Adrenal insufficiency in a man with non-classical 21-hydroxylase deficiency: consequence or coincidence?

Deficiency of the adrenal enzyme 21-hydroxylase, which is required for cortisol synthesis, appears in two forms: a rare classical variant with severe enzyme deficiency, usually presenting in neonates with ambiguous genitalia (from androgen overproduction) or adrenal crisis (from glucocorticoid and mineralocorticoid underproduction), and a common (1% of the general population) non-classical variant with mild enzyme deficiency, usually presenting in young adults with findings of androgen excess but without clinical evidence of decreased steroid hormone production. We describe a 22-year-old man who had clinical and biochemical findings consistent with adrenal insufficiency, including a favorable response to hydrocortisone replacement, in whom elevated serum levels of the cortisol precursor 17-hydroxyprogesterone were diagnostic of non-classical 21-hydroxylase deficiency and in whom no other cause of adrenal insufficiency could be identified. These findings raise the possibility that non-classical 21-hydroxylase deficiency, an extremely frequent disorder which is generally thought to be without significant morbidity, might cause or contribute to adrenal insufficiency in adults.     

In vivo dihydrotachysterol2 metabolism in normal man: 1 alpha- and 1 beta-hydroxylation of 25-hydroxydihydrotachysterol2 and effects on plasma parathyroid hormone and 1 alpha,25-dihydroxyvitamin D3 concentrations

It has recently been shown that in the rat, dihydrotachysterol (DHT) is extensively metabolized in the side-chain in vivo along pathways similar to those of vitamin D. In addition 25-hydroxy-DHT2 [25OHDHT2] is hydroxylated at C1, producing both 1 alpha- and 1 beta- hydroxy compounds. An in vivo study in 1988 demonstrated that in normal adult subjects receiving oral DHT2, plasma 1 alpha,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations fell, but with unchanged plasma PTH levels. Down-regulation of 1,25-(OH)2D3 production by 25-(OH)DHT2 or some other unknown metabolite was also suggested as an explanation for these observations. To investigate whether either of the newly characterized 1 alpha,25- or 1 beta,25-(OH)2DHT2 was formed in vivo in normal man, DHT2 (approximately 1 mg/day, orally) was administered to healthy volunteers (three males and one female). Plasma was analyzed by high performance liquid chromatography and gas chromatography-mass spectrometry, demonstrating the formation of both 1 alpha,25- and 1 beta,25-(OH)2DHT2 in vivo in normal human subjects. Plasma levels of 1,25-(OH)2D3, PTH, ionized and total calcium, inorganic phosphate, and alkaline phosphatase were monitored. The plasma concentrations of DHT2, 25OHDHT2, and 1 alpha,25- and 1 beta,25-(OH)2DHT2 were measured by gas chromatography-mass spectrometry. In all volunteers, plasma ionized calcium increased slightly during DHT2 administration; 1,25-(OH)2D3 and PTH concentrations fell. Plasma levels of DHT2 and its metabolites rose over the same period. The average fall in the level of plasma 1,25-(OH)2D (60-70 pmol/L) was mirrored by a rise in the concentration of 1 alpha,25-(OH)2DHT2 (550 pmol/L). This ratio is appropriate, because it has previously been shown that in a reconstituted COS cell, 1 alpha,25-(OH)2DHT3 has roughly one tenth the potency of 1,25-(OH)2D3. At maximum concentration, the ratios of DHT2/25OHDHT2/1 beta,25-(OH)2DHT2/1 alpha,25-(OH)2DHT2 were approximately 10:1:2:0.1. The concentration of 1 beta,25-(OH)2DHT2 was greater than that of 25OHDHT2, and the ratio of 1 alpha,25- to 1 beta,25-(OH)2DHT2 (1:20) was substantially lower than that in rat plasma (3:10). The data presented here suggest that the active DHT2 metabolite in man is 1 alpha,25-(OH)2DHT2 and that the fall in plasma 1,25-(OH)2D seen during DHT therapy may be partly the result of suppressed PTH secretion.     

Enzymatically Modified Shea Butter and Palm Kernel Oil as Potential Lipid Drug Delivery Matrices

Drug formulations based on lipids can enable a significantly better delivery of a pharmaceutically active substance and thus enhance their bioavailability. However, natural fats and oils usually have properties, which do not allow their direct use for drug delivery. Therefore, we have modified palm kernel oil (PKO) and shea butter (SB) via lipase‐catalyzed transesterification using either glycerol – to create a diglyceride‐enriched lipid – or using hexanoic acid via acidolysis – to alter their fatty acid composition – and hence to improve drug solubility of Celecoxib serving as model compound. The most suitable enzyme was immobilized Thermomyces lanuginosus lipase (Novozyme TL IM). The solubility of Celecoxib as determined in SB, pharmaceutical grade SB, glycerol‐modified SB, hexanoic acid‐modified SB, PKO, glycerol‐modified PKO, and hexanoic acid‐modified PKO. Incorporation of one or two equivalents of hexanoic acid enabled higher Celecoxib solubilization than the diglyceride rich oil. Although structured SB and PKO (15.8 ± 0.4 mg mL^?1) do not differ significantly (p < 0.05) as per the amount of Celecoxib dissolved, the use of the modified oils enhanced Celecoxib solubility in SB (15.5 ± 1.3 mg mL^?1) in comparison to shea butter (7.9 ± 0.5 mg mL^?1). The lipase‐catalyzed modification also improved the miscibility of the oils with surfactants such as Tween 20 and resulted in reduced droplet sizes (<70 nm at oil/surfactant ratios of 1:2 and 1:1) and reduced polydispersity index values of the resulting emulsions. Practical Application: The structured triglycerides synthesized in this work on the basis of natural shea butter oils could function as suppository bases and oil phase in oral and parenteral lipid‐based formulations for improving the solubility and absorption of poorly soluble drugs. As various lipases with distinct selectivity are available for the enzymatic synthesis of structured triglycerides and useful for this purpose, further tailor‐designed formations should be accessible. With the aim of developing novel lipid drug delivery matrices palm kernel oil (PKO) and shea butter (SB) were modified via lipase‐catalyzed transesterification to alter their fatty acid composition and hence to improve drug solubility of the model compound Celecoxib. Incorporation of one or two equivalents of hexanoic acid enabled better Celecoxib solubilization than the diglyceride‐rich oil. Overall, the successful modification process yielded structured lipids with promising miscibility with selected surfactants and potential enhancement of Celecoxib solubility and thus represents a promising approach for the development of novel safe and effective lipid‐based delivery systems.

     

Surface impedance studies on the electrodynamical response of organic superconductors

We have performed detailed measurements of the surface impedance in the normal and superconducting state of κ- (BEDT-TTF)₂Cu(NCS)₂in the millimeter wave frequency range (1 cm^{− 1} to 3 cm^{− 1}) and have evaluated the complex conductivity for different crystallographic orientations. Above the transition temperature, the material behaves like a metal with a scattering rate of approximately 20 cm^{− 1}. In the superconducting state the electrodynamics of both materials is in good agreement with calculations based on a BCS ground state: the penetration depth is temperature independent for T → 0; while the penetration depth and the coherence length are strongly anisotrop, the superconducting energy gap shows no indications of line nodes.     

Frequency and temperature dependence of the millimeter wave conductivity of epitaxial YBa2Cu3O7 films

A millimeter wave spectrometer for frequencies between 100 and 350 GHz consisting of continuously tunable backward wave oscillators as sources and a quasioptical interferometer in the Mach-Zehnder configuration was used to measure the transmittivity in phase and amplitude of YBa₂Cu₃O₇ thin films on NdGaO₃ substrates. From the measured spectra we derived the real and imaginary part of the dynamic conductivity= ₁+i ₂ in the superconducting state as a function of temperature. The ₁(T) and ₂(T) values at 300 GHz were compared to corresponding values at 19 GHz determined by surface impedance measurements of the same films using a shielded dielectric resonator. Our observed frequency dependence of both ₁(T) and ₂(T) is consistent with a strong reduction of the quasiparticle scattering rate ^–1(T) with decreasing temperature belowT _c .     

Surveillance of tuberculosis in Europe. Working Group of the World Health Organization (WHO) and the European Region of the International Union Against Tuberculosis and Lung Disease (IUATLD) for uniform reporting on tuberculosis cases

Consensus-based recommendations have been developed by a Working Group of the World Health Organization (WHO) and the European Region of the International Union Against Tuberculosis and Lung Disease (IUATLD) on uniform reporting of tuberculosis surveillance data in the countries of Europe. A uniform case definition and a minimum set of variables for reporting on each case have been agreed which, when collated on a national basis, will allow comparison of the epidemiology of tuberculosis in different European countries. The Working Group recommends that the case definition includes "definite" cases, where the diagnosis has been confirmed by culture (or supported by microscopy findings in countries where diagnostic culture facilities are not available), and "other than definite cases" based on a clinical diagnosis of tuberculosis combined with the intention to treat with a full course of antituberculosis therapy. Both "definite" and "other than definite" cases should be notified by physicians and, in addition, laboratories should be required to report "definite" cases. The minimum set of variables to be collected on each case of tuberculosis should include: date of starting treatment, place of residence, date of birth, gender, and country of origin, to characterize the patient. Recommended disease-specific variables include: site of disease, bacteriological status (microscopy and culture), and history of previous antituberculosis chemotherapy. The minimum set of variables should be collated on all patients and should be as complete as possible. Additional variables may be collected for individual, local or national purposes, but, in general, completeness of reporting on cases is likely to be better if the information requested is kept to a minimum. Timely reporting of cases is essential for appropriate public health action. Cases should be reported to the health authority at the local and/or regional level within 1 week of starting treatment. Individual-case based information should be reported to the national level by the local or regional level. Feedback to reporters is essential. At the national level, preliminary quarterly reports should be produced and final reports should be published annually.     

Comparative clinical pharmacology of short-acting mu opioids in drug abusers

The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteers with agonist and antagonist sensitivity measures. Two studies used within-subject, placebo-controlled, crossover designs. In study 1, fentanyl (0.125, 0.25 mg/70 kg i.v.) was followed at 0, 20, 60 and 180 min by naloxone (10 mg/70 kg i.m.). Agonist effects during 180-min and 0-min (control; simultaneous fentanyl-naloxone i.v. infusion) challenge sessions were compared. Fentanyl rapidly constricted pupils, depressed respiration and produced subjective "high" and opiate symptoms lasting 60 to 120 min, depending on the measure. Naloxone precipitated withdrawal symptoms of comparable intensity at each challenge point. In study 2, fentanyl (0.125, 0.25 mg/70 kg i.v.), alfentanil (1, 2 mg/70 kg i.v.) and saline were followed at 1 and 6 hr by naloxone (10 mg/70 kg i.m.). Agonist effects were examined during 6-hr challenge sessions. The two drugs produced a comparable range of effects with similar peak magnitude for 0.125 mg/70 kg fentanyl and 1 mg/70 kg alfentanil and for 0.25 mg/70 kg fentanyl and 2 mg/70 kg alfentanil. Alfentanil's duration of action was brief ( < 60 min). Withdrawal was precipitated at 6 hr only after 0.25 mg/70 kg fentanyl. These findings support typical mu opioid characteristics (pleasurable subjective effects, physical dependence) for both drugs, differential duration of action (fentanyl > alfentanil) and peak effects consistent with a 1:8 (fentanyl/alfentanil) potency ratio.