Hormone replacement therapy and age-related brain shrinkage: regional effects

Neuroprotective properties of estrogen have been established in animal models, but clinical trials of hormone replacement therapy (HRT) produced contradictory results. We examined the impact of HRT on age-related regional changes in human brain volume. Six brain regions were measured twice, five years apart, in 12 healthy women who took HRT and in matched controls who did not. The controls showed a typical pattern of differential brain shrinkage in the association cortices and the hippocampus with no change in the primary visual cortex. In contrast, women who took HRT showed comparable shrinkage of the hippocampus but no significant shrinkage of the neocortex. Future large scale studies may benefit from applying regional rather than global measures in assessment of brain integrity.     

Interstitial cystitis and panic disorder: a potential genetic syndrome

BACKGROUND: Evidence from a genetic linkage study had suggested a possible syndrome in some families with panic disorder (PD). This syndrome includes bladder problems (possibly urinary interstitial cystitis [IC]), thyroid disorders, chronic headaches/migraine, and/or mitral valve prolapse. In 19 multiplex families with PD, one marker (D13S779) on chromosome 13 gave a logarithm of odds score of more than 4 when individuals with any of the syndrome conditions were analyzed as affected. Families with the bladder problems yielded the highest logarithm of odds scores. These findings were replicated in an extended sample of 60 families. Whereas PD had been well characterized by direct interview, the urologic problems had been found only via medical history checklists and records. A case review by a board-certified urologist suggested they could be IC. OBJECTIVE: To determine whether patients diagnosed as having IC by urodynamics and/or cystoscopy and their first-degree relatives (FDRs) have increased rates of the syndrome conditions, thus validating that the bladder problems observed in the linkage study could be IC and providing further support for the panic syndrome. DESIGN: Case-control and family history study. SETTING: Two metropolitan urology clinics. PARTICIPANTS: One hundred forty-six probands (67 with IC and 79 with other urologic disorders) and 815 FDRs. MAIN OUTCOME MEASURES: Lifetime rates of syndrome conditions in probands and FDRs who were blind to urologic or psychiatric diagnoses in the proband. RESULTS: Compared with patients without IC, patients with IC had a significantly higher lifetime prevalence of PD (controlling for age and sex) (odds ratio, 4.05; 95% confidence interval, 1.22-13.40; P =.02) and a higher lifetime prevalence of any of the syndrome disorders (controlling for age and sex) (odds ratio, 2.22; 95% confidence interval, 0.89-5.54; P =.09). First-degree relatives of probands with (vs without) IC were significantly more likely to have PD, thyroid disorder, urologic problems, and any of the syndrome disorders (controlling for age and sex of the relative and sex of the proband) (adjusted odds ratio, 1.95; 95% confidence interval, 1.13-3.38; P =.02). These results in relatives were not influenced by PD in probands, and did not change substantially when controlling for the proband-relative relationship, modeling age as a categorical (vs continuous) variable, or excluding FDRs with PD. There were no interactions between proband IC status and sex of the relative. CONCLUSIONS: The increased frequency of seemingly disparate disorders in patients with IC and their FDRs is consistent with the genetic linkage findings in families with PD. These findings suggest that the bladder problems observed in the linkage study may be IC. The hypothesis that there is a familial, possibly pleiotropic, syndrome that may include IC, PD, thyroid disorders, and other disorders of possible autonomic or neuromuscular control deserves further investigation.     

Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial

BACKGROUND: Intravenous immunoglobulin (IVIg) has been reported to reduce disease activity in patients with relapsing-remitting multiple sclerosis. We assessed the effect of IVIg treatment in patients after the first neurological event suggestive of demyelinative disease and evaluated the occurrence of a second attack and dissemination in time demonstrated by brain magnetic resonance imaging within the first year from onset. METHODS: We conducted a randomized, placebo-controlled, double-blind study in 91 eligible patients enrolled within the first 6 weeks of neurological symptoms. Patients were randomly assigned to receive IVIg treatment (2-g/kg loading dose) or placebo, with boosters (0.4 g/kg) given once every 6 weeks for 1 year. Neurological and clinical assessments were done every 3 months, and brain magnetic resonance imaging was performed at baseline and the end of the study. RESULTS: The cumulative probability of developing clinically definite multiple sclerosis was significantly lower in the IVIg treatment group compared with the placebo group (rate ratio, 0.36 [95% confidence interval, 0.15-0.88]; P = .03). Patients in the IVIg treatment group had a significant reduction in the volume and number of T2-weighted lesions and in the volume of gadolinium-enhancing lesions as compared with the placebo group (P = .01, P = .01, and P = .03, respectively). Treatment was well tolerated, compliance was high, and incidence of adverse effects did not differ significantly between groups. CONCLUSIONS: Intravenous immunoglobulin treatment for the first year from onset of the first neurological event suggestive of demyelinative disease significantly lowers the incidence of a second attack and reduces disease activity as measured by brain magnetic resonance imaging.     

Treatment of severe cholestasis in neonatal Dubin-Johnson syndrome with ursodeoxycholic acid

We report a case of Dubin-Johnson Syndrome in a neonate presenting with severe direct hyperbilirubinemia, which failed to respond to phenobarbital treatment. Ursodeoxycholic Acid added to therapy was well tolerated, and resulted in declining bilirubin concentration. We suggest ursodeoxycholic acid in treatment for Dubin-Johnson Syndrome with severe direct hyperbilirubinemia presenting in the neonatal age.     

DNA-based vaccines for allergic disease

Allergen-specific immunotherapy, although efficacious, is now less frequently used because of potential adverse reactions. Recently, two new types of allergen immunotherapy have been developed that appear to overcome this problem, namely allergen gene vaccination and vaccination with allergen-immunstimulatory DNA conjugates. In animal models of allergy, both have been shown to induce nonallergic T-helper cell type 1 immune responses to allergens and downregulate pre-existing T-helper cell type 2 responses. In initial clinical trials with allergic patients, allergen-immunostimulatory DNA conjugates were well-tolerated, induced immunoglobulin-G but not immunoglobulin-E antibodies and appeared to have great potential as a novel, safe and efficacious type of allergen specific immunotherapy.     

Predominant factors associated with bone loss in liver transplant patients - after prolonged post-transplantation period

INTRODUCTION: Osteoporosis is a major cause of morbidity in liver transplant recipients and is associated with multiple factors. OBJECTIVES: To evaluate bone mineral density (BMD), bone turnover and calcium-regulating hormones in 29 patients (17 men, 12 women) 2-12 yrs following liver transplantation for non-alcoholic liver diseases. RESULTS: Fifteen patients (52%) were on immunosuppressive treatment with tacrolimus and 14 (48%) with cyclosporine. Eleven patients (38%) were currently on prednisone, 18 patients (62%) had stopped glucocorticoid treatment 6 months to 11 yrs prior to the study. Nineteen patients (65.5%) had decreased BMD according to WHO criteria, 17 (58.2%) at the femoral neck, 13 (44.8%) at the lumbar spine. Nineteen patients (65.5%) had a subnormal (<15 ng/mL) serum level of 25 (OH) D3. These patients had significantly lower BMD at the femoral neck (p = 0.02). Femoral neck BMD negatively correlated with serum parathyroid hormone level (p = 0.06, r = -0.35), length of the post-transplantation period (p = 0.025, r = -0.416) and duration of glucocorticoid treatment (p = 0.029, r = -0.406), regardless of its cumulative dose. Symptomatic fractures were less frequent in tacrolimus treated patients than in cyclosporine users (p = 0.03). CONCLUSIONS: Decreased BMD is frequent following liver transplantation and is affected by vitamin D deficiency, cyclosporine use, and the duration of glucocorticoid therapy, but not by its cumulative dose. Achievement and maintenance of optimal vitamin D status and shortening of glucocorticoid treatment period may have a favorable effect on bone preservation.     

Bone density in axial and appendicular skeleton in patients with lactose intolerance: influence of calcium intake and vitamin D status

BACKGROUND: Lactose intolerance (LI) is a common enzymatic insufficiency, manifesting by poor tolerance of dairy products, leading to low calcium intake and poor calcium absorption from dairy products. These changes might lead to an impairment of bone metabolism [1]. OBJECTIVES: To evaluate the impact of LI on quantitative bone parameters in axial and appendicular skeletal sites. To assess the impact of calcium intake from dairy and non-dairy nutritional sources, calcium regulating hormones and bone turnover on quantitative bone parameters in LI patients. METHODS: We evaluated calcium intake and bone status in sixty-six patients with LI, 49 women and 17 men, aged 20 to 78. Bone mass was assessed at the lumbar spine (LS), total hip (TH) and femoral neck (FN) by dual-energy x-ray absorptiometry (DEXA) and at the radius, tibia, phalanx by quantitative ultrasound. Serum calcium, albumin, inorganic phosphate, calcium regulating hormones and markers of bone turnover were evaluated. RESULTS: Total daily calcium intake was below the recommended by the American Dietetic Association [2] in all study participants (mean 692 mg/day +/- 162). Elevated level of urinary deoxypyridinoline crosslinks (DPD) was observed in 63 (96%) patients and was negatively correlated with total daily calcium intake (r = -0.998, p = 0.025) and with nondairy calcium intake (r = -0.34, p = 0.015). Parathyroid hormone (PTH) level in the upper third of normal range (45-65 ng/L) was observed in 11 (17%) patients. Parathyroid hormone (PTH) was inversely correlated with total calcium intake (r = -0.4, p = 0.001), dairy calcium intake (r = -0.83, p = 0.05), non-dairy calcium intake (r = -0.29, p = 0.043), 25OHD(3) serum level (r = -0.3, p = 0.007) and positively correlated with bone turnover markers (deoxypyridinoline crosslinks [DPD], r = 0.36, p = 0.01 and bone specific alkaline phosphatase [BSAP] r = 0.36, p = 0.01). Decrease in quantitative bone parameters compared to age-matched controls was observed in the axial and in the appendicular skeleton in men and in postmenopausal women: mean z-score for LS -0.87 +/- 0.22 and -1.32 +/- 0.65, p = 0.004 and 0.015, tibia -1.15 +/- 0.53 and -0.44 +/- 0.044, p < 0.001 and 0.27, phalanx -0.98 +/- 0.22 and -0.52 +/- 0.98, p < 0.001. We observed decrease in bone mass in patients with serum PTH in the upper tertile of normal range in the FN (z-score -0.57 +/- 0.6 versus -0.03 +/- 0.9, p = 0.025), TH (-0.51 +/- 0.96 versus 0.04 +/- 0.9, p = 0.05) and radius (-1.84 +/- 0.27 versus -0.07 +/- 1.61, p = 0.025, respectively). z-scores in FN and TH positively correlated with serum 25OHD(3) level (r = 0.31, 0.29; p = 0.014, 0.019). In postmenopausal women serum 25OHD(3) level correlated also with LS z-scores (r = 0.52, p = 0.004); FN and TH z-scores negatively correlated with DPD level (r = -0.51, p = 0.02 and r = -0.55, p = 0.04). CONCLUSION: LI state may lead to increased bone turnover and decreased bone mass especially in men and postmenopausal women. Impaired vitamin D status and low calcium intake may be deleterious to bone in this condition.     

Differential expression of galectin-3 in pituitary tumors

Galectin-3 (Gal-3), a beta-galactoside-binding protein, has been implicated in a variety of biological functions, including cell proliferation and differentiation, tumor cell adhesion, angiogenesis, apoptosis, tumor progression, and metastasis. We investigated the role of Gal-3 in the development and progression of pituitary tumors. Immunohistochemical and Western blot analysis of normal and neoplastic human pituitaries showed that only lactotroph (PRL) and corticotroph (ACTH) hormone-producing cells and tumors expressed Gal-3. Gal-3 was present in 24 of 38 (63.2%) PRL adenomas, 5 of 6 (83.3%) PRL carcinomas, 19 of 41 (46.3) ACTH adenomas, and 7 of 8 (87.5%) ACTH carcinomas, but not in 112 other pituitary adenomas and carcinomas. Pituitary folliculo-stellate cells, which have macrophage-type functions in the anterior pituitary, also expressed Gal-3. Hyperplastic and neoplastic pituitaries from p27(Kip1) (p27)-null mice, which produce mainly ACTH, showed increased Gal-3 expression levels compared with control mice. Treatment with transforming growth factor beta1, which regulates pituitary cell proliferation, reduced Gal-3 as well as p27 expression levels in cultured HP75 pituitary cells and Gal-3 in cultured pituitary cells from p27-null mice, suggesting that p27 is not necessary for the inhibitory effects of transforming growth factor beta1 on the cell cycle in the pituitary. The role of Gal-3 in pituitary cell function was examined by RNA interference experiments. Inhibition of Gal-3 gene expression by RNA interference decreased HP75 cell proliferation and increased apoptosis. These results indicate that Gal-3 has an important role in pituitary cell proliferation and tumor progression.