Technological innovation of Continuous Glucose Monitoring (CGM) as a tool for commercial aviation pilots with insulin-treated diabetes and stakeholders/regulators: A new chance to improve the directives?

Civil aviation pilots who develop insulin-treated diabetes and want to renew a Commercial Pilot License (CPL) represent a medical, social and regulatory problem. This depends on justified concerns about hypoglycemia, the most threatening event for people who carry out jobs requiring a high level of concentration and reliability. This negatively affects social and working aspects of pilots' lives, who have a high profile and a high-cost professional qualification. It could be possible now to revise this attitude thanks to the availability of Continuous Glucose Monitoring (CGM) devices. CGM clearly showed to prevent hypoglycemic events in insulin-treated diabetic patients by allowing strict monitoring and trend prediction of glucose levels. By systematizing available data on such devices and present regulations in CPL issuance worldwide, our review can be used as handy tool for a fruitful discussion among the scientific community, national and international civil aviation regulators, stakeholders and pilots, aimed at evaluating the evidence-based opportunity to revise CPL issuance criteria for insulin-treated diabetic pilots. For the above-mentioned reasons, there are, among the regulatory administrations of Civil Aviation around the globe, several different approaches and limitations set for the subjects with insulin-treated diabetes who want to obtain, or renew, a CPL.

Gastric emptying and intragastric balloon in obese patients.

BACKGROUND: Intragastric balloons have been proposed to induce weight loss in obese subjects. The consequences of the balloon on gastric physiology remain poorly studied. We studied the influence of an intragastric balloon on gastric emptying in obese patients. PATIENTS AND METHODS: 12 patients were included in the study, with BMI (mean +/- SD) of 38.51 +/- 4.32 kg/m2. The balloon was inserted under light anaesthesia and endoscopic control, inflated with 700 ml saline, and removed 6 months later. Body weight and gastric emptying (T1/2 and T lag) using 13C-octanoic acid breath test were monitored before balloon placement, during its permanence and 2 months after removal. RESULTS: Mean weight loss was: 6.2 +/- 2.3 kg after one month; 12.4 +/- 5.8 kg after 3 months; 14.4 +/- 6.6 kg after 6 months and 10.1 +/- 4.3 kg two months after BIB removal. Gastric emptying rates were significantly decreased in the first periods with balloon in place, and returned to pre-implantation values after balloon removal. T1/2 was: 87 +/- 32 min before BIB positioning, 181 +/- 91 min after 1 month, 145 +/- 99 min after 3 months, 104 +/- 50 min after 6 months and 90 +/- 43 min 2 months after removal. T lag was 36 +/- 18 min before BIB positioning, 102 +/- 82 min after 1 month, 77 +/- 53 min after 3 months, 59 +/- 28 min after 6 months and 40 +/- 21 min. 2 months after removal. CONCLUSIONS: BIB in obese patients seems to be a good help in following the hypo caloric diet, especially during the first three months when the gastric emptying is slower and the sense of repletion is higher. After this period gastric emptying starts to return to normal and the stomach adapts to BIB loosing efficacy in weight loss.

Differential expression of nuclear 11beta-hydroxysteroid dehydrogenase type 2 in mineralocorticoid receptor positive and negative tissues.

Corticosteroid hormone action is controlled at a pre-receptor level by the activity of two isoforms of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), catalyzing the interconversion of hormonally active cortisol to inactive cortisone. In particular 11beta-HSD2 protects the mineralocorticoid receptor (MR) from glucocorticoid excess, enabling aldosterone to interact with the MR. We have analyzed the subcellular localization of 11beta-HSD2 in relation to the expression of the MR in human colon and placenta. 3H-aldosterone binding studies confirmed expression of the MR in human colon but not term placental trophoblast. Enzyme activity studies and Western blot analyses carried out on subcellular fractions confirmed the presence of 11beta-HSD2 in microsomes. In colon, but not placenta, 11beta-HSD2 was also localized to the microsome-free, nuclear fraction. Protection upon the MR by 11beta-HSD2 in "classical" mineralocorticoid target tissues such as colon can be subserved at both a nuclear and extra-nuclear level. Tissue specific factors are responsible for the subcellular localization of 11beta-HSD2 and we postulate that one such factor may be the MR itself.

Immunodetection of 11 beta-hydroxysteroid dehydrogenase type 2 in human mineralocorticoid target tissues: evidence for nuclear localization.

11 beta-Hydroxysteroid dehydrogenase (11 beta HSI) is an enzyme complex responsible for the conversion of hormonally active cortisol to inactive cortisone; two isoforms of the enzyme have been cloned and characterized. Clinical observations from patients with the hypertensive syndrome apparent mineralocorticoid excess, recently explained on the basis of mutations in the human 11 beta HSD2 gene, suggest that it is the 11 beta HSD2 isoform that serves a vital role in dictating specificity upon the mineralocorticoid receptor (MR). We have raised a novel antibody in sheep against human 11 beta HSD2 using synthetic multiantigenic peptides and have examined the localization and subcellular distribution of 11 beta HSD2 in mineralocorticoid target tissues. The immunopurified antibody recognized a single band of approximately 44 kDa in placenta, trophoblast, and distal colon. In kidney tissue, two bands of approximately 44 and 48 kDa were consistently observed. No signal was seen in decidua, adrenal, or liver. Immunoperoxidase studies on the mineralocorticoid target tissues, kidney, colon, and parotid gland indicated positive staining in epithelial cells known to express the MR: respectively, renal collecting ducts, surface and crypt colonic epithelial cells, and parotid duct epithelial cells. No staining was seen in these tissues in other sites. The intracellular localization of 11 beta HSD2 in kidney and colon epithelial cells was addressed using confocal laser microscopy. Parallel measurements of 11 beta HSD2 and nuclear propidium iodide fluorescence on sections scanned through an optical section of approximately 0.1 micron indicated significant 11 beta HSD2 immunofluorescence in the nucleus. In human kidney, colon, and salivary gland, 11 beta HSD2 protects the MR from glucocorticoid excess in an autocrine fashion. Furthermore, within these tissues, 11 beta HSD2, which had been considered to be a microsomal enzyme, is also found in the nucleus, suggesting that the interaction between the MR and aldosterone or cortisol is in part a nuclear event.

TGF-beta 1 immunohistochemistry in goiter: comparison of patients with recurrence or no recurrence.

The aim of this work was to establish whether the immunohistochemical pattern for TGF-beta 1 in goiters that recur after thyroid surgery is different when compared with goiters that do not recur postoperatively. Twelve goiters, surgically removed by partial resection between 1977 and 1982, were studied. Ten years after surgery, 6 patients had recurrence of goiter or thyroid nodules (group 1); the others did not have any recurrence (group 2). The presence and location of TGF-beta 1 were evaluated a posteriori by immunohistochemistry in histological samples of the tissue that was removed. In each goiter specimen, 50 randomly selected subcapsular follicles were studied to evaluate the percentage of follicles negative or positive for TGF-beta 1 and the protein's intrathyrocyte location. In the slides of group 1, the percentage of TGF-beta 1-positive follicles was statistically (p < 0.01) greater (93.1%) than in group 2 (71.4%). No difference in the location of TGF-beta 1 was found. The authors found a greater percentage of positive follicles for the TGF-beta 1 protein in group 1 patients. In conclusion, TGF-beta 1 production in goiter is variable, time dependent, and may be a marker of active cellular proliferation due to chronic exposure to a goitrogen stimulus. Thus, the more TGF-beta 1 found, the more the cell is stimulated and, therefore, the greater the risk of relapse.

TGF beta 1 immunostaining patterns and locations in adenoma which later recurred.

To investigate whether the immunohistochemical pattern of TGF beta 1 may be a marker of relapse for adenomatous pathology, 18 follicular adenomas, surgically removed by hemithyroidectomy between 1977 and 1982, were studied. The adenomas were divided into two groups according to the presence (group 1, N = 9) or absence (group 2, N = 9) of nodules recurring in the residual thyroid tissue. The presence and location of TGF beta 1 were evaluated a posteriori by immunohistochemistry in the removed adenoma. Fifty randomly selected subcapsular follicles were studied in each adenoma in order to evaluate the percentage of positive follicles and TGF beta 1 intra-thyrocyte location. In adenoma of group 1, the percentage of positive follicles for TGF beta 1 was lower (80%) than in adenoma of group 2 (84%); this was, however, not statistically significant. The location of TGF beta 1 was mainly at the cell base of the epithelial cells in the microfollicles of group 1, but was dominant at the cell apex in group 2 (p < 0.01). In conclusion, adenoma recurrence is independent of TGF beta 1 production; it may be due to an abnormal TGF beta 1 regulation in response to hyperplasiogenic stimuli.

Apparent mineralocorticoid excess: type I and type II.

The syndrome of apparent mineralocorticoid excess (AME) is a heritable form of hypertension due to an inborn error of cortisol metabolism and is characterized by hypokalemia and low renin levels despite subnormal or normal levels of aldosterone and other known mineralocorticoids. The syndrome is attributable to congenital deficiency of the enzyme 11 beta-hydroxydehydrogenase (11 beta-HSD), which converts cortisol (F) to biologically inactive cortisone. This results in a prolonged half-life of F, which acts at the kidney level as a potent mineralocorticoid (MC). In fact, both F and aldosterone have similar affinities in vitro for type I MC receptor (MR), and 11 beta-HSD activity protects the MR in vivo from the higher circulating levels of F. The biochemical marker of this disorder is an increased ratio of tetrahydrocortisol (THF) + allo-THF/tetrahydrocortisone (THE) in the urine, which has been found in more than 20 patients described to date, together with evidence of a more general defect in steroid ring A reduction. Only a few cases (the so-called type II form) described in Italy differ from the classic form having a normal THF/THE ratio, but in both forms the ratio of free urinary F/E has recently been found to be similarly high. Dexamethasone is the treatment of choice but is often inadequate in long term control of high blood pressure. Acquired forms of AME are those consequent on abuse of licorice or carbenoxolone, which both inhibit 11 beta-HSD; the latter also inhibits the reverse 11-oxoreductase reaction leading to somewhat different abnormalities of urinary cortisol/cortisone. So far, two isoenzymes of 11 beta-HSD have been purified and cloned; 11 beta-HSD type 1 is NADP-dependent, abundant in liver, lung, and testis, and catalyzes both 11 beta-dehydrogenation and 11 beta-oxoreduction; no mutation in its gene was detected in patients with AME. A second NAD-dependent isoenzyme is present in kidney and placenta and catalyzes dehydrogenation only. Very recently (1995) two groups have independently demonstrated the presence of mutations in its gene, located in chromosome 16q22. New and co-workers found a point mutation in exon 6 of two affected siblings of an Iranian family, while White and co-workers in parallel studies showed point mutations or small deletions in both alleles in nine unrelated patients; importantly, expression studies showed minimal or absent activity for almost all the mutant sequences. No definite mutations have been so far identified in patients with AME type II. AME is thus the third single gene cause of human hypertension to be described, after glucocorticoid remediable aldosteronism in 1992 and Liddle's syndrome in 1994.

Enhanced expression of transforming growth factor beta1 in rat thyroid hyperplasia is thyrotropin induced and time dependent.

Forty-three 8-week-old male Wistar rats were studied to evaluate temporal changes of transforming growth factor beta1, (TGF-beta1) mRNA levels in thyroid tissue during pharmacologically induced goiter. Four rats were treated with purified bovine thyrotropin (TSH; Ambinon, 2 mU/day sc) for 7 days before being sacrificed. Thirty-one were treated with propylthiouracil (PTU), added to their drinking water at a concentration of 0.2 g%, and subsequently were sacrificed as follows: five after 1 week (PTU-1): five after 2 weeks (PTU-2); five after 4 weeks (PTU-4); five after 8 weeks (PTU-8); five after 12 weeks (PTU-12). In six rats, after 12 weeks of treatment. PTU was withdrawn for 2 months and subsequently started again in three rats which were sacrificed after 2 weeks (PTU-R); the remaining three rats were sacrificed without any further treatment (PTU-R control). Eight rats (control rats) were never treated and served as controls. After sacrifice, blood was drawn for determination of total thyroxine and the thyroid was excised and subdivided into two lobes. Northern analysis for TGF-beta1 was performed in one lobe. while histological and immunohistochemical studies were performed in the other lobe. Gene expression of TGF-beta1 was induced in TSH- and PTU-treated rats. In TSH-treated rats TGF-beta1 gene expression was less detectable than in PTU-treated rats, where it became evident after 2 weeks and remained through weeks 4-8. Gene expression of TGF-beta1 wits also seen in PTU-R rats, but not in the control and in the PTU-R control. Immunohistochemical analysis showed a different presence and location for the TGF-beta1 protein, which appears to be dependent on the time of exposure to mitogenic stimulus. In conclusion, TGF-beta1 is produced in response to both a direct (TSH by itself) and indirect (TSH induced by PTU-induced hypothyroidism) cellular proliferative stimulus and is not linked to an adaptative phenomenon secondary to hypothyroidism. The immunohistochemical location of TGF-beta1 within the thyrocytes is influenced by mitogen exposure time. A TGF-beta1 immunohistochemical evaluation may be important to define exposure time and activity of goitrogenic stimuli.

[Anti-microsomal, anti-thyroglobulin antibodies and thyroid stimulants in hyperthyroid subjects. Analysis of 315 patients followed-up for 3 years at a single medical center]. / Anticorpi anti micrsomi, anti tireoglobulina e tiroido stimolanti in soggetti ipertiroidei. Analisi di 315 pazienti seguiti per tre anni presso un unico centro medico.

The objective of the study was to evaluate the significance of the determination of antithyroid antibodies in hyperthyroid patients. Two-hundred-fifteen untreated Graves' hyperthyroid patients (active toxic diffuse goiter-TDG), 54 Plummer's hyperthyroid patients (focal hyperthyroidism) and 46 subjects with other forms of hyperthyroidism were studied. Serum levels of T4, T3, TSH, TSH receptor antibody (TRAb), microsomal antibody (TMAb), and thyroglobulin antibody (TGAb) were evaluated before starting treatment, at regular intervals during therapy, and during the follow-up period after therapy was withdrawn. The antibodies were positive in all patients with active and non-active TGD but positive in only two patients (3.7%) with focal hyperthyroidism. During the treatment interval, TRAb, TMAb and TGAb serum levels fell with a nadir in the 7th month of therapy. In particular, TRAb fell to normal levels in all patients who had basal levels less than 500 U/l (97.7% of the cases) while TMAb and TGAb remained positive. Relapses, following the completion of therapy, occurred in 20.4% after one year and in 33% after two years. Relapses were always linked to a new increase in TRAb. In conclusion, TRAb can be useful in the determination of early disease and in diagnosing remission. It did not appear useful as a prognostic indicator for relapse in individual patients.