Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium

While tobacco smoke has been conclusively identified as a lung carcinogen, there is much debate over which smoke constituent(s) are primarily responsible for its carcinogenicity. Previous studies in our laboratory suggested that highly lipophilic carcinogens are slowly absorbed in the thicker epithelium of the conducting airways, potentially allowing for substantial local metabolism. The bioactivation of polycyclic aromatic hydrocarbons in airway epithelium may, hence, be important in tobacco smoke-induced carcinogenesis. In the present study, the hypothesis of slow absorption and substantial local metabolic activation of highly lipophilic carcinogen in airway epithelium was tested in dogs. A single dose of tritiated benzo[a]pyrene (BaP) dissolved in a saline/phospholipid suspension was instilled in the trachea, just anterior to the carina. At intervals of a few minutes up to 30 min over a 3-h period, blood samples were drawn from the azygous vein, which drains the area around the point of instillation, and from the systemic circulation. Tissue samples were taken at the end of the experiment. The concentration of BaP with depth into the tracheal mucosa was determined with autoradiography. BaP was slowly absorbed into the trachea with a half-time of approximately 73 min, which is consistent with diffusion-limited passage through the epithelium and lead to local doses in the tracheal epithelium that were more than a 1000-fold those of other tissues. The long retention of BaP in the epithelium provided the local metabolizing enzymes with high substrate levels over a long period, resulting in extensive metabolism. At 3 h after the exposure, 23% of the BaP-equivalent activity remained in the tracheal mucosa. Of this fraction, 13% was parent compound, 28% was organic extractable, 31% was water-soluble, and 28-7% of the instilled dose was bound to tracheal tissues. These results explain the tendency of highly lipophilic carcinogens, such as BaP, to induce tumors at the site of entry and, furthermore, indicate that the highly lipophilic components of tobacco smoke and polluted air may be the most important contributors to lung tumors of the conducting airways.      

Need for follow up in coeliac disease

The use of follow up studies was evaluated in 128 patients with coeliac disease during their first visit to a department for adults. The original diagnosis had been made in childhood in all patients. Fifty eight (45%) of the subjects were following a gluten free diet, 23 (18%) were following a gluten free diet but with occasional gluten consumption, and 47 (37%) had adopted an unrestricted, gluten containing diet for a mean of 11.2 years. There was no correlation in individual subjects between the presence of symptoms, biochemical and immunological abnormalities, severity of histological findings, and the amount of dietary gluten, despite the greater frequency of symptoms in the group following an unrestricted diet than in the other two groups. Short stature and epilepsy with cerebral calcifications only occurred in patients following an unrestricted diet. As only diagnosis based on two or three biopsy samples and regular follow up correlated positively with dietary compliance, it is suggested that a histologically confirmed diagnosis of coeliac disease and regular lifelong follow up are essential in the management of these patients.     

Elderly Patients with Suppressed Serum TSH but Normal Free Thyroid Hormone Levels Usually Have Mild Thyroid Overactivity and are at Increased Risk of Developing Overt Hyperthyroidism

The clinical and biochemical characteristics of 15 elderly patientswith low levels of thyrotrophin (TSH) (<0.1 mU/L) but normalfree tri-iodothyronine, (T3) and free thyroxine (T4) (groupS) were compared with 10 euthyroid subjects (group E) and 10hyperthyroid patients (group T). Free T3 and free T4 were significantlyhigher (p<0.05) in group S(6.3±0.5 and 18.6±1.0pmol/l, respectively) than in group E(4.6±0.3, 12.6+0.6).In common with elderly hyperthyroid patients (group T)patientsin group S had few signs or symptoms of thyrotoxocosis, butthe Wayne score (clinical index of hyperthyroidism) was higherin group S than in euthyroid subjects (p<0.05). Thyroid microsomal,thyrogolobulin or thyrotrophin receptor antibodies were commonin group T (n=9)but not in groups S(n=2) or E(n=1). This suggestsa low prevalence of Graves' disease in group S compared to groupT. Combined thyrotrophin releasing hormone (TRH; 200 µgi.v.) and gonadotrophin releasing hormone GnRH; 100 µgi.v.) tests were performed; no cases of low TSH due to hypopituitarismwere identified in group S. During a mean of 7.9 (4–12)months of observation TSH reverted to the normal range (>0.2mU/L)in 7 of 15 patients in group S; thyroid hormone concentrationsrose above the normal range in four, however, only two patientsrequired treatment for hyperthyroidism. It is unlikely thatthe suppressed TSH of patients in group S was due to mild thyroidhormone excess; although this is often a transitory phenomenon,these patients are at increased risk of developing overt hyperthyroidism.     

Concentrations of hypoxanthine, xanthine, uridine and urate in amniotic fluid at caesarean section and the association of raised levels with prenatal risk factors and fetal distress

Samples of amniotic fluid were obtained at caesarean section from 33 of 80 consecutive unselected patients in whom the membranes were intact. Concentrations of the ATP metabolites, hypoxanthine and xanthine, as well as uridine and urate were determined using high pressure liquid chromatography. Independent 'clinical' factors associated with reduced fetal growth and well-being were identified and the patients were assigned to one of three groups: those with no recognized risk, those with moderate risk and a small group of four patients with high risk. The mean hypoxanthine concentration was higher in the moderate-risk group than in the group with no risk. Two of the three patients with proteinuric hypertension in the high-risk group had normal hypoxanthine concentrations. There were seven patients with fetal distress, and concentrations of hypoxanthine, xanthine, uridine and urate were significantly higher in the three patients who had meconium stained amniotic fluid in addition to abnormal fetal heart rate tracings than in the remaining four who had fetal heart rate abnormalities only. It is suggested that fetal distress at emergency caesarean sections might be quantitated by such analysis.     

Studies on avian erythrocyte metabolism. VII. Effect of inositol pentaphosphate and other organic phosphates on oxygen affinity of the embryonic and adult-type hemoglobins of the turkey embryo.

The effects of 2, 3-diphosphoglyceric acid (2, 3-DPG), adenosine triphosphate (ATP), inositol tetraphosphate (ITP), inositol pentaphosphate (IPP), and inositol hexaphosphate (IHP) on oxygen affinity of whole stripped hemoglobin (WSH), hemoglobin H (Hb-H; hatching hemoglobin), hemoglobin A (Hb-A), and hemoglobin D (Hb-D) isolated from erythrocytes (RBC) of the 25-day turkey embryo have been studied. The order of the decrease in oxygen affinity induced by these organic phosphates, at molar ratios of phosphate compound to hemoglobin (tetramer) between 2 and 4, is 2, 3-DPG less than ATP less than ITP less than IPP less than IHP. 2, 3-DPG shows a slightly greater effect on reducing oxygen affinity of Hb-H than on either adult-type hemoglobin. The effect of IPP upon lowering the oxygen affinity of either WSH, Hb-H, Hb-A, or Hb-D is approximately 20 percent less than IHP. The effects of the various organic phosphates upon the Hill constant, n, of these purified hemoglobins is variable but appears to reach a maximum when the molar ratio of organic phosphate to hemoglobin (tetramer) is 2 or greater. None of the physiologically occurring organic phosphates has a significant preferential interaction with any specific hemoglobin. These experiments strengthen and support our earlier conclusion, that the changes in whole blood oxygen affinity which occur during avian development result from the changes in composition of the intraerythrocytic organic phosphates.