Divergent Effects of Glucocorticoids on Cortical and Trabecular Compartment BMD in Childhood Nephrotic Syndrome

Glucocorticoid (GC) effects on skeletal development have not been established. The objective of this pQCT study was to assess volumetric BMD (vBMD) and cortical dimensions in childhood steroid‐sensitive nephrotic syndrome (SSNS), a disorder with minimal independent deleterious skeletal effects. Tibia pQCT was used to assess trabecular and cortical vBMD, cortical dimensions, and muscle area in 55 SSNS (age, 5–19 yr) and >650 control participants. Race‐, sex‐, and age‐, or tibia length‐specific Z‐scores were generated for pQCT outcomes. Bone biomarkers included bone‐specific alkaline phosphatase and urinary deoxypyridinoline. SSNS participants had lower height Z‐scores (p < 0.0001) compared with controls. In SSNS, Z‐scores for cortical area were greater (+0.37; 95% CI = 0.09, 0.66; p = 0.01), for cortical vBMD were greater (+1.17; 95% CI = 0.89, 1.45; p < 0.0001), and for trabecular vBMD were lower (?0.60; 95% CI, = ?0.89, ?0.31; p < 0.0001) compared with controls. Muscle area (+0.34; 95% CI = 0.08, 0.61; p = 0.01) and fat area (+0.56; 95% CI = 0.27, 0.84; p < 0.001) Z‐scores were greater in SSNS, and adjustment for muscle area eliminated the greater cortical area in SSNS. Bone formation and resorption biomarkers were significantly and inversely associated with cortical vBMD in SSNS and controls and were significantly lower in the 34 SSNS participants taking GCs at the time of the study compared with controls. In conclusion, GCs in SSNS were associated with significantly greater cortical vBMD and cortical area and lower trabecular vBMD, with evidence of low bone turnover. Lower bone biomarkers were associated with greater cortical vBMD. Studies are needed to determine the fracture implications of these varied effects.     

Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in obesity

Excessive glucocorticoid exposure (Cushing's syndrome) results in increased adiposity associated with dysmetabolic features (including insulin resistance, hyperlipidaemia, and hypertension). Circulating cortisol levels are not elevated in idiopathic obesity, although cortisol production and clearance are increased. However, tissue glucocorticoid exposure may be altered independently of circulating levels by 11β-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme which generates active glucocorticoid within tissues, including in adipose tissue. Transgenic overexpression of 11HSD1 in mice causes obesity. In human obesity, 11HSD1 is altered in a tissue-specific manner with reduced levels in liver but elevated levels in adipose, which may lead to glucocorticoid receptor activation and contribute to the metabolic phenotype. The reasons for altered 11HSD1 in obesity are not fully understood. Although some polymorphisms have been demonstrated in intronic and upstream regions of the HSD11B1 gene, the functional significance of these is not clear. In addition, there is mounting evidence that 11HSD1 may be dysregulated secondarily to factors that are altered in obesity, including substrates for metabolism, hormones, and inflammatory mediators. 11HSD1 is a potential therapeutic target for the treatment of the metabolic syndrome. 11HSD1 knockout mice are protected from diet-induced obesity and associated metabolic dysfunction. Although many specific inhibitors of 11HSD1 have now been developed, and published data support their efficacy in the liver to reduce glucose production, their efficacy in enhancing insulin sensitivity in adipose tissue remains uncertain. The therapeutic potential of 11HSD1 in human obesity therefore remains highly promising but as yet unproven.     

Sex differences in response to steroids in preterm sheep lungs are not explained by glucocorticoid receptor number or binding affinity.

We recently reported that prenatal glucocorticoid therapy is less effective at promoting an improvement in lung function in male than in female sheep. This observation, and the higher incidence of respiratory distress syndrome in human males, suggests that the male fetal lung may be less responsive to glucocorticoids than is the female fetal lung. Since glucocorticoids are known to exert their effects via specific cytoplasmic glucocorticoid receptors (GR), we hypothesized that there may be sexual dimorphism in either the number or binding affinity of lung GR. To test the hypothesis, binding of dexamethasone (a synthetic glucocorticoid, 0.5-40 nM) by cytosolic fractions of male (n = 16) and female (n = 16) fetal sheep lung was measured at 125 days gestation (term = 148 days). Scatchard analysis of dexamethasone binding showed that the total number of GR (Bmax) did not significantly differ between male (346 +/- 42 fmol/mg protein) and female (277 +/- 23 fmol/mg protein) fetuses. The measured binding affinity (Kd) in male fetal lungs (6.85 +/- 0.43 nM) was not significantly different from that in females (8.46 +/- 1.02 nM). In conclusion, this study suggests that sex differences in fetal sheep lung responses to glucocorticoid therapy are not due to differences in the number or binding affinity of lung GR.     

慢性阻塞性肺疾病急性加重期糖皮质激素序贯治疗的策略

目的比较慢性阻塞性肺疾病急性加重期（AECOPD）糖皮质激素序贯治疗两种策略的疗效。方法120例AECOPD患者随机分为两组，小于7天组或7天以上组，均在常规应用抗生素，平喘止咳化痰的基础上，静脉给予地塞米松5～10mg治疗。前者于3～5d后序贯口服强的松治疗后吸入糖皮质激素（3—5d），而后出院，院外继续应用吸入激素＋长效p2受体兴奋剂治疗。后者则序贯时间为地塞米松用7天后，余同前。对比分析各项疗效指标以及平均住院天数。结果小于7天组的患者的平均住院天数较7天以上组明显减少，其余观察指标无统计学差异。结论使用地塞米松小于7天的序贯治疗可以起到一定的疗效，并减少平均住院天数。     

Treatment with Glucocorticoids or Calcineurin Inhibitors in Primary FSGS

Background and objectives

In primary FSGS, calcineurin inhibitors have primarily been studied in patients deemed resistant to glucocorticoid therapy. Few data are available about their use early in the treatment of FSGS. We sought to estimate the association between choice of therapy and ESRD in primary FSGS.

Design, setting, participants, & measurements

We used an inception cohort of patients diagnosed with primary FSGS by kidney biopsy between 1980 and 2012. Factors associated with initiation of therapy were identified using logistic regression. Time–dependent Cox models were performed to compare time to ESRD between different therapies.

Results

In total, 458 patients were studied (173 treated with glucocorticoids alone, 90 treated with calcineurin inhibitors with or without glucocorticoids, 12 treated with other agents, and 183 not treated with immunosuppressives). Tip lesion variant, absence of severe renal dysfunction (eGFR≥30 ml/min per 1.73 m²), and hypoalbuminemia were associated with a higher likelihood of exposure to any immunosuppressive therapy. Only tip lesion was associated with initiation of glucocorticoids alone over calcineurin inhibitors. With adjusted Cox regression, immunosuppressive therapy with glucocorticoids and/or calcineurin inhibitors was associated with better renal survival than no immunosuppression (hazard ratio, 0.49; 95% confidence interval, 0.28 to 0.86). Calcineurin inhibitors with or without glucocorticoids were not significantly associated with a lower likelihood of ESRD compared with glucocorticoids alone (hazard ratio, 0.42; 95% confidence interval, 0.15 to 1.18).

Conclusions

The use of immunosuppressive therapy with calcineurin inhibitors and/or glucocorticoids as part of the early immunosuppressive regimen in primary FSGS was associated with improved renal outcome, but the superiority of calcineurin inhibitors over glucocorticoids alone remained unproven.     

Extreme lymphocytopenia associated with toxic shock syndrome

Galus MA, Stern J (Medical University of South Carolina, Charleston and Pennsylvania Hospital, Philadelphia, USA). Extreme lymphocytopenia associated with toxic shock syndrome (Case Report). J Intern Med 1998; 244 : 351–354. We report an unusual case of extreme lymphocytopenia associated with staphylococcal toxic shock syndrome. A young, sexually promiscuous man presented with high fevers, productive cough, nausea with occasional vomiting, mild headache and right midthoracic and shoulder pain. His initial lymphocyte count was 72. Such a presentation in an inner city hospital, where about 15% of admissions are AIDS-related, put the diagnosis of AIDS high on the differential list. However, the CD4:CD8 ratio was 1.7, which was inconsistent with AIDS diagnosis. Further work-up led to diagnosis of toxic shock syndrome due to staphylococcal epidural abscess. The patient's lymphocyte count normalized with antibiotic treatment. A 30-year-old man presented because of high fevers, chills, productive cough, nausea with occasional vomiting and mild headache for 3 days. He also complained of right midthoracic back pain and right shoulder pain which started after he lifted a heavy object a few days earlier. He had no diarrhoea. His primary physician treated him with amoxicillin, darvocet and flexeril without significant improvement. Past medical history was significant for three episodes of meningitis in childhood. He denied intravenous drug use, but admitted to having sex with many partners. He looked ill, his temperature was 40 °C, blood pressure was 98/50 mmHg, with a pulse of 160 min^?1 and respiratory rate of 24 min^?1. After intravenous fluids, his blood pressure rose to 120/70 mm Hg with a pulse of 130 min^?1. There was a faint diffuse macular erythematous rash on the trunk and extremities. There was no nuchal rigidity. Cardiac examination revealed no gallops or murmurs. There were crackles at the right lung base. Examination of the abdomen was benign. There was tenderness to palpation of the right paraspinal muscles at midthoracic level, but no pain along the extent of the cervical and thoracic spinous processes. Neurological examination was non-focal. The results of blood tests are listed in Table 1. Chest X-ray showed increased interstitial markings. A sputum Gram stain showed Gram-positive cocci in clusters, and sputum culture grew normal flora. Lumbar puncture revealed 43 leucocytes mm^?3 with 84% of polymorphonuclear neutrophils and 16% of monocytes, glucose 64 mg dL^?1, protein 59 mg dL^?1 and no organisms were seen. No India ink examination was performed. The patient was started on broad antibiotic coverage. Chest X-ray repeated after intravenous fluid administration revealed bibasilar infiltrates and generalized increase in interstitial markings, suggesting opportunistic infection. Increased alveolar–arterial gradient persisted. Cerebrospinal fluid, blood and throat cultures showed no growth of bacteria after 24 h. Liver function tests showed slightly elevated transaminases, total bilirubin and alkaline phosphatase. Empiric therapy for Pneumocystis carinii pneumonia was begun. The patient underwent bronchoscopy which revealed acute inflammation but no Pneumocystis carinii or acid-fasting bacilli. Rapid respiratory panel was also negative after 24 h. HIV test and RPR were non-reactive. CD4 count was 43, and CD8 25 with a ratio of 1.7. Therapy for Pneumocystis carinii was discontinued, and broad antibiotic coverage was continued. On the fourth day of hospitalization, the patient started to feel better, but was still febrile. Although unlikely, doxycycline was added to cover Rocky Mountain spotted fever, leptospirosis and ehrlichiosis. A skin biopsy revealed slight chronic inflammation and telangiectasia consistent with a viral exanthem. An abdominal ultrasound was normal. Hepatitis panel was negative and rubella titres were negative. There was a low level of rubeola IgG antibodies; mono-spot and rapid respiratory panel were negative for viral infections. By the sixth day of hospitalization, clinically the patient improved further. He was feeling much better, had more energy, no shorthness of breath, only a low-grade temperature, and his rash had cleared. He still complained of some right midthoracic pain and right shoulder pain. He developed desquamation of skin of the face and palms, which he insisted was an old recurrent problem secondary to an occupational exposure preceding this illness. Ehrlichia antibodies were negative, cold agglutinin titre was low, parvovirus IgG antibodies were positive with a negative IgM; R. typhi < 1:64, R. rickettsii < 1:64. His white cell count remained persistently elevated at 14 000 mm^?3, but left shift with bandaemia resolved. The plan was to complete a 10-day antibiotic course and discharge the patient home. Despite clinical improvement, his alkaline phosphatase rose to 850 units L^?1, total bilirubin of 2.3 mg dL^?1, with normal transaminases. A repeat abdominal ultrasound was unremarkable. Following antecubital placement of heplock on the 10th day in hospital, the patient started to complain of numbness and weakness of the right hand. Neurological examination revealed weakness in the right upper extremity in a multiple nerve distribution. The neurologist suggested that the weakness might be factitious; however, he recommended an MRI of the cervical spine. The MRI revealed an epidural abscess at the level of C7–T1 and T1 osteomyelitis. The patient underwent emergent laminectomy and drainage of 10 mL of pus. Cultures grew methicillin-susceptible Staphylococcus aureus. The patient was discharged to home in a stable condition to complete a prolonged course of intravenous antibiotic therapy as an outpatient. Weakness in his hand improved after a neurosurgical procedure. Just before discharge the patient gave additional history of recent contact dermatitis of the palms for which he was receiving weekly intramuscular steroid injections.     

Interferon‐γ‐ and glucocorticoid‐mediated pathways synergize to enhance death of CD4+ CD8+ thymocytes during Salmonella enterica serovar Typhimurium infection

Thymic atrophy is known to occur during infections; however, there is limited understanding of its causes and of the cross-talk between different pathways. This study investigates mechanisms involved in thymic atrophy during a model of oral infection by Salmonella enterica serovar Typhimurium (S. typhimurium). Significant death of CD4⁺ CD8⁺ thymocytes, but not of single-positive thymocytes or peripheral lymphocytes, is observed at later stages during infection with live, but not heat-killed, bacteria. The death of CD4⁺ CD8⁺ thymocytes is Fas-independent as shown by infection studies with lpr mice. However, apoptosis occurs with lowering of mitochondrial potential and higher caspase-3 activity. The amounts of cortisol, a glucocorticoid, and interferon-γ (IFN-γ), an inflammatory cytokine, increase upon infection. To investigate the functional roles of these molecules, studies were performed using Ifnγ^−/− mice together with RU486, a glucocorticoid receptor antagonist. Treatment of C57BL/6 mice with RU486 does not affect colony-forming units (CFU), amounts of IFN-γ and mouse survival; however, there is partial rescue in thymocyte death. Upon infection, Ifnγ^−/− mice display higher CFU and lower survival but more surviving thymocytes are recovered. However, there is no difference in cortisol amounts in C57BL/6 and Ifnγ^−/− mice. Importantly, the number of CD4⁺ CD8⁺ thymocytes is significantly higher in Ifnγ^−/− mice treated with RU486 along with lower caspase-3 activity and mitochondrial damage. Hence, endogenous glucocorticoid and IFN-γ-mediated pathways are parallel but synergize in an additive manner to induce death of CD4⁺ CD8⁺ thymocytes during S. typhimurium infection. The implications of this study for host responses during infection are discussed.     

Use of inhaled and oral glucocorticoids, severity of inflammatory disease and risk of hip/femur fracture: a population-based case-control study

BACKGROUND: Patients using higher dosages of inhaled or oral glucocorticoids (GCs) have an increased risk of hip/femur fractures. The role of the underlying disease in the aetiology of this increased risk has not been widely studied. OBJECTIVE: To evaluate the contribution of the underlying disease to the risk of hip/femur fracture in patients using inhaled or oral GCs. DESIGN AND SUBJECTS: A case-control study within the Dutch PHARMO-RLS database was conducted. Cases (n = 6763) were adult patients with a first hip/femur fracture during enrolment. Each case was matched to four controls by age, gender and region. RESULTS: The risk of hip/femur fracture increased with current use of inhaled GCs (crude OR 1.30, 95% CI:1.16-1.47) and with current use of oral GCs (crude OR 1.66, 95% CI: 1.46-1.90). After adjustment for disease severity, the risk of hip/femur fracture was no longer statistically significantly increased in inhaled GC users (adjusted OR 1.08, 95% CI: 0.91-1.27), whilst it remained elevated in oral GC users (adjusted OR 1.43, 95% CI: 1.22-1.67). Patients using inhaled GCs without any exposure to oral GCs had no increased risk of fracture (adjusted OR 0.98, 95% CI: 0.79-1.22). CONCLUSION: Inhaled GC users had no increased risk of femur/hip fracture after adjustment for underlying disease severity. Our data suggest that, even at higher dosages, inhaled GC use is not an independent risk factor for fracture. In contrast, oral GC use was associated with an increased risk of fracture, which was not fully explained by the underlying disease severity.