In vitro fertilization exacerbates stroke size and neurological disability in wildtype mice.

BACKGROUND AND PURPOSE: Assisted reproductive technologies (ART) induce premature vascular aging in human offspring. The related alterations are well-established risk factors for stroke and predictors of adverse stroke outcome. However, given the young age of the human ART population there is no information on the incidence and outcome of cerebrovascular complications in humans. In mice, ART alters the cardiovascular phenotype similarly to humans, thereby offering the possibility to study this problem. METHODS: We investigated the morphological and clinical outcome after ischemia/reperfusion brain injury induced by transient (45 min) middle cerebral artery occlusion in ART and control mice. RESULTS: We found that stroke volumes were almost 3-fold larger in ART than in control mice (P < 0.001). In line with these morphological differences, neurological performance assessed by the Bederson and RotaRod tests 24 and 48 h after artery occlusion was significantly worse in ART compared with control mice. Plasma levels of TNF-alpha, were also significantly increased in ART vs. control mice after stroke (P < 0.05). As potential underlying mechanisms, we identified increased blood-brain barrier permeability evidenced by increased IgG extravasation associated with decreased tight junctional protein claudin-5 and occludin expression, increased oxidative stress and decreased NO-bioactivity in ART compared with control mice. CONCLUSIONS: In wildtype mice, ART predisposes to significantly worse morphological and functional stroke outcomes, related at least in part to altered blood-brain barrier permeability. These findings demonstrate that ART, by inducing premature vascular aging, not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. TRANSLATIONAL PERSPECTIVE: This study highlights that ART not only is a likely risk factor for stroke-occurrence, but also a mediator of adverse stroke-outcome. The findings should raise awareness in the ever-growing human ART population in whom these techniques cause similar alterations of the cardiovascular phenotype and encourage early preventive and diagnostic efforts.

Effects of a 3-month weight-bearing and resistance exercise training on circulating osteogenic cells and bone formation markers in postmenopausal women with low bone mass.

Osteoporosis is a health issue in postmenopausal women. Physical activity is recommended in these subjects, since it has positive effects on bone mass. Cellular mechanisms underlying this effect are still unclear. Osteogenic cells, released after physical exertion, could be a key factor in exercise-induced bone formation. INTRODUCTION: The aim of our research was to explore if a weight-bearing and resistance exercise program could positively affect circulating osteogenic cells (OCs), markers of bone formation and quality of life (QoL) in osteopenic postmenopausal women. METHODS: We recruited 33 postmenopausal women with a T-score at lumbar spine or femoral neck between - 1 and - 2.5 SD. Anthropometric and fitness parameters, bone-remodeling markers, OCs, and QoL were evaluated at the time of enrolment, after 1-month run-in period, and after 3 months of weight-bearing and resistance exercise. RESULTS: After 3 months of training, the pro-collagen type 1 N-terminal peptide (P1NP) and the number of OCs were significantly increased, with no significant increase of the type 1 collagen cross-linked C-telopeptide (sCTX). We also observed a significant increase in body height, one-repetition maximum (1RM) on the pull-down lat machine and leg press, and mean VO2max. The increase of immature circulating OCs was significantly correlated with the improvement of 1RM both of the upper and lower limbs. Moreover, QoL was significantly improved with regard to pain, physical function, mental function, and general QoL. The improvement in QoL, namely in the overall score and in the pain score, was significantly correlated with the increase in height. CONCLUSIONS: The exercise program we trialed is able to increase the markers of bone formation and the commitment of immature OCs with no significant increase in the markers of bone resorption. Our results confirm that combined weight-bearing and resistance physical activity is an effective tool to improve QoL of postmenopausal women with low bone mass. TRIAL REGISTRATION: NCT03195517.

Unusual presentation of gouty tophus in the liver with subsequent appearance in the same site of HCC: a correlate diagnosis? Case report.

BACKGROUND: Although gout is a common disease, the presence of gouty tophi outside joints is rare and in literature, there is to date only one report of hepatic tophaceous nodule. We would like to highlight here the difficult diagnostic workup in a patient with history of cancer and the presence of a tophus inside the liver. Moreover, we address the possible etiologic role of chronic inflammation related to tophi and liver cancer. CASE PRESENTATION: We present the case of a 72-year-old man with a localization of gouty tophus in the liver, who thereafter developed a hepatocellular carcinoma (HCC) in the same site. The patient was followed up after surgery for left renal cancer from 1992 to 2011, when a hepatic nodule was discovered for the first time. After a detailed evaluation, the nodule was classified as a urate tophus of the liver. However, further follow-up showed that the nodule increased in size and changed its characteristics, bringing to the diagnosis of HCC. CONCLUSIONS: With the present case report, we would discuss the possible neoplastic degeneration of a gouty tophus and its etiologic role favouring cellular degeneration linked to chronic inflammation. We would also highlight the importance of histopathological evaluation of hepatic lesions in gouty patients at high risk of liver neoplasm, due to the difficulty in characterizing gouty tophi by imaging.

Increased Bone Resorption: A Possible Pathophysiological Link Between Hypovitaminosis D and Peripheral Arterial Disease.

OBJECTIVE/BACKGROUND: Vitamin D deficiency has been associated with the prevalence and severity of peripheral arterial disease (PAD); nevertheless, data on bone turnover in patients with PAD is lacking. The present study investigates a possible relationship between the markers of bone turnover and the presence and severity of PAD. METHODS: The study examined 143 patients, with a mean ± SD age of 75.3 ± 8.5 years (range 50.0-93.0 years), of both sexes, admitted to a department of internal medicine. All patients underwent ankle brachial index (ABI) assessment by Doppler velocimetry. Serum levels of 25(OH) vitamin D and two markers of bone turnover, C-terminal telopeptide of type I collagen (sCTX) and bone isoenzyme of alkaline phosphatase, were measured. The differences between patients with normal ABI and patients with PAD were analyzed. Pearson and Spearman correlation coefficients were calculated and independent predictors were identified through a stepwise linear regression analysis. Odds ratios were calculated with a logistic regression model. RESULTS: Compared with patients with a normal ABI (≥0.90), patients with PAD (ABI < 0.90) presented with significantly lower levels of 25(OH) vitamin D (12.2 ± 9.6 ng/mL vs. 16.7 ± 8.7 ng/mL; p = .006) and a significantly higher concentration of sCTX (1.1 ± 0.7 ng/mL vs. 0.6 ± 0.4 ng/mL; p < .001). There was a positive correlation between ABI and serum concentration of 25 (OH) vitamin D (r = 0.3; p < .001), whereas ABI was inversely correlated with the concentration of sCTX (r = -0.358; p < .001). At logistic regression analysis, age, cigarette smoking, and both vitamin D and sCTX were independent predictors of an ABI < 0.90. CONCLUSION: These results support the hypothesis that hypovitaminosis D and increased bone turnover are risk factors for the presence and severity of PAD. Furthermore, the presence of PAD, even if asymptomatic and diagnosed by a reduced ABI, could identify a population at risk for osteoporosis and osteomalacia.

Factors influencing survival after hepatectomy for metastases from gastric cancer.

PURPOSE: To investigate clinical factors influencing the prognosis of patients submitted to hepatectomy for metastases from gastric cancer and their clinical role. METHODS: Retrospective multi-center chart review. We evaluated how survival from surgery was influenced by patient-related, gastric cancer-related, metastasis-related and treatment-related candidate prognostic factors. RESULTS: One hundred and five patients submitted to hepatectomy for metastases from gastric cancer, in the synchronous and metachronous setting of the disease. In 89 cases a R0 resection was achieved, while in 16 a R+ hepatic resection was performed. Adjuvant chemotherapy was administered to 29 patients. Surgical mortality was 1% and morbidity 13.3%. Median disease-free survival was 10 months, median overall survival was 14.6 months. Overall 1, 3, and 5-year survival rates were 58.2%, 20.3%, and 13.1%, respectively. Survival was influenced independently by the factor T of the gastric primary (p < 0.001), by the curativity of surgical procedure (p = 0.001), by the timing of hepatic involvement (p < 0.001) and by adjuvant chemotherapy (p < 0.001). T4 gastric cancer, R+ resection, synchronous metastases, and abstention from adjuvant chemotherapy were associated with a worse prognosis; T4 gastric cancer and R+ resections displayed a cumulative effect (p < 0.001). CONCLUSIONS: Our data show that R0 resection must be pursued whenever possible. Furthermore, in the synchronous setting, the coexistence of T4 gastric primaries and R+ resections suggests prudence and probably abstention from hepatectomy. Finally, a multimodal treatment associating surgery and chemotherapy offers the best survival results.

Lymphatic endothelial cells derived from metastatic and non-metastatic lymph nodes of human colorectal cancer reveal phenotypic differences in culture.

Colorectal cancer is one of the most frequent causes of death in Western countries. Most patients develop metastasis traveling through the lymphatic system, and regional lymph node metastasis is considered a marker for dissemination, increased stage, and worse prognosis. Despite rapid advances in tumor biology, the processes that underpin lymphatic invasion and lymph node metastasis remain poorly understood. The aim of this study was to establish an easy protocol for isolation of pure tumor lymphatic endothelial cells derived from lymph nodes to study differences compared with normal endothelial cells of uninvolved tissue from the same patients. Cells were isolated with very high purity via magnetic cell sorting and express the specific lymphatic markers Prox-1 and Lyve-1. They show differences in expression of adhesion molecules, chemokines, and growth factor secretion, and capability to form capillaries when seeded on basal membrane, thereby, revealing important differences between the two cell type. These cultures may provide a promising platform for the comparative analysis of both cell types at the molecular and biological level and to optimize treatment strategies.