Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness

OBJECTIVE: We tested the hypothesis that impaired tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 21 subjects with type 1 diabetes underwent a standardized insulin infusion protocol to produce a stepwise decrease in plasma glucose to 45-min plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum responses for adrenergic and neuroglycopenic symptoms, and counterregulatory hormones were determined. Patients were classified as hypoglycemia unaware if the initiation of adrenergic symptoms occurred at a plasma glucose level 2 SD below that of nondiabetic volunteers. beta-Adrenergic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above baseline (I25) in resting subjects. RESULTS: Subjects with type 1 diabetes and hypoglycemia unawareness experienced the onset of adrenergic symptoms at a lower plasma glucose level than did those with awareness (2.5+/-0.1 vs. 3.7+/-0.1 mmol/l, P < 0.001), whereas neuroglycopenic symptoms occurred at similar glucose levels (2.7+/-0.2 vs. 2.8+/- 0.1 mmol/l). The plasma glucose levels for counterregulatory hormone secretion (epinephrine 2.9+/-0.2 vs. 4.1+/-0.2 mmol/l; norepinephrine 2.7+/-0.1 vs. 3.2+/-0.2 mmol/l; cortisol 2.5+/-0.2 vs. 3.3+/-0.2 mmol/l, P < 0.01) were also lower in subjects with unawareness. The maximal epinephrine (1,954+/-486 vs. 5,332+/- 1,059 pmol/l, P < 0.01), norepinephrine (0.73 +/- 0.14 vs. 1.47+/-0.21 nmol/l, P = 0.04), and cortisol (276+/-110 vs. 579+/-83 nmol/l, P < 0.01) responses were reduced in the unaware group. I25 was greater in unaware subjects than in subjects without unawareness (1.5+/-0.3 vs. 0.8+/-0.2 microg), where I25 was not different from that of controls (0.8 +/-0.2 microg). CONCLUSIONS: We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced beta-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.     

1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosophodiesterase 4 for the treatment of asthma

Evaluation of a variety of PDE4 inhibitors in a series of cellular and in vivo assays suggested a strategy to improve the therapeutic index of PDE4 inhibitors by increasing their selectivity for the ability to inhibit PDE4 catalytic activity versus the ability to compete for high affinity [3H]rolipram-binding sites in the central nervous system. Use of this strategy led ultimately to the identification of cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyl ic acid (1, SB 207499, Ariflo), a potent second-generation inhibitor of PDE4 with a decreased potential for side effects versus the archetypic first generation inhibitor, (R)-rolipram.     

Influence of dexaminoglutethimide, an optical isomer of aminoglutethimide, on the disposition of estrone sulfate in postmenopausal breast cancer patients

Aminoglutethimide (AG) has been the most widely used aromatase inhibitor in breast cancer patients to date. Commercially, AG (Orimeten) is available as a racemate (DL-AG). Previous studies suggested the stereoisomers of AG (D-AG and L-AG) to differ considerably in their affinities and potencies to inhibit different cytochrome P-450-dependent enzymes, with D-AG being the potent aromatase inhibitor. DL-AG, apart from being an aromatase inhibitor, is known to enhance the metabolism of plasma estrone sulfate (E1S). In the present study we compared the effects of D-AG (500 mg daily) and DL-AG (1000 mg daily) on plasma estrogen levels and estrone (E1) and E1S clearance rates, determined after the injection of [14C]E1 and [3H]E1S, in a cross-over study involving 12 postmenopausal breast cancer patients. Treatment with DL-AG and D-AG suppressed plasma E1S to 18.6% and 15.0% of pretreatment levels, whereas E1 and estradiol E2 levels fell to 18.6% and 23.4% of their pretreatment levels during treatment with DL-AG and to 17.7% and 23.4% during treatment with D-AG, respectively. Thus, both treatment options suppressed all estrogens measured to a similar extent. The clearance rate of E1S increased from a mean pretreatment value of 5.9 to 14.0 and 10.0 L/h during treatment with DL-AG and D-AG, respectively (P < 0.05, comparing the two on-treatment situations), whereas the production rate of E1S decreased from a pretreatment value of 1.44 to 0.64 nmol/h with DL-AG and 0.36 nmol/h with D-AG (P < 0.05, comparing on-treatment values). These findings are consistent with the hypothesis that the D- as well as the L-form of AG may enhance the clearance rate of E1S. The finding of a higher estrogen production rate during treatment with DL-AG compared to D-AG probably reflects an increased plasma level of the estrogen precursor androstenedione (mean levels of androstenedione of 2.54 and 1.27 nmol/L during treatment with D-AG and DL-AG, respectively; P < 0.05).     

The introduction of obstetric forceps in Norway--a 250-year anniversary

Johan Gottfried Erichsen (1713-68), born in Germany and chief medical officer in Bergen from 1747, was probably the first to perform a forceps delivery in Norway, on 14 February 1748. The mother, who had been in labour for five days, survived; the child, however, did not. The obstetric forceps had been a secret in the Chamberlen family and had become more widely known only a few decades earlier. Erichsen, who was the first man-midwife in Norway, had learned obstetrics in Paris by the younger Grégoire. He mastered both the techniques of internal version and forceps delivery. This article describes Erichsen's medical and obstetric background and his qualifications for operative obstetrics. He worked in the period when the obstetric forceps changed obstetrics, birth delivery became an arena also for men, and a part of medicine. Obstetrics was established as a science and physicians had a tool whereby also children could be saved during complicated delivery.     

Detection of human herpesviruses 6 and 7 in heart transplant recipients by a multiplex polymerase chain reaction method

Cystic lesions of the pancreas are relatively uncommon. We describe the case of a young man with a complex cystic mass located within the head of the pancreas. The patient underwent exploration with resection of the mass. Pathology revealed a ciliated epithelial cyst, a rare cystic lesion of the pancreas.     

Intervention with PTCA and CABG following thrombolysis for acute myocardial infarction. Australian data from GUSTO 1 (1991-3) and International Study Group r-TPA-Streptokinase Mortality (1989) trials. Global Utilisation of Streptokinase and Tissue

Genotoxic stress triggers signalling pathways that either mediate cell killing or protection of affected cells. While induction of p53 is observed for most of the genotoxins, activation of MAPK/SAPK cascades is not a general response. The role of MAPK/SAPK activation on cell fate, seems to be dependent, in some systems, on the balanced response among both cascades. We have here examined the effect of cis and trans-DDP on the activation of ERK and JNK activities. While no significant induction of ERK was observed with the compounds, both of them are able to strongly activate JNK. Trans-DDP response is rapid and transient while the cis-DDP one is slow and persistent. In contrast with the observed nuclear translocation of JNK in response to U.V. light, none of the platinum compounds induces translocation, on the contrary, activation of JNK occurs in both the nuclear and cytoplasmic compartments. Inhibition of tyrosine phosphatases by orthovanadate pretreatment prolongs the time of JNK induction in response to both platinum compounds. The positive modulation of JNK activation correlates with an increase in toxicity that, for cis-DDP corresponds to a tenfold decrease in the IC50. A strong increase in MKP-1 levels was observed only in response to trans-DDP suggesting the involvement of this activity in the downregulation of JNK activity in response to this compound. Altogether the results suggest that the prolonged activation of JNK in response to cis-DDP contributes to cell death induction.     

Studies of bioaccumulation and biotransformation of PCBs in mustelids based on concentration and congener patterns in predators and preys

Bioaccumulation of non-, mono-, and di-ortho-substituted chlorobiphenyls (CBs) was investigated in four species of mustelids (weasel, stoat, polecat, and otter) and their preys, from a restricted area in the northern part of The Netherlands. Diets of these mustelids ranged from terrestrial (weasel, stoat, and polecat) to aquatic (otter). Diet-specific biomagnification factors (BMFs), CB in diet relative to CB in mustelids, were calculated for the sum of 28 congeners (SigmaCB), for the sum of the toxic equivalent concentration (SigmaTEQ) and on an individual congener basis. Biotransformation was studied in relation to structural CB properties (vicinal H-atom substitution). In addition, the methylsulphonyl CB-metabolites were determined. The concentration of SigmaCB on lipid weight basis increased in the order weasel < stoat < polecat < otter. On the basis of SigmaTEQ, the order changed to weasel < polecat < stoat < otter. Most of the differences in BMFs between the CBs could be explained by the vicinal H-atom structure-activity rules. For all mustelids, the lowest BMFs were found for congeners with vicinal H-atoms in the meta, para position. Indications were found that all mustelid species can metabolize these congeners. For some of the CBs, their methylsulphonyl-CB metabolites were determined and found to be present in concentrations up to 350-fold higher than those of the parent compounds. In addition, the non-ortho CBs 126 and 169 are selectively retained in the liver of weasel, stoat, and otter. These CBs had the highest BMFs of all congeners. However, rather surprisingly, in polecat the highest BMFs were found for di-ortho-substituted CBs. This animal was able to metabolize all congeners with vicinal H-atoms in the ortho and meta position (non- and mono-ortho CBs). The information concerning the differences in bioaccumulation of CBs for closely related mustelid species increased the understanding of reported differences in PCB toxicity between mink and ferrets, and suggest that weasel, stoat, and otter are at least as sensitive to CBs as are mink, while polecats are less sensitive. As otter is exposed to much higher concentrations of CBs trough their diet than weasel and stoat, the toxic threat of CBs will be the greatest for this animal.