Advances in the management of pediatric pulmonary hypertension

Pulmonary hypertension is a rare disease in neonates, infants, and children, and is associated with substantial morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking. Moreover, a minority of research is focused specifically on neonatal and pediatric populations. Although therapeutic options have increased over the past several decades, they remain limited. In advanced pulmonary hypertension, progressive pulmonary vascular functional and structural changes ultimately cause increased pulmonary vascular impedance, right-ventricular failure, and death. Management includes the prevention and/or treatment of active pulmonary vasoconstriction, the support of right-ventricle function, treatment of the underlying disease (if possible), and the promotion of regressive remodeling of structural pulmonary vascular changes. Most currently available therapies augment or inhibit factors, or mediators of their downstream signaling cascades, that originate in the pulmonary vascular endothelium. These pathways include nitric-oxide/cyclic guanosine monophosphate (cGMP), prostacyclin, and endothelin-1. The ability to reverse advanced structural changes remains an as yet unattained goal. This paper reviews the epidemiology, pathophysiology, current treatments, and emerging therapies related to neonatal and pediatric pulmonary hypertension.     

The genotoxic and antigenotoxic effects of tannic acid in human lymphocytes

The genotoxicity of tannic acid (TA, tannin) were investigated using chromosome aberration (CA), sister chromatid exchange (SCE), and micronucleus (MN) test systems in human peripheral lymphocytes. Also, the antigenotoxicity of TA against known mutagen EMS was also examined. The lymphocytes were treated with 1.74?×?10(-5), 3.49?×?10(-5), and 6.98?×?10(-5) μM of TA for 24- and 48-hour treatment periods. For the antigenotoxicity of TA, the lymphocytes were treated with three different concentrations of TA and 2.71 μM of EMS. TA synergically induced the CA alone and with the mixture of EMS. However, TA did not induce the SCE alone, whereas TA and EMS as a mixture also synergically induced SCE. TA alone showed no clear effect on micronucleus formation, and it did not induce the MN when used with EMS as a mixture. In addition, TA showed a synergistic cytotoxic effect by decreasing the mitotic and nuclear division indices. The replication index was decreased at all concentrations for 48 hours of treatment time by TA and EMS as a mixture.     

Resistance to angiogenesis inhibitors in renal cell carcinoma

Antiangiogenic drugs are now available for treatment of renal cell carcinoma and are utilized sequentially to prolong clinical benefit in patients with recurrent disease. These antiangiogenic agents are disease stabilizing in most cases, and resistance eventually develops over time. Because different combinations and sequences are tested in clinical trials, resistance patterns and mechanisms should be investigated. Much effort has been devoted to understanding the biology and elucidating the pathways and additional targets during tumorigenesis and metastasis. Resistance appears to be either primary nonresponsiveness, or it is acquired over time and related to various evasive/escape mechanisms that the tumor develops in response to therapy. Primary resistance is less common, but may be due to an intrinsic redundancy of available angiogenic signals for the tumor, causing unresponsiveness to vascular endothelial growth factor (VEGF)-targeted therapies. During acquired resistance, tumors may activate an "angiogenic switch," which leads to either upregulation of the existing VEGF pathway or recruitment of alternative factors responsible for tumor revascularization. Rationally designed preclinical and clinical trials will shed additional light on our understanding of the potential mechanisms of resistance to antiangiogenic drugs.     

Detecting retroviral sequences in chronic fatigue syndrome

XMRV or xenotropic murine leukemia virus-related retrovirus, a recently discovered retrovirus, has been linked to both prostate cancer and chronic fatigue syndrome (CFS). Recently, the teams of Drs. Shyh-Ching Lo and Harvey Alter discovered the presence of sequences closely related to XMRV in the blood of 86.5% of patients with CFS [1]. These findings are important because since the initial discovery of XMRV in CFS, several studies have failed to find XMRV in specimens collected from CFS patients. While the current study also did not find XMRV in CFS, Lo et al. did detect sequences that belong to polytropic mouse endogenous retroviruses (PMV), which share considerable similarity with XMRV. Criteria for future studies that will help bring greater clarity to the issue of retroviral sequences in CFS are proposed below.     

Endostatin, an Inhibitor of Angiogenesis, Decreases After Bidirectional Superior Cavopulmonary Anastamosis

Pulmonary arteriovenous malformations (PAVMs) are a common source of morbidity after bidirectional superior cavopulmonary anastomosis (Glenn). The diversion of hepatic venous effluent away from the pulmonary circulation after Glenn appears to play a significant role in the pathogenesis of PAVMs. Although the liver is known to produce factors that regulate vascular development, specific hepatic inhibitors of angiogenesis have not been described in the post-Glenn population. Endostatin, produced from its precursor collagen XVIII, is a potent inhibitor of angiogenesis produced by the liver. This study aimed to investigate the hypothesis that endostatin levels decrease in patients after Glenn. Levels of endostatin and its precursor, long-type collagen XVIII, were determined by enzyme-linked immunoassay and immunoprecipitation, respectively, for serum samples from 38 patients undergoing Glenn, total cavopulmonary anastomosis (Fontan), or biventricular repair of cardiac defects. Samples were obtained before surgery and 24 h afterward. In patients undergoing a bidirectional Glenn procedure, endostatin levels decreased after surgery (n = 17; 4.42 vs 3.34 ng/ml; p < 0.001), and long type-collagen XVIII levels increased by 200 % (n = 10; p = 0.0001). However, endostatin levels did not change after surgery in patients undergoing Fontan (n = 13) or biventricular repair (n = 8). In patients undergoing Fontan, long-type collagen XVIII increased by 18 % (p < 0.01), whereas in control subjects, the levels were unchanged. These data suggest that the diversion of hepatic blood flow away from the pulmonary circulation in patients after the Glenn procedure inhibits endostatin production from collagen XVIII, resulting in decreased circulating serum endostatin levels. A decrease in endostatin may promote angiogenesis. The mechanism whereby the pulmonary circulation processes endostatin and its potential role in the pathogenesis of PAVMs warrant further study.     

Fundamental limits on persistent activity in networks of noisy neurons

Neural noise limits the fidelity of representations in the brain. This limitation has been extensively analyzed for sensory coding. However, in short-term memory and integrator networks, where noise accumulates and can play an even more prominent role, much less is known about how neural noise interacts with neural and network parameters to determine the accuracy of the computation. Here we analytically derive how the stored memory in continuous attractor networks of probabilistically spiking neurons will degrade over time through diffusion. By combining statistical and dynamical approaches, we establish a fundamental limit on the network’s ability to maintain a persistent state: The noise-induced drift of the memory state over time within the network is strictly lower-bounded by the accuracy of estimation of the network’s instantaneous memory state by an ideal external observer. This result takes the form of an information-diffusion inequality. We derive some unexpected consequences: Despite the persistence time of short-term memory networks, it does not pay to accumulate spikes for longer than the cellular time-constant to read out their contents. For certain neural transfer functions, the conditions for optimal sensory coding coincide with those for optimal storage, implying that short-term memory may be co-localized with sensory representation.     

Detection of Microcalcification Clusters Using Hessian Matrix and Foveal Segmentation Method on Multiscale Analysis in Digital Mammograms

Mammography is the most efficient technique for detecting and diagnosing breast cancer. Clusters of microcalcifications have been mainly targeted as a reliable early sign of breast cancer and their earliest detection is essential to reduce the probability of mortality rate. Since the size of microcalcifications is very tiny and may be overlooked by the observing radiologist, we have developed a Computer Aided Diagnosis system for automatic and accurate cluster detection. A three-phased novel approach is presented in this paper. Firstly, regions of interest that corresponds to microcalcifications are identified. This can be achieved by analyzing the bandpass coefficients of the mammogram image. The suspicious regions are passed to the second phase, in which the nodular structured microcalcifications are detected based on eigenvalues of second order partial derivatives of the image and microcalcification pixels are segmented out by exploiting the foveal segmentation in multiscale analysis. Finally, by combining the responses coming out from the second order partial derivatives and the foveal method, potential microcalcifications are detected. The detection performance of the proposed method has been evaluated by using 370 mammograms. The detection method has a TP ratio of 97.76 % with 0.68 false positives per image. We have examined the performance of our computerized scheme using free-response operating characteristics curve.     

Surgical complications in 448 gynecological 3D laparoscopic surgeries adopting the Clavien—Dindo classification

The aim of this study is to present and report the perioperative outcomes, intraoperative, and postoperative complications according to the Clavien—Dindo classification. Clinical data of 448 patients who underwent 3D laparoscopy in a single center over 1 year was retrospectively analyzed, and the postoperative complications were stratified adopting the Clavien—Dindo (CD) classification. During the study period, 448 patients underwent gyneclogical 3 D laparoscopic surgery, TLH (259), laparoscopic myomectomy(104), surgery for endometriosis(20), ovarian cyst(24), and miscellaneous(41). The overall rate of intraoperative complications were 0.9 %. There were two cases of bowel injury (0.4 %), one with intra-operative bladder injury (0.2 %) and one with ureteric injury (0.2 %). In all the above cases, recovery was uneventful and no further intervention was needed. There were no incidences of vascular injury, clinical thromboembolism, ICU admission, or death. The incidence of CD Grade I complications was 1.1 %. There were two cases of postoperative vertigo which was treated with betahistine dihydrochloride. One case each of urinary tract infection and vault infection treated with antibiotics and one case of postoperative dysuria treated with flavoxate hydrochloride. Blood transfusions were required in four patients. The incidence of CD Grade II complications was 2.0 %. Two patients (0.4 %) of TLH underwent vault re-suturing under general anesthesia (CD Grade IIIb). There were no cases of CD Grade IV and Grade V complications. The complication rate in our study compares favorably with those reported by other large studies. The authors believe that a widespread implementation of a common standardized system for reporting of complications is essential for comparability of clinical data.     

Oxidative free radicals scavenging activity (in vitro and in vivo assay) of standardized fractions from the seeds of Argyreia speciosa (Ghav-patta) a traditional Indian medicine

Traditional pertinenceArgyreia speciosa Sweet (Linn.), belongs to the family convolvulaceae, a traditional Indian medicinal herb, has been used to treat acute/chronic ulcers, gonorrhea, rheumatoid arthritis and several nervous disorders having a long history.Aim of the studyA broad spectrum approach of this work was to find out the antioxidant activity of Argyreia speciosa seeds, in vitro and in vivo antioxidant assay were performed.Material and methodsTotal phenolic content (TPC), reducing power (RP), antioxidant activity (AOA), ${\text{O}}_2^{\text{·}-}$ (superoxide anion), DPP? (1,1-diphenyl-2-picrylhydrazyl) and ?OH (hydroxyl) radicals scavenging activities, GSH (glutathione), CAT (catalase), SOD (superoxide dismutase) and LPO (lipid peroxidase) are the major parameters which were studied for determining in vitro and in vivo antioxidant property of seed extract & their six fractions obtained from A. speciosa. Carbon tetrachloride (CCl₄) induced rat model was used to determine in vivo antioxidant assay of extract and its fractions.ResultsButanol fraction (AS-BF) showed strong antioxidant property and protected oxidative DNA damage. AS-BF was found best as compared to all other fraction for determining antioxidant property of seeds with the reduction in lipid peroxide formation and increment in GSH, CAT and SOD. AS-BF showed the presence of phenolic compounds viz. gallic acid, chlorogenic acid, and ellagic acid.ConclusionFrom these results, it was proved that A. speciosa seeds prevent tissue damage due to oxidative stress with strong antioxidant activity.