Therapeutic perspectives for adiponectin: an update.

In obesity, the expansion of dysfunctional adipose tissue leads to augmented production of pro-inflammatory adipokines that mediate metabolic changes through their paracrine and/or endocrine actions. By contrast, the secretion and plasma concentration of adiponectin, an adipokine with cardiovascular protective, anti-diabetic and anti-inflammatory properties, are markedly decreased in obesity and its related pathologies. Epidemiological studies on different ethnic groups have identified hypoadiponectinemia as an independent risk factor for type 2 diabetes, hypertension, coronary heart disease and several types of cancers. In animals, replenishment of recombinant adiponectin or transgenic expression of adiponectin can reverse these obesity-related pathological conditions. Although there is currently no direct clinical evidence demonstrating that adiponectin is effective in treating obesity-related cardiometabolic diseases, therapeutic benefits of several anti-diabetic and cardiovascular drugs, such as the agonists of peroxisome proliferator-activated receptor (PPAR) γ and PPAR α and statins, are associated with increased plasma adiponectin in humans. In addition, a number of medicinal herbs and natural compounds with beneficial effects on cardiometabolic diseases, have been shown to increase adiponectin secretion in adipocytes. This review highlights recent advances on multiple beneficial effects of adiponectin and discusses the potential therapeutic interventions for obesity-related cardiometabolic syndromes by targeting adiponectin.

Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials.

The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique ß-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.

Macromolecular scaffolds for immobilizing small molecule microarrays in label-free detection of protein-ligand interactions on solid support.

We explored two macromolecular scaffolds, bovine serum albumin (BSA) and polyvinyl alcohol (PVA), as chemically complementary platforms for immobilizing small molecule compounds on functionalized glass slides. We conjugated biotin molecules to BSA and amine-derivatized PVA and subsequently immobilized the conjugates on epoxy-functionalized glass slides through reaction of free amine residues on BSA and PVA with surface-bound epoxy groups. We studied binding reactions of such immobilized small molecule targets with solution-phase protein probes using an oblique-incidence reflectivity difference scanning optical microscope. The results showed that both BSA and amine-derivatized PVA were effective and efficient as carriers of small molecules with NHS residues and fluoric residues and for immobilization on epoxy-coated solid surfaces. A significant fraction of the conjugated small molecules retain their innate chemical activity.

Inadequate dietary calcium intake in elderly patients with hip fractures.

INTRODUCTION: Calcium supplementation and pharmacotherapy are recommended in the preventive management of osteoporosis. Many previous studies report of underdiagnosis and undertreatment of osteoporosis among elderly patients with hip fractures. We undertook this study to determine the dietary calcium levels in our local elderly population who were admitted with hip fractures. METHODS: 77 patients, between the ages of 60 and 98 years of age, and admitted to our department between January 2001 and September 2001 for hip fractures, were studied. The dietary calcium intakes of these patients were determined by a food frequency questionnaire and a detailed diet history. Bone mineral density (BMD) studies were performed on 55 of these patients to confirm the diagnosis of osteoporosis. RESULTS: The mean daily calcium intake was found to be 650 mg. Only six of our hip fracture patients (7.8 percent) had a daily calcium intake above the recommended levels of 1,000 mg per day. For the 55 patients who had BMD performed, only one patient had a BMD within the normal range. 34 patients (64.2 percent) had hip T-scores in the osteoporotic range and 18 patients (33.9 percent) had hip T-scores in the osteopenic range. We found that the patients with BMD in the osteoporotic and osteopenic ranges had no significant difference in the dietary calcium intake. CONCLUSION: The dietary calcium intake of our elderly patients with hip fractures is insufficient. They would benefit from dietary education and calcium supplements to prevent deterioration in bone density and subsequent osteoporotic fractures.

A comparison of teriparatide and calcitonin therapy in postmenopausal Asian women with osteoporosis: a 6-month study.

OBJECTIVE: The number of hip fractures is expected to double in the next 20 years, with current estimates that Asia will account for 37% of these cases. As bone mineral density (BMD) may be used as a measure of fracture risk, we sought to compare the effects of teriparatide with salmon calcitonin treatment on changes in BMD, biochemical bone markers, and safety in postmenopausal Asian women with osteoporosis. METHODOLOGY: A total of 104 patients (n = 47 teriparatide [20 g/day subcutaneously] and n = 57 calcitonin [100 IU/day subcutaneously]) were enrolled in Hong Kong, Singapore, Philippines, Malaysia, and Thailand. Calcium (> or = 500 mg/day) and vitamin D (200-400 IU/day) supplements were taken throughout the 6-month controlled, randomized study. RESULTS: Teriparatide was associated with a 5.03 +/- 4.77% increase in lumbar spine BMD (p < 0.0001, mean +/- SD change from baseline), whereas changes in lumbar spine BMD for patients on calcitonin were not statistically significant (mean change of 0.36 +/- 4.12%, p = 0.16). Comparison of the two groups indicated that teriparatide treatment improved lumbar spine BMD statistically significantly more than calcitonin (p < 0.0001). No statistically significant changes were observed for total hip or femoral neck BMD. Serum bone-specific alkaline phosphatase (BSAP) increased by 55.9% (median change from baseline, p < 0.0001) in the teriparatide group, and remained stable with calcitonin (5.0% change, p = 0.24); osteocalcin increased by 156.15% (median change from baseline, p < 0.0001) with teriparatide, and decreased with calcitonin (-15.25%, p = 0.03). Similar rates of adverse events were observed, with nausea and dizziness the most commonly reported for both groups (teriparatide versus calcitonin, 13.0% versus 23.2% p = 0.21, 10.9% versus 21.4% p = 0.19, respectively). There were no clinically relevant changes observed in laboratory parameters. CONCLUSIONS: Both treatments were similarly tolerated, however teriparatide was associated with greater increases in lumbar spine BMD and bone formation markers, demonstrating the unique mechanism of action and safety of this treatment for osteoporosis in these Asian women.

Randomised controlled trial of qigong in the treatment of mild essential hypertension.

Exercise and relaxation decrease blood pressure. Qigong is a traditional Chinese exercise consisting of breathing and gentle movements. We conducted a randomised controlled trial to study the effect of Guolin qigong on blood pressure. In all, 88 patients with mild essential hypertension were recruited from the community and randomised to Goulin qigong or conventional exercise for 16 weeks. The main outcome measurements were blood pressure, health status (SF-36 scores), Beck Anxiety and Depression Inventory scores. In the qigong group, blood pressure decreased significantly from 146.3+/-7.8/93.0+/-4.1 mmHg at baseline to 135.5+/-10.0/87.1+/-7.7 mmHg at week 16. In the exercise group, blood pressure also decreased significantly from 140.9+/-10.9/93.1+/-3.5 mmHg to 129.7+/-11.1/86.0+/-7.0 mmHg. Heart rate, weight, BMI, waist circumference, total cholesterol, renin and 24 h urinary albumin excretion significantly decreased in both groups after 16 weeks. General health, bodily pain, social functioning and depression also improved in both groups. No significant differences between qigong and conventional exercise were found. In conclusion, Guolin qigong and conventional exercise have similar effects on blood pressure in patients with mild hypertension. While no additional benefits were identified, it is nevertheless an alternative to conventional exercise in the nondrug treatment of hypertension.

Deep vein thrombosis following hip fracture and prevalence of hyperhomocysteinaemia in the elderly.

INTRODUCTION: The prevalence of deep vein thrombosis (DVT) in the West is reported to be as high as 50% after hip surgery. A study performed 14 years ago showed the incidence in Singapore to be <10%. Lately, some case-control and cross-sectional studies have suggested hyperhomocysteinaemia as an independent risk factor for DVT. This study investigates the local incidence of DVT and plasma hyperhomocysteinaemia in elderly patients presenting with proximal hip fracture. MATERIALS AND METHODS: We recruited 104 consecutive patients from April 2001 to November 2001 who satisfy certain criteria. Firstly, patients of both genders who were >55 years old with radiological diagnosis of neck of femur fracture, intertrochanteric or subtrochanteric fracture. Secondly, these patients must not have any haemorrhagic or thrombogenic disease. Thirdly, patients were not given folate and B complex pre- or postoperation. Duplex ultrasound was then done for these patients on the 5th to 7th postoperative day. RESULTS: The incidence of DVT above the trifurcation was 7.7%, no incidence of pulmonary embolism (PE) was detected. The incidence of hyperhomocysteinaemia was 52.3%. CONCLUSIONS: The incidence of DVT in the local population after proximal hip fracture is much lower than in the West. The use of DVT prophylaxis in Asians should be selective to avoid incurring extra cost and its associated morbidity. Case-control studies and cross-sectional studies clearly indicate that hyperhomocysteinaemia is an independent risk factor for venous thrombosis. Given the high incidence of hyperhomocysteinaemia in our elderly with hip fracture, the prophylactic correction of hyperhomocysteinaemia with folate and vitamin B supplements is justified.

Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study.

OBJECTIVE: To determine the efficacy of acarbose, compared with placebo, on the metabolic control of NIDDM patients inadequately controlled on maximal doses of conventional oral agents. RESEARCH DESIGN AND METHODS: In this three-center double-blind study, 90 Chinese NIDDM patients with persistent poor glycemic control despite maximal doses of sulfonylurea and metformin were randomly assigned to receive additional treatment with acarbose 100 mg thrice daily or placebo for 24 weeks, after 6 weeks of dietary reinforcement. Efficacy was assessed by changes in HbA1c, fasting and 1-h postprandial plasma glucose and insulin levels, and fasting lipid levels. RESULTS: Acarbose treatment was associated with significantly greater reductions in HbA1c (-0.5 +/- 0.2% vs. placebo 0.1 +/- 0.2% [means +/- SEM], P = 0.038), 1-h postprandial glucose (-2.3 +/- 0.4 mmol/l vs. placebo 0.7 +/- 0.4 mmol/l, P < 0.001) and body weight (-0.54 +/- 0.32 kg vs. placebo 0.42 +/- 0.29 kg, P < 0.05). There was no significant difference between the two groups regarding changes in fasting plasma glucose and lipids or fasting and postprandial insulin levels. Flatulence was the most common side effect (acarbose vs. placebo: 28/45 vs. 11/44, P < 0.05). One patient on acarbose had asymptomatic elevations in serum transaminases that normalized in 4 weeks after acarbose withdrawal. Another patient on acarbose developed severe hypoglycemia; glycemic control was subsequently maintained on half the baseline dosage of sulfonylurea. CONCLUSIONS: In NIDDM patients inadequately controlled on conventional oral agents, acarbose in moderate doses resulted in beneficial effects on glycemic control, especially postprandial glycemia, and mean body weight. Additional use of acarbose can be considered as a useful alternative in such patients if they are reluctant to accept insulin therapy.

Antiresorptive therapy in asthmatic patients receiving high-dose inhaled steroids: a prospective study for 18 months.

BACKGROUND: Inhaled steroid therapy is an effective and well tolerated mode of therapy for asthma. Although systemic side-effects of inhaled steroids are much less common than those found with systemic steroids, the drugs may be absorbed through mucosal surfaces. Inhaled steroids have been reported to disturb normal bone metabolism, and they are associated with a decrease in bone mineral density. OBJECTIVE: We conducted this study to investigate bone density in asthmatic subjects receiving long-term high-dose inhaled steroids and the effects of supplementation with oral calcium with or without etidronate. METHODS: We evaluated thirty-eight Chinese subjects (24 men and 14 premenopausal women; 28 patients and 10 healthy control subjects) in this prospective study. Patients were randomized into three arms: those receiving no supplement, those receiving 1000 mg/day calcium supplement, and those receiving 400 mg/day cyclical sodium etidronate with 1000 mg/day calcium, respectively. The patients and control subjects were matched for age, sex, and dose of inhaled steroids. Bone density at lumbar spine and hip region was measured by dual energy x-ray absorptiometry with a densitometer at baseline and at 6, 12, and 18 months for the asthmatic groups and at baseline and at 12 and 18 months for the control group. Serum calcium, phosphate, alkaline phosphatase, osteocalcin, parathyroid hormone, 25-hydroxyvitamin D, and urinary hydroxyproline/creatine were measured simultaneous to bone density assessments. RESULTS: There were 10 control subjects, 10 asthmatic subjects receiving no supplement, eight asthmatic subjects receiving calcium supplement, and 10 asthmatic subjects receiving calcium and etidronate therapy, respectively. The mean (+/- SEM) dosages of beclomethasone or budesonide for the three groups of asthmatic subjects were 2.2 +/- 0.3, 2.0 +/- 0.2, and 2.0 +/- 0.2 mg/day, respectively. Mean dietary calcium intake of the study subjects was 766 +/- 39 mg/day. At baseline, bone mineral density of the spine in the group receiving no supplement was significantly lower than that found in the control group (p < 0.05). At 18 months, patients receiving no supplement had significantly greater bone loss at the lumbar spine than patients receiving etidronate plus calcium lactate-gluconate (CaLG) or CaLG alone (p < 0.05). The increase in bone mineral density versus baseline observed in patients receiving CaLG with or without etidronate (p < 0.05) probably did not result from increased bone formation because serum osteocalcin levels showed a significant reduction in all three groups of patients (p < 0.05). An increase in mean serum calcium (p < 0.05) was seen in patients receiving CaLG with or without etidronate. CONCLUSION: Our results suggest that long-term administration of high-dose inhaled steroid (>1.5 mg/day) induces bone loss that is preventable with calcium supplementation with or without cyclical etidronate. Long-term studies involving more patients should follow to confirm these preliminary findings.

Surgical treatment for primary hyperparathyroidism.

OBJECTIVE: To document the recent surgical results in the treatment of primary hyperparathyroidism (HPT) at Queen Mary Hospital. METHODS: From 1995 to 1996, 30 patients underwent 31 operations for primary HPT. The data of 11 men and 19 women with ages ranging from 19 to 86 years (median: 57 years) were prospectively recorded with emphasis on the need of preoperative localization. RESULTS: Symptoms of hypercalcemia were present in 20 (67%) and complications in 17 (57%) patients, respectively. Seventy-seven localization studies were performed in 28 patients (average: 2.6 tests/patient). Localization was accurate in 12 of 23 (52%) ultrasonographies, 11 of 26 (42%) CT scans and 16 of 27 (59%) scintigraphies. Twenty-six patients had a single adenoma excised while 3 patients with multiple endocrine neoplasia type I (MEN I) had subtotal parathyroidectomy for multiglandular hyperplasia during cervical exploration. Immediate normocalcemia was achieved in 29 patients. One patient had persistent hypercalcemia due to a supernumerary fifth gland in the superior mediastinum that was successfully excised in a second operation. One patient had a unilateral vocal cord paralysis and 4 patients needed calcium supplement on discharge. During a median follow-up of 5 months, all patients were normocalcemic with one requiring calcium supplements. CONCLUSION: Surgical treatment for primary HPT is a safe procedure and is associated with a high success rate. In our experience routine preoperative localization study is not cost-effective.

Gene expression of hypothalamic somatostatin and growth hormone-releasing hormone in dexamethasone-treated rats.

Supraphysiological doses of glucocorticoids inhibit growth hormone (GH) secretion in man and experimental animals. We investigated whether glucocorticoids inhibit GH secretion through changes in the gene expression of GH, hypothalamic somatostatin (SS) and GH-releasing hormone (GHRH), and whether such changes vary with the dose and duration of glucocorticoid excess. Male rats, 6 weeks of age, were treated with injections of either saline or different doses of dexamethasone (40, 200, 500 or 1,000 micrograms/kg/day) intraperitoneally for 3 or 8 days. Total RNA extracted from the anterior pituitary and hypothalamus was analyzed by Northern blot hybridization. SS mRNA level was also assessed in smaller hypothalamic fragments containing predominantly the periventricular and paraventricular nuclei, and by in situ hybridization. A biphasic effect on SS mRNA levels was observed such that a significant increase (p < 0.001) was demonstrated in the periventricular nucleus after 3 days of dexamethasone 1,000 micrograms/kg/day, but a reduction in hypothalamic SS mRNA was seen after 8 days for all doses employed (p < 0.05 or p < 0.01). On the other hand, hypothalamic GHRH mRNA levels showed a reduction which appeared to increase with the dose and duration of treatment and became statistically significant after 8 days at doses > or = 200 micrograms/kg/day (p < 0.05). Pituitary GH mRNA levels were increased after 3 days at doses > or = 500 micrograms/kg/day (p < 0.05) but showed no significant change at all doses after 8 days. We conclude that glucocorticoid excess is associated with changes in the gene expression of GH, hypothalamic SS and GHRH, which vary with the dose and duration of glucocorticoid treatment. Glucocorticoids inhibit GH secretion in vivo through a reduction in hypothalamic GHRH gene expression and, in animals with shorter duration of glucocorticoid excess also through an increase in SS gene expression in the periventricular nucleus.

Bifunctional scaffolds as templates for synthetic combinatorial libraries.

A small-molecule synthetic combinatorial library was designed and synthesized that features potential pharmacophores attached to a variety of small cyclic scaffolds. The synthesis of the library involved randomization of three types of building blocks: 20 amino acids, 10 aromatic hydroxy acids and 21 alcohols, totaling a library complexity of 4200 compounds. Mitsunobu polymer-supported etherification was used in the last randomization. The library compounds were attached to beads via an ester-bond linkage enabling both on-bead as well as in-solution screening. When the library was tested against a model target, streptavidin, specific binders were found. The structures of the most active compounds were determined from the fragmentation pattern in MS/MS experiments.

Gene expression of hypothalamic somatostatin, growth hormone releasing factor, and their pituitary receptors in hypothyroidism.

Thyroid hormones are important to growth in mammals and have been shown to rapidly stimulate the rate of GH gene transcription. In this study, we investigated whether thyroid hormones modulate GH secretion through their effects on the gene expression of GRF, somatostatin (SS), GRF receptor, and receptor subtype 2 for SS (SSTR2). Male adult Sprague-Dawley rats were rendered hypothyroid with a single injection of propylthiouracil followed by methimazole in drinking water (0.02%) for 1 day to 12 weeks. Total RNA extracted from the anterior pituitary and hypothalamus was analyzed by Northern hybridization. GH messenger RNA (mRNA) level in the anterior pituitary was significantly reduced in the hypothyroid animals (P < 0.0001 vs. controls for all treatment duration > or = 1 week). An increase in hypothalamic GRF mRNA level, by 2- and 4-fold, respectively, was seen after 3 and 12 weeks of antithyroid treatment (both P < 0.001 vs. controls). Hypothalamic GRF content, studied in 12-week hypothyroid rats only, was decreased compared with controls (P < 0.05). A reduction in pituitary GRF receptor mRNA level was observed after 1 week of antithyroid treatment (P < 0.01 after 1 week, P < 0.001 after 3 weeks). Total hypothalamic SS content and SS mRNA level in hypothalamic fragments consisting predominantly of the paraventricular and periventricular nuclei became significantly decreased (P < 0.05 and P < 0.005 respectively) after 12-weeks of antithyroid treatment. The reduction in SS gene expression in the periventricular nuclei was confirmed by in situ hybridization. No significant change in the mRNA level of pituitary SSTR2 was observed up to 12 weeks of antithyroid treatment. In conclusion, we have demonstrated a reduction in the gene expression of GRF receptor and SS in the hypothyroid rat. Our results suggest that the changes in hypothalamic GRF and SS gene expression in hypothyroid rats may be compensatory in nature and are likely to be secondary to the reduction in GH synthesis and secretion in these animals. The reduction in basal and GRF-stimulated GH secretion in hypothyroidism can be explained by the observed reduction in GH and GRF receptor gene expression.

Cholesterol-lowering therapy may retard the progression of diabetic nephropathy.

There is experimental evidence to suggest that hypercholesterolaemia may play a pathogenetic role in progressive glomerular injury. We investigated the effect of cholesterol-lowering therapy on the progression of diabetic nephropathy in 34 patients with non-insulin-dependent diabetes mellitus. Patients were randomly assigned in a single-blind fashion to treatment with either lovastatin, an HMG CoA reductase inhibitor (n = 16; mean dose 30.0 +/- 12.6 mg/day) or placebo (n = 18) for 2 years. Renal function was assessed by serially measuring the serum creatinine, glomerular filtration rate (using Cr51-EDTA), and 24-h urinary protein excretion. Lovastatin treatment was associated with significant reductions in total cholesterol (p < 0.001), LDL-cholesterol (p < 0.001) and apo B (p < 0.01), the reductions at 24 months being 26, 30 and 18%, respectively. Beneficial effects on serum triglyceride, HDL-cholesterol and apo A1 levels were also observed. Lp(a) showed no significant change in both groups. Glomerular filtration rate deteriorated significantly in the placebo group after 24 months (p < 0.025) but showed no significant change in the lovastatin-treated patients. The increase in serum creatinine was statistically significant (p < 0.02) in placebo-treated patients at 12 and 24 months, and in the lovastatin group after 24 months. Twenty-four hour urinary protein excretion increased in both groups (p < 0.05). Lovastatin treatment was not associated with significant elevations in liver or muscle enzymes. We conclude that effective normalisation of hypercholesterolaemia may retard the progression of diabetic nephropathy.

Dexamethasone decreases somatostatin mRNA levels in the periventricular nucleus of the rat hypothalamus.

Glucocorticoid excess inhibits somatic growth in man and laboratory animals. While the mechanism involved is likely to be multifactorial, indirect evidence suggesting the role of an enhanced endogenous somatostatin (SS) tone has been reported. However, there has been no direct evidence indicating an increased synthesis or secretion of hypothalamic SS. In this study, we investigated the effects of glucocorticoids on hypothalamic SS expression by measuring the peptide and mRNA content of SS in whole hypothalamic blocks of male Sprague-Dawley rats sacrificed 4 weeks after adrenalectomy or sham operation. Adrenalectomy decreased the SS content in the rat hypothalamus (p < 0.05), an effect which was reversed by dexamethasone treatment for 10 days. On the other hand, total hypothalamic SS mRNA levels were unaffected by adrenalectomy, but became significantly decreased following dexamethasone treatment (p < 0.05). Using in situ hybridization, this reduction in SS gene expression was shown to occur consistently in the periventricular nucleus and in the parvocellular subdivision of the paraventricular nucleus. The effects of adrenalectomy and dexamethasone on SS mRNA levels were further quantitated in hypothalamic fragments containing predominantly the periventricular and paraventricular nuclei. Somatostatin mRNA levels in these tissue fragments were marginally increased by adrenalectomy (p < 0.05), but showed a 50% reduction following dexamethasone treatment (p < 0.0001). In conclusion, our findings suggest that the inhibitory effect of glucocorticoids on somatic growth is probably not mediated via an effect on hypothalamic SS gene expression.

Hypopituitarism after tuberculous meningitis in childhood.

OBJECTIVE: To study the prevalence and pathogenesis of hypopituitarism following tuberculous meningitis in childhood. DESIGN: A retrospective cross-sectional study. SETTING: A university teaching hospital and a tuberculosis referral center. PATIENTS: Forty-nine patients, aged 23.4 +/- 6.0 years (mean +/- SD), who had tuberculous meningitis in childhood (age at diagnosis, 5.9 +/- 5.0 years) were studied. MEASUREMENTS: A detailed assessment of hypothalamic-pituitary function, including conventional stimulation tests and responses to four hypothalamic releasing hormones, was done. Magnetic resonance imaging of the hypothalamic-pituitary region was performed in patients with abnormal endocrine function. RESULTS: Ten patients were found to have abnormal pituitary function: Seven had growth hormone deficiency, four of whom also had gonadotropin deficiency; the other three had gonadotropin deficiency, corticotropin deficiency, and mild hyperprolactinemia, respectively; none had diabetes insipidus. Among those with growth hormone deficiency, a significant correlation (r = 0.749, P < 0.05) was found between the height standard deviation score and the age at diagnosis of tuberculous meningitis. Growth hormone, corticotropin, and gonadotropin responses to growth hormone releasing hormone, corticotropin releasing hormone, and gonadotropin releasing hormone, respectively, suggested a hypothalamic defect in five patients. Magnetic resonance imaging scans of the hypothalamic-pituitary region were abnormal in five patients. CONCLUSIONS: Hypopituitarism was documented in 20% of a small subset of patients years after recovery from tuberculous meningitis in childhood. The cause appears to be tuberculous lesions affecting the hypothalamus, pituitary stalk and, directly or indirectly, the pituitary itself. Early recognition and treatment can be beneficial.

Divergent effects of glucocorticoid on the gene expression of vasoactive intestinal peptide in the rat cerebral cortex and pituitary.

We investigated the effects of glucocorticoid on the expression of the vasoactive intestinal peptide (VIP) gene, a neuropeptide and an established prolactin (PRL)-releasing factor, in the rat brain and pituitary. The mRNA and peptide contents of VIP in the cerebral cortex, hypothalamus and anterior pituitary of male Sprague-Dawley rats were quantitated 4 weeks after adrenalectomy or sham-operation. Following adrenalectomy, VIP mRNA content increased in the anterior pituitary but showed no significant change in the cerebral cortex and hypothalamus. Dexamethasone treatment for 10 days abolished the effect of adrenalectomy and decreased significantly pituitary VIP mRNA content in sham-operated rats. In the cerebral cortex, however, dexamethasone treatment resulted in an enhancement in VIP mRNA levels in both sham-operated and adrenalectomized animals. Hypothalamic VIP mRNA content remained unchanged. These changes in VIP mRNA levels were accompanied by parallel changes in VIP concentrations in the tissues studied, suggesting that glucocorticoid regulates the synthesis of VIP in the cerebral cortex and anterior pituitary. On the other hand, serum PRL level increased after adrenalectomy but became suppressed following dexamethasone administration, in parallel with changes in pituitary VIP synthesis. These findings suggest that the effect of glucocorticoid on PRL secretion may be mediated, at least in part, via changes in VIP synthesis and secretion. We conclude that glucocorticoid regulates the expression of VIP in the rat brain, resulting in divergent changes in the cerebral cortex and pituitary. Changes in VIP synthesis and secretion may contribute to the disturbances in brain function and PRL secretion in conditions of glucocorticoid excess.

Idiopathic hypercalciuria causing osteoporosis and hypocalcemia.

Idiopathic hypercalciuria, though a common cause of nephrolithiasis, has not been recognized to cause hypocalcemia and severe bone disease. We describe an adolescent with idiopathic hypercalciuria who presented initially with severe hypocalcemia and osteoporosis and this was later complicated by recurrent renal calculi formation after calcium and vitamin D supplement. After treatment with thiazide, hypercalciuria was controlled and serum biochemistry normalized. While idiopathic renal hypercalciuria may cause a negative calcium balance in adults, a variant of this syndrome with severe renal calcium leak occurring in a growing subject could lead to severe hypocalcemia and osteoporosis.

Vasoactive intestinal peptide in the hypothalamus and pituitary.

Data are presented to show that vasoactive intestinal peptide (VIP) is synthesized and secreted by the hypothalamus and anterior pituitary and that it participates in the regulation of pituitary functions. Immunoreactive VIP in the hypothalamus and pituitary is increased following estrogen treatment and adrenalectomy and is reduced in hyperprolactinemic states. The level of VIP mRNA in the hypothalamus is increased during lactation and sexual maturation, while that in the anterior pituitary shows a sexual dimorphism and is increased with estrogen treatment and hypothyroidism. All these findings suggest a physiological regulation of hypothalamic and pituitary VIP gene expression in relation to its potential role as a neuroendocrine hormone. Furthermore, VIP stimulates prolactin (PRL) release at concentrations attainable in the hypophyseal-portal blood. Passive immunoneutralization studies with anti-VIP antisera suggest that endogenous VIP acts at multiple loci in the hypothalamic-pituitary axis to regulate PRL secretion, interacting possibly with other regulators of PRL secretion such as estrogen, serotonin, cholecystokinin, prostaglandins, galanin and oxytocin. Regarding other pituitary functions, although VIP has been shown to release growth hormone, ACTH, and vasopressin in vivo and in vitro, the physiological significance of these findings remains to be determined.