The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis

Diabetes insipidus is a well-recognized complication of Langerhans-cell histiocytosis (histiocytosis X), but its frequency and natural history are not well defined. Of 52 children with histiocytosis whom we studied, 12 (23 percent) had diabetes insipidus. Only two children had diabetes insipidus at presentation with histiocytosis, but the cumulative risk that it would develop during the first four years after the presentation and diagnosis of histiocytosis was found to be 42 percent. Diabetes insipidus occurred most often among children with multisystem disease and those with proptosis. To determine the natural history of diabetes insipidus in children with histiocytosis, we measured the response of urinary arginine vasopressin to water deprivation every six months in 21 children who did not have diabetes insipidus and who had had histiocytosis for less than four years. Five of the 21 children (24 percent) had subnormal responses during the initial test. One subsequently had spontaneous improvement in the functioning of the posterior pituitary, and diabetes insipidus subsequently developed in two, as it did in one of the children who initially had normal function of the posterior pituitary. Two of the children received irradiation to the pituitary within two to four weeks after diabetes insipidus developed, but they had no improvement in pituitary function. However, diabetes insipidus improved transiently during prednisolone therapy in one of these children and improved permanently after etoposide therapy in another child. We conclude that prospective study with the use of a simple water-deprivation test will allow partial defects of posterior-pituitary function to be detected in patients with histiocytosis and will permit a more appropriate evaluation of the effects of therapeutic intervention.     

Heparins as essential antioxidants

Chronically inflamed tissues contain significant concentrations of oxygen radicals, possibly generated by transition metal species such as Fe(II) and Cu(I). In addition, the pH of such tissues may well be lower than that of normal counterpart tissues. In this communication, the effect of variation of pH on the antioxidant activity of caeruloplasmin (a copper-containing acute-phase protein possessing important ferroxidase and other antioxidant activities) and of heparin are reported. Heparin, unlike caeruloplasmin, retains antioxidant activity at low pH. Heparins possess a variety of metal cation-binding chemical groups allowing them to bind damaging Cu(I) and Fe(II) ions and consequently prevent their redox involvement in oxygen radical-generating Fenton reactions. In conclusion, heparins may function as endogenous antioxidants and sequestration and/or oxidation by them, of ions such as Fe(II), may contribute to their effectiveness.

     

The influence of molecular structure on the affinity and efficacy of some β-adrenoceptor agonists

Summary The affinity and efficacy of a number of sympathomimetic amines structurally related to prenalterol and the selective ₁-adrenoceptor agonist RO 363 were determined using a combination of radioligand binding and organ bath techniques. Affinity of the molecules (pK _D) was calculated from their ability to displace the radioligand [¹²⁵I]iodocyanopindolol ([¹²⁵I]CYP) from -adrenoceptor sites in left atrial (₁) and uterine (₂) membrane homogenates. These pK _D values were used to calculate efficacy from the positive inotropic and uterine relaxant responses elicited by the drugs in organ bath experiments. The drugs studied were either arylethanolamines i.e., (–)-isoprenaline (ISO), p-hydroxyisoprenaline (pOH-ISO), compounds XIV and XVI or aryloxypropanolamine-derivatives, i.e., oxymethylene-isoprenaline (OM-ISO), prenalterol and Compound XI which possessed ap-phenol or catechol ring and an isopropyl or a homoveratryl amine substituent. Only ISO, OM-ISO, pOH-ISO and Compound XVI were active as agonists in both tissue preparations. These drugs were partial agonists which exhibited a wide range of pD₂ values and did not display any marked selectivity for either -adrenoceptor subtype. Compound XI and prenalterol were inactive as agonists and together with the partial agonists behaved as competitive antagonists to ISO in the two preparations. All drugs tested displaced [¹²⁵I]CYP from -adrenoceptor sites, however, there was also a wide range of potency amongst the drugs.Analysis of the structure-affinity and structure-efficacy relationships indicated that removal of the 3-hydroxyl group from the catechol ring reduces both affinity and efficacy without altering the selectivity of the drug for either -adrenoceptor subtype. While aryloxypropanolamine derivatives have generally higher affinities than arylethanol-amines, especially at -adrenoceptor sites, their efficacies are generally reduced at both -adrenoceptors. The presence of a homoveratryl group in aryloxypropanolamines enhances slightly the affinity for ₁- and reduces affinity for ₂-adrenoceptors. With this amine group, efficacy is markedly reduced at ₂- as opposed to ₂-adrenoceptor sites.Thus for prenalterol, the small degree of cardioselectivity can be attributed to the oxymethylene group whilst its lack of agonist activity (i.e., efficacy) reflects a combined action of this group and the absence of the 3-hydroxyl group on the phenyl ring. In RO363 it can be deduced that the oxymethylene group, together with the homoveratryl substituent are responsible for the observed selective affinity of the drug for ₁- as opposed to ₂-adrenoceptors.     

Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system

From a multivariate analysis of more than 14,200 patient-years' experience with papillary thyroid carcinoma (PTC), we devised a prognostic scoring system based on patient age, tumor grade, extent, and size (AGES). This scoring system can identify patients at increased risk of PTC mortality and was employed as an adjustment variable for analyzing the role of different types of surgical treatment in 860 PTC patients. Cancer mortality at 25 years in patients with an AGES score of 3.99 or less was 1% after ipsilateral lobectomy (n = 131) and 2% after bilateral resection (n = 603), whether subtotal or total (p = 0.15). Of patients with an AGES score of 4 or more, those who underwent lobectomy alone (n = 30) had a mortality rate from PTC at 25 years of 65%, while those undergoing bilateral resection (n = 86) had a lower rate of 35% (p = 0.06). For patients at minimal risk (score of 3.99 or less) of PTC death, no improvement in survival was demonstrable when patients underwent more than ipsilateral lobectomy. However, in a subgroup (score of 4 or more) identified to be at significant risk of PTC death, the survival after bilateral resection was much higher than after ipsilateral lobectomy alone. In neither the "minimal" nor the "higher" risk subgroup was PTC survival significantly improved by the performance of total thyroidectomy.     

Mechanism of the selective toxicity of amphotericin B incorporated into liposomes

Previously, it has been shown that incorporation of the membrane channel-forming polyene antibiotic, amphotericin B (AMB), into liposomes composed of dimyristoyl phosphatidylcholine/dimyristoyl phosphatidylglycerol (7:3 ratio) results in reduced drug toxicity to animals with full retention of therapeutic activity against systemic fungal infections. In this report we explore the cellular and biochemical bases of the enhanced therapeutic index of liposomal amphotericin B (L-AMB). AMB and L-AMB are equally potent and both promptly induce rapid cation efflux from Candida albicans cells. By contrast, AMB, but not L-AMB, induces cation efflux and cell lysis in mammalian erythrocytes, demonstrating the selectivity of L-AMB at the cellular level. The characteristics of the lipid of the erythrocyte membrane seem to be the most important determinant of cellular sensitivity, since AMB, but not L-AMB, induces cation release from large unilamellar liposomes composed of red cell membrane lipids, thus paralleling the observations on intact cells. The ability of L-AMB to induce cation release and cause toxicity to erythrocytes, however, can be modulated by changing the lipid composition of the liposome carrier. Thus, AMB-containing liposomes composed of phospholipids with saturated acyl chains are nontoxic, whereas AMB liposomes composed of phospholipids containing unsaturated acyl chains are almost as toxic as AMB itself. The acyl chain composition rather than the head group composition seems most important, although substitution of anionic phosphatidylglycerols for phosphatidylcholines contributes somewhat to the protective effect. Analysis of several types of liposomes containing AMB at concentrations up to 5 mol %, using electron paramagnetic resonance and freeze fracture electron microscopy, shows that the drug is incorporated in the lipid bilayer but produces only modest disruptive effects on bilayer structure. Current results are interpreted in terms of a selective transfer of AMB from "donor" liposomes to "target" cell membranes. The transfer process probably occurs by diffusion of AMB through the solvent but is regulated by the physical properties of both donor and target membranes.     

The value of regular replacement of low water content contact lenses for extended wear

Adverse effects were evaluated in 48 myopic patients who wore low water content hydrogel lenses for an average of 48 +/- 19 weeks. Only one acute "red eye" occurred in the regular replacement group (2% of patients), whereas seven cases (15%) occurred in the non-replacement lens wearing eye. The major cause of clinical failure was giant papillary conjunctivitis (GPC), but the incidence was similar in both the replaced (15%) and non-replaced (15%) lens wearing eyes. These findings indicate that the acute red eye incidence can be reduced by regular replacement, that unilateral lens replacement does not reduce the incidence of GPC and that regularly replacing low water content lenses does not minimize the chronic corneal changes that occur during extended wear.     

Perioperative transcutaneous oxygen monitoring in thoracic anaesthesia

Transcutaneous oxygen tension (PtcO2) was measured in 30 patients scheduled for elective pulmonary resection requiring one-lung ventilation during anaesthesia. Simultaneous PtcO2 and arterial oxygen tension (PaO2) measurements were taken preoperatively (preop), intraoperatively during two-lung endotracheal (ET) and one-lung endobronchial ventilation (EB), and postoperatively (postop). There was a significant correlation (r) between PtcO2 and PaO2 at all time periods: 0.97 (preop); 0.91 (ET); 0.83 (EB); 0.81 (postop). There were no significant differences among the transcutaneous oxygen indices (tcO2 index = PtcO2/PaO2) in the preop (0.69 +/- 0.09), ET (0.68 +/- 0.10) and postop (0.71 +/- 0.12) time period. The tcO2 index was significantly lower during one-lung anaesthesia (0.61 +/- 0.14). The PtcO2 was consistently lower than the corresponding PaO2 measurement, thus providing a continuous estimation of the "minimum" PaO2 level throughout anaesthesia and recovery. In four patients a marked drop in PtcO2 occurred just after the initiation of one-lung ventilation. In three, this was associated with arterial hypoxaemia and in one, haemodynamic compromise. In all four cases the PtcO2 was the first monitored parameter to change. As there is a substantial risk of developing hypoxaemia during thoracic anaesthesia, PtcO2 monitoring provides valuable early warning of impending hypoxaemia or haemodynamic compromise, thereby facilitating early therapeutic intervention.     

Cardioplegic solution: a contamination crisis

Eleven patients were given varying doses of cardioplegic solution contaminated with Enterobacter cloacae. Five patients died. Early bleeding, necessitating reoperation, occurred in eight patients and a total of 126 units of blood and 203 units of platelets were given (range 2 to 19 and 15 to 47 units, respectively). Mycotic aneurysms developed in four patients, rupturing between the ninth and eleventh postoperative day. Only one of these patients survived. Other complications included adult respiratory distress syndrome (three patients), renal failure (four patients), sternal infections (six patients), and organic brain syndrome (five patients). Although some factors of gram-negative septicemia were identified in retrospect, others were masked by the clinical setting in which it occurred. We recommend that each dose of cardioplegic solution be prepared on an individual basis and used immediately. We also recommend that "sternal blood" be cultured on all patients. The subtle features of "gram-negative septicemia" necessitate urgent investigation and treatment. The combination of low white cell count, high cardiac output, and low peripheral vascular resistance should be assumed to indicate septicemia until proved otherwise. A full coagulation screen including platelet function and fibrin degradation products should be performed in any and all patients with these findings. Mycotic aneurysms mandate urgent reoperation with interposition of a saphenous vein segment of these patients are to survive.