Functional mechanism of tracheal relaxation,antiasthmatic, and toxicological studies of 6-hydroxyflavone

Previously, we described tracheal rat rings relaxation by several flavonoids, being 6-hydroxyflavone (6-HOF) the most active derivative of the series. Thus, its mechanism of action was determined in an ex vivo tracheal rat ring bioassay. The anti-asthmatic effect was assayed in in vivo OVAlbumin (OVA)-sensitized guinea pigs. Finally, the toxicological profile of 6-HOF was studied based on Organization of Economic Cooperation and Development guidelines with modifications. 6-HOF–induced relaxation appears to be related with receptor-operated calcium channel and voltage-operated calcium channel blockade as the main mechanism of action, and also through the production of relaxant second messengers NO and cGMP. Molecular docking supports that 6-HOF acts as calcium channel blocker and by activation of nitric oxide synthase. In addition, the in vivo anti-asthmatic experiments demonstrate the dose-dependent significant anti-allergic effect of 6-HOF induced by OVA, with best activity at 50 /kg. Finally, toxicological studies determined a LD50 > 2,000 mg/kg and, after 28 day of treatment with 6-HOF (50 mg/kg) by intragastric route, mice did not exhibit evidence of any significant toxicity. In conclusion, experiments showed that 6-HOF exerts significant relaxant activity through calcium channel blockade, and possibly, by NO/cGMP-system stimulation on rat trachea, which interferes with the contraction mechanism of smooth muscle cells in the airways. In addition, the flavonoid shows potential anti-asthmatic properties in an anti-allergic pathway. Furthermore, because the pharmacological and safety evidence, we propose this flavonoid as lead for the development of a novel therapeutic agent for the treatment of asthma and related respiratory diseases.     

Angiogenesis and lymphangiogenesis in mucoepidermoid carcinoma of minor salivary glands

J Oral Pathol Med (2012) 41: 603-609 Background: Mucoepidermoid carcinoma is the most common malignant tumor of salivary glands. This tumor is characterized by a great variability in clinical behavior, and little is known about the pathological mechanisms involved in its variance. Angiogenesis is an important step in tumor progression and is believed to be an essential event for metastatic dissemination. Methods: We aimed to investigate angiogenesis and lymphangiogenesis in mucoepidermoid carcinoma measuring the density of neoformed and lymphatic vessels using CD105 and D2-40 antibodies, respectively, and by immunohistochemical evaluation of VEGF-A and VEGF-C proteins. It was also investigated the expression of D2-40 in neoplastic cells. Results: We studied 26 cases of mucoepidermoid carcinoma, which showed great angiogenic activity measured by neoformed vessel density. However, a low density of lymphatics was observed. VEGF-A, VEGF-C, and D2-40 were commonly detected in mucoepidermoid carcinoma, but only VEGF-A expression correlated with neoformed vessel density. Recurrence and nodal metastasis were associated with low VEGF-A expression and low neoformed vessel density, indicating that impaired angiogenesis could lead to an aggressive phenotype. Conclusions: Angiogenesis seems important in the modulation of mucoepidermoid carcinoma pathogenesis; however, none of the parameters analyzed could predict tumor behavior.     

In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior

Background

Cyclin D1-positive B cells are occasionally found in the mantle zones of reactive lymphoid follicles, a condition that has been called “in situ mantle cell lymphoma”. The clinical significance of this lesion remains uncertain.

Design and Methods

The clinical and pathological characteristics, including SOX11 expression, of 23 cases initially diagnosed as in situ mantle cell lymphoma were studied.

Results

Seventeen of the 23 cases fulfilled the criteria for in situ mantle cell lymphoma. In most cases, the lesions were incidental findings in reactive lymph nodes. The t(11;14) was detected in all eight cases examined. SOX11 was positive in seven of 16 cases (44%). Five cases were associated with other small B-cell lymphomas. In two cases, both SOX11-positive, the in situ mantle cell lymphoma lesions were discovered after the diagnosis of overt lymphoma; one 4 years earlier, and one 3 years later. Twelve of the remaining 15 patients had a follow-up of at least 1 year (median 2 years; range, 1–19.5), of whom 11 showed no evidence of progression, including seven who were not treated. Only one of 12 patients with an in situ mantle cell lymphoma lesion and no diagnosis of mantle cell lymphoma at the time developed an overt lymphoma, 4 years later; this case was also SOX11-positive. The six remaining cases were diagnosed as mantle cell lymphoma with a mantle zone pattern. Five were SOX11-positive and four of them were associated with lymphoma without a mantle zone pattern.

Conclusions

In situ mantle cell lymphoma lesions are usually an incidental finding with a very indolent behavior. These cases must be distinguished from mantle cell lymphoma with a mantle zone pattern and overt mantle cell lymphoma because they may not require therapeutic intervention.     

Metal presence in hair after metal‐on‐metal resurfacing arthroplasty

The elevation of metal levels in serum and urine during post‐operative follow‐up is a frequent find following the implantation of certain models of metal‐on‐metal hip prostheses. Among 45 patients with the same resurfacing prostheses, chromium (Cr) and cobalt (Co) levels in serum and urine were determined at 3, 4, 5, and 6 years after surgery. In the same period, levels of Cr, Co and molibdene (Mo) in scalp hair were also measured. Mean Cr and Co levels in serum were 8.29 µg/L (SD 17.97) and 8.38 µg/L (SD 21.97), respectively, whereas in urine levels were 16.20 µg/L (SD SD 32.55) and 75.40 µg/L (SD 190.86), respectively. In hair, mean Cr level were 163.27 µg/g (SD 300.62), mean Co level 61.98 µg/g (SD 126.48), and Mo 31.36 µg/g (SD 37.86). A high concordance was observed between chromium‐urine and chromium‐serum and between cobalt‐urine and cobalt‐hair. A moderate concordance was present between cobalt‐urine and cobalt‐serum, and between cobalt‐hair and cobalt‐serum. Eleven patients required revision surgery, five of them due to metallosis and periarticular cyst. At 1 year after reintervention, analytics were performed again and the following decrease rates were found: 42.8% in Cr levels, 51.1% in Mo levels, and 90.3% in Co levels. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:2025–2031, 2013     

Preserving Continence During Robotic Prostatectomy

Preservation of postoperative urinary continence remains the primary concern of all men and their surgeons following robot-assisted radical prostatectomy (RARP). Without doubt, continence is the most important quality of life issue following radical prostatectomy. Identification of difficulties and lessons learned over time has helped focus efforts in order to improve urinary quality of life and continence. This review will examine definitions of continence and urinary quality of life evaluation, technical aspects and the impact of patient-related factors affecting time to and overall continence.     

Amyloid-β25–35 induces a permanent phosphorylation of HSF-1, but a transitory and inflammation-independent overexpression of Hsp-70 in C6 astrocytoma cells

Two hallmarks of Alzheimer diseases are the continuous inflammatory process, and the brain deposit of Amyloid b (Aβ), a cytotoxic protein. The intracellular accumulation of Aβ_25–35 fractions, in the absence of Heat Shock proteins (Hs?s), could be responsible for its cytotoxic activity. As, pro-inflammatory mediators and nitric oxide control the expression of Hs?s, our aim was to investigate the effect of Aβ_25–35 on the concentration of IL-1β, TNF-α and nitrite levels, and their relation to pHSF-1, Hsp-60, -70 and -90 expressions, in the rat C6 astrocyte cells. Interleukin-specific ELISA kits, immunohistochemistry with monoclonal anti-Hsp and anti pHSF-1 antibodies, and histochemistry techniques, were used. Our results showed that Aβ_25–35 treatment of C6 cells increased, significantly and consistently the concentration of IL-1β, TNF-α and nitrite 3 days after initiating treatment. The immunoreactivity of C6 cells to Hsp-70 reached its peak after 3 days of treatment followed by an abrupt decrease, as opposed to Hsp-60 and -90 expressions that showed an initial and progressive increase after 3 days of Aβ_25–35 treatment. pHSF-1 was identified throughout the experimental period. Nevertheless, progressive and sustained cell death was observed during all the treatment times and it was not caspase-3 dependent. Our results suggest that Hsp-70 temporary expression serves as a trigger to inhibit casapase-3 pathway and allow the expression of Hsp-60 and -90 in C6 astrocytoma cells stimulated with Aβ_25–35.