Congenital adrenal hyperplasia (CAH) is a recognized cause of precocious pseudopuberty. Some children with CAH also develop true precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis. We have seen four such children (three boys and one girl) who had the diagnosis of CAH made between the ages of 3 and 6 yr. These patients were treated with standard doses of hydrocortisone and fludrocortisone. A diagnosis of true precocious puberty was made because of testicular enlargement in the boys, breast development in the girl, progressive pubic hair development, rapid growth, and rapid bone age maturation. Plasma steroid levels were elevated for age, and gonadotropin levels were within the normal pubertal range, both basally and in response to LHRH stimulation. We treated these children with daily sc injections of a LHRH analog (LHRHa) for 6-18 months in addition to the standard hydrocortisone and fludrocortisone therapy for CAH. LHRHa significantly decreased basal plasma LH and FSH, peak LH and FSH responses to native LHRH, and testosterone levels. Testis size decreased in the males, and breast development regressed in the female. LHRHa therapy led to significant decreases in linear growth rate, ulnar growth rate, and rate of bone age advancement. These results suggest that LHRHa is an effective adjunct to hydrocortisone and fludrocortisone in the treatment of true precocious puberty complicating CAH.

BACKGROUND

Chronic lung disease (CLD) remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat CLD because of their potent anti-inflammatory effects.

OBJECTIVE

To determine if postnatal corticosteroid treatment is of benefit in the prevention of chronic lung disease (CLD) in preterm infants. This review examines the outcome of trials where preterm infants at risk of CLD were given postnatal corticosteroids within the first seven days of life.

METHODS

Randomised controlled trials (RCTs) of postnatal corticosteroid therapy were sought from the Cochrane Controlled Trials Register, MEDLINE (1966 - May 2008), hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. Authors of all studies were contacted, where possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported.

METHODS

Randomised controlled trials of postnatal corticosteroid treatment within the first 7 days of life (early) in high risk preterm infants were selected for this review. Most studies evaluated the use of dexamethasone but we also included studies that assessed hydrocortisone, even if it was used to manage hypotension.

METHODS

Data regarding clinical outcomes including mortality, CLD (including late rescue with corticosteroids, and need for home oxygen therapy), death or CLD, failure to extubate, complications during the primary hospitalisation (including infection, hyperglycaemia, hypertension, pulmonary air leak, patent ductus arteriosus (PDA), severe intraventricular haemorrhage (IVH), periventricular leucomalacia (PVL), necrotising enterocolitis (NEC), gastrointestinal bleeding, intestinal perforation, severe retinopathy of prematurity (ROP), and long-term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability) were abstracted and analysed using RevMan 5.

RESULTS

Twenty-eight RCTs enrolling a total of 3740 participants were eligible for inclusion in this review. A meta-analysis of these trials demonstrated significant benefits as regards earlier extubation and decreased risks of CLD at both 28 days and 36 weeks' postmenstrual age (PMA), death or CLD at 28 days and 36 weeks' PMA, PDA and ROP, including severe ROP. There were no significant differences in the rates of neonatal or subsequent mortality, infection, severe IVH, PVL, NEC or pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects and the risks of hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure were also increased. In the twelve trials that reported late outcomes, several adverse neurological effects were found at follow-up examinations including developmental delay (not defined), cerebral palsy and abnormal neurological examination. However, major neurosensory disability was not significantly increased, either overall in the seven studies where this outcome could be determined, or in the two individual studies where the rates of cerebral palsy or abnormal neurological examination were significantly increased. Moreover, the rates of the combined outcomes of death or cerebral palsy, or of death or major neurosensory disability were not significantly increased. Dexamethasone was the drug used in most studies (n = 20); only eight studies used hydrocortisone. In subgroup analyses by type of corticosteroid, most of the beneficial and harmful effects were attributable to dexamethasone; hydrocortisone had little effect on any outcomes except for an increase in intestinal perforation and a borderline reduction in PDA.

CONCLUSIONS

The benefits of early postnatal corticosteroid treatment (</= 7 days), particularly dexamethasone, may not outweigh the known or potential adverse effects of this treatment. Although early corticosteroid treatment facilitates extubation and reduces the risk of chronic lung disease and patent ductus arteriosus, it causes short-term adverse effects including gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure. Long-term follow-up studies report an increased risk of abnormal neurological examination and cerebral palsy. However, the methodological quality of the studies determining long-term outcomes is limited in some cases; the surviving children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. There is a compelling need for the long-term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomised trials of early postnatal corticosteroid treatment. Hydrocortisone in the doses and regimens used in the reported RCTs has few beneficial or harmful effects and cannot be recommended for prevention of CLD.

BACKGROUND

Osteopenia is common in the era of effective antiretroviral therapy (ART), yet the etiology is unclear. We evaluated the association of host factors, disease severity, and ART to changes in total body bone mineral density (total BMD) over time in HIV-infected men (n = 283) and women (n = 96).

METHODS

Total BMD was measured annually by whole-body dual-energy absorptiometry (DXA), and medical, dietary, and behavioral history was collected. The median time from first to last DXA was 2.5 years (range 0.9-6.8 years). Using a repeated measures regression model, we identified variables independently associated with percent change in total BMD between consecutive DXA exams (n = 799 intervals), adjusted for age, race, sex, menopause, and smoking. We estimated percent change in total BMD over an average interval (1 year) standardized for representative levels of each determinant in males, premenopausal women, and postmenopausal women.

RESULTS

Median baseline age, CD4, and viral load were 42 years, 364 cells per cubic millimeter, and 2.7 log10 copies per milliliter, respectively. The estimated change in total BMD for those not on ART was -0.37% per year [95% confidence interval (CI) -0.76 to -0.02] for men, -0.08% per year (95% CI -0.49 to 0.33) for premenopausal women, and -1.07% per year (95% CI -1.86 to -0.28) for postmenopausal women. Greater loss of total BMD was associated with lower albumin, lower body mass index, prednisone/hydrocortisone use, tenofovir use, and longer duration of didanosine. Strength training and long duration of d4T and saquinavir prevented or mitigated bone loss. For those on ART for 3 years (not including the above agents), the rate of loss was -0.57% per year (95% CI -1.00 to -0.14) for men, -0.28% (95% CI -0.71 to 0.15) for premenopausal women, and -1.27% (95% CI -2.07 to -0.47) for postmenopausal women. Postmenopausal women had greater loss than premenopausal women and men.

CONCLUSIONS

Low body weight, low albumin, catabolic steroid use, and menopause may accelerate bone loss, and strength training may be protective. Tenofovir and didanosine may also have a deleterious effect on BMD.

BACKGROUND. Many extremely low birth weight infants (<1000 g) show biochemical evidence of adrenal insufficiency in the first week of life, correlating with subsequent development of chronic lung disease (CLD).

METHODS

We conducted a randomized, double-masked, placebo-controlled pilot study to test whether early treatment with low-dose hydrocortisone for 12 days (1 mg/kg/day for 9 days followed by.5 mg/kg/day for 3 days), begun before 48 hours of life, would increase the likelihood of survival without CLD.

RESULTS

Forty patients were enrolled at two centers. Birth weight and gestation were similar for treatment and placebo groups: 732 +/- 135 g versus 770 +/- 135 g and 25.2 +/- 1.3 weeks versus 25.4 +/- 1.5 weeks. More infants treated with hydrocortisone achieved study success, defined as survival without supplemental oxygen at 36 weeks' postconception (12/20 [60%] vs 7/20 [35%]). Lower birth weight, histologic chorioamnionitis, and preeclampsia were significant risk factors, whereas study center, prenatal steroids, sex, and ethnicity were not significant. Hydrocortisone treatment decreased days on >40% oxygen, days on >25% oxygen, days on ventilator, and oxygen at discharge. Among infants exposed to chorioamnionitis, hydrocortisone treatment also was associated with increased enteral intake during the first month of life and with increased weight at 36 weeks' postconception. Five treated infants and 6 placebo infants developed sepsis; 3 in each group died.

CONCLUSIONS

First, early treatment with low-dose hydrocortisone in this population of extremely low birth weight infants increased the likelihood of survival without CLD. Second, the benefit was particularly apparent in infants with chorioamnionitis. Third, a larger multicenter trial is needed to verify the primary outcome and to better evaluate risks and benefits.

Osteoprotegerin (OPG) is a recently cloned member of the tumour necrosis factor receptor family. It has been suggested that this secreted glycoprotein acts as an inhibitor of osteoclastic differentiation. Expression of OPG has previously been demonstrated in a number of tissues. However, it is still unclear whether or not OPG is expressed by human osteoblasts. We have used the RNase protection assay to demonstrate the OPG transcript in primary cultured human osteoblast-like cells, human marrow stroma cells and osteosarcoma cell lines. Furthermore, we have studied the effect of glucocorticoids on OPG mRNA levels in these cells. We demonstrate that glucocorticoids decrease the OPG transcript in a dose- and time-dependent manner. The time-course study reveals that hydrocortisone (10(-6) M) decreases OPG mRNA levels within 2 h. This decrease is transient, reaching control levels again after 24 h. Our findings demonstrate that human osteoblasts express the mRNA corresponding to OPG, an inhibitor of osteoclast differentiation. The finding that OPG mRNA levels are decreased by glucocorticoids indicates that a reduced production of OPG from osteoblasts and/or marrow stroma cells could, in part, explain glucocorticoid-induced bone resorption.

OBJECTIVE

Cyclosporin, FK-506 and rapamycin have similar but distinct modes of interaction with cyclophilins, calcineurins and transcription factors. These immunosuppressive drugs have also been shown to inhibit cytotoxic and inflammatory responses in macrophage. Therefore, we evaluated the mechanism of action of these drugs on iNOS and COX-2 expression by macrophages, the products of which (NO and PGE2) have cytotoxic and proinflammatory activities.

METHODS

The murine macrophage cell line RAW 264.7 was grown as monolayer cultures. The effects of pharmacologically relevant concentrations of cyclosporin, rapamycin and FK-506 were evaluated in the presence and absence of lipopolysaccharide (LPS) which is a known inducer of iNOS and COX-2. Subsequently the expression of iNOS and COX-2 were analyzed by Western and Northern analysis. The production of NO and PGE2 were assayed by Greiss and RIA respectively.

RESULTS

Cyclosporin (1-5 microg/ml) and rapamycin (1.0-10 nM) but not FK-506 (5-10 nM) inhibited both iNOS and COX-2 expression at mRNA level which led to significant inhibition of NO and PGE2 production.

CONCLUSIONS

These studies characterize differential mechanistic capacity of the immunophilin-binding immunosuppressive drugs (comparable to hydrocortisone) to inhibit both iNOS and COX-2 expression. Inhibition of iNOS and COX-2 mRNA accumulation by cyclosporin and rapamycin seem to be distinct. These studies also highlight potential anti-inflammatory properties of these drugs in addition to their known immunosuppressive activity.

1. Airway smooth muscle proliferation is a significant component of the airway wall remodelling that occurs in asthma. In this study, the effects of glucocorticoids on mitogenic responses of human airway smooth muscle have been examined. 2. Pretreatment of smooth muscle cells with dexamethasone (100 nM, 60 min) inhibited thrombin-induced increases in [3H]-thymidine incorporation (DNA synthesis) and cell number. 3. Inhibition of thrombin-induced [3H]-thymidine incorporation was also observed with hydrocortisone (0.01-1 microM) and methylprednisolone (0.001-0.1 microM) pretreatment. In contrast, pretreatment with either testosterone (0.001-1 microM) progesterone (0.001-1 microM), 17 beta-oestradiol (0.001-1 microM), or aldosterone (0.001-1 microM) had no effect on the response to thrombin. 4. Responses to a range of mitogens including thrombin (0.01-. 10 u ml-1), epidermal growth factor (EGF, 3-3000 pM), basic fibroblast growth factor (bFGF, 0.3-300 pM) and foetal calf serum (FCS, 0.1-10% v/v) were inhibited by dexamethasone (100 nM) pretreatment. However, the magnitude of the inhibitory effect was dependent on the mitogen, with EGF being the least, and thrombin being the most sensitive to the inhibitory effect. 5. The potency of hydrocortisone as an inhibitor of [3H]-thymidine incorporation was reduced when FCS (10% v/v, which caused a 40 fold increase in [3H]-thymidine incorporation) was used as the mitogen in place of thrombin (0.3 u ml-1, which caused a 10 fold increase in [3H]-thymidine incorporation). 6. The effect of post-treatment with dexamethasone (100 nM) indicated that addition of the glucocorticoid up to 17-19 h after thrombin (0.3 u ml-1) produced similar degrees of inhibition to those obtained when it was added as a pretreatment. Dexamethasone no longer produced an inhibitory effect if added 21 h or more after the addition of thrombin. 7. These results suggest that glucocorticoids regulate airway smooth muscle proliferation initiated by a range of stimuli. This effect may be of importance in the therapeutic actions of these compounds in asthma, particularly when they are used for prolonged periods of time.

BACKGROUND

Chronic fatigue syndrome (CFS) is associated with a dysregulated hypothalamic-pituitary adrenal axis and hypocortisolemia.

OBJECTIVE

To evaluate the efficacy and safety of low-dose oral hydrocortisone as a treatment for CFS.

METHODS

A randomized, placebo-controlled, double-blind therapeutic trial, conducted between 1992 and 1996.

METHODS

A single-center study in a tertiary care research institution.

METHODS

A total of 56 women and 14 men aged 18 to 55 years who met the 1988 Centers for Disease Control and Prevention case criteria for CFS and who withheld concomitant treatment with other medications.

METHODS

Oral hydrocortisone, 13 mg/m2 of body surface area every morning and 3 mg/m2 every afternoon, or placebo, for approximately 12 weeks.

METHODS

A global Wellness scale and other self-rating instruments were completed repeatedly before and during treatment. Resting and cosyntropin-stimulated cortisol levels were obtained before and at the end of treatment. Patients recorded adverse effects on a checklist.

RESULTS

The number of patients showing improvement on the Wellness scale was 19 (54.3%) of 35 placebo recipients vs 20 (66.7%) of 30 hydrocortisone recipients (P =.31). Hydrocortisone recipients had a greater improvement in mean Wellness score (6.3 vs 1.7 points; P=.06), a greater percentage (53% vs 29%; P=.04) recording an improvement of 5 or more points in Wellness score, and a higher average improvement in Wellness score on more days than did placebo recipients (P<.001). Statistical evidence of improvement was not seen with other self-rating scales. Although adverse symptoms reported by patients taking hydrocortisone were mild, suppression of adrenal glucocorticoid responsiveness was documented in 12 patients who received it vs none in the placebo group (P<.001).

CONCLUSIONS

Although hydrocortisone treatment was associated with some improvement in symptoms of CFS, the degree of adrenal suppression precludes its practical use for CFS.

The mechanism whereby glucocorticosteroids are immunosuppressive is unknown. One potential mechanism of action of these compounds is inhibition of arachidonic acid metabolism. We found that the inhibition of lymphocyte proliferation by hydrocortisone or dexamethasone was mimicked by nonspecific lipoxygenase inhibitors and also by a specific 5-lipoxygenase inhibitor, but not by a specific cyclooxygenase inhibitor. Mitogen-stimulated cultures of T cells produce approximately 5 X 10(-9) M leukotriene B4 (LTB4) in 24 h. This production of LTB4 is completely inhibited by concentrations of hydrocortisone or lipoxygenase inhibitors that inhibit mitogen-induced [3H]thymidine incorporation. The inhibition of lymphocyte proliferation by either hydrocortisone or by the 5-lipoxygenase inhibitor was totally reversed by LTB4 but not by leukotriene C4 or leukotriene D4. LTB4 had no effect on the inhibition of lymphocyte proliferation by noncorticosteroids such as prostaglandin E2, histamine, or gamma-interferon. The inhibition of interleukin 2 (IL-2) production by hydrocortisone or dexamethasone was also completely reversed by exogenous LTB4. LTB4 alone did not cause IL-2 production or cell proliferation when added to resting lymphocytes. Thus, endogenous LTB4 production appears to be necessary but not sufficient for phytohemagglutinin-induced IL-2 production and lymphocyte proliferation. Glucocorticosteroids inhibit IL-2 production and lymphocyte proliferation by inhibiting endogenous LTB4 production.

Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders where there is impairment of cortisol biosynthesis. CAH due to 21-hydroxylase deficiency accounts for 95% of cases and shows a wide range of clinical severity. Treatment of the classic or severe form of CAH is targeted at replacing cortisol and aldosterone and effectively controlling excess androgen symptoms by using the lowest possible glucocorticoid dose. Treatment of the mild or nonclassic form is targeted at controlling excess androgen symptoms and may or may not involve glucocorticoid therapy. Hydrocortisone is the treatment of choice for children, but there is no consensus on how patients should be treated as adults. Current glucocorticoid therapy is suboptimal because it is often difficult to reduce excess androgen without giving excess glucocorticoid, and patients may experience hypercortisolism, androgen excess, or a combination of these states. Treatment of CAH, especially in the adult patient, remains controversial given the lack of prospective randomized controlled trials comparing treatment regimens. Nevertheless, patients benefit from careful individualized therapy with avoidance of Cushingoid side effects and optimization of reproductive, sexual, and bone health.

We characterized the alkaline phosphatase activity of the human osteogenic sarcoma cell line, SAOS-2, and studied the regulation of this enzyme and 3',5'-cyclic adenosine monophosphate levels by 1,25-dihydroxyvitamin D3 and triamcinolone acetonide. We report that the basal alkaline phosphatase activity of SAOS-2 cells was 100-1000 times greater than that of other established human osteogenic sarcoma cell lines. The enzymatic activity was thermolabile, could be inhibited by levamisole and L-homoarginine, but not by L-phenylalanine, and was immunoprecipitable with anti-bone/liver/kidney, but not with anti-placental antibody, confirming that it is the tissue-unspecific or bone/liver/kidney isoenzyme. However, in contrast to other established human osteosarcoma cell lines (TE-85, SAOS-1), in which alkaline phosphatase activity is stimulated several-fold by the steroid hormones 1,25-dihydroxyvitamin D3 and hydrocortisone, the alkaline phosphatase activity of SAOS-2 cells was not affected by 1,25-dihydroxyvitamin D3 treatment despite the presence of classical receptors for this hormone. Furthermore, administration of the potent glucocorticoid analogue, triamcinolone acetonide, induced only a modest increase in activity. The SAOS-2 cell line expressed low basal cAMP levels (28 pmol/10(6) cells) which could be increased 25-40 times by pretreatment with parathyroid hormone. However, unlike other osteoblastic models, in which PTH-induced cAMP stimulation is modulated by 1,25-dihydroxyvitamin D3 and glucocorticoids, neither of these hormones had an effect on the PTH-stimulated cAMP levels in SAOS-2 cells. We conclude that the SAOS-2 cell line is an osteoblastic cell model which expresses high levels of tissue-unspecific alkaline phosphatase activity and exhibits limited responsiveness to two steroid hormones.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor-promoting 12-O-tetradecanoyl-phorbol-13-acetate and phorbol-12, 13-di-decanoate, but not the non-tumor-promoting 4alpha-phorbol-12, 13-di-decanoate, stimulated deacylation of cellular lipids, prostaglandin biosynthesis, and morphological changes in cultured MDCK cells. The increased prostaglandin biosynthesis and morphological changes required at least 24 h for expression. Cycloheximide inhibited the stimulated prostaglandin biosynthesis, the changes in morphology, and the increased lipid deacylation, but hydrocortisone (1.0 microgram/ml) did not. Indomethacin (0.5 microgram/ml) completely inhibited the stimulated prostaglandin biosynthesis and also inhibited some deacylation of cellular lipids. Indomethacin, however, did not effect the 12-O-tetradecanoyl-phorbol-13-acetate-stimulated changes in morphology.

We have initiated an analysis of the action of prolactin in a human breast cancer cell line (T-47D) by isolating and sequencing cDNA clones for a prolactin-inducible protein (PIP). PIP cDNA (approximately 600 base pairs) was isolated from a lambda gt11 expression library prepared from mRNA extracted from T-47D cells treated with prolactin and hydrocortisone. The identity of PIP cDNA was confirmed by hybrid-selected translation. PIP mRNA is a single mRNA species of approximately 900 bases which responds to lactogenic hormones (human prolactin and growth hormone) in a time- and dose-dependent manner. Treatment of T-47D cells with human growth hormone (hGH) increased PIP mRNA levels by 4.6-fold, while the combination of hGH and hydrocortisone or dihydrotestosterone had a more dramatic, 12.4-fold, effect. The latter steroid was the most potent. Dihydrotestosterone plus hGH increased transcription of the PIP gene by 3.7-fold. Dihydrotestosterone alone was as effective as dihydrotestosterone plus hGH in increasing the transcription rate, while hGH alone had no effect. Thus, lactogen may regulate PIP gene expression at a post-transcriptional step. PIP mRNA was expressed at low levels in other human breast cancer cell lines which were prolactin receptor-positive; MCF-7 and EFM-19 lines were exceptions. PIP cDNA had an open reading frame of 146 amino acids, sufficient to encode the precursor form of the secreted PIP protein (approximately 14.5 kDa). The similarity of the predicted amino acid sequence of PIP to the sequence of a protein encoded by a gene expressed in the mouse submaxillary gland prompted us to look for PIP in human saliva. Western blot analysis confirmed the presence of PIP in human saliva. Therefore, the PIP gene is useful in studying the molecular actions of the prolactin/growth hormone polypeptide hormone family and the interaction with androgen, in mammary and other potential target cells.

BACKGROUND

Ocular hypertension and open-angle glaucoma are well-known side-effects of treatment with topical ophthalmic glucocorticoids. There is uncertainty about the risk of these disorders with oral glucocorticoid therapy.

METHODS

Data from the Quebec universal health insurance programme for the elderly were used to identify 9793 patients with a new diagnosis of ocular hypertension or open-angle glaucoma, or on newly prescribed treatment for these disorders (cases). 38,325 controls were randomly selected from ophthalmology patients seen in the same month and year as the case (index date). Current use of oral glucocorticoids was defined as that within 14 days of the index date. All glucocorticoid doses were converted to the equivalent amount of hydrocortisone. The case-control analysis was done by conditional logistic regression and adjusted for age, sex, systemic hypertension, diabetes mellitus, ophthalmic glucocorticoids, glucocorticoid injections, and variables related to general health.

RESULTS

The mean ages of cases and controls were similar (74.9 [SD 6.3] vs 74.7 [6.4]). The adjusted odds ratio of ocular hypertension or open-angle glaucoma for current users of oral glucocorticoids compared with non-users was 1.41 (95% CI 1.22-1.63). There was a dose-related increase in the adjusted odds ratios for current users: 1.26 (1.01-1.56) for less than 40 mg per day of hydrocortisone, 1.37 (1.06-1.76) for patients on 40-79 mg per day, and 1.88 (1.40-2.53) for patients on 80 mg or more per day. The odds ratios also increased with the duration of treatment over the first 11 months of exposure.

CONCLUSIONS

The use of oral glucocorticoids increases the risk of ocular hypertension or open-angle glaucoma in elderly patients. In patients in this age-group who need long-term treatment with high doses of oral glucocorticoids, monitoring of intraocular pressure may be justified.

The effectiveness of an emollient as an adjunct to topical corticosteroid therapy for the treatment of mild to moderate atopic dermatitis was studied for 3 weeks in 25 children 3 to 15 years of age in comparison with corticosteroid therapy alone. The adjunctive regimen of a once-daily application each of hydrocortisone 2.5% cream and of a water-in-oil cream was equivalent in efficacy to the comparative regimen of twice-daily applications of hydrocortisone 2.5% cream. Both treatment regimens elicited significant improvement in skin condition by day 7 ( p < 0.005) and further significant improvement by day 14 (p < 0.005). No significant differences between the two treatment regimens were observed in the rates of improvement (p>> 0.545) or in the reductions in mean lesion size (p>> 0.98). No differences were observed in parental evaluations, except for ease of application where a slight preference was expressed for the hydrocortisone 2.5% cream preparation (p < 0.038). We conclude that emollient adjunctive therapy offers a steroid-sparing alternative to topical corticosteroids alone in the treatment of mild to moderate atopic dermatitis.

Myxedema coma, the extreme manifestation of hypothyroidism, is an uncommon but potentially lethal condition. Patients with hypothyroidism may exhibit a number of physiologic alterations to compensate for the lack of thyroid hormone. If these homeostatic mechanisms are overwhelmed by factors such as infection, the patient may decompensate into myxedema coma. Patients with hypothyroidism typically have a history of fatigue, weight gain, constipation and cold intolerance. Physicians should include hypothyroidism in the differential diagnosis of every patient with hyponatremia. Patients with suspected myxedema coma should be admitted to an intensive care unit for vigorous pulmonary and cardiovascular support. Most authorities recommend treatment with intravenous levothyroxine (T4) as opposed to intravenous liothyronine (T3). Hydrocortisone should be administered until coexisting adrenal insufficiency is ruled out. Family physicians are in an important position to prevent myxedema coma by maintaining a high level of suspicion for hypothyroidism.

OBJECTIVE

Improvement in health-related quality of life is a major object of cardiac surgery. However, high stress exposure during the perioperative period of cardiac surgery can result in the formation of traumatic memories and symptoms of chronic stress or even posttraumatic stress disorder, which can have negative effects on health-related quality-of-life outcome. In this controlled study we examined whether exogenously administered stress doses of hydrocortisone during cardiac surgery reduce perioperative stress exposure and the long-term incidence of chronic stress symptoms and improve health-related quality of life after cardiac surgery.

METHODS

Thirty-six high-risk patients undergoing cardiac surgery were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Of 28 available patients at 6 months after cardiac surgery, 14 had received hydrocortisone, and 14 had received placebo. Traumatic memories, chronic stress symptoms (posttraumatic stress disorder scores), and health-related quality of life were measured by using validated questionnaires.

RESULTS

Compared with patients from the placebo group, patients from the hydrocortisone group had a significantly shorter duration of intensive care unit treatment, required lower doses of the stress hormone norepinephrine during cardiac surgery, and had significantly fewer stress symptoms and a better health-related quality of life regarding physical function, chronic pain, general health, vitality, and mental health during follow-up. The groups did not differ with regard to the number or type of intensive care unit-related traumatic memories.

CONCLUSIONS

The use of stress doses of hydrocortisone in high-risk cardiac surgical patients reduces perioperative stress exposure, decreases chronic stress symptoms, and improves health-related quality of life at 6 months after cardiac surgery.

We prospectively evaluated infusion-related toxicities in 82 recipients of autologous bone marrow grafts. The grafts were cryopreserved in 10% dimethylsulfoxide and stored in liquid nitrogen. All grafts were concentrated and buffy-coat cells were collected. Forty-seven grafts were treated ex vivo with 4-hydroperoxycyclophosphamide (4-HC) at 100 micrograms/mL; 26 grafts were further processed using density-gradient separation and treated with 4-HC at 60 micrograms/mL. Nine buffy-coat concentrates were frozen without drug treatment. Before infusion, patients were medicated with mannitol, hydrocortisone, and diphenhydramine. Grafts were rapidly thawed and immediately infused without further manipulation. During the infusions, 33 (70%) recipients of treated buffy-coat, 5 (56%) recipients of untreated buffy-coat, and 6 (23%) recipients of density-gradient separated grafts experienced varying symptoms including nausea, abdominal cramping, and flushing. Forced vital capacities for 83% of the recipients of treated buffy-coat concentrates decreased after the graft infusion; six of these patients complained of dyspnea and one patient experienced an acute episode of respiratory decompensation. Decreased heart rates were observed in 98% of the recipients of treated buffy-coat cells with asymptomatic bradycardia occurring in 45%. Forty-five patients (96%) in this group experienced transient hypertension, with 18 (38%) requiring additional medications within 6 hours after the infusion for control of blood pressure. Similar cardiovascular changes were observed in the recipients of untreated buffy-coat concentrates. One recipient of an untreated buffy-coat concentrate had 2 degrees heart block after the graft infusion. Twenty-three (88%) recipients of density-gradient separated grafts had decreased heart rates and 21 (81%) had increased blood pressure. However, the degrees of change were less than those experienced by the recipients of treated buffy-coat cells (P less than .01). Forced vital capacities were not affected by the infusion of the density-gradient separated grafts. No renal failure or obvious hemolytic episodes occurred for any patient group. Minor to moderate toxicities were associated with cryopreserved graft infusions. Recipients of buffy-coat separated grafts, both treated and untreated, experienced more complications than the recipients of density-gradient separated grafts. These toxicities may relate to the volumes of cryoprotectant and cell lysis products infused, which were less for the more highly purified density-gradient separated grafts.

The role of insulin in milk protein synthesis is unresolved in the bovine mammary gland. This study examined the potential role of insulin in the presence of two lactogenic hormones, hydrocortisone and prolactin, in milk protein synthesis. Insulin was shown to stimulate milk protein gene expression, casein synthesis and (14)C-lysine uptake in mammary explants from late pregnant cows. A global assessment of changes in gene expression in mammary explants in response to insulin was undertaken using Affymetrix microarray. The resulting data provided insight into the molecular mechanisms stimulated by insulin and showed that the hormone stimulated the expression of 28 genes directly involved in protein synthesis. These genes included the milk protein transcription factor, ELF5, translation factors, the folate metabolism genes, FOLR1 and MTHFR, as well as several genes encoding enzymes involved in catabolism of essential amino acids and biosynthesis of non-essential amino acids. These data show that insulin is not only essential for milk protein gene expression, but stimulates milk protein synthesis at multiple levels within bovine mammary epithelial cells.

Stromal cells are essential components of the bone marrow (BM) microenvironment that regulate and support the survival of different tumors, including chronic lymphocytic leukemia (CLL). In this study, we investigated the role of Notch signaling in the promotion of survival and chemoresistance of human CLL cells in coculture with human BM-mesenchymal stromal cells (hBM-MSCs) of both autologous and allogeneic origin. The presence of BM-MSCs rescued CLL cells from apoptosis both spontaneously and following induction with various drugs, including Fludarabine, Cyclophosphamide, Bendamustine, Prednisone and Hydrocortisone. The treatment with a combination of anti-Notch-1, Notch-2 and Notch-4 antibodies or γ-secretase inhibitor XII (GSI XII) reverted this protective effect by day 3, even in presence of the above-mentioned drugs. Overall, our findings show that stromal cell-mediated Notch-1, Notch-2 and Notch-4 signaling has a role in CLL survival and resistance to chemotherapy. Therefore, its blocking could be an additional tool to overcome drug resistance and improve the therapeutic strategies for CLL.

Cell-matrix interaction is crucial in regulating osteoblast differentiation and function. These interactions are themselves regulated, at least in part, by integrins. Although there are some data from mammalian models, few studies have compared integrin expression at different stages of the osteoblast lineage. Here, primary human mandibular osteoblast cultures were grown in the presence of epidermal growth factor (EGF), giving a proliferative, less differentiated phenotype, or of vitamin D(3) and hydrocortisone (D+Hc), giving a more differentiated phenotype. These cultures were compared with those of cells prepared in the absence of EGF or D+Hc by fluorescence-activated cell sorter using a panel of monoclonal antibodies to specific integrin heterodimers. To provide in vivo correlation, the same panel of antibodies was used to stain fresh-frozen, undemineralised sections of human mandibular bone. Under baseline conditions the alpha(3), alpha(5), alpha(v), alpha(v)beta(3), beta(3) and beta(1) integrin subunits were expressed strongly by the cells, with low-level expression of the alpha(1), alpha(2) and alpha(4) subunits. In the presence of EGF there was increased alpha(2) expression. With D+Hc, alpha(3) and alpha(5) expression was elevated. Immunohistochemical analysis demonstrated alpha(2), alpha(3), alpha(5), alpha(v)beta(3), beta(1) and beta(3) subunits in cells of the osteoblast lineage; alpha(2) staining was restricted to cells close to the bone surface whilst alpha(v)beta(3) and beta(3) were most frequently localised in the osteocytes. The results provide evidence that cells at successive stages of the osteoblast lineage show different patterns of integrin expression. These integrins may be important in cell-matrix interactions leading to osteoblast differentiation.

Exogenous cortisol's modulation of the acoustic startle reflex (ASR) was tested alone and during exposure to affectively valenced photographs in healthy men and women. During nonmodulated startle, oral hydrocortisone had a biphasic dose effect, with 5 mg increasing and 20 mg decreasing, eyeblink reflex magnitude compared to placebo. During emotion modulation, 20 mg of hydrocortisone reduced reflex magnitude without affecting the usual pattern of modulation across positive, neutral, and negatively affective slides. Gender differences were not found in either relationship. These findings illustrate dose-dependent effects of cortisol on the startle pathway independent of emotional state and consistent across genders.