Inflammation and altered metabolism impede efficacy of functional electrical stimulation in critically ill patients.

BACKGROUND: Critically ill patients suffer from acute muscle wasting, which is associated with significant physical functional impairment. We describe data from nested muscle biopsy studies from two trials of functional electrical stimulation (FES) that did not shown improvements in physical function. METHODS: Primary cohort: single-centre randomized controlled trial. Additional healthy volunteer data from patients undergoing elective hip arthroplasty. Validation cohort: Four-centre randomized controlled trial. INTERVENTION: FES cycling for 60-90min/day. ANALYSES: Skeletal muscle mRNA expression of 223 genes underwent hierarchal clustering for targeted analysis and validation. RESULTS: Positively enriched pathways between healthy volunteers and ICU participants were "stress response", "response to stimuli" and "protein metabolism", in keeping with published data. Positively enriched pathways between admission and day 7 ICU participants were "FOXO-mediated transcription" (admission = 0.48 ± 0.94, day 7 = - 0.47 ± 1.04 mean log2 fold change; P = 0.042), "Fatty acid metabolism" (admission = 0.50 ± 0.67, day 7 = 0.07 ± 1.65 mean log2 fold change; P = 0.042) and "Interleukin-1 processing" (admission = 0.88 ± 0.50, day 7 = 0.97 ± 0.76 mean log2 fold change; P = 0.054). Muscle mRNA expression of UCP3 (P = 0.030) and DGKD (P = 0.040) decreased in both cohorts with no between group differences. Changes in IL-18 were not observed in the validation cohort (P = 0.268). Targeted analyses related to intramuscular mitochondrial substrate oxidation, fatty acid oxidation and intramuscular inflammation showed PPARγ-C1α; (P < 0.001), SLC25A20 (P = 0.017) and UCP3 (P < 0.001) decreased between admission and day 7 in both arms. LPIN-1 (P < 0.001) and SPT1 (P = 0.044) decreased between admission and day 7. IL-18 (P = 0.011) and TNFRSF12A (P = 0.009) increased in both arms between admission and day 7. IL-1ß (P = 0.007), its receptor IL-1R1 (P = 0.005) and IL-6R (P = 0.001) decreased in both arms between admission and day 7. No between group differences were seen in any of these (all p > 0.05). CONCLUSIONS: Intramuscular inflammation and altered substrate utilization are persistent in skeletal muscle during first week of critical illness and are not improved by the application of Functional Electrical Stimulation-assisted exercise. Future trials of exercise to prevent muscle wasting and physical impairment are unlikely to be successful unless these processes are addressed by other means than exercise alone.

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease.

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Study of Efficacy and Replication of Recombinant Vector Vaccines by Using Turkey Herpesvirus Combined with Other Marek's Disease Vaccines.

Several recombinant turkey herpesviruses (rHVTs) have been developed within the past decades, and they are now used commercially worldwide. In broiler chickens, rHVTs are usually administered alone, but in long-living birds they are used in combination with Marek's disease (MD) vaccines of other serotypes (i.e., CVI988). The objectives of this work were to 1) evaluate protection against MD conferred by HVT and two rHVTs when combined with CVI988 and 2) optimize the use of rHVT in combination with CVI988 to maximize replication of rHVT without compromising MD protection. Various vaccine protocols, all using rHVT or HVT at the recommended dose (RD), were evaluated. Protocols evaluated included in ovo vaccination with HVT+CVI988 or rHVT+CVI988 (using either the double dose [DD] or the RD of CVI988), day of age vaccination of rHVT+CVI988 at DD, and revaccination protocols using rHVT in ovo followed by CVI988 at DD at day of age. Our results show that, when combined with CVI988, HVT and rHVTs confer a similar level of protection against MD (>90%) regardless of whether CVI988 was used at RD or at DD. However, the combination of rHVT with CVI988 at DD resulted in reduced replication rates of rHVT (60%-76% vs. 95%-100%). Our results show that such a negative effect could be avoided without jeopardizing MD protection by administering CVI988 at RD (if combined in ovo with rHVT) or administered rHVT first in ovo followed by CVI988 at DD at day of age.

Estudio de la eficacia y replicación de vacunas con vectores recombinantes mediante el uso del virus del herpes del pavo combinado con otras vacunas contra la enfermedad de Marek. Varios herpesvirus de pavo recombinantes (rHVT) se han desarrollado en las últimas décadas y ahora se utilizan comercialmente en todo el mundo. En pollos de engorde, los rHVT generalmente se administran solos, pero en aves de vida larga se usan en combinación con vacunas contra la enfermedad de Marek (MD) de otros serotipos (especialmente, CVI988). Los objetivos de este trabajo fueron 1) evaluar la protección contra la enfermedad de Marek conferida por herpesvirus de pavo (HVT9 y por dos rHVT cuando se combinan con la cepa CVI988 y 2) optimizar el uso de rHVT en combinación con la cepa CVI988 para maximizar la replicación de rHVT sin comprometer la protección contra la enfermedad de Marek. Se evaluaron varios protocolos de vacunas, todos con rHVT o con HVT a la dosis recomendada (RD). Los protocolos evaluados incluyeron la vacunación in ovo con HVT + CVI988 o rHVT + CVI988 (usando la dosis doble o la dosis recomendada de la cepa CVI988), la vacunación al día de la edad con rHVT + CVI988 con dosis doble, y los protocolos de revacunación usando rHVT seguido por la cepa CVI988 con dosis doble al día de edad. Los resultados muestran que cuando se combinan con CVI988, HVT y rHVT confieren un nivel de protección similar contra la enfermedad de Marek (> 90%) independientemente de que la cepa CVI988 se haya usado a la dosis recomendada o con dosis doble. Sin embargo, la combinación de rHVT con la cepa CVI988 con doble dosis produjo una reducción en las tasas de replicación de rHVT (60% ­76% vs. 95% ­100%). Estos resultados muestran que dicho efecto negativo podría evitarse sin poner en peligro la protección contra la enfermedad de Marek administrando la cepa CVI988 a la dosis recomendada (si se combina in ovo con rHVT) o administrando rHVT primero in ovo, seguido de CVI988 con dosis doble al día de la edad.

Field and laboratory findings following the large-scale use of intermediate type infectious bursal disease vaccines in Denmark.

Following a period of clinical outbreaks of very virulent infectious bursal disease virus (vvIBDV) in Denmark, the histological bursal lesion score (HBLS) was used on a national scale to screen broiler flocks vaccinated with intermediate IBD vaccines for lesions indicative of IBDV challenge. High lesion scores were detected in a high percentage of healthy and well performing flocks despite the lack of other indications of the presence of vvIBDV. RT-PCR and subsequent sequencing showed the frequent presence of H253Q and H253N IBDV strains that were genetically close to the sequence of the intermediate vaccines with a relative risk ratio of 13.0 (P < 0.0001) in intermediate vaccine A or B vaccinated flocks compared to unvaccinated flocks. The relevance of these H253Q and H253N strains was tested under experimental conditions using a protocol derived from the European Pharmacopoeia for safety of live IBD vaccines. The results confirmed the higher pathogenicity for the bursa of these strains compared to intermediate vaccines as well as the negative effect on antibody response to a Newcastle disease (ND) vaccination performed at the peak of the bursa damage. The efficacy of the ND vaccination was still 100% showing that the H253N and H253Q IBDV strains would be considered as safe vaccine viruses. In conclusion, the use of the HBLS to screen commercial broiler flocks vaccinated with intermediate IBD vaccines for the presence of vvIBDV does not seem to be a reliable method due to the frequent occurrence of H253N and H253Q strains in those flocks. For screening of IBD vaccinated flocks for the presence of vvIBDV or other field strains, the RT-PCR with subsequent sequencing seems to be most suitable.

Muscle-specific deletion of SOCS3 does not reduce the anabolic response to leucine in a mouse model of acute inflammation.

Excessive inflammation reduces skeletal muscle protein synthesis leading to wasting and weakness. The janus kinase/signal transducers and activators of transcription-3 (JAK/STAT3) pathway is important for the regulation of inflammatory signaling. As such, suppressor of cytokine signaling-3 (SOCS3), the negative regulator of JAK/STAT signaling, is thought to be important in the control of muscle homeostasis. We hypothesized that muscle-specific deletion of SOCS3 would impair the anabolic response to leucine during an inflammatory insult. Twelve week old (n=8 per group) SOCS3 muscle-specific knockout mice (SOCS3-MKO) and littermate controls (WT) were injected with lipopolysaccharide (LPS, 1mg/kg) or saline and were studied during fasted conditions or after receiving 0.5g/kg leucine 3h after the injection of LPS. Markers of inflammation, anabolic signaling, and protein synthesis were measured 4h after LPS injection. LPS injection robustly increased mRNA expression of inflammatory molecules (Socs3, Socs1, Il-6, Ccl2, Tnfα and Cd68). In muscles from SOCS3-MKO mice, the Socs3 mRNA response to LPS was significantly blunted (∼6-fold) while STAT3 Tyr705 phosphorylation was exacerbated (18-fold). Leucine administration increased protein synthesis in both WT (∼1.6-fold) and SOCS3-MKO mice (∼1.5-fold) compared to basal levels. LPS administration blunted this effect, but there were no differences between WT and SOCS3-MKO mice. Muscle-specific SOCS3 deletion did not alter the response of AKT, mTOR, S6 or 4EBP1 under any treatment conditions. Therefore, SOCS3 does not appear to mediate the early inflammatory or leucine-induced changes in protein synthesis in skeletal muscle.

Increased level of protection of respiratory tract and kidney by combining different infectious bronchitis virus vaccines against challenge with nephropathogenic Brazilian genotype subcluster 4 strains.

Genotyping of seven infectious bronchitis virus (IBV) strains isolated in Brazil showed that all belonged to the common Brazilian genotype and that these strains were closest to the subcluster of strain IBV/Brazil/2007/USP-19. Pathotyping of four selected Brazilian strains showed that they all caused a considerable level of ciliostasis in the trachea but at a somewhat lower level than did M41 and Brazilian strains 50/96, 57/96, 62/96 and 64/96 representing four different serotypes that had been reported earlier. In contrast to the M41 challenge strain, all Brazilian isolates replicated in kidney tissue in a high percentage of non-vaccinated challenged birds, clearly showing that they are nephropathogenic. As for the tracheal protection, the results using Massachusetts (Mass) vaccination against the recent strains seemed to show protection higher on average than for the strains reported earlier. A single or twofold vaccination with a Mass vaccine resulted in a mean tracheal protection level against the four challenge strains of 92% and 90%, respectively, whereas a single and twofold vaccination with a Mass vaccine halved the percentage of infected kidneys (14% and 13%, respectively, P < .05) compared to that of the unvaccinated birds (27%). The combination of the Mass and the 793B vaccine provided on average a tracheal protection of 99% and a reduction of the percentage of infected kidneys to a mean of 2%. This was a significantly (P < .05) higher protection than that achieved by a single or twofold Mass vaccination, showing the added value of the 793B vaccination following priming with a vaccine of the Mass type.

Determining primary care physician information needs to inform ambulatory visit note display.

BACKGROUND: With the increase in the adoption of electronic health records (EHR) across the US, primary care physicians are experiencing information overload. The purpose of this pilot study was to determine the information needs of primary care physicians (PCPs) as they review clinic visit notes to inform EHR display. METHOD: Data collection was conducted with 15 primary care physicians during semi-structured interviews, including a third party observer to control bias. Physicians reviewed major sections of an artificial but typical acute and chronic care visit note to identify the note sections that were relevant to their information needs. Statistical methods used were McNemar-Mosteller's and Cochran Q. RESULTS: Physicians identified History of Present Illness (HPI), Assessment, and Plan (A&P) as the most important sections of a visit note. In contrast, they largely judged the Review of Systems (ROS) to be superfluous. There was also a statistical difference in physicians' highlighting among all seven major note sections in acute (p = 0.00) and chronic (p = 0.00) care visit notes. CONCLUSION: A&P and HPI sections were most frequently identified as important which suggests that physicians may have to identify a few key sections out of a long, unnecessarily verbose visit note. ROS is viewed by doctors as mostly "not needed," but can have relevant information. The ROS can contain information needed for patient care when other sections of the Visit note, such as the HPI, lack the relevant information. Future studies should include producing a display that provides only relevant information to increase physician efficiency at the point of care. Also, research on moving A&P to the top of visit notes instead of having A&P at the bottom of the page is needed, since those are usually the first sections physicians refer to and reviewing from top to bottom may cause cognitive load.

Visualizing the strain evolution during the indentation of colloidal glasses.

We use an analog of nanoindentation on a colloidal glass to elucidate the incipient plastic deformation of glasses. By tracking the motion of the individual particles in three dimensions, we visualize the strain field and glass structure during the emerging deformation. At the onset of flow, we observe a power-law distribution of strain indicating strongly correlated deformation, and reflecting a critical state of the glass. At later stages, the strain acquires a Gaussian distribution, indicating that plastic events become uncorrelated. Investigation of the glass structure using both static and dynamic measures shows a weak correlation between the structure and the emerging strain distribution. These results indicate that the onset of plasticity is governed by strong power-law correlations of strain, weakly biased by the heterogeneous glass structure.

Probing incipient plasticity by indenting colloidal glasses.

Glasses are lucrative engineering materials owing to their superior mechanical properties such as high strength and large elastic strain. A central question concerns incipient plasticity - the onset of permanent deformation - that is central to their relaxation, aging, yield and fracture. Here, we use an analogue of nano-indentation performed on a colloidal glass to obtain direct images of the incipient plasticity, allowing us to elucidate the onset of permanent deformation. We visualize the microscopic strain by following distorted nearest neighbor configurations, and observe a surprising hierarchical structure of deformation: at the onset of irreversible deformation, the strain acquires a robust fractal structure, and we measure its fractal dimension. These results give direct evidence that the onset of permanent deformation has the hallmarks of a critical point, in agreement with recent theoretical works.

The production of intrinsically labeled milk protein provides a functional tool for human nutrition research.

Oral or intravenous administration of labeled, free amino acids does not allow the direct assessment of protein digestion and absorption kinetics following dietary protein intake. Consequently, dietary protein sources with labeled amino acids incorporated within the protein are required. The aim of this study was to produce milk proteins intrinsically labeled with l-[1-(13)C]phenylalanine that would allow the assessment of protein digestion and absorption kinetics and the subsequent muscle protein synthetic response to dietary protein intake in vivo in humans. Two Holstein cows (body weight of 726 +/- 38 kg) were continuously infused with l-[1-(13)C]phenylalanine at 402 micromol/min for 44 to 48 h, during and after which plasma samples and milk were collected. After milk protein separation, casein was used in a subsequent human proof-of-principle experiment. Two healthy males (aged 61 +/- 1 yr; body mass index of 22.4 +/- 0.1 kg/m(2)) ingested 35 g of casein highly enriched with [1-(13)C] phenylalanine. Plasma samples were collected at regular intervals, and skeletal muscle biopsies were collected before and 6 h after casein ingestion. In the initial experiment, a total of 5.83 kg of l-[1-(13)C]phenylalanine-enriched milk protein (casein enrichment was 29.4 molar percent excess) was collected during stable isotope infusion in the cows. In the proof-of-principle study, ingestion of 35 g of intrinsically labeled casein resulted in peak plasma l-[1-(13)C]phenylalanine enrichments within 90 min after protein ingestion (9.75 +/- 1.47 molar percent excess). Skeletal muscle protein synthesis rates calculated over the entire 6-h period averaged 0.058 +/- 0.012%/h. The production of intrinsically labeled milk protein is feasible and provides dietary protein that can be used to investigate protein digestion and absorption and the subsequent muscle protein synthetic response in vivo in humans.

Impact of the population at risk of diabetes on projections of diabetes burden in the United States: an epidemic on the way.

AIMS/HYPOTHESIS: The aim of this study was to make projections of the future diabetes burden for the adult US population based in part on the prevalence of individuals at high risk of developing diabetes. MATERIALS AND METHODS: Models were created from data in the nationally representative National Health and Nutrition Examination Survey (NHANES) II mortality survey (1976-1992), the NHANES III (1988-1994) and the NHANES 1999-2002. Population models for adults (>20 years of age) from NHANES III data were fitted to known diabetes prevalence in the NHANES 1999-2002 before making future projections. We used a multivariable diabetes risk score to estimate the likelihood of diabetes incidence in 10 years. Estimates of future diabetes (diagnosed and undiagnosed) prevalence in 2011, 2021, and 2031 were made under several assumptions. RESULTS: Based on the multivariable diabetes risk score, the number of adults at high risk of diabetes was 38.4 million in 1991 and 49.9 million in 2001. The total diabetes burden is anticipated to be 11.5% (25.4 million) in 2011, 13.5% (32.6 million) in 2021, and 14.5% (37.7 million) in 2031. Among individuals aged 30 to 39 years old who are not currently targeted for screening according to age, the prevalence of diabetes is expected to rise from 3.7% in 2001 to 5.2% in 2031. By 2031, 20.2% of adult Hispanic individuals are expected to have diabetes. CONCLUSIONS/INTERPRETATION: The prevalence of diabetes is projected to rise to substantially greater levels than previously estimated. Diabetes prevalence within the Hispanic community is projected to be potentially overwhelming.

Plasmodium falciparum-infected red blood cells selected for binding to cultured syncytiotrophoblast bind to chondroitin sulfate A and induce tyrosine phosphorylation in the syncytiotrophoblast.

An important pathogenic complication of malaria during human pregnancy is sequestration of Plasmodium-infected red blood cells (iRBCs) in the placental intervillous spaces. This sequestration is thought to be mediated in part by binding of the iRBCs to receptors expressed on the syncytiotrophoblast (ST) membrane. We report here the use of a dynamic system to study the consequences of this cytoadherence on ST function using human syncytiotrophoblast and the choriocarcinoma cell line, BeWo. Laboratory isolates of Plasmodium falciparum were selected for their ability to bind to ST and used to investigate binding-induced cellular changes in the ST. Treatment of the ST cells with chondroitinase ABC suggested that the selected parasites bind predominantly to chondroitin sulfate A, but other receptors for parasite binding may be involved. Intracellular signaling in the ST induced by iRBCs binding was investigated by assessing tyrosine phosphorylation of ST proteins following iRBC binding. We demonstrate for the first time that iRBC cytoadherence to syncytiotrophoblast enhances tyrosine phosphorylation of a series of proteins in these cells. This approach will be useful in further studies of ST function in the malaria-infected placenta, the dynamics of selection of syncytiotrophoblast-binding parasites, and the identification of new receptors for parasite cytoadherence in the placenta.

Inhibition of adipose tissue lipolysis increases intramuscular lipid use in type 2 diabetic patients.

AIMS/HYPOTHESIS: In the present study, we investigated the consequences of adipose tissue lipolytic inhibition on skeletal muscle substrate use in type 2 diabetic patients. MATERIALS AND METHODS: We studied ten type 2 diabetic patients under the following conditions: (1) at rest; (2) during 60 min of cycling exercise at 50% of maximal workload capacity and subsequent recovery. Studies were done under normal, fasting conditions (control trial: CON) and following administration of a nicotinic acid analogue (low plasma non-esterified fatty acid trial: LFA). Continuous [U-13C]palmitate and [6,6 -2H2]glucose infusions were applied to quantify plasma NEFA and glucose oxidation rates, and to estimate intramuscular triacylglycerol (IMTG) and glycogen use. Muscle biopsies were collected before and after exercise to determine net changes in lipid and glycogen content specific to muscle fibre type. RESULTS: Following administration of the nicotinic acid analogue (Acipimox), the plasma NEFA rate of appearance was effectively reduced, resulting in lower NEFA concentrations in the LFA trial (p<0.001). Plasma NEFA oxidation rates were substantially reduced at rest, during exercise and subsequent recovery in the LFA trial. The lower plasma NEFA oxidation rates were compensated by an increase in IMTG and endogenous carbohydrate use (p<0.05). Plasma glucose disposal rates did not differ between trials. In accordance with the tracer data, a greater net decline in type I muscle fibre lipid content was observed following exercise in the LFA trial (p<0.05). CONCLUSIONS/INTERPRETATION: This study shows that plasma NEFA availability regulates IMTG use, and that adipose tissue lipolytic inhibition, in combination with exercise, could be an effective means of augmenting intramuscular lipid and glycogen use in type 2 diabetic patients in an overnight fasted state.

Are ethnic differences in insulin sensitivity explained by variation in carbohydrate intake?

AIMS/HYPOTHESIS: Minority populations are disproportionately affected by diabetes. This health disparity may be due to less healthy diets and/or heritable factors in minority populations. These factors must be assessed concurrently to better appreciate their contribution to insulin sensitivity. METHODS: We analysed overweight, healthy adults using the National Health and Nutrition Examination Survey 1999-2000. Means for dietary intake variables and insulin sensitivity were calculated by ethnicity. Linear regressions were performed to evaluate the association between ethnicity, dietary variables, dietary glycaemic index and insulin sensitivity. Fasting insulin was used to characterise insulin sensitivity. RESULTS: Non-Hispanic whites have higher energy and fat intake, while Hispanics have higher carbohydrate intake and African-Americans have lower fibre intake. In unadjusted analyses both Hispanics and African-Americans have lower insulin sensitivity, but only Hispanics are more likely to have lower insulin sensitivity after controlling for dietary variables and BMI. CONCLUSIONS/INTERPRETATION: Ethnic differences in insulin sensitivity remain after controlling for dietary differences and other factors, suggesting that inherent metabolic differences exist. Further studies are needed to define inherent metabolic factors, as well as other non-dietary factors that affect insulin sensitivity.

Having a regular physician and attempted weight loss after screening for hypertension or hypercholesterolemia.

OBJECTIVE: To examine the relationship between having a regular physician, results of screening tests for cardiovascular risk (hypertension, hypercholesterolemia) and efforts to lose weight among obese adults. DESIGN: Analysis of a population-based telephone survey (2002 Behavioral Risk Factor Surveillance System). SETTING: Four states (Iowa, South Carolina, South Dakota, Virginia) in the US. PARTICIPANTS: Adults (> or =18 y old) who were obese (body mass index > or =30 kg/m(2)) (unweighted n=1735). MAIN OUTCOME MEASURES: Currently attempting to lose weight; changes in diet or exercise as strategies to lose weight. RESULTS: Obese individuals with a personal physician were more likely to report attempts to lose weight in the face of screening normal for hypertension or hypercholesterolemia than those without a personal physician (75.6 vs 60.5% for hypercholesterolemia, P=0.03; 74.6 vs 57.7% for hypertension, P=0.01). In adjusted models, obese individuals screening normal for hypertension but having a personal physician were significantly more likely to attempt to lose weight than individuals without a personal physician (OR 1.71, 95% CI 1.12-2.60). CONCLUSIONS: Having a regular physician is associated with a higher likelihood of attempted weight loss among obese individuals who believe that they do not have hypertension or hypercholesterolemia, than their counterparts with no regular physician. This suggests a previously unrecognized benefit of having a personal physician.

Potential effect of patient-assisted teledermatology on outpatient referral rates.

We carried out a pilot study on the feasibility and accuracy of store-and-forward teledermatology based on patient-provided images and history as a triage tool for outpatient consultation. Patients referred by their general practitioner provided a history and images via the Internet. The information was reviewed by one of 12 teledermatologists and the patient then visited a different dermatologist in person within two days. Three independent dermatologists compared the remote and in-person diagnoses in random order to determine diagnostic agreement. Broader agreement was also measured, by comparing the main disease groups into which the two diagnoses fell. The teledermatologists indicated whether an in-person consultation or further investigations were necessary. There were 105 eligible patients, aged four months to 72 years, who were willing to participate. For the 96 cases included in the analysis, complete diagnostic agreement was found in 41% (n=39), partial diagnostic agreement in 10% (n=10) and no agreement in 49% (n=47). There was disease group agreement in 66% of cases (n=63). Nearly a quarter (23%) of participating patients could have safely been managed without an in-person visit to a dermatologist.

Intramyocellular lipid content is increased after exercise in nonexercising human skeletal muscle.

Intramyocellular lipid (IMCL) content has been reported to decrease after prolonged submaximal exercise in active muscle and, therefore, seems to form an important local substrate source. Because exercise leads to a substantial increase in plasma free fatty acid (FFA) availability with a concomitant increase in FFA uptake by muscle tissue, we aimed to investigate potential differences in the net changes in IMCL content between contracting and noncontracting skeletal muscle after prolonged endurance exercise. IMCL content was quantified by magnetic resonance spectroscopy in eight trained cyclists before and after a 3-h cycling protocol (55% maximal energy output) in the exercising vastus lateralis and the nonexercising biceps brachii muscle. Blood samples were taken before and after exercise to determine plasma FFA, glycerol, and triglyceride concentrations, and substrate oxidation was measured with indirect calorimetry. Prolonged endurance exercise resulted in a 20.4 +/- 2.8% (P < 0.001) decrease in IMCL content in the vastus lateralis muscle. In contrast, we observed a substantial (37.9 +/- 9.7%; P < 0.01) increase in IMCL content in the less active biceps brachii muscle. Plasma FFA and glycerol concentrations were substantially increased after exercise (from 85 +/- 6 to 1450 +/- 55 and 57 +/- 11 to 474 +/- 54 microM, respectively; P < 0.001), whereas plasma triglyceride concentrations were decreased (from 1498 +/- 39 to 703 +/- 7 microM; P < 0.001). IMCL is an important substrate source during prolonged moderate-intensity exercise and is substantially decreased in the active vastus lateralis muscle. However, prolonged endurance exercise with its concomitant increase in plasma FFA concentration results in a net increase in IMCL content in less active muscle.

The bias in regression-based indices of premorbid IQ.

Formulas for premorbid intelligence estimates are typically derived by linear regression and are therefore biased in individual cases because of regression to the mean. It is shown that it is inappropriate to compare such IQ estimates with current IQ scores to determine whether a decline from premorbid levels has occurred. This widespread practice grossly overestimates the probability of an IQ decline in the below-average range and grossly underestimates it in the above-average range, with serious implications for clinical practice. The authors present a formula for computing unbiased estimates of IQ decline as well as a test of the null hypothesis of no decline. Corresponding tables for several combinations of test indices and estimation methods are included for practical reference.