Insulin- and exercise-stimulated skeletal muscle blood flow and glucose uptake in obese men

OBJECTIVE: Insulin resistance in obese subjects results in the impaired use of glucose by insulin-sensitive tissues, e.g., skeletal muscle. In the present study, we determined whether insulin resistance in obesity is associated with an impaired ability of exercise to stimulate muscle blood flow, oxygen delivery, or glucose uptake. RESEARCH METHODS AND PROCEDURES: Nine obese (body mass index = 36 +/- 2 kg/m(2)) and 11 age-matched nonobese men (body mass index = 22 +/- 1 kg/m(2)) performed one-legged isometric exercise during hyperinsulinemia. Rates of femoral muscle blood flow, oxygen consumption, and glucose uptake were measured simultaneously in both legs using [(15)O]H(2)O, [(15)O]O(2), [(18)F]fluoro-deoxy-glucose, and positron emission tomography. RESULTS: The obese subjects exhibited resistance to insulin stimulation of glucose uptake in resting muscle, regardless of whether glucose uptake was expressed per kilogram of femoral muscle mass (p = 0.001) or per the total mass of quadriceps femoris muscle. At similar workloads, oxygen consumption, blood flow, and glucose uptake were lower in the obese than the nonobese subjects when expressed per kilogram of muscle, but similar when expressed per quadriceps femoris muscle mass. DISCUSSION: We conclude that obesity is characterized by insulin resistance of glucose uptake in resting skeletal muscle regardless of how glucose uptake is expressed. When compared with nonobese individuals at similar absolute workloads and under identical hyperinsulinemic conditions, the ability of exercise to increase muscle oxygen uptake, blood flow, and glucose uptake per muscle mass is blunted in obese insulin-resistant subjects. However, these defects are compensated for by an increase in muscle mass.     

Occupational exposures and gastrointestinal cancers among Finnish women

A cohort including all female workers born 1906 through 1945 (n = 413,877) in Finland was identified through the Population Census of Finland of 1970. Incident cases of cancers of the gastrointestinal tract were explored during 1971 to 1995. Job titles in census records were converted to exposures of 31 occupational agents through a job-exposure matrix. For each agent, the product of level and probability of exposures was calculated and subdivided in three categories: zero, low and medium/high. Poisson regression models estimated relative risks (RR) for each agent, standardized for birth cohort, follow-up period, and socioeconomic status. Adjustment at job title level was done for alcohol use for cancers of the esophagus and liver and smoking for pancreatic cancer. The results showing either statistically significant RR at the medium/high level of exposure (RRH) or statistically significant trend (P < 0.05) over the exposure categories were considered as positive findings. Colon cancer risk (2009 cases) was positively associated with sedentary work (RRH 1.3, 95% CI = 1.1-1.6; P trend 0.001) and negatively associated with perceived workload (P trend = 0.007). For stomach cancer (1881 cases), we observed an association with exposure to electromagnetic fields (RRH 1.44, 95% CI = 1.01-2.05) and man-made vitreous fibers (MMVF) (p trend 0.03). Rectal cancer (1323 cases) showed an association with chromium (RRH 1.9, 95% CI = 1.2-3.1) and oil mist (RR 2.0; 95% CI = 1.0-3.9). For pancreas cancer (1302 cases) we found associations with exposure to chromium (RRH 1.8; 95% CI = 1.0-3.1; P trend 0.01), electromagnetic fields (RRH 1.8; 95% CI = 1.2-2.8; P trend 0.02), and sedentary work (RRH 1.3; 95% CI = 1.0-1.7; P trend 0.05). We found no significant associations between any FINJEM agents and cancers of the esophagus (389 cases), liver (389 cases), and gallbladder (651 cases). Having examined the associations between seven cancer sites and over 30 exposures there exists the real possibility that some of the associations detected are chance findings. Therefore, the associations observed should need to be confirmed in other studies.     

Use of biomarkers in risk assessment.

The systematic development and application of biomarkers in environmental health risk assessment is a relatively new field. At first, the major interest was in biomarkers of exposure, borrowing concepts from pharmacology, then it moved from the external estimates of exposure to internal measures of dose, and ultimately, to markers of target dose. While these markers provide evidence of exposures, they do not provide evidence of that toxicological damage has occurred. For this reason, measurements of DNA adducts and protein adducts are of interest, since they may provide bridges between exposures and disease end-points. In parallel, more quantitative and more sensitive end-points for diseases have been sought. Again, with advancing techniques in cytogenetics, extensive studies were conducted on such markers as chromosomal aberrations, micronuclei and other changes deemed to represent genomic damage. However, these types of end-points are quite unspecific for application to new hazards of uncertain human toxic (carcinogenic) potential. Recent work focusing on more specific early-effect markers such as certain oncogenes and tumour-suppressor genes have substantial promise as shown by work with aflatoxins and vinyl chloride. Such studies have also enhanced mechanistic insight. The advances in molecular genetics have led to an upsurge in interest in most susceptibility factors, and identification of polymorphisms of various enzymes has become possible. Ongoing search for "ultra-high risk" individuals may be fruitful, but probably only relevant to a small segment of potentially exposed populations. Factors associated with a small differential risk, however theoretically or mechanistically important, offer only little practical use.     

Occupational exposures and cancers of the endometrium and cervix uteri in Finland

BACKGROUND: Endometrial cancer incidence rates are low in Asia and Africa and high in North America and Northern Europe. Cervical cancer is often the most common female cancer in developing countries, and infection with human papillomavirus (HPV) is its main risk factor. However, other factors, such as occupational exposures may modify the HPV-related risk. We conducted an exploratory register-linkage study in Finland to assess the role of occupational exposures on incidence rates of cancers of the endometrium and cervix uteri. METHODS: Occupational risk factors for endometrial and cervical cancers were explored in a 25-year follow-up of female workers born 1906-1945 (N = 413,877) identified through the Population Census of Finland of 1970. Job titles in census records were converted to exposures of 31 occupational agents through a job-exposure matrix. Poisson regression models estimated relative risks (RR) for each agent, standardized for birth cohort, follow-up period, and socio-economic status. For each agent, the product of level and probability of exposure was calculated and subdivided in three categories: zero, low, and medium/high. Adjustment at the job title level was done for the turnover rate (endometrial and cervical cancers), mean parity, and age at first birth (endometrial cancer). RESULTS: Endometrial cancer (2,833 cases) was associated with exposure to animal dust (RR 1.2, low level, 174 cases) and sedentary work (RR 1.3, high level, 145 cases). Cervical cancer (1,101 cases) was associated with exposure to aliphatic and alicyclic (RR 1.3, low level, 91 cases), aromatic (RR 1.2, low level, 318 cases; RR 1.4, high level, 41 cases), and chlorinated hydrocarbon solvents (RR 1.3, low level, 50 cases), silica dust (RR 1.2, low level, 251 cases), and wood dust (RR 1.2, low level, 249 cases). CONCLUSIONS: This study suggests that occupational exposures may be associated with increased risk of endometrial and cervical cancers.     

Antigliadin IgE--indicator of wheat allergy in atopic dermatitis

BACKGROUND: Cereal grains are recognized as the cause of adverse reactions in some patients exposed to grain or flour by either inhalation or ingestion. Cereal-related diseases, such as celiac disease and baker's asthma, have been well studied and the causative cereal proteins have been characterized. Although cereals form an essential part of daily nutrition, the allergenic proteins causing symptoms on ingestion in atopic dermatitis (AD) have remained obscure. In this study, we have investigated the allergenic fraction of wheat in AD. METHODS: Skin prick tests (SPT) with a NaCl wheat suspension and the ethanol-soluble wheat gliadin were performed on 18 wheat-challenge-positive or -negative children with AD, six adult AD patients with suspected cereal allergy, and one adult with wheat-dependent exercise-induced urticaria/anaphylaxis. Serum total IgE and specific IgE-antibody levels to wheat and gluten were measured with the radioallergosorbent test (RAST) simultaneously. In addition serum samples of all 25 patients were analyzed by IgE immunoblotting with the ethanol-soluble wheat-protein extract. RESULTS: Thirteen of the AD children were wheat-challenge-positive, 11/12 of them appeared to be positive with gliadin SPT, and all had an elevated gluten RAST value. Those challenge-negative were negative with both gliadin SPT and gluten RAST. Positive wheat SPT and RAST alone were not associated with positive challenges. Four of the adult patients responded to a cereal-free diet, although only two of them appeared to be positive with gliadin SPT and gluten RAST. A broad and intensive staining of gliadin peptides in IgE-immunoblotting studies was seen in challenge-positive children with positive gliadin SPT and/ or gluten RAST. Besides staining of peptides in the main gliadin area of 30-46 kDa, a characteristic finding was the staining of small, <14-kDa proteins with sera of challenge- and gliadin-SPT-positive patients. CONCLUSIONS: We found that wheat-allergic AD patients have IgE antibodies against gliadin that can be detected by both SPT and the sensitive immunoblotting method. This suggests that gliadin peptides are important allergens, and ingestion of wheat causes symptoms of AD. A broad and intensive IgE staining was seen of gliadin peptides against both the previously characterized peptides in the main gliadin area and small, previously uncharacterized peptides of less than 14 kDa. The gliadin SPT and gluten RAST are good screening methods. Further characterization of the IgE-stained gliadin proteins is needed.     

Quantification of T-cell progenitors during ontogeny: thymus colonization depends on blood delivery of progenitors

An in vivo thymus reconstitution assay based on intrathymic injection of hematopoietic progenitors into irradiated chicks was used to determine the number of T-cell progenitors in peripheral blood, paraaortic foci, bone marrow (BM), and spleen during ontogeny. This study allowed us to analyze the regulation of thymus colonization occurring in three waves during embryogenesis. It confirmed that progenitors of the first wave of thymus colonization originate from the paraaortic foci, whereas progenitors of the second and the third waves originate from the BM. The analysis of the number of T-cell progenitors indicates that each wave of thymus colonization is correlated with a peak number of T-cell progenitors in peripheral blood, whereas they are almost absent during the periods defined as refractory for colonization. Moreover, injection of T-cell progenitors into the blood circulation showed that they homed into the thymus without delay during the refractory periods. Thus, thymus colonization kinetics depend mainly on the blood delivery of T-cell progenitors during embryogenesis.     

Mechanisms of transplantation tolerance in B-cell-chimeric chickens. Impairment of tolerance by T cell growth factor

Transplantation tolerance was induced in cyclophosphamide-treated, B-cell-depleted chickens by transfer of allogeneic bursal cells. To study the presence of specific suppressor cells in tolerant birds, mitomycin-C-treated peripheral blood lymphocytes (PBL) from tolerant recipients were cocultured in mixed lymphocyte cultures of normal syngeneic responder and allogeneic stimulator cells. No evidence of suppression was detected, since responses in cultures with tolerant cocultured cells were on the same level as the mixed lymphocyte reaction (MLR) of normal responders without cocultured cells. However, responses in cultures with normal cocultured cells were significantly higher. If cocultured cells were not treated with mitomycin C, responses to tolerizing alloantigen were equally high in cultures with tolerant cocultured cells as in cultures with normal cocultured cells. Likewise, when lymphocytes from tolerant chickens were mixed with normal syngeneic cells in graft-versus-host (GVH) splenomegaly assay, no suppression was detected, but the GVH reaction was even stronger than the reaction induced by the mixture of cells from two normal chickens. Furthermore, administration of chicken T cell growth factor (TCGF) into the cultures enhanced considerably the MLR of tolerant cells against the tolerizing alloantigen, but not against syngeneic or third-party stimulator cells. These results indicate that the transplantation tolerance in B-cell-chimeric chickens is due to lack of alloantigen-specific helper cells. When exogenous help is offered to tolerant cells either by normal syngeneic cells or by exogenous TCGF, the reactivity of tolerant cells against the tolerogen is reestablished.     

Carcinogenic properties of pharmaceutical agents evaluated in the IARC Monographs programme

Almost 200 pharmaceutical chemicals and groups of drugs have been evaluated for their carcinogenic properties by working groups convened by the International Agency for the Research on Cancer. Therapeutic agents are exceptional environmental carcinogens in that humans are exposed to relatively pure substances at well-defined dosages. Of those evaluated, 20 are conclusively carcinogenic to humans and 52 are probably or possibly carcinogenic. The human tissues most often affected are bone marrow, skin, urinary bladder, liver, lymphatic tissue and endometrium. In cases in which there is sufficient evidence for carcinogenicity from both epidemiological and experimental studies, the similarity between humans and animals with regard to the target organs involved is close (85%). Since data on carcinogenicity exist for several groups of pharmaceuticals, risk versus benefit evaluations should be made carefully in relation to possible clinical applications.