Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy: a randomized controlled trial

BACKGROUND: Many women using hormone replacement therapy (HRT) will discontinue HRT and lose its bone-protective effect. Methods to preserve bone density in these women need to be explored. This multicenter, international, randomized, blinded, 12-month study was conducted to assess the effect of alendronate sodium on bone density in women who had recently discontinued HRT. METHODS: The 144 postmenopausal women included in the study were diagnosed as having low bone mineral density (BMD) and had recently discontinued HRT. They were randomized to receive either a daily dose of 10 mg of alendronate sodium or matching placebo. The main outcome measures were spine, hip, and total body BMD; biochemical markers of bone turnover; and tolerability. RESULTS: Alendronate treatment was associated with a 2.3% mean increase (95% confidence interval [CI], 1.7%-3.0%) in spine BMD compared with a mean loss of 3.2% (95% CI, - 4.6% to - 1.7%) in patients receiving placebo, for a difference of 5.5% (95% CI, 4.2%-6.8%) between alendronate and placebo. Greater hip and total body BMD preservation was also observed with alendronate use. Bone turnover decreased significantly with alendronate (bone-specific alkaline phosphatase levels decreased by 20% and urinary N-telopeptide/creatinine ratio by 47%), but increased in the placebo group (by 18% and 36%, respectively). Alendronate was well tolerated, with no increase in adverse events compared with placebo. CONCLUSIONS: A high rate of bone loss was observed in the first 12 to 15 months after discontinuation of HRT in postmenopausal women with low BMD. Treatment with alendronate increased or maintained both spine and hip BMD and prevented the increase in bone resorption seen with withdrawal of HRT in this population.     

Role of angiotensin II in the response to endothelin-1 of goat cerebral arteries after ischemia–reperfusion

As angiotensin II may underlie the deleterious effects of some vascular diseases, we have examined the role of this peptide on the cerbrovascular endothelin-1 action after ischemia–reperfusion. In anesthetized goats, 1 hour-occlusion followed by 1 hour-reperfusion of the left middle cerebral artery (MCA) was induced, and then segments 3-mm in length from branches of the right MCA (control) and the left MCA (ischemic) were obtained for isometric tension recording. Endothelin-1 (10^− 11–10^− 7 M) produced a contraction that was higher in ischemic than in control arteries, and in control but not in ischemic arteries this contraction was potentiated by angiotensin II (10^− 7 M). Losartan (3 × 10^− 6 M), antagonist of AT₁ receptors, did not affect the response to endothelin-1 in control arteries, but reduced it both in ischemic arteries and angiotensin II-treated control arteries. PD123,319 (3 × 10^− 6 M), antagonist of AT₂ receptors, or the inhibitor of nitric oxide synthesis l-NAME (10^− 4 M) did not alter the arterial effects of endothelin-1. Therefore, angiotensin II may potentiate the constriction to endothelin-1 in normal cerebral arteries by activating AT₁ receptors. The observed cerebrovascular increased response to endothelin-1 after ischemia–reperfusion might be related in part to activation of AT₁ receptors under this condition.     

Anti‐tumour immune response in GL261 glioblastoma generated by Temozolomide Immune‐Enhancing Metronomic Schedule monitored with MRSI‐based nosological images

Glioblastomas (GB) are brain tumours with poor prognosis even after aggressive therapy. Improvements in both therapeutic and follow‐up strategies are urgently needed. In previous work we described an oscillatory pattern of response to Temozolomide (TMZ) using a standard administration protocol, detected through MRSI‐based machine learning approaches. In the present work, we have introduced the Immune‐Enhancing Metronomic Schedule (IMS) with an every 6‐d TMZ administration at 60 mg/kg and investigated the consistence of such oscillatory behaviour. A total of n = 17 GL261 GB tumour‐bearing C57BL/6j mice were studied with MRI/MRSI every 2 d, and the oscillatory behaviour (6.2 ± 1.5 d period from the TMZ administration day) was confirmed during response. Furthermore, IMS‐TMZ produced significant improvement in mice survival (22.5 ± 3.0 d for controls vs 135.8 ± 78.2 for TMZ‐treated), outperforming standard TMZ treatment. Histopathological correlation was investigated in selected tumour samples (n = 6) analyzing control and responding fields. Significant differences were found for CD3+ cells (lymphocytes, 3.3 ± 2.5 vs 4.8 ± 2.9, respectively) and Iba‐1 immunostained area (microglia/macrophages, 16.8% ± 9.7% and 21.9% ± 11.4%, respectively). Unexpectedly, during IMS‐TMZ treatment, tumours from some mice (n = 6) fully regressed and remained undetectable without further treatment for 1 mo. These animals were considered “cured” and a GL261 re‐challenge experiment performed, with no tumour reappearance in five out of six cases. Heterogeneous therapy response outcomes were detected in tumour‐bearing mice, and a selected group was investigated (n = 3 non‐responders, n = 6 relapsing tumours, n = 3 controls). PD‐L1 content was found ca. 3‐fold increased in the relapsing group when comparing with control and non‐responding groups, suggesting that increased lymphocyte inhibition could be associated to IMS‐TMZ failure. Overall, data suggest that host immune response has a relevant role in therapy response/escape in GL261 tumours under IMS‐TMZ therapy. This is associated to changes in the metabolomics pattern, oscillating every 6 d, in agreement with immune cycle length, which is being sampled by MRSI‐derived nosological images.     

Características clínicas y polisomnográficas del síndrome de apneas durante el sueño localizado en la fase REM

Objective

The aim of this study was to analyze the clinical and polysomnographic features of rapid eye movement (REM)–specific sleep disordered-breathing (SDB).

Patients and methods

All cases of sleep apnea-hypopnea syndrome (SAHS) (apnea-hypopnea index [AHI]?>10/h) diagnosed using overnight polysomnography during the period 2004 to 2006 were analyzed retrospectively. Those cases in which the ratio of AHI during REM sleep to AHI during non-REM sleep was more than 2 were classified as REM-specific SDB. We recorded the following data: clinical signs and symptoms related to SAHS, PSG results, cardiovascular risk factors, and previous cardiovascular events. Logistic regression analysis was used to identify predictors of REM-specific SDB and to analyze the possible interactions between variables.

Results

A total of 419 patients were analyzed, of whom 138 (32.9%) presented REM-specific SDB. This condition was more common in patients with mild to moderate SAHS than in those with more severe cases (odds ratio, 8.21; 95% confidence interval, 4.83–14.03). The variables independently associated with REM-specific SDB in the logistic regression analysis were female sex, lower AHI, and higher body mass index. No interactions between the main variables studied were found. There were no differences between patients with REM-specific SDB and those with non-REM-specific SDB with regard to signs and symptoms related to SAHS, excessive daytime sleepiness, sleep architecture, cardiovascular risk factors, or history of cardiovascular episodes.

Conclusions

REM-specific SDB could be considered an initial stage of SAHS that mainly affects obese women with mild to moderate sleep disorders, and that does not differ from non-REM-specific SDB in terms of clinical presentation, sleep architecture, or cardiovascular comorbidity.     

CVID-associated TACI mutations affect autoreactive B cell selection and activation

Common variable immune deficiency (CVID) is an assorted group of primary diseases that clinically manifest with antibody deficiency, infection susceptibility, and autoimmunity. Heterozygous mutations in the gene encoding the tumor necrosis factor receptor superfamily member TACI are associated with CVID and autoimmune manifestations, whereas two mutated alleles prevent autoimmunity. To assess how the number of TACI mutations affects B cell activation and tolerance checkpoints, we analyzed healthy individuals and CVID patients carrying one or two TACI mutations. We found that TACI interacts with the cleaved, mature forms of TLR7 and TLR9 and plays an important role during B cell activation and the central removal of autoreactive B cells in healthy donors and CVID patients. However, only subjects with a single TACI mutation displayed a breached immune tolerance and secreted antinuclear antibodies (ANAs). These antibodies were associated with the presence of circulating B cell lymphoma 6–expressing T follicular helper (Tfh) cells, likely stimulating autoreactive B cells. Thus, TACI mutations may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance, whereas residual B cell responsiveness in patients with one, but not two, TACI mutations enables autoimmune complications.     

Detection of Norovirus in Saliva Samples from Acute Gastroenteritis Cases and Asymptomatic Subjects: Association with Age and Higher Shedding in Stool

Norovirus infections are a leading cause of acute gastroenteritis outbreaks worldwide and across all age groups, with two main genogroups (GI and GII) infecting humans. The aim of our study was to investigate the occurrence of norovirus in saliva samples from individuals involved in outbreaks of acute gastroenteritis in closed and semiclosed institutions, and its relationship with the virus strain, virus shedding in stool, the occurrence of symptoms, age, and the secretor status of the individual. Epidemiological and clinical information was gathered from norovirus outbreaks occurring in Catalonia, Spain during 2017–2018, and stool and saliva samples were collected from affected and exposed resident individuals and workers. A total of 347 saliva specimens from 25 outbreaks were analyzed. Further, 84% of individuals also provided a paired stool sample. For GII infections, norovirus was detected in 17.9% of saliva samples from symptomatic cases and 5.2% of asymptomatic individuals. Positivity in saliva occurred in both secretors and nonsecretors. None of the individuals infected by norovirus GI was positive for the virus in saliva. Saliva positivity did not correlate with any of the studied symptoms but did correlate with age ≥ 65 years old. Individuals who were positive in saliva showed higher levels of virus shedding in stool. Mean viral load in positive saliva was 3.16 ± 1.08 log₁₀ genome copies/mL, and the predominance of encapsidated genomes was confirmed by propidium monoazide (PMA)xx-viability RTqPCR assay. The detection of norovirus in saliva raises the possibility of oral-to-oral norovirus transmission during the symptomatic phase and, although to a lesser extent, even in cases of asymptomatic infections.     

Regional vulnerability of hippocampal subfields to aging measured by structural and diffusion MRI

In the past few years, there has been an increasing awareness of the regional vulnerability of the hippocampus to age‐related processes. However, to date, no studies have assessed the effects of age on different structural magnetic resonance parameters in the specific hippocampal subfields. In this study, we measured volume, mean diffusivity (MD) and fractional anisotropy (FA) in the presubiculum, subiculum, fimbria, cornu ammonis (CA) 1,2‐3,4‐DG and the whole hippocampus in fifty cognitively intact elder adults between 50 and 75 years of age (20 men, 30 women). Segmentation of hippocampal subfields was performed using FreeSurfer. Individual MD and FA images were coregistered to T1‐weighted volumes using FLIRT of FSL. Linear regression analyses were performed to assess the effects of age on the anatomical measures of each subfield. In addition, multiple regression analyses were also carried out to assess which of the anatomical measures that showed a correlation with age in the previous analyses, were the best age predictors in the hippocampus. In agreement with previous studies, our results showed a significant association between age and volume (P < 0.001) as well as MD (P < 0.001) in the whole hippocampus. Regarding the specific hippocampal subfields, we found that age had a significant negative effect on volume in CA2‐3 (P < 0.001) and CA4‐DG (P < 0.001). Importantly, we found a positive effect of age on MD in CA2‐3 (P < 0.001) and fimbria (P < 0.001) as well as a negative age effect on FA in the subiculum (P < 0.001). Multiple regression analyses revealed that the best overall predictors of age in the hippocampus were MD in the fimbria and volume of CA2‐3, which explained 73.8% of the age variance. These results indicate that age has an effect both on volume and diffusion tensor imaging measures in different subfields, suggesting they provide complementary information on age‐related processes in the hippocampus. © 2013 Wiley Periodicals, Inc.     

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease that mainly affects women, particularly at fertile age. It is sporadic or associated with tuberous sclerosis complex. It is characterised by an abnormal proliferation of immature smooth muscle cells (SMC), which grow aberrantly in the airway, parenchyma, lymphatics and pulmonary blood vessels and which can gradually lead to respiratory failure. It affects several systems, affecting the lymphatic ganglia and causing abdominal tumours. Given its very low prevalence, a difficult to establish early diagnosis, absence of curative treatment and the difficulty in obtaining information, places LAM under the heading of the so-called Rare Diseases. There is a growing interest in the study of this disease which has led to the setting up of patient registers and an exponential growth in LAM research, both at a clinical level and cellular level.