Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform

BACKGROUND: Glucocorticoid-resistant bronchial asthma is characterized by failure of corticosteroids to suppress key asthma-relevant, cell-mediated inflammatory responses in the airways. OBJECTIVE: The mechanism of this phenomenon is not clear but may involve aberrant expression of the beta-isoform of the glucocorticoid receptor. METHODS: We have measured expression of the alpha- and beta-glucocorticoid receptor isoforms in tuberculin-driven cutaneous cell-mediated inflammatory lesions in people with asthma who are glucocorticoid sensitive and resistant after 9 days of therapy with oral prednisolone (40 mg/day) or matching placebo in a random order, crossover design. RESULTS: After placebo therapy, the mean numbers of cells expressing glucocorticoid receptor alpha immunoreactivity in the lesions evoked in glucocorticoid-sensitive and -resistant patients with asthma were statistically equivalent. The numbers of cells expressing glucocorticoid receptor beta were significantly elevated in the patients who were glucocorticoid resistant, resulting in an 8-fold higher ratio of expression of glucocorticoid receptor alpha/glucocorticoid receptor beta in the patients who were glucocorticoid sensitive. Glucocorticoid receptor alpha/glucocorticoid receptors beta were colocalized to the same cells. Oral prednisolone therapy was associated with a significant decrease in the numbers of cells expressing glucocorticoid receptor alpha but not glucocorticoid receptor beta in the subjects who were glucocorticoid sensitive. No significant change was found in the numbers of cells expressing glucocorticoid receptor alpha and glucocorticoid receptor beta in the patients who were glucocorticoid resistant. Prednisolone therapy reduced the ratio of glucocorticoid receptor alpha/glucocorticoid receptor beta expression for the patients who were glucocorticoid sensitive to a level seen in the patients who were glucocorticoid resistant before therapy. CONCLUSION: Because glucocorticoid receptor beta inhibits alpha-glucocorticoid receptor-mediated transactivation of target genes, the increased expression of glucocorticoid receptor beta in inflammatory cells might be a critical mechanism for conferring glucocorticoid resistance.     

Alcohol use following liver transplantation: a comparison of follow-up methods

Alcoholic cirrhosis is one of the most common indications for liver transplantation. Previous researchers have studied rates of return to drinking following transplantation, however, few have employed prospective measures of alcohol use. The authors prospectively studied the alcohol use of patients transplanted for alcoholic liver disease. The authors improved the accuracy of monitoring alcohol use by using various methods for tracking patient's alcohol consumption, and we report on the time to first alcohol use after transplantation comparing these different methods. The authors found that alcohol use can occur very early after transplantation, even within the first 3 months posttransplant. Thirty-eight percent of the patients consumed any alcohol after transplantation. The clinical interviews by the psychiatrist were the most successful method for identifying posttransplant alcohol use. Posttransplant alcohol use was significantly associated with prior nonalcohol substance use (P < 0.025), family history of alcoholism in a first-degree relative (P < 0.025), and prior alcohol rehabilitation experience (P < 0.05) but not with a prior psychiatric history or less than 6 months of pretransplant sobriety. The authors indicate that prospective monitoring, using a combination of methods, is the most accurate approach to identify alcohol consumption. With this type of accuracy, risk factors can be identified and alcohol use can be compared with alcohol-related morbidity posttransplant.     

Macular deposits in galactokinase deficiency

Deficiency of the enzyme, galactokinase, is a recognized cause of "juvenile" lens opacities; these opacities are felt to be its only clinical expression. The deficiency itself is inherited as an autosomal recessive and as such is expected to be clinically manifest in the homozygote. We have recently demonstrated cataracts and associated bilateral macular deposits in a white male who is heterozygous for the deficiency of the enzyme and whose dietary intake of milk and its products is extremely high. To our knowledge, intraretinal deposits have not previously been described in patients with galactokinase deficiency, and their clinical significance and biochemical makeup can only be speculative. Dietary restriction of galactose is recommended for all individuals proven to be deficient in this enzyme, whether homozygous or heterozygous.     

Ligament reconstruction for the painful "prearthritic" thumb carpometacarpal joint

An extraarticular ligament reconstruction to stabilize the painful, hypermobile trapeziometacarpal (basal) joint by routing a portion of the flexor carpi radialis (FCR) through the thumb metacarpal has been performed in 25 "prearthritic" (Stage I) and 17 minimally involved (Stage II) basal joints. At an average follow-up examination of 5.2 years, 100% of the Stage I patients had achieved good or excellent results, having little or no pain with return of strength and stability. Eighty-two percent of Stage II patients had similar results. Intractable pain was the primary surgical indication. Pain was dramatically relieved in all Stage I cases and in 70% of the Stage II cases. The presence and degree of crepitus correlated closely to the result and was a good prognostic indicator. Direct inspection of both the basal and scaphotrapezial joints is essential to determine whether ligament reconstruction or another surgical procedure is the procedure of choice. The procedure was particularly useful in patients with untreated Bennett's fractures. Follow-up roentgenograms showed no further degeneration, suggesting that the procedure was reliable, reproducible, and durable, and that it might even retard future joint degeneration.     

The application of operative ultrasound immediately following carotid endarterectomy

One hundred and seventy-five carotid bifurcations have been scanned using intraoperative ultrasonic imaging. The technique is simple, reproducible, rapid, and reliable. Intimal flaps, clamp stenoses, residual plaques, and platelet accumulations were detected by this method. Most technical defects occurred in the external carotid artery (12%), and it is recommended that significant lesions remaining in this vessel should be removed. Defects in the internal carotid artery and common carotid artery were much less common (7%) and most of these were quite small, not requiring reopening. In fact, only 2% required reopening. In 1% of patients there were defects detected that led to stroke, which would have been removed on present criteria. Although there were other causes of stroke, technical error remains an immediately reversible source of postoperative stroke that can be avoided by the use of operative ultrasonic imaging. Long-term minor defects, as followed by noninvasive tests, rarely became significant and bore no relationship to the development of restenosis.

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Resumen Ciento setenta y cinco bifurcaciones carotídeas han sido estudiadas intraoperatoriamente al cierre de la arteriotomía para endarterectomía y una vez que los clamps y asas habían sido retirados y el flujo restaurado, mediante la imagenología de ultrasonido. La técnica es simple, reproducible, rápida, y confiable. Pliegues (flaps) de la íntima, estenosis por clamps, placas residuales, y acumulaciones plaquetarias fueron detectadas por este método. La mayoría de los defectos de técnica operatoria se presentaron en la carótida externa (12%) y por ello se recomienda que lesiones de significación que queden presentes en este vaso deben ser removidas. Los defectos en la arteria carótida interna y en la carótida primitiva fueron mucho menos frecuentes (7%) y su mayoría fueron mínimos y no requirieron reapertura del vaso. En 1% de los pacientes se presentaron defectos que dieron lugar a accidente cerebral los cuales, bajo criterios actuales, habrían sido removidos. Aunque hubo otras causas de accidente cerebral, los errores técnicos siguen siendo una fuente reversible inmediata de accidente cerebral postoperatorio que puede ser evitado con el uso de imagenología de ultrasonido intraoperatoria. Los defectos menores estudiados a largo plazo por medios no invasivos muy rara vez probaron ser de significación y no aparecieron relacionados con el desarrollo de reestenosis.

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Résumé Cent soixante-quinze fourches carotidiennes ont été soumises à une échographie per-opératoire. La méthode d'exploration est simple, aisée à répéter et fiable. Les lambeaux d'intima, les sténoses secondaires au clampage, les plaques laissées en place, les accumulations de plaquettes peuvent être détectées par cette exploration. La majorité des impairs opératoires s'observent au niveau de la carotide externe (12% des cas) et imposent la correction des lésions patentes. Les malfaçons au niveau de la carotide interne et de la carotide primitive sont moins fréquentes (7% des cas). Les lésions sont souvent peu importantes, leur correction ne s'imposant que dans 2% des cas. Dans 1% des cas, ces lésions artérielles opératoires aboutissent à une lésion cérébrale qui aurait pu être évitée. En effet, bien que d'autres causes de lésion cérébrale existent, les altérations imputables à l'acte chirurgical sont réversibles dès lors qu'elles sont mises en évidence par l'échographie opératoire. Les lésions mineures persistantes qui sont décelées par les tests non-invasifs ne sont que rarement à l'origine d'une sténose artérielle post-opératoire.

     

Spoilage of hydrogel contact lenses by lipid deposits. Tear-film potassium depression, fat, protein, and alcohol consumption

"Jelly-bump" deposits, which are composed mainly of lipids, on high water content, extended-wear hydrogel lenses, are a clinically significant problem of unknown etiology. The authors explored the effect of nutrition on the frequency of deposition of these jelly bumps. Forty-three patients were included in this masked case-control study from five contact lens practices in North America. Thirty patients were lipid-depositor cases and 13 were controls. Tear specimens were drawn and analyzed for potassium by atomic-absorption spectrophotometry. Detailed dietary histories were conducted and diet nutrient composition was computed. Patients with diminished tear-potassium concentrations have an increased risk of jelly-bump deposition. Elevated intake of protein, alcohol, and cholesterol also appeared to be correlated significantly with increased jelly-bump deposition. The authors found that diabetics and the use of diuretics, anticholinergics, sympathomimetics, were associated with tear-film potassium depletion and lipid deposit formation.     

Comparison of the α-adrenoceptor antagonist profiles of idazoxan (RX 781094), yohimbine,rauwolscine and corynanthine

Summary In the present studies the potency and selectivity of idazoxan (RX 781094) were compared with yohimbine and its diastereoisomers rauwolscine and corynanthine in both functional studies and radioligand binding experiments. Prejunctional ₂- and postjunctional ₁-adrenoceptor antagonist potencies were assessed by determining pA₂ values against clonidine on the stimulated rat vas deferens and noradrenaline on the anococcygeus muscle, respectively. The rank order of prejunctional ₂-adrenoceptor antagonist potency was idazoxan > yohimbine > rauwolscine corynanthine. At postjunctional ₁-adrenoceptors the rank order of antagonist potency was rauwolscine > corynanthine > yohimbine > idazoxan. The selectivity values (₂/₁) for idazoxan, yohimbine, rauwolscine and corynanthine were 245, 45, 3 and 0.03 respectively. The selectivity and potency profiles established for these antagonists in functional studies were confirmed in radioligand binding studies utilising ³H-idazoxan (₂) and ³H-prazosin (₁) in rat cerebral cortex.In pithed rats intravenously administered idazoxan, yohimbine and rauwolscine fully reversed the inhibitory effects of clonidine on electrically-induced contractions of the vas deferens; idazoxan was approximately ten times more potent than both yohimbine and rauwolscine. Corynanthine was inactive. Idazoxan and yohimbine also fully antagonised the inhibitory effects of guanabenz on electrically-induced contractions of the anococcygeus muscle; idazoxan again was more than ten times more potent than yohimbine in this model. The inhibitory effects of guanabenz were less readily antagonised by rauwolscine indicating that the selectivity of this compound is less than that of yohimbine in this tissue. Corynanthine was again inactive.Studies were also undertaken in which the effects of an extended range of antagonists were examined on contractions of the anococcygeus muscle induced either by electrical stimulation or intra-arterial phenylphrine. Selective ₁-adrenoceptor antagonists produced a parallel block of the effects of stimulation and phenylephrine indicating that the postjunctional receptor in this tissue is predominantly ₁- character. In this tissue idazoxan potentiated nerve stimulation without inhibiting phenylephrine responses; of the compounds studied only idazoxan failed to influence phenylephrine responses.Under the present experimental conditions idazoxan only produced antagonist properties at -adrenoceptors and consistently displayed improved ₂-selectivity and potency with respect to yohimbine and rauwolscine.     

Exploring Differences in Work Disability Duration by Size of Firm in Canada and Australia

Journal of Occupational Rehabilitation - Purpose To identify whether there were differences in work disability duration between injured workers employed by small, medium, large, and self-insured...     

蒙药毛勒日—达布斯—4汤中微量元素及氨基酸含量的测定

目的：测定蒙药毛勒日-达布斯-4汤中微量元素和氨基酸的含量。方法：用原子吸收分光光度计,测定蒙药毛勒日-达布斯-4汤中几种重要的微量元素含量;用氨基酸自动分析仪测定氨基酸的含量。结果与结论：蒙药毛勒日-达布斯-4汤中含有较高的Mn、Fe、Zn和Mg;含有17种氨基酸,包括7种人体必需氨基酸,氨基酸总量为4.615%（mg/g）。     

Lessons learned from lower urinary tract complications of anorectoplasty for imperforate anus with rectourethral/rectovesical fistula: Laparoscopy-assisted versus posterior sagittal approaches

PurposeTo report the sequelae of and preventive strategies for selected lower urinary tract (LUT) complications, i.e., posterior urethral diverticulum (PUD), intraoperative LUT injuries, postoperative dysuria, and fistula recurrence in male imperforate anus (IA) with rectourethral/rectovesical (RU/RV) fistula after laparoscopy-assisted anorectoplasty (LAARP) or posterior sagittal anorectoplasty (PSARP).Methods153 boys with IA and RU/RV fistula treated 1986–2019 by LAARP (n = 56) or PSARP (n = 97) at two unrelated institutes were studied retrospectively.ResultsAfter mean follow-up of 17.0 years (range: 36.5 days-32.0 years), the overall incidences of LUT complications were: LAARP (6/56; 10.7%); PSARP (7/97; 7.2%); p = 0.55, comprising PUD: LAARP (n = 5), PSARP (n = 0); p = 0.006; injuries: LAARP (n = 0), PSARP (n = 5); p = 0.16; dysuria: LAARP (n = 1), PSARP (n = 1); p>0.999; and recurrence: LAARP (n = 0), PSARP (n = 1); p>0.999. Mean onset of PUD was 5.1 years (range: 1.0–15.1 years). Treatment: PUD: surgery (n = 2/5), conservative (n = 3/5); injuries: intraoperative repair (n = 5/5); dysuria: conservative (n = 2/2), and recurrence: redo PSARP (n = 1/1).ConclusionsStrategies devised to improve dissection accuracy resolved the specific technical issues causing LUT complications (remnant RU fistula dissection in LAARP and blind posterior access in PSARP). Currently, the incidence of new cases of PUD and LUT injuries is zero.Level of Evidence: Level III