Two peculiar cases of cranial fractures running through craniotomy burr holes: may this be a kind of “exception” to the Puppe rule

International Journal of Legal Medicine - A correct assessment on the position, path, and direction of fracture lines is crucial when the sequence of different injuries on the skull has to be...     

Coexisting chronic conditions associated with mortality and morbidity in adult patients with asthma

Objective: Many asthma patients suffer from chronic conditions other than asthma. We investigated the specific contribution of common comorbidities on mortality and morbidity in adult asthma. Methods: In an observational study of adults with incident asthma identified between 1999 and 2003 using National Veterans Affairs and Centers for Medicare and Medicaid Services encounter databases (n?=?25?975, follow-up 3.0?±?1.7 years), association between 13 most prevalent comorbidities (hypertension, ischemic heart disease (IHD), osteoarthritis, rheumatoid arthritis, diabetes, mental disorders, substance/drug abuse, enlarged prostate, depression, cancer, alcoholism, HIV and heart failure) and four conditions previously associated with asthma (sleep apnea, gastroesophageal reflux disease (GERD), rhinitis and sinusitis) and mortality, hospitalizations and asthma exacerbations were assessed using multivariate regression analyses adjusted for other clinically important covariates. Results: HIV followed by alcoholism and mental disorders among 18–45-years old, and heart failure, diabetes, IHD and cancer among those ≥65 years old were associated with an increased risk of all-cause mortality. Many conditions were associated with increased risk for all-cause hospitalizations, but the increased risk was consistent across all ages for mental disorders. For asthma exacerbations, mental disorder followed by substance abuse and IHD were associated with increased risk among those 18–45 years old, and chronic sinusitis, mental disorder and IHD among those ≥65-years old. GERD was associated with decreased risk for asthma exacerbation in all ages. Conclusions: Many comorbidities are associated with poor outcome in adult asthmatics and their effect differs by age. Mental disorders are associated with increased risk of mortality and morbidity across ages.     

Impact of sarcopenia on treatment tolerance in United States veterans with diffuse large B‐cell lymphoma treated with CHOP‐based chemotherapy

While sarcopenia has been associated with decreased overall survival in diffuse large B‐cell (DLBCL) patients, the impact of sarcopenia on treatment tolerance has not been well‐studied. We evaluated the association of sarcopenia with febrile neutropenia hospitalization, treatment‐related mortality, and ability to complete standard number of cycles in a retrospective cohort of United States veterans diagnosed with DLBCL between 1998 and 2008 and treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab. Baseline body composition parameters were evaluated using computed tomography analysis. In total, 522 patients were included in the study, of whom 245 (47%) had baseline sarcopenia. After controlling for other variables, baseline sarcopenia was independently associated with increased risk of febrile neutropenia hospitalization (adjusted Odds Ratio (aOR) 1.64, 95% confidence interval (CI) 1.01–2.65) and inability to complete standard number of treatment cycles (aOR 1.49, 95% CI 1.02–2.16) compared with no baseline sarcopenia. There was a non‐statistically significant trend toward higher treatment‐related mortality in sarcopenic patients than non‐sarcopenic patients (aOR 1.77, 95% CI 0.92–3.41). Sarcopenia is associated with increased risk of treatment intolerance and may be useful in guiding treatment planning and supportive care measures. Am. J. Hematol. 91:1002–1007, 2016. © 2016 Wiley Periodicals, Inc.     

The biguanides metformin and phenformin inhibit angiogenesis,local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells

The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide Metformin (Met), commonly used for Type 2 diabetes, might have activity against BC and was found to inhibit angiogenesis in vivo. We studied Met and another biguanide, phenformin (Phe), in vitro and in vivo in BC models. In vitro, biguanides activated AMPK, inhibited Complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells. In coculture, biguanides inhibited the production of several angiogenic proteins. In vivo, biguanides inhibited local and metastatic growth of triple negative and HER2+ BC in immune‐competent and immune‐deficient mice orthotopically injected with BC. Biguanides inhibited local and metastatic BC growth in a genetically engineered murine model model of HER2+ BC. In vivo, biguanides increased pimonidazole binding (but not HIF‐1 expression) of WAT progenitors, reduced tumor microvessel density and altered the vascular pericyte/endothelial cell ratio, so that cancer vessels displayed a dysplastic phenotype. Phe was significantly more active than Met both in vitro and in vivo. Considering their safety profile, biguanides deserve to be further investigated for BC prevention in high‐risk subjects, in combination with chemo and/or targeted therapy and/or as post‐therapy consolidation or maintenance therapy for the prevention of BC recurrence.     

A long pentraxin-3-derived pentapeptide for the therapy of FGF8b-driven steroid hormone-regulated cancers

Fibroblast growth factor-8b (FGF8b) affects the epithelial/stromal compartments of steroid hormone-regulated tumors by exerting an autocrine activity on cancer cells and a paracrine pro-angiogenic function, thus contributing to tumor progression. The FGF8b/FGF receptor (FGFR) system may therefore represent a target for the treatment of steroid hormone-regulated tumors. The soluble pattern recognition receptor long pentraxin-3 (PTX3) binds various FGFs, including FGF2 and FGF8b, thus inhibiting the angiogenic and tumorigenic activity of androgen-regulated tumor cells. Nevertheless, the complex/proteinaceous structure of PTX3 hampers its pharmacological exploitation. In this context, the acetylated pentapeptide Ac-ARPCA-NH₂ (ARPCA), corresponding to the N-terminal amino acid sequence PTX3(100-104), was identified as a minimal FGF2-binding peptide able to antagonize the biological activity of FGF2. Here, we demonstrate that ARPCA binds FGF8b and inhibits its capacity to form FGFR1-mediated ternary complexes with heparan sulphate proteoglycans. As a FGF8b antagonist, ARPCA inhibits FGFR1 activation and signalling in endothelial cells, hampering the angiogenic activity exerted in vitro and in vivo by FGF8b. Also, ARPCA suppresses the angiogenic and tumorigenic potential of prototypic androgen/FGF8b-dependent Shionogi 115 mammary carcinoma cells and of androgen/FGF8b/FGF2-dependent TRAMP-C2 prostate cancer cells. In conclusion, ARPCA represents a novel FGF8b antagonist with translational implications for the therapy of steroid hormone-regulated tumors.     

Functional connectivity of the insula in the resting brain

The human insula is hidden in the depth of the cerebral hemisphere by the overlying frontal and temporal opercula, and consists of three cytoarchitectonically distinct regions: the anterior agranular area, posterior granular area, and the transitional dysgranular zone; each has distinct histochemical staining patterns and specific connectivity. Even though there are several studies reporting the functional connectivity of the insula with the cingulated cortex, its relationships with other brain areas remain elusive in humans. Therefore, we decided to use resting state functional connectivity to elucidate in details its connectivity, in terms of cortical and subcortical areas, and also of lateralization. We investigated correlations in BOLD fluctuations between specific regions of interest of the insula and other brain areas of right-handed healthy volunteers, on both sides of the brain. Our findings document two major complementary networks involving the ventral-anterior and dorsal-posterior insula: one network links the anterior insula to the middle and inferior temporal cortex and anterior cingulate cortex, and is primarily related to limbic regions which play a role in emotional aspects; the second links the middle-posterior insula to premotor, sensorimotor, supplementary motor and middle-posterior cingulate cortices, indicating a role for the insula in sensorimotor integration. The clear bipartition of the insula was confirmed by negative correlation analysis. Correlation maps are partially lateralized: the salience network, related to the ventral anterior insula, displays stronger connections with the anterior cingulate cortex on the right side, and with the frontal cortex on the left side; the posterior network has stronger connections with the superior temporal cortex and the occipital cortex on the right side. These results are in agreement with connectivity studies in primates, and support the use of resting state functional analysis to investigate connectivity in the living human brain.