Update in the Percutaneous Management of Coronary Chronic Total Occlusions

Percutaneous coronary intervention (PCI) for chronic total occlusions (CTOs) has been rapidly evolving during recent years. With improvement in equipment and techniques, high success rates can be achieved at experienced centers, although overall success rates remain low. Prospective, randomized-controlled data regarding optimal use and indications for CTO PCI remain limited. CTO PCI should be performed when the anticipated benefit exceeds the potential risk. New high-quality studies of the clinical outcomes and techniques of CTO PCI are needed, as is the expansion of expert centers and operators that can achieve excellent clinical outcomes in this challenging patient and lesion subgroup. In the current review the authors summarize the latest publications in CTO PCI and provide an overview of the current state of the field.     

Challenges in managing proximal hypospadias: A 17-year single-center experience

BackgroundThere are only a few publications in the medical literature reporting on complication rates in proximal hypospadias surgery, particularly with regard to long-term follow-up.MethodsOver a 17.5-year period, we operated 100 patients with penoscrotal, scrotal and perineal hypospadias. Sixty-four had a single-stage repair, including 15 who received a buccal mucosa inlay “Snodgraft” repair. Thirty-six had a two-stage Bracka repair of which 19 received buccal or lower lip grafts and 17 had preputial grafts. Overall, 34 patients received buccal grafts. The median follow-up was eight years (range 1–16 years). Three patients were operated for residual chordee years later.ResultsUrethral fistulae occurred in a total of 26/100 (26.0%) cases, meatal stenosis in 16/100 (16.0%), wound breakdown in six (6.0%) and graft failure in one (1.0%). The fistula rate after the single-stage approach was 15/64 (23.4%), whereas it was 11/36 (30.6%) following two-stage repair (P = 0.4811).ConclusionsProximal hypospadias remains a challenging condition to treat. It is possible to perform a single-stage repair in 64.0% of cases. This brings down the median number of operations to only two. Lower lip grafts were used in 34.0% but are now used in redo-surgeries only. Our fistula rate was 26.0% but has decreased significantly in recent years.Level of evidenceLevel III.     

Insight into the impact of vitamin D on cardiovascular outcomes in chronic kidney disease

Patients with chronic kidney disease (CKD) experience excess cardiovascular morbidity and mortality that is unexplained by traditional cardiovascular risk factors. Vitamin D deficiency is highly prevalent in CKD and is associated with increased cardiovascular mortality in both the general population and in CKD patients. Vitamin D supplementation is a reasonably safe and simple intervention and meta‐analyses of observational studies have suggested that vitamin D supplementation in CKD improves cardiovascular mortality. However, randomized controlled trials examining the impact of vitamin D supplementation in improving surrogate markers of cardiovascular structure and function remain inconclusive. This review investigates the impact of vitamin D supplementation on surrogate end‐points and cardiovascular events from trials in CKD; and discusses why results have been heterogenous, particularly critiquing the effect of different dosing regimens and the failure to take into account the implications of vitamin D supplementation in study participants with differing vitamin D binding protein genotypes.     

CDKN2A-p53 mediated antitumor effect of Lupeol in head and neck cancer

Purpose

The tumor suppressor protein p53 is known to control cell cycle arrest and apoptosis. Lupeol is a phytochemical that has been found to induce apoptosis in different cancer types through the extrinsic pathway. As yet, however, its role in the induction of cell cycle arrest and apoptosis through the intrinsic pathway in head and neck cancer has not been investigated. Here, we aimed at understanding the mechanism underlying the antitumor effect of Lupeol in head and neck cancer.

Methods

The antitumor effect of Lupeol on oral and laryngeal carcinomas was assessed using two in vitro 2D cell line models (HEp-2, UPCI:SCC-131) and, subsequently, an ex vivo 3D tumor explant culture platform that maintains key features of the native tumor microenvironment. The mechanism underlying Lupeol-mediated antitumor responses was delineated using MTT, colony formation, flow cytometry, immunofluorescence, Western blotting and immunohistochemistry assays.

Results

We found that Lupeol induced an enhanced expression of p53 in both cell line models tested and, subsequently, cell cycle arrest at the G1 phase. In addition we found that, following Lupeol treatment, p53 induced Bax expression and activated the intrinsic apoptotic pathway (as measured by Caspase-3 cleavage). Interestingly, Lupeol was also found to trigger G1 cell cycle arrest through up-regulation of the expression of CDKN2A, but not p21, resulting in inhibition of CyclinD1. In an ex vivo platform Lupeol was found to impart a potent antitumor response as defined by inhibition of Ki67 expression, decreased cell viability and concomitant activation (cleavage) of Caspase-3. Finally, we found that Lupeol can re-sensitize primary head and neck squamous cell carcinoma (HNSCC) tumor samples that had clinically progressed under a Cisplatin treatment regimen.

Conclusion

Together, our data indicate that Lupeol may orchestrate a bifurcated regulation of neoplastic growth and apoptosis in head and neck cancers and may serve as a promising agent for the management of tumors that have progressed on a platinum-based treatment regimen.

     

A fatal case of meningitis caused by Cryptococcus neoformans var. grubii in an immunocompetent male

The incidence of cryptococcal infection is high in developing countries such as India. Cryptococcal meningitis is considered rare in immunocompetent patients and is mainly a disease of immunocompromised patients. Prognosis in immunocompetent patients is generally considered good. We report a fatal case of cryptococcal meningitis in an immunocompetent male caused by Cryptococcus neoformans var. grubii. Whether the patient is immunocompromised or immunocompetent, the outcome of the disease can be severe unless the disease is diagnosed early in the course of illness.     

Structure-activity study to develop cationic lipid-conjugated haloperidol derivatives as a new class of anticancer therapeutics

Haloperidol (HP), a neuroleptic drug, shows high affinity toward σ receptors (SR). HP and reduced-HP at higher concentration were known to induce apoptosis in SR-overexpressing carcinomas and melanomas. Herein, we report the development of cationic lipid-conjugated haloperidol as a new class of anticancer therapeutics. In comparison to HP, the C-8 carbon chain analogue (HP-C8) showed significantly high, SR-assisted antiproliferative activity against cancer cells via caspase-3-mediated apoptosis and down-regulation of pAkt. Moreover, melanoma tumor aggressiveness in HP-C8-treated mice was significantly lower than that in HP-treated mice. HP-C8 simultaneously reduced Akt-protein level and increased Bax/Bcl-2 ratio in vascular endothelial cells, thereby indicating a possible protein kinase down-regulatory and apoptosis inducing role in tumor-associated vascular cells. In conclusion, we developed σ receptor-targeting cationic lipid-modified HP derivatives as a promising class of anticancer therapeutic that concurrently affects cancer and tumor environment associated angiogenic vascular cells through induction of apoptosis and Akt protein down-regulation.     

Curcumin enhances dasatinib‐induced inhibition of growth and transformation of colon cancer cells

Colorectal cancer is the third most common form of malignancy, behind prostate and lung cancers. Despite recent advances in medicine, mortality from colorectal cancer remains high, highlighting the need for improved therapies. Numerous studies have demonstrated increased activation of EGFR and its family members (EGFRs), IGF‐1R as well as c‐Src in colorectal cancer. The current study was undertaken to examine the effectiveness of combination therapy of dasatinib (BMS‐354825; Bristol‐Myers Squibb), a highly specific inhibitor of Src family kinases (SFK) and a nontoxic dietary agent; curcumin (diferuloylmethane), in colorectal cancer in in vitro and in vivo experimental models. For the latter, we utilized C57BL/6 APC^Min+/? mice. Initial in vitro studies revealed synergistic interactions between the two agents. Additionally, we have observed that combination treatment causes a much greater inhibition of the following metastatic processes than either agent alone: (i) colony formation, (ii) invasion through extracellular matrix and (iii) tubule formation by endothelial cells. Dasatinib affects the cell adhesion phenotype of colon cancer HCT‐116 cells whereas the combination therapy enhances this effect to a greater extent. Preclinical investigation revealed that the combination therapy to be highly effective causing an over 95% regression of intestinal adenomas in Apc^Min+/? mice, which could be attributed to decreased proliferation and increased apoptosis. In conclusion, our data suggest that combination treatment of dasatinib and curcumin could be a potential therapeutic strategy for colorectal cancer.