevi and 637 leg naevi. Compared with homogeneous naevi, globular and complex naevi were more commonly observed on the back than the legs [odds ratio (OR) 29·39, 95% confidence interval (CI) 9·53-90·65, P < 0·001 and OR 6·8, 95% CI 2·7-17·14, P < 0·001, respectively], whereas reticular lesions were less likely to be observed on the back than on the legs (OR 0·67, 95% CI 0·54-0·84, P = 0·001). Naevi containing any globules were more prevalent on the back than on the legs (25% vs. 3·6%, P < 0·001). Naevi containing any network were more prevalent on the legs than on the back (56% vs. 40·6%, P < 0·001). CONCLUSIONS: These findings add to a robust body of literature suggesting that dermoscopically defined globular and reticular naevi represent biologically distinct naevus subsets that differ in histopathological growth pattern, age- and anatomical-site-related prevalence, molecular phenotype and aetiological pathways.

Time-dependent effects of short-term training on muscle metabolism during the early phase of exercise.

In this study, we investigated the hypothesis that the metabolic adaptations observed during steady-state exercise soon after the onset of training would be displayed during the nonsteady period of moderate exercise and would occur in the absence of increases in peak aerobic power (Vo2peak) and in muscle oxidative potential. Nine untrained males [age = 20.8 +/- 0.70 (SE) yr] performed a cycle task at 62% Vo2peak before (Pre-T) and after (Post-T) training for 2 h/day for 5 days at task intensity. Tissue samples extracted from the vastus lateralis at 0 min (before exercise) and at 10, 60, and 180 s of exercise, indicated that at Pre-T, reductions (P < 0.05) in phosphocreatine and increases (P < 0.05) in creatine, inorganic phosphate, calculated free ADP, and free AMP occurred at 60 and 180 s but not at 10 s. At Post-T, the concentrations of all metabolites were blunted (P < 0.05) at 60 s. Training also reduced (P < 0.05) the increase in lactate and the lactate-to-pyruvate ratio observed during exercise at Pre-T. These adaptations occurred in the absence of change in Vo2peak (47.8 +/- 1.7 vs. 49.2 +/- 1.7 mlxkg(-1)xmin(-1)) and in the activities (molxkg protein(-1)xh(-1)) of succinic dehydrogenase (3.48 +/- 0.21 vs. 3.77 +/- 0.35) and citrate synthase (7.48 +/- 0.61 vs. 8.52 +/- 0.65) but not cytochrome oxidase (70.8 +/- 5.1 vs. 79.6 +/- 6.6 U/g protein; P < 0.05). It is concluded that the tighter metabolic control observed following short-term training is initially expressed during the nonsteady state, probably as a result of increases in oxidative phosphorylation that is not dependent on changes in Vo2peak while the role of oxidative potential remains uncertain.

Failure of hypoxia to exaggerate the metabolic stress in working muscle following short-term training.

This study investigated the effects of hypoxia (experiment 1) and the effects of hypoxia following short-term training (experiment 2) on metabolism in working muscle. In experiment 1, eight males with a peak aerobic power (VO2peak) of 45 +/- 1.7 ml x kg(-1) x min(-1) (x +/- SE) cycled for 15 min at 66.1 +/- 2.1% VO2peak while breathing room air [normoxia (N)] or 14% O(2) [hypoxia (H)]. In experiment 2, nine males with a VO2peak of 43.3 +/- 1.6 ml x kg(-1) x min(-1) performed a similar protocol at 60.7 +/- 1.4% VO2peak during N and during H following 5 days of submaximal exercise training (H + T). Tissue samples extracted from the vastus lateralis before exercise and at 1, 3, and 15 min of exercise indicated that compared with N, H resulted in lower (P < 0.05) concentrations (mmol/kg dry wt) of creatine phosphate and higher (P < 0.05) concentrations of creatine, inorganic phosphate, and lactate, regardless of exercise time. When the exercise was performed at H + T and compared with N, no differences were observed in creatine phosphate, creatine, inorganic phosphate, and lactate, regardless of duration. Given the well-documented effects of the short-term training model on elevating VO2 kinetics and attenuating the alterations in high-energy phosphate metabolism and lactate accumulation, it would appear that the mechanism underlying the reversal of these adaptations during H is linked to a more rapid increase in oxidative phosphorylation, mediated by increased oxygen delivery and/or mitochondrial activation.

Muscle fiber type characteristics in females with chronic obstructive pulmonary disease. A preliminary study.

Chronic obstructive pulmonary disease (COPD) is known to elicit intrinsic abnormalities in male skeletal muscle. However, it is unclear to what extent these changes occur in women and whether they are fiber-type specific. We investigated fiber-type specific differences in selected histochemical properties in muscle obtained from women with moderate to severe COPD compared to healthy control (CON) women. Tissue was obtained from the vastus lateralis in five COPD patients (age 66.9 +/- 2.6 years; FEV1 = 43 +/- 7%) and eight CON (age 68 +/- 4.9 years; FEV1 = 113 +/- 4.2%). Compared to CON, the distribution (30.6 +/- 5.2 vs. 57.9 +/- 4.6%) and cross sectional area of type I (CSA, 5660 +/- 329 vs. 3586 +/- 257 microm2) and type IIA (2770 +/- 302 vs. 2099 +/- 206 microm2) were lower (P < 0.05) and higher (P < 0.05), respectively, in COPD. Disease state did not alter either the distribution or CSA of the IIA, IIAX or type X subtypes. Although differences were found between fiber types in the number of capillary contacts (n) (I > IIAX, IIX; IIA > IIX) and the capillaries per CSA (microm210(-3)) (I < IIA, IIAX, IIX), no differences were found between CON and COPD. Succinic dehydrogenase activity and sarcoplasmic reticulum (SR) Ca2+-ATPase activity, measured photometrically (OD units), were higher (P < 0.05), and lower (P < 0.05), respectively, in type I compared to the type II fiber subtypes. These properties were not altered with COPD. COPD in females is accompanied by a higher percent of type II fibers, a larger CSA of type I and type IIA fibers, both of which occur in the absence of differences in oxidative potential and the potential for SR Ca2+-sequestration.

Altered metabolic and transporter characteristics of vastus lateralis in chronic obstructive pulmonary disease.

To investigate energy metabolic and transporter characteristics in resting muscle of patients with moderate to severe chronic obstructive pulmonary disease [COPD; forced expiratory volume in 1 s (FEV(1)) = 42 +/- 6.0% (mean +/- SE)], tissue was extracted from resting vastus lateralis (VL) of 9 COPD patients and compared with that of 12 healthy control subjects (FEV(1) = 114 +/- 3.4%). Compared with controls, lower (P < 0.05) concentrations (mmol/kg dry wt) of ATP (19.6 +/- 0.65 vs. 17.8 +/- 0.69) and phosphocreatine (81.3 +/- 2.3 vs. 69.1 +/- 4.2) were observed in COPD, which occurred in the absence of differences in the total adenine nucleotide and total creatine pools. Higher concentrations were observed in COPD for several glycolytic metabolites (glucose-1-phosphate, glucose-6-phosphate, fructose-6-phosphate, pyruvate) but not lactate. Glycogen storage was not affected by the disease (289 +/- 20 vs. 269 +/- 20 mmol glucosyl units/kg dry wt). Although no difference between groups was observed for the glucose transporter GLUT1, GLUT4 was reduced by 28% in COPD. For the monocarboxylate transporters, MCT4 was 35% lower in COPD, with no differences observed for MCT1. These results indicate that in resting VL, moderate to severe COPD results in a reduction in phosphorylation potential, an apparent elevation of glycolytic flux rate, and a potential defect in glucose and lactate transport as a result of reduced levels of the principal isoforms.

Identification of biomarkers for the antiangiogenic and antitumour activity of the superoxide dismutase 1 (SOD1) inhibitor tetrathiomolybdate (ATN-224).

Tetrathiomolybdate (choline salt; ATN-224), a specific, high-affinity copper binder, is currently being evaluated in several phase II cancer trials. ATN-224 inhibits CuZn superoxide dismutase 1 (SOD1) leading to antiangiogenic and antitumour effects. The pharmacodynamics of tetrathiomolybdate has been followed by tracking ceruloplasmin (Cp), a biomarker for systemic copper. However, at least in mice, the inhibition of angiogenesis occurs before a measurable decrease in systemic copper is observed. Thus, the identification and characterisation of other biomarkers to follow the activity of ATN-224 in the clinic is of great interest. Here, we present the preclinical evaluation of two potential biomarkers for the activity of ATN-224: (i) SOD activity measurements in blood cells in mice and (ii) levels of endothelial progenitor cells (EPCs) in bonnet macaques treated with ATN-224. The superoxide dismutase activity in blood cells in mice is rapidly inhibited by ATN-224 treatment at doses at which angiogenesis is maximally inhibited. Furthermore, ATN-224 dosing in bonnet macaques causes a profound and reversible decrease in EPCs without significant toxicity. Thus, both SOD activity measurements and levels of EPCs may be useful biomarkers of the antiangiogenic activity of ATN-224 to be used in its clinical development.

The effects of increased rehabilitation therapy after brain injury: results of a prospective controlled trial.

OBJECTIVE: The objective was to investigate the effect of increased intensity of rehabilitation therapy provided to brain-injured subjects on the rate at which independence was regained and the duration of hospital admission. DESIGN: A two-centre, prospective, controlled study with random allocation to groups. SETTING: Two district general hospitals on the south coast of England. SUBJECTS: Fifty-six people with moderate and severe head injury consecutively admitted to Southampton and Poole hospitals between June 1995 and September 1997. INTERVENTIONS: Increased intensity of rehabilitation therapy input without change in content. RESULTS: Subjects receiving more intensive therapy made more rapid progress and were discharged home sooner. The different intensities of therapy employed in this study showed no evidence of a 'ceiling' effect and the 'intervention group' made significantly more rapid progress on tests of dependency during the period of admission. A clear response to increased therapy input was seen in one of the centres with more rapid functional improvement and a shorter length of hospital stay. This centre already had more therapy and better community facilities. No such benefits were seen at the other centre where the intervention group had a longer hospital stay than the routine group. CONCLUSION: Increasing the hours per week of therapy given to adults recovering from brain injury in hospital can accelerate the rate of recovery of personal independence and result in their being discharged from hospital sooner. Increased rehabilitation therapy after brain injury is associated with enhanced functional recovery and shorter hospital stay if provided in the context of an integrated service that can provide ongoing community support. There is no evidence of any ceiling effect of therapeutic intensity beyond which no further response is observed.

Prolonged exercise following diuretic-induced hypohydration: effects on cardiovascular and thermal strain.

To examine the role of a reduction in plasma volume (PV) on the cardiovascular and thermoregulatory responses to submaximal exercise, ten untrained males (VO2 peak = 3.96 +/- 0.14 L x min(-1); mean +/- SE) performed 60 min of cycle exercise at -61% of VO2 peak while on a diuretic (DIU) and under control (CON) conditions. Participants consumed either Novotriamazide (100 mg triameterene + 50 mg hydrochlorothiazide, a diuretic) or a placebo, in random order, for 4 days prior to the exercise. Diuretic resulted in a calculated 14.6% reduction (P < 0.05) in resting PV. Heart rate was higher (P < 0.05) at rest and throughout exercise for DIU compared with CON. No differences were observed for cardiac output (Qc) and stroke volume (SV) at rest for the two conditions, but during exercise both Qc and SV were lower (P < 0.05) with DIU. Exercise VO2 (L x min(-1)) for CON and DIU at 30 min (2.39 +/- 0.09 vs 2.43 +/- 0.08) and 60 min (2.56 +/- 0.08 vs 2.53 +/- 0.12) were similar between conditions. Whole body a-vO2 difference was significantly greater (P < 0.05) for DIU both at rest and during exercise as compared with CON. Rectal temperature (Tre) was significantly higher (P < 0.05) during DIU from 15 min to the end of exercise. Blood concentrations of norepinephrine were higher (P < 0.05) with DIU compared to CON at 15 min of exercise and beyond. For blood epinephrine, no differences were observed between DIU and CON. These results suggest that reductions in PV led to greater circulating concentrations of norepinephrine which likely resulted from increased cardiac and thermoregulatory stresses. In addition, reductions in PV do not appear to increase cardiovascular instability during prolonged dynamic exercise.

Chromosome arm 17p deletion analysis reveals molecular genetic heterogeneity in supratentorial and infratentorial primitive neuroectodermal tumors of the central nervous system.

The current World Health Organization (WHO) classification groups together both infratentorial neoplasms (medulloblastomas) and their supratentorial counterparts as primitive neuroectodermal tumors (PNETs), implying a common origin. Previous analyses of medulloblastoma have shown loss of chromosome arm 17p as the most frequent genetic abnormality: the molecular genetic constitution of supratentorial PNETS has not been systematically studied. We therefore examined 8 hemispheric PNETs and 35 medulloblastomas with 17p restriction fragment length polymorphism (RFLP) and microsatellite markers. We also examined the TP53 tumor suppressor gene by a combined polymerase chain reaction-denaturing gradient gel (PCR-DGGE) technique. Our results showed that all of the 17p markers tested were preserved in all of the supratentorial PNET specimens. In contrast, loss of distal chromosome arm 17p was detected in 37% of the medulloblastomas. Analysis of the TP53 gene showed 2 mutations in the medulloblastomas and no mutations in the supratentorial tumors. These results show that the most common molecular genetic abnormality in infratentorial PNETS is absent in their supratentorial counterparts and suggests that alternative pathways and genetic events may be involved in their etiology.

Coordination of expression of Zymomonas mobilis glycolytic and fermentative enzymes: a simple hypothesis based on mRNA stability.

Although Zymomonas mobilis is prototrophic, glycolytic and fermentative enzymes (ethanologenic enzymes) constitute over half of the cytoplasmic protein. In this study, transcript stability, functional message pools, and the abundance of cytoplasmic products were compared for genes encoding eight of these essential enzymes. The transcripts of all were very stable, with half-lives ranging from 8 to 18 min. This transcript stability is proposed as an important feature in Z. mobilis that may distinguish highly expressed genes for energy generation from biosynthetic genes, which are required at much lower levels. The evolution of multiple promoters to enhance transcription from single-copy genes, of structural features that alter translational efficiency, and of differences in protein turnover is hypothesized to serve a subordinate role in the regulation of Z. mobilis gene expression. Among the eight ethanologenic genes examined, differences in transcript stability were found to directly correlate with differences in functional message pools and cytoplasmic protein levels. These differences in transcript stability are hypothesized to have evolved as a primary mechanism to balance the levels of individual enzymes within the glycolytic and fermentative pathways.

Molecular characterization of the Zymomonas mobilis enolase (eno) gene.

The Zymomonas mobilis gene encoding enolase was cloned by genetic complementation of an Escherichia coli eno mutant. An enzyme assay and sodium dodecyl sulfate-polyacrylamide gel electrophoresis confirmed the overexpression of enolase in E. coli clones carrying the Z. mobilis eno gene. The eno gene is present in a single copy of the Z. mobilis genome. Nucleotide sequence analysis of the eno region revealed an open reading frame of 1,293 bp that encodes a protein of 428 amino acids with a predicted molecular weight of 45,813. Comparison of the sequence of Z. mobilis enolase with primary amino acid sequences for other enolases indicates that the enzyme is highly conserved. Unlike all of the previously studied glycolytic genes from Z. mobilis that possess canonical ribosome binding sites, the eno gene is preceded by a modest Shine-Dalgarno sequence. The transcription initiation site was mapped by primer extension and found to be located within a 115-bp sequence that is 55.7% identical to a highly conserved consensus sequence found within the regulatory regions of highly expressed Z. mobilis genes. Northern RNA blot analysis revealed that eno is encoded on a 1.45-kb transcript. The half-life of the eno mRNA was determined to be 17.7 +/- 1.7 min, indicating that it is unusually stable. The abundance of the eno message is proposed to account for enolase being the most prevalent protein in Z. mobilis.

In vitro microelectrode study of neuromuscular transmission in a case of botulism.

We performed in vitro microelectrode studies in the anconeus muscle biopsy of a 6-week-old infant intoxicated with Clostridium botulinum toxin B. The most striking abnormalities were the severe reduction of the endplate potential (EPP) quantal content and the marked variability of EPP latencies. The increased variability was often limited to a "single quantum" component of the EPP. Neither the amplitudes nor the frequencies of spontaneous miniature endplate potentials (MEEPs) were decreased. However, there was a wide range of amplitudes and frequencies of MEPPs. This unique combination of electrophysiologic findings indicates a severe presynaptic failure of neuromuscular transmission, which appears to result from an impairment of the process of synaptic vesicle release taking place after the stimulus induced influx of calcium into the motor nerve terminals.

Early muscular and metabolic adaptations to prolonged exercise training in humans.

A short-term training program involving 2 h of daily exercise at 59% of peak O2 uptake (VO2max) repeated for 10-12 consecutive days was employed to determine the significance of adaptations in energy metabolic potential on alterations in energy metabolism and substrate utilization in working muscle. The initial VO2max determined before training on the eight male subjects was 53.0 +/- 2.0 (SE) ml.kg-1.min-1. Analysis of samples obtained by needle biopsy from the vastus lateralis muscle before exercise (0 min) and at 15, 60, and 99 min of exercise indicated that on the average training resulted (P less than 0.05) in a 6.5% higher concentration of creatine phosphate, a 9.9% lower concentration of creatine, and a 39% lower concentration of lactate. Training had no effect on ATP concentration. These adaptations were also accompanied by a reduction in the utilization in glycogen such that by the end of exercise glycogen concentration was 47.1% higher in the trained muscle. Analysis of the maximal activities of representative enzymes of different metabolic pathways and segments indicated no change in potential in the citric acid cycle (succinate dehydrogenase, citrate synthase), beta-oxidation (3-hydroxyacyl CoA dehydrogenase), glucose phosphorylation (hexokinase), or potential for glycogenolysis (phosphorylase) and glycolysis (pyruvate kinase, phosphofructokinase, alpha-glycerophosphate dehydrogenase, lactate dehydrogenase). With the exception of increases in the capillary-to-fiber area ratio in type IIa fibers, no change was found in any fiber type (types I, IIa, and IIb) for area, number of capillaries, capillary-to-fiber area ratio, or oxidative potential with training.(ABSTRACT TRUNCATED AT 250 WORDS)

Muscle energetics during prolonged cycling after exercise hypervolemia.

This study examined the question of whether increases in plasma volume (hypervolemia) induced through exercise affect muscle substrate utilization and muscle bioenergetics during prolonged heavy effort. Six untrained males (19-24 yr) were studied before and after 3 consecutive days of cycling (2 h/day at 65% of peak O2 consumption) performed in a cool environment (22-23 degrees C, 25-35% relative humidity). This protocol resulted in a 21.2% increase in plasma volume (P less than 0.05). During exercise no difference was found in the blood concentrations of glucose, lactate, and plasma free fatty acids at either 30, 60, 90, or 120 min of exercise before and after the hypervolemia. In contrast, blood alanine was higher (P less than 0.05) during both rest and exercise with hypervolemia. Measurement of muscle samples extracted by biopsy from the vastus lateralis muscle at rest and at 60 and 120 min of exercise indicated no effect of training on high-energy phosphate metabolism (ATP, ADP, creatine phosphate, creatine) or on selected glycolytic intermediate concentrations (glucose 1-phosphate, glucose 6-phosphate, fructose 6-phosphate, lactate). In contrast, training resulted in higher (P less than 0.05) muscle glucose and muscle glycogen concentrations. These changes were accompanied by blunting of the exercise-induced increase (P less than 0.05) in both blood epinephrine and norepinephrine concentrations. Plasma glucagon and serum insulin were not affected by the training. The results indicate that exercise-induced hypervolemia did not alter muscle energy homeostasis. The reduction in muscle glycogen utilization appears to be an early adaptive response to training mediated either by an increase in blood glucose utilization or a decrease in anaerobic glycolysis.

Glycogen utilization in rat respiratory muscles during intense running.

Glycogen concentration in the adult rat diaphragm and intercostal muscles has been examined following heavy treadmill exercise to determine the recruitment strategy and the significance of glycogen as a substrate to satisfy the elevated energy requirements accompanying hyperpnea. Short-term continuous running at 60 m/min and a 12 degree grade resulted in a reduction (p less than 0.05) in the concentration of glycogen (39%) in the costal region of the rat diaphragm. Similarly, glycogen concentration was significantly reduced (p less than 0.05) with this exercise protocol in all respiratory muscles studied, with the exception of the sternal region of the diaphragm. With the less intense running protocols, glycogen degradation continued to be pronounced (p less than 0.05) in the majority of the respiratory muscles sampled. The significance of muscle glycogen as a substrate for energy metabolism in the respiratory muscles was not affected by the procedure used to prepare the animal for tissue sampling (Somnitol, diethyl ether, decapitation). Examination of selected locomotor muscles revealed extensive glycogen loss in muscles composed of essentially slow oxidative fibres (soleus), fast oxidative glycolytic fibres (vastus lateralis red), and fast glycolytic fibres (vastus lateralis white). It is concluded that during heavy exercise in the rat, recruitment of motor units occurs in all regions of the diaphragm and in the intercostal muscles. At least for the costal region of the diaphragm and as evidenced by the modest (two- to four-fold) but significant (p less than 0.05) increases in lactate concentration, the increased ATP requirements in these muscles are met to a large degree by increases in aerobic metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Fiber type specific glycogen utilization in rat diaphragm during treadmill exercise.

To examine the significance of endogenous stores of glycogen in specific fiber types (I, IIa, IIb) of the costal region of the diaphragm, adult male Wistar rats performed continuous running (25 m/min, 8 degrees grade) exercise for either 30 min or until fatigue. At 30 min of exercise, glycogen loss, as measured microphotometrically using the periodic acid-Schiff technique averaged between 73 and 80% (P less than 0.05) in the different fiber types. When exercise was performed to exhaustion, representing an additional 94 min, no further reduction in glycogen was observed in any fiber type. Biochemical determinations of glycogen from the diaphragm confirmed the extensive reduction in glycogen concentration with exercise. Large reductions (P less than 0.05) in glycogen were also noted in the soleus, plantaris, and vastus lateralis red. Although significant depletion (P less than 0.05) occurred in the vastus lateralis white, it was not as pronounced as in these other muscles. Repletion to preexercise glycogen concentration was complete by 4 h of recovery in all muscles except the vastus lateralis white. It is concluded that endogenous glycogen is a significant substrate in all muscles sampled regardless of fiber composition. In the case of the costal region of the diaphragm, the increased work of breathing resulting from heavy exercise leads to the recruitment of all fiber types, and each fiber type depends on glycogen as a substrate at least early in the exercise.