Nitric oxide synthase 2 and pressure-overload-induced left ventricular remodelling in mice

Nitric oxide synthase 2 (NOS2) has been reported to increase in hypertrophied cardiomyocytes; however, whether NOS2 plays a role in the development of hypertrophy is unknown. To investigate the relationship of NOS2 with left ventricular (LV) remodelling and hypertrophy following prolonged pressure overload, we studied 18 male wild-type (WT) and 20 male NOS2-deficient (NOS2-/-) mice before and 7, 14 and 28 days after transverse aortic constriction (TAC) using echocardiography. A subgroup of eight WT and eight NOS2-/- mice were studied 42 days after TAC. Haemodynamic measurements were obtained before killing. Left ventricular size and function were similar for both genotypes at baseline. After TAC for 28 days, both groups developed LV hypertrophy, with echo-derived LV mass increasing from 78 +/- 2 to 147 +/- 10 mg in WT and from 86 +/- 3 to 142 +/- 10 mg in NOS2-/- mice. Twenty-eight days after TAC, LV weight and cardiomyocyte width were also similar in both genotypes. Fractional shortening (FS) decreased on day 7 from 57 +/- 1 to 48 +/- 2% in WT and from 59 +/- 1 to 49 +/- 2% in NOS2-/- mice. Although this decrease in FS was transient in WT mice, it persisted in NOS2-/- mice. Invasively measured parameters of systolic and diastolic function, however, were similar in the two genotypes both 28 and 42 days after TAC. A load-independent index of contractility, Emax, was similar in both strains 42 days after TAC. In conclusion, NOS2 does not appear to have a critical role in the development of LV hypertrophy after chronic pressure overload.     

Adenoid cystic carcinoma of the maxillary sinus with gradual histologic transformation to high-grade adenocarcinoma: a comparative report with dedifferentiated carcinoma

We report a unique case of adenoid cystic carcinoma (ACC) of the maxillary sinus, with gradual histologic transformation from lower-grade ACC (cribriform and tubular types) to high-grade adenocarcinoma (HGA) showing a sequential histologic spectrum via solid-type ACC. A 74-year-old man presented with swelling and mild pain of the right cheek. CT scan showed a mass measuring approximately 4 cm, with marked bone destruction in the right maxillary sinus. A surgically resected specimen revealed that the tumor was comprised of three different components: HGA and solid-type ACC in the central portion and lower-grade ACC in the periphery. The tumor was discriminated from a dedifferentiated carcinoma or hybrid tumor. Autopsy specimens also demonstrated both solid-type ACC and HGA components in the lung and spleen. Immunohistochemically, positive staining of p53 protein was detected on both solid-type ACC and HGA cells, but cyclin D1 and HER2/neu was only seen in HGA cells. Solid-type ACC cells were immunoreactive for CD117 (c-kit), but lower-grade ACC and HGA cells were negative. This case suggests that the overexpression of CD117, p53 protein, cyclin D1, and HER2/neu might be involved in the progression from lower-grade ACC to solid-type ACC and HGA.     

Variety of morphological and electrophysiological properties of area postrema neurons in adult rat brain slices

Whole-cell recordings were performed to examine the morphological properties of electrophysiologically classified area postrema (AP) neurons in rat brain slices. Using electrophysiological criteria, AP neurons were subdivided into three groups: (1) cells displaying both the hyperpolarization-activated cation current (I(h)) and the fast transient outward current (fast I(to)); (2) cells displaying only the fast I(to); (3) cells displaying only the slow I(to). All AP neurons had a single axon that was distinctly thinner than the cells' dendrites. No systematic differences, across groups, in the orientation of dendrites or axons were identified. Mean values of cell size and capacitance of neurons from group 3 were significantly larger than those of the other groups. Interestingly, a number of cells from groups 1 and 3 but not group 2 were found to extend their dendrites into the nucleus tractus solitarius (NTS), suggesting that AP neurons could receive vagal afferent inputs at their dendritic termini within the NTS. Although the AP has been implicated to contain uniformly shaped neurons, this study indicates the presence of significantly different subpopulations of AP neurons, which were characterized not only electrophysiologically but also morphologically.     

Finding a Panacea among combination cancer therapies

Because each cancer is a heterogeneous mix of cancer cells at different stages of development, we are faced with trying to treat many different diseased cells all at once. An authentic approach is to build a genomic and proteomic profile of a patient, identify the target oncogenes, and prescribe the combination of targeted drugs tailored for that patient. However, there are many practical problems with this personalized medicine approach: (i) cancers often generate treatment-resistant phenotypes, (ii) the treatment could be enormously expensive, and (iii) most of the targeted drugs have not been developed yet. We propose a different approach: therapies that combine 2-deoxyglucose (2DG) with Bcl-2 antagonist such as ABT-263/737 (ABT). Proapoptotic protein Bak is normally sequestered by Mcl-1 and Bcl-xL. Only when Bak is released from both Mcl-1 and Bcl-xL can it induce apoptosis. 2DG can prime highly glycolytic cells by dissociating Bak-Mcl-1 complex. Some brain cells and most cancer cells are primed by 2DG. ABT can bind to Bcl-xL, dissociating Bak-Bcl-xL complex, freeing Bak and inducing apoptosis. Because ABT cannot cross blood-brain barrier, the only cells exposed to both agents are highly glycolytic cancer cells located outside the brain. Because ABT directly triggers apoptosis at the step very near the terminal point of apoptosis, 2DG-ABT combination therapies are applicable to many types of cancer at all stages of development, with little side effect.     

Microsurgical free flap transfer in previously irradiated and operated necks: feasibility and safety

Objectives

Microsurgery is difficult to perform in necks that have been previously irradiated and operated upon because of the limited availability of recipient vessels. The objective of this study was to clarify the feasibility and safety of performing microsurgery in necks that are scarred and fibrous owing to previous treatment.

Methods

Twenty patients whose necks were previously irradiated and operated upon and who underwent free tissue transfer were included in this study. All patients had been previously administered an average of 60.7 (range, 30–95) Gy of radiotherapy. Thirteen patients had undergone hemilateral neck dissections, 5 patients had undergone bilateral neck dissections, 8 patients had undergone (pharyngo)laryngectomies, and 10 patients had undergone prior flap transfer. The success rate of microsurgery and the selection of recipient vessels were examined.

Results

All recipient vessels could be adopted in the neck field without vessel grafting. One patient developed necrosis of the flap, which was salvaged with retransfer of another flap after trimming the same cervical vessels. For the remaining 19 patients, free tissue transfers were successful.

Conclusions

Suitable recipient vessels are residual and available even in the previously irradiated and operated neck field. When performed properly, free tissue transfer in the previously treated neck is not as risky a surgery as was generally believed.     

Regulation of cardiovascular TRP channel functions along the NO-cGMP-PKG axis

There is growing body of evidence that nitric oxide (NO)-cGMP-PKG signaling plays a central role in negative regulation of cardiovascular (CV) responses and its disorders through suppressed Ca(2+) dynamics. Other lines of evidence also reveal the stimulatory effects of this signaling on some CV functions. Recently, transient receptor potential (TRP) channels have received much attention as non-voltage-gated Ca(2+) channels involved in CV physiology and pathophysiology. Available information suggests that these channels undergo both inhibition and activation by NO via PKG-mediated phosphorylation and S-nitrosylation, respectively, and also act as upstream regulators to promote endothelial NO production. This review summarizes the roles of NO-cGMP-PKG signaling pathway, particularly in regulating TRP channel functions with their associated physiology and pathophysiology.