Muscle mass and peripheral fatigue: a potential role for afferent feedback?

AIM: The voluntary termination of exercise has been hypothesized to occur at a sensory tolerance limit, which is affected by feedback from group III and IV muscle afferents, and is associated with a specific level of peripheral quadriceps fatigue during whole body cycling. Therefore, the purpose of this study was to reduce the amount of muscle mass engaged during dynamic leg exercise to constrain the source of muscle afferent feedback to the central nervous system (CNS) and examine the effect on peripheral quadriceps fatigue. METHOD: Eight young males performed exhaustive large (cycling - BIKE) and small (knee extensor - KE) muscle mass dynamic exercise at 85% of the modality-specific maximal workload. Pre- vs. post-exercise maximal voluntary contractions (MVC) and supramaximal magnetic femoral nerve stimulation (Q(tw,pot)) were used to quantify peripheral quadriceps fatigue. RESULT: Significant quadriceps fatigue was evident following both exercise trials; however, the exercise-induced changes in MVC (-28 ± 1% vs. -16 ± 2%) and Q(tw,pot) (-53 ± 2% vs. -34 ± 2%) were far greater following KE compared to BIKE exercise, respectively. The greater degree of quadriceps fatigue following KE exercise was in proportion to the greater exercise time (9.1 ± 0.4 vs. 6.3 ± 0.5 min, P < 0.05), suggestive of a similar rate of peripheral fatigue development. CONCLUSION: These data suggest that when the source of skeletal muscle afferent feedback is confined to a small muscle mass, the CNS tolerates a greater magnitude of peripheral fatigue and likely a greater intramuscular metabolic disturbance. An important implication of this finding is that the adoption of small muscle mass exercise may facilitate greater exercise-induced muscular adaptation.

HLA class II DPB1 and DRB1 polymorphisms associated with genetic susceptibility to beryllium toxicity.

OBJECTIVES: Chronic beryllium disease (CBD) is a hypersensitivity granulomatous pulmonary disease caused by exposure to the metal beryllium (Be²âº). Our objective was to extend current knowledge of the genetics of beryllium disease by examining all HLA-DPB1 and HLA-DPR1 gene polymorphisms and the interactions between them. METHODS: DNA-based typing of HLA-DPB1 and HLA-DRB1 loci at the allele level was performed on 65 CBD, 44 beryllium sensitised (BeS) but without CBD and 288 non-affected, beryllium exposed controls. RESULTS: The DPßE69 residue regardless of zygosity, but particularly if present on non-*0201 alleles, was of primary importance for the development of CBD and BeS, while other negatively charged residues DPßDE55, 56 and DPßDE84, 85 incrementally increased, although not independently, the risk. The DPßE69 positive alleles with charge -7 or -9 were associated with both CBD and BeS. The polymorphic residues DPßE69, DPßDE55, 56 and DPßDE84, 85 were responsible for the -9 charge and the first two residues for the -7 charge. CONCLUSIONS: In the absence of DPßE69, DRßE71 is a risk factor for CBD and BeS. DPßE69 and DRßE71 are adjacent to other amino acids that are also negatively charged, suggesting that the positively charged Be²âº modifies the local environment of the epitopes in a way that promotes interactions between peptides and T cells and results in CBD. Finally, the protective effect of the DPB1*0201 positive haplotype may involve particular polymorphisms outside of the DPB1 gene.

HLA and environmental interactions in sarcoidosis.

Sarcoidosis is a systemic granulomatosis of unknown etiology despite being described over 100 years ago. While both genetic predisposition and environmental exposures have been proposed as playing a role in this disease, there have not been any systematic investigations of gene-environmental interaction in this disease. In the ACCESS dataset, detailed environmental histories and high resolution HLA class II typing were performed on 476 cases of newly diagnosed sarcoidosis and 476 matched controls from the patients' community. We evaluated gene-environmental interactions in exposures or HLA class II alleles that were present in > 5% of the population and had an odd ratio of > 1.0. Four exposures and four HLA Class II alleles met these criteria and were evaluated. Significant interaction was observed between HLA DRB1*1101 and insecticide exposure at work (p < 0.10) and suggestive interaction was observed between HLA DRB1*1101 and exposure to mold and musty odors and DRB1*1501 and insecticide exposure at work (P < 0.15). In addition, HLA DRB1*1101 and insecticide exposure at work was associated with extrapulmonary sarcoidosis, specifically cardiac sarcoidosis and hypercalcemia (p<0.05) and HLA DRB1*1101 and exposure to molds and musty odors was associated with pulmonary only sarcoidosis (P < 0.05). These studies suggest that sarcoidosis is due to an interaction of genetic predisposition and environmental exposure in at least some cases of sarcoidosis. Future studies in defined phenotypes of sarcoidosis may be necessary to define environmental and genetic associations with sarcoidosis.

Decontamination of beef subprimal cuts intended for blade tenderization or moisture enhancement.

The prevalence of Escherichia coli O157:H7 on beef subprimal cuts intended for mechanical tenderization was evaluated. This evaluation was followed by the assessment of five antimicrobial interventions at minimizing the risk of transferring E. coli O157:H7 to the interior of inoculated subprimal cuts during blade tenderization (BT) or moisture enhancement (ME). Prevalence of E. coli O157:H7 on 1,014 uninoculated beef subprimals collected from six packing facilities was 0.2%. Outside round pieces inoculated with E. coli O157:H7 at 10(4) CFU/100 cm2 were treated with (i) no intervention, (ii) surface trimming, (iii) hot water (82 degrees C), (iv) warm 2.5% lactic acid (55 degrees C), (v) warm 5.0% lactic acid (55 degrees C), or (vi) 2% activated lactoferrin followed by warm 5.0% lactic acid (55 degrees C) and then submitted to BT or ME. Prevalence (n=196) of internalized (BT and ME) E. coli O157:H7 was 99%. Enumeration of E. coli 0157:H7 (n=192) revealed mean surface reductions of 0.93 to 1.10 log CFU/100 cm2 for all antimicrobial interventions. E. coli O157:H7 was detected on 3 of the 76 internal BT samples and 73 of the 76 internal ME samples. Internal ME samples with no intervention had significantly higher mean E. coli O157:H7 populations than did those internal samples treated with an intervention, but there were no significant differences in E. coli O157:H7 populations among internal BT samples. Results of this study demonstrate that the incidence of E. coli O157:H7 on the surface of beef subprimal cuts is low and that interventions applied before mechanical tenderization can effectively reduce the transfer of low concentrations of E. coli O157:H7 to the interior of beef subprimal cuts.

Fecal prevalence of Escherichia coli O157, Salmonella, Listeria, and Bacteriophage Infecting E. coli O157:H7 in feedlot cattle in the Southern Plains region of the United States.

Escherichia coli O157:H7, Salmonella, and Listeria are foodborne pathogens of critical importance that often colonize cattle. E. coli O157:H7 can be specifically killed by lytic bacteriophage, and lytic bacteriophage treatment has been suggested as a pre-harvest intervention strategy to reduce foodborne pathogens in cattle. To date, no systematic approach to determine the incidence of E. coli O157:H7-infecting lytic bacteriophage has been published. Therefore, the current study was designed to determine (1) the incidence of E. coli O157, Salmonella spp., and Listeria and (2) the incidence of E. coli O157:H7-infecting bacteriophage in the feces of feedlot steers in commercial feedlots in the United States. Fecal samples (n=60) were collected from four feedlots in two Southern Great Plains states (total (n=240 fecal samples). Salmonella and E. coli O157:H7 were found in 3.8% and 11.7% of the fecal samples, respectively. Bacteriophage targeting E. coli O157:H7 were found in all four feedlots, in 15% of the individual fecal samples, and in 55% of the cattle pens. Our results indicate that such bacteriophage are widespread in feedlot cattle, suggesting that further research into the ecological role of bacteriophage in the gastrointestinal tract is needed.

Presenting characteristics as predictors of duration of treatment in sarcoidosis.

BACKGROUND: Some sarcoidosis patients never need therapy, but many still require therapy more than 2 years after initial diagnosis. AIM: To determine what features at initial presentation are associated with treatment 2 years later. METHODS: Patients with biopsy-confirmed sarcoidosis enrolled in the ACCESS (A Case Control Etiologic Study of Sarcoidosis) study were initially evaluated within 6 months of diagnosis. Pulmonary function, chest X-ray and dyspnoea score were measured, and systemic therapy for the sarcoidosis recorded. Organ involvement was assessed using a standardized instrument. A subset (n = 215) were seen 18-24 months later for follow-up, and these patients constitute our study group. RESULTS: Ten patients had only received therapy before the first visit, with no further therapy, and were excluded from analysis. Of the remaining 205, 95 were not on therapy at the initial visit and 75 (79%) of these were never treated during follow-up. Of the 110 initially on therapy, 52 (47%) remained on therapy at follow-up. Other initial features associated with continued therapy were the level of dyspnoea and predicted vital capacity. On logistic regression, only dyspnoea and therapy at initial visit remained significant. Patients on systemic therapy at initial evaluation were more likely to be on therapy at follow-up (OR 3.6, p = 0.003). Neither ethnicity nor gender independently predicted therapy at follow-up. DISCUSSION: This study group represents a sample of newly diagnosed sarcoidosis patients. However, this is a referral population, and there was no set protocol for treatment. Use of systemic therapy within the first 6 months after diagnosis appears to be strongly associated with continued use of therapy 2 years later.

Role of curli fimbriae in mediating the cells of enterohaemorrhagic Escherichia coli to attach to abiotic surfaces.

AIMS: The objectives of this study were to evaluate the role of curli in assisting the cells of enterohaemorrhagic Escherichia coli (EHEC) in attaching to abiotic surfaces and to determine the influence of cell-surface contact time on the efficiency of the attachment. METHODS AND RESULTS: Three pairs of EHEC cultures, each with a curli-expressing and a noncurli-expressing variant (O111:H- 7-57C+ and O157:H7 5-9C-, O157:H7 5-11C+ and 5-11C-, as well as O103:H2 7-52C+ and 7-52C-), were allowed to interact with polystyrene, glass, stainless steel and rubber surfaces at 28 degrees C for 24 h (short-term attachment) or 7 days (long-term attachment). The quantities of the cells that attached to the surfaces were measured daily in the long-term attachment study, and in 4 h intervals in the short-term attachment study. Quantification of the cells that attached to the surfaces was accomplished with a crystal violet binding assay. The results of the long-term attachment study indicated that 7-57C+ attached to the polystyrene and glass surfaces more efficiently (P < 0.05) than did 5-9C-. The curli-expressing variant of 5-11 possessed a better ability to adhere to the polystyrene and glass surfaces than did its noncurli-expressing counterpart (P < 0.05). The differences in attachment between 7-52C+ and 7-52C- on polystyrene and stainless steel surfaces were statistically significant (P < 0.05). However, the attachment of the pair on the glass surfaces was statistically insignificant (P > 0.05). In addition, the two members of all three EHEC pairs attached equally well to rubber surfaces (P > 0.05). In the short-term attachment study, only the pair of 7-52 attached differently on glass and stainless steel surfaces (P < 0.05). CONCLUSIONS: These results suggest that curli could be an important cell surface component to mediate the attachment of some EHEC cells to certain abiotic surfaces. Cell-surface contact time could have a significant influence on EHEC attachment to abiotic surfaces. SIGNIFICANCE AND IMPACT OF THE STUDY: The study signifies a possible role of curli in assisting the cells of EHEC in attaching to food-contact surfaces. It underlines the importance of cleaning and sanitizing food-contact surfaces regularly and thoroughly, and of identifying chemical agents that can effectively remove the attached EHEC cells from these surfaces.

Genome-wide search for sarcoidosis susceptibility genes in African Americans.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman-Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.

Clinical characteristics of patients in a case control study of sarcoidosis.

Sarcoidosis may be affected by sex, race, and age. A Case Control Etiologic Study of Sarcoidosis (ACCESS) enrolled 736 patients with sarcoidosis within 6 mo of diagnosis from 10 clinical centers in the United States. Using the ACCESS sarcoidosis assessment system, we determined organ involvement for the whole group and for subgroups differentiated by sex, race, and age (less than 40 yr or 40 yr and older). The study population was heterogeneous in terms of race (53% white, 44% black), sex (64% female, 36% male), and age (46% < 40 yr old, 54% > or = 40 yr old). Women were more likely to have eye and neurologic involvement (chi(2) = 4.74, p < 0.05 and chi(2) = 4.60, p < 0.05 respectively), have erythema nodosum (chi(2) = 7.28, p < 0.01), and to be age 40 yr or over (chi(2) = 6.07, p < 0.02) whereas men were more likely to be hypercalcemic (chi(2) = 7.38, p < 0.01). Black subjects were more likely to have skin involvement other than erythema nodosum (chi(2) = 5.47, p < 0.05), and eye (chi(2) = 13.8, p < 0.0001), liver (chi(2) = 23.3, p < 0.0001), bone marrow (chi(2) = 18.8, p < 0.001), and extrathoracic lymph node involvement (chi(2) = 7.21, p < 0.01). We conclude that the initial presentation of sarcoidosis is related to sex, race, and age.

Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS).

Despite reports of familial clustering of sarcoidosis, little empirical evidence exists that disease risk in family members of sarcoidosis cases is greater than that in the general population. To address this question, we estimated sarcoidosis familial relative risk using data on disease occurrence in 10,862 first- and 17,047 second-degree relatives of 706 age, sex, race, and geographically matched cases and controls who participated in the multicenter ACCESS (A Case-Control Etiology Study of Sarcoidosis) study from 1996 to 1999. Familial relative risk estimates were calculated using a logistic regression technique that accounted for the dependence between relatives. Sibs had the highest relative risk (odds ratio [OR] = 5.8; 95% confidence interval [CI] = 2.1-15.9), followed by avuncular relationships (OR = 5.7; 95% CI = 1.6-20.7), grandparents (OR = 5.2; 95% CI = 1.5-18.0), and then parents (OR = 3.8; 95% CI = 1.2-11.3). In a multivariate model fit to the parents and sibs data, the familial relative risk adjusted for age, sex, relative class, and shared environment was 4.7 (95% CI = 2.3-9.7). White cases had a markedly higher familial relative risk compared with African-American cases (18.0 versus 2.8; p = 0.098). In summary, a significant elevated risk of sarcoidosis was observed among first- and second-degree relatives of sarcoidosis cases compared with relatives of matched control subjects.

Dual time point 18F-FDG PET imaging for differentiating malignant from inflammatory processes.

UNLABELLED: The aim of this study was to investigate the difference in the rates of FDG uptake between malignant and inflammatory cells and processes. IN VITRO STUDIES: (18)F-FDG uptake by different tumor cell lines (human mesothelioma [REN]; rat mesothelioma [II45]; mice melanoma [B18F10]; mice mesothelioma [AB12]; human myeloma [GM1500]; and human ovarian cancer [SKOV3]) and peripheral blood mononuclear cells isolated from 8 healthy human volunteers was measured 20 and 60 min after FDG was added into growth medium. Animal studies: II45 cells were implanted into the left flank of rats (n = 5) and a focal inflammatory reaction (mechanical irritation) was generated in the right flank. PET images at 45 and 90 min after injection of FDG were obtained and standardized uptake values (SUVs) were determined. Patient studies: Seventy-six patients who had dual time FDG PET scans were retrospectively analyzed. All results were expressed as the percentage change in SUV of the later time image from that of the earlier time (mean +/- SD). IN VITRO STUDIES: Except for the SKOV3 cell line, which had only minimally increased FDG uptake (+10% +/- 26%; P > 0.3), all other tumor cell lines tested showed significantly increased FDG uptake over time (GM1500, +59% +/- 19%; B18F10, +81% +/- 15%; AB12, 93% +/- 21%; II45, +161% +/- 21%; REN, +198% +/- 48%; P < 0.01 for all). By contrast, FDG uptake in mononuclear cells was decreased in 7 of 8 donors. Animal studies: SUVs of tumors from 90-min images were significantly higher than those from 45-min images (+18% +/- 8%; P < 0.01), whereas the SUVs of inflammatory lesions decreased over time (-17% +/- 13% of the early images; P < 0.05). CLINICAL STUDIES: The SUVs of delayed images from the known malignant lesions compared with those of earlier scans increased over time (+19.18% +/- 9.58%; n = 31; P < 0.001; 95% confidence interval, 15.8%-22.6%). By contrast, the SUVs of benign lung nodules decreased slightly over time (-6.3% +/- 8.1%; n = 12; P < 0.05; 95% confidence interval, -10.9% to -1.7%). The SUV of inflammatory lesions caused by radiation therapy (+1.16% +/- 7.23%; n = 8; P > 0.05; 95% confidence interval, -3.9%-6.2%) and the lesions of painful lower limb prostheses (+4.03% +/- 11.32%; n = 25; P > 0.05; 95% confidence interval, -0.4%-8.5%) remained stable over time. CONCLUSION: These preliminary data show that dual time imaging appears to be useful in distinguishing malignant from benign lesions. Further research is necessary to confirm these results.

Do high glucose levels have differential effect on FDG uptake in inflammatory and malignant disorders?

BACKGROUND: The association of hyperglycaemia with reduced fluorodeoxyglucose (FDG) uptake by tumour cells is well established. Therefore, it is standard practice that all patients must fast for at least several hours prior to FDG positron emission tomography (PET) imaging. However, the effect of hyperglycaemia on FDG uptake by inflammatory and infectious lesions is unknown. The aim of this study was to investigate this important issue. METHODS: For in vitro studies human mononuclear cells were isolated from 12 normal volunteers and FDG uptake was determined in medium containing differing concentrations of glucose. FDG uptake by human mesothelioma cells was also measured for comparison. For studies involving patients, 416 FDG PET scans of patients with confirmed malignancy (n=321) or benign lesions (n=95) were reviewed retrospectively. The relationship between serum glucose level and FDG uptake by the lesions was assessed utilizing the standardized uptake value (SUV) technique. RESULTS: In the in vitro studies, while FDG uptake by mesothelioma cells decreased as glucose concentration increased, there was no differential uptake of FDG uptake by mononuclear cells at glucose concentrations less than 250 mg x dl(-1). In clinical patients, FDG uptake by malignant lesions was slightly, but negatively affected by serum glucose level (r= -0.21, P<0.01) (glucose range 49-187 mg x dl(-1)). In contrast, FDG uptake by inflammatory lesions was positively associated with serum glucose level (r=0.43, P<0.01) (glucose range 54-215 mg x dl(-1)). DISCUSSION AND CONCLUSION: While the degree of FDG uptake is primarily influenced by the nature of the underlying lesion, serum glucose concentration appears to have a small effect on FDG uptake, which differs between malignant disorders and inflammatory processes. Our data suggest that below a certain level, elevated glucose concentration might not have a negative effect on FDG uptake in inflammatory cells, contrary to that observed in malignant disorders.

Chronic beryllium disease: a hypersensitivity disorder.

Chronic beryllium disease (CBD) is one of two pulmonary syndromes caused by environmental exposure to beryllium. Acute beryllium disease was first described in 1943 and is an acute toxic reaction to beryllium. CBD was first described in 1946 and the pathogenesis of this disorder was not fully appreciated until the development of fiberoptic bronchoscopy allowed sampling of bronchoalveolar lung cells. Because CBD was associated with a delayed skin test reaction to beryllium, occurred in only 1-5 percent of individuals, was not associated with a clear-cut dose-response curve, and was associated with a granulomatous reaction, a hypersensitivity to beryllium was suspected as the cause. The hypothesis that CBD was due to hypersensitivity was not proven until the 1980s when samples of bronchoalveolar cells obtained by bronchoscopy demonstrated that not only did every individual with CBD have lymphocytes that could respond to beryllium (lymphocyte proliferation assay), but, also, that there was an accumulation of these cells at the site of active disease. The immunological reaction in CBD was associated with CD4+ lymphocytes responding to a beryllium-influenced but unknown peptide(s) that was (were) presented by HLA molecules on antigen-presenting cells. Genetic studies also demonstrated an association of CBD with HLA-DPB1 alleles that contain glutamine at position 69 in up to 97 percent of subjects with CBD but also 30-40 percent of controls. The understanding that CBD is a hypersensitivity disorder has had important implications for the diagnosis, screening, and environmental control precautions necessary for its prevention.

Depression in sarcoidosis.

Sarcoidosis, a chronic, multisystem disease, impacts quality of life and may increase depression risk. No previous study has reported the depression prevalence among U.S. sarcoid patients. This cross-sectional study examined sociodemographic and disease morbidity factors associated with depression. Patients diagnosed for > or = 1 yr and treated at one of six centers were eligible (n = 176); 154 completed a questionnaire of demographics, treatment, access to medical care, and a short-form Center for Epidemiologic Studies- Depression Scale (CES-D). The primary outcome variable was a CES-D score of > or = 9, indicating clinical depression. The prevalence of depression was 60%. Gender, income, access to medical care, dyspnea on exertion, and number of systems involved were associated with depression. Female sex, decreased access to medical care, and increased dyspnea predicted depression (odds ratio [OR] = 3.33, 11.64, and 2.78, respectively) after adjusting for race, income, and steroid therapy. Despite tertiary care access, patients reported medical care limitation. Health care providers must be sensitive to multiple barriers faced by chronic sarcoid patients; acknowledging depression risk and improving access to medical care will promote better overall health among sarcoid patients. Future studies of sarcoidosis will need to address depression diagnosis and treatment.

Beryllium, an adjuvant that promotes gamma interferon production.

Beryllium is associated with a human pulmonary granulomatosis characterized by an accumulation of CD4(+) T cells in the lungs and a heightened specific lymphocyte proliferative response to beryllium (Be) with gamma interferon (IFN-gamma) release (i.e., a T helper 1 [Th1] response). While an animal model of Be sensitization is not currently available, Be has exhibited adjuvant effects in animals. The effects of Be on BALB/c mice immunized with soluble leishmanial antigens (SLA) were investigated to determine if Be had adjuvant activity for IFN-gamma production, an indicator of the Th1 response. In this strain of Leishmania-susceptible BALB/c mice, a Th2 response is normally observed after in vivo SLA sensitization and in vitro restimulation with SLA. If interleukin-12 (IL-12) is given during in vivo sensitization with SLA, markedly increased IFN-gamma production and decreased IL-4 production are detected. We show here that when beryllium sulfate (BeSO(4)) was added during in vivo sensitization of BALB/c mice with SLA and IL-12, significantly increased IFN-gamma production and decreased IL-4 production from lymph node and spleen cells were detected upon in vitro SLA restimulation. No specific responses were observed to Be alone. Lymph node and spleen cells from all mice proliferated strongly and comparably upon in vitro restimulation with SLA and with SLA plus Be; no differences were noted among groups of mice that received different immunization regimens. In vivo, when Be was added to SLA and IL-12 for sensitization of BALB/c mice, more effective control of Leishmania infection was achieved. This finding has implications for understanding not only the development of granulomatous reactions but also the potential for developing Be as a vaccine adjuvant.