Percutaneous fluoroscopically-guided transcervical retrograde access facilitates successful thoracic duct embolization after failed antegrade transabdominal access.

The purpose of this study was to demonstrate the feasibility of percutaneous fluoroscopically-guided transcervical retrograde access into the thoracic duct following unsuccessful transabdominal cisterna chyli cannulation to perform thoracic duct embolization for the treatment of chylothorax. Five patients, including three (60%) women and two (40%) men, with median age of 62 years, underwent percutaneous transcervical thoracic duct access and embolization after failed transabdominal cisterna chyli cannulation for the treatment of chylothorax. In all patients, fluoroscopically-guided percutaneous transcervical retrograde access into the distal thoracic duct was achieved using a 21-gauge needle and an 0.018-inch wire. Following advancement of a microcatheter, retrograde lymphangiography was performed to identify the location of thoracic duct injury. A combination of 2:1 ethiodized oil to cyanoacrylate mixtures, platinum microcoils, or stent-grafts were used to treat the chylous leaks. Technical successes, procedure durations, fluoroscopy times, blood losses, immediate adverse events, clinical successes, and follow-up durations were recorded. Technical success was defined as cannulation of the distal thoracic duct using a transcervical approach followed by treatment of the thoracic duct injury. Adverse events were classified according to the Society of Interventional Radiology guidelines. Clinical success was defined as resolution of the presenting chylothorax. Percutaneous transcervical retrograde thoracic duct access and treatment was technically successful in all patients (n=5). Median procedure duration was 173 minutes (range: 136-347 minutes) with a median fluoroscopy time of 94.7 minutes (range: 47-125 minutes). Median blood loss was 10 mL (range: 5-20 mL). No minor or major adverse occurred. Clinical success was achieved in all patients (n=5). Median follow-up was 372 days (range: 67-661 days). Percutaneous fluoroscopically- guided transcervical retrograde thoracic duct access is an effective and safe method to perform thoracic duct embolization following unsuccessful transabdominal cisterna chyli cannulation for the treatment of chylothorax.

Direct trans-cervical endolymphatic thoracic duct stent-graft for plastic bronchitis.

Plastic bronchitis is a poorly understood and uncommon diagnosis, arising from multiple etiologies. Traditional treatment consists of steroids and vasodilators, with thoracic duct embolization emerging as a new procedural therapy. Herein, abnormal lymphatic vessels were noted on lymphangiography in an adult patient with debilitating plastic bronchitis, but anterograde lymphatic access was not feasible due to the patient's morbid obesity and non-visualization of retroperitoneal lymphatics. After trans-venous thoracic duct access could not be established, direct trans-cervical thoracic duct access was performed. A thoracic duct stent-graft was placed, excluding the abnormal bronchial lymphatics and maintaining physiologic anterograde flow through the central lymphatics. At three-month follow-up, the patient's condition had resolved.

Synthesis and biological evaluation of novel 2 (4`-hydroxynaphthyl) chromen-4-one as a CK2 inhibitor.

Protein kinase CK2 is a potential drug target for many diseases including cancer, inflammatory disorders, Alzheimer's disease, Parkinson's disease and viral infections. Significant efforts have been made for the discovery of potent inhibitors of this enzyme. Herein, we report on the synthesis, characterization, and biological evaluation of novel flavonoid compounds as CK2 inhibitors. The tested compounds were 2 (4`-hydroxynaphthyl) chromen-4-one which is a naphthyl backbone flavonoid with an IC50 value of 0.45±0.059 µM and 2(4-hydroxyphenyl)-4H-chromen-4-one a phenyl based derivative with an IC50 value of 0.33±0.048 µM. Cell viability was tested using MCF-7 cells. Both compounds were able to reduce the cell viability around 50 % in concentration of 100 µM after 48 h. Molecular modeling studies were performed to understand the binding mode of both compounds.

Drug Delivery and Nanoformulations for the Cardiovascular System.

Therapeutic delivery to the cardiovascular system may play an important role in the successful treatment of a variety of disease state, including atherosclerosis, ischemic-reperfusion injury and other types of microvascular diseases including hypertension. In this review we evaluate the different options available for the development of suitable delivery systems that include the delivery of small organic compounds [adenosin A2A receptor agonist (CGS 21680), CYP-epoxygenases inhibitor (N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy] benzoic acid), soluble epoxide hydrolase inhibitor (N-methylsulfonyl-12,12-dibromododec-11-enamide), PPARγ agonist (rosiglitazone) and PPARγ antagonist (T0070907)], nanoparticles, peptides, and siRNA to the cardiovascular system. Effective formulations of nanoproducts have significant potential to overcome physiological barriers and improve therapeutic outcomes in patients. As per the literature covering targeted delivery to the cardiovascular system, we found that this area is still at infancy stage, as compare to the more mature fields of tumor cancer or brain delivery (e.g. blood-brain barrier permeability) with fewer publications focused on the targeted drug delivery technologies. Additionally, we show how pharmacology needs to be well understood when considering the cardiovascular system. Therefore, we discussed in this review various receptors agonists, antagonists, activators and inhibitors which will have effects on cardiovascular system.

DMRTA2 (DMRT5) is mutated in a novel cortical brain malformation.

Lissencephaly is a phenotypically and genetically heterogeneous group of cortical brain malformations due to abnormal neuronal migration. The identification of many causative genes has increased the understanding of normal brain development. A consanguineous family was ascertained with three siblings affected by a severe prenatal neurodevelopmental disorder characterised by fronto-parietal pachygyria, agenesis of the corpus callosum and progressive severe microcephaly. Autozygosity mapping and exome sequencing identified a homozygous novel single base pair deletion, c.1197delT in DMRTA2, predicted to result in a frameshift variant p.(Pro400Leufs*33). DMRTA2 encodes doublesex and mab-3-related transcription factor a2, a transcription factor key to the development of the dorsal telencephalon. Data from murine and zebrafish knockout models are consistent with the variant of DMTRA2 (DMRT5) as responsible for the cortical brain phenotype. Our study suggests that loss of function of DMRTA2 leads to a novel disorder of cortical development.

Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects.

BACKGROUND: Darier disease (DD) is a rare genodermatosis caused by heterozygous mutations in the ATP2A2 gene. It has been associated with neuropsychiatric manifestations. OBJECTIVES: To investigate the genetic basis of Israeli patients with DD, and its association with the neuropsychiatric phenotype. METHODS: A cohort of 32 families comprising 74 affected individuals and 13 unaffected family members was recruited from the Haemek Dermatology Department and other dermatology clinics in Israel. The individuals were evaluated by detailed questionnaires, physical examination and genetic analysis. The main outcome measures were genetic mutations, psychiatric profile and their association. RESULTS: Twenty-three mutations in ATP2A2 were scattered over the entire gene, 14 of them novel. Two families shared the same mutation. Twenty-one patients (28%) had a history of psychiatric disorders, most of them mood disorders. Another seven patients (9%) were highly suspected of having a psychiatric disorder; 21 (28%) reported suicidal thoughts and five (7%) had attempted suicide. The psychiatric phenotype demonstrated inter- and intrafamilial variability, and was not associated with disease severity, family history of psychiatric disease or mutation location. CONCLUSIONS: The cohort demonstrated genetic heterogeneity with no mutation cluster along the gene, and a high prevalence of psychiatric disorders. Although no clear genotype-phenotype correlation was found, the results point to a major effect of genetic background on psychiatric phenotype, together with other modifiers.

Deleterious mutation in the FYB gene is associated with congenital autosomal recessive small-platelet thrombocytopenia.

BACKGROUND: The FYB gene encodes adhesion and degranulation-promoting adaptor protein (ADAP), a hematopoietic-specific protein involved in platelet activation, cell motility and proliferation, and integrin-mediated cell adhesion. No ADAP-related diseases have been described in humans, but ADAP-deficient mice have mild thrombocytopenia and increased rebleeding from tail wounds. PATIENTS AND METHODS: We studied a previously reported family of five children from two consanguineous sibships of Arab Christian descent affected with a novel autosomal recessive bleeding disorder with small-platelet thrombocytopenia. Homozygosity mapping and exome sequencing were used to identify the genetic lesion causing the disease phenotype on chromosome 5. Bone-marrow morphology and platelet function were analyzed. Platelets were characterized by scanning electron microscopy. RESULTS: We identified a homozygous deleterious nonsense mutation, c.393G>A, in FYB. A reduced percentage of mature megakaryocytes was found in the bone marrow. Patients' platelets showed increased basal expression of P-selectin and PAC-1, and reduced increments of activation markers after stimulation with ADP, as detected by flow cytometry; they also showed reduced pseudopodium formation and the presence of trapped platelets between the fibrin fibers after thrombin addition, as observed on scanning electron microscopy. CONCLUSIONS: This is the first report of a disease caused by an FYB defect in humans, manifested by remarkable small-platelet thrombocytopenia and a significant bleeding tendency. The described phenotype shows ADAP to be important for normal platelet production, morphologic changes, and function. It is suggested that mutation analysis of this gene be included in the diagnosis of inherited thrombocytopenia.

Impact of ligand and protein desolvation on ligand binding to the S1 pocket of thrombin.

In the present study, we investigate the impact of a tightly bound water molecule on ligand binding in the S1 pocket of thrombin. The S1 pocket contains a deeply buried deprotonated aspartate residue (Asp189) that is, due to its charged state, well hydrated in the uncomplexed state. We systematically studied the importance of this water molecule by evaluating a series of ligands that contains pyridine-type P1 side chains that could potentially alter the binding properties of this water molecule. All of the pyridine derivatives retain the original hydration state albeit sometimes with a slight perturbance. In order to prevent a direct H-bond formation with Asp189, and to create a permanent positive charge on the P1 side chain that is positioned adjacent to the Asp189 carboxylate anion, we methylated the pyridine nitrogen. This methylation resulted in displacement of water but was accompanied by a loss in binding affinity. Quantum chemical calculations of the ligand solvation free energy showed that the positively charged methylpyridinium derivatives suffer a large penalty of desolvation upon binding. Consequently, they have a substantially less favorable enthalpy of binding. In addition to the ligand desolvation penalty, the hydration shell around Asp189 has to be overcome, which is achieved in nearly all pyridinium derivatives. Only for the ortho derivative is a partial population of a water next to Asp189 found. Possibly, the gain of electrostatic interactions between the charged P1 side chain and Asp189 helps to compensate for the desolvation penalty. In all uncharged pyridine derivatives, the solvation shell remains next to Asp189, partly mediating interactions between ligand and protein. In the case of the para-pyridine derivative, a strongly disordered cluster of water sites is observed between ligand and Asp189.

Laparoscopic-assisted management of severe necrotizing pancreatitis with obstructive jaundice: a case report.

We report a severely infected necrotizing pancreatitis managed with hand-assisted laparoscopic necrosectomy along with a review of the relevant literature. Minimally invasive necrosectomy has been shown to be efficient and advantageous in managing necrotizing pancreatitis. Multiple techniques have been advocated over the last decade. Laparoscopic pancreatic debridement is a feasible option for some patients with necrotizing pancreatitis. We selected hand-assisted laparoscopic pancreatic necrosectomy, which has gained some favor over open necrosectomy because of the morbidity and mortality associated with laparotomy. We report on an Indian male patient who presented with acute abdomen and severe jaundice. A CT scan of the abdomen showed severe necrotizing pancreatitis. After conservative management failed, a hand-assisted laparoscopic pancreatic necrosectomy was performed. The patient recovered and was discharged 4 weeks after surgery.

Skoura - a genetic island for congenital insensitivity to pain and anhidrosis among Moroccan Jews, as determined by a novel mutation in the NTRK1 gene.

Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV is a rare, autosomal recessive neurologic disorder, characterized by absence of reaction to painful stimuli, mental retardation, self- mutilating behavior, anhidrosis, and recurrent episodes of hyperthermia. Mutations in the neurotrophic tyrosine kinase receptor 1, a receptor phosphorylated by nerve growth factor, have been documented in diverse ethnic groups. We identified the same novel nonsense mutation in two unrelated families of Moroccan Jewish descent, each with two affected siblings. This possible founder mutation may trace to the rural Jewish village in southern Morocco from where both these families originated. Genetic screening for the causative mutation among 300 unrelated Moroccan Jews did not reveal carriers for the causative mutation, thus excluding high risk for CIPA in this ethnic subpopulation.

Chronic lung disease and cystic fibrosis phenotype in prolidase deficiency: a newly recognized association.

Six families with prolidase deficiency (PD) and chronic lung disease are reported, a previously unrecognized association. In one family with a classic cystic fibrosis (CF) phenotype, no evidence for CF Transmembrane Conductance Regulator (CFTR)-related mutations could be found. Chronic lung disease and CFTR-mutation negative CF may be associated with PD.

Neutral carriers based polymeric membrane electrodes for selective determination of mercury (II).

The potentiometric response characteristics of mercury ion-selective membrane electrodes based on 2-amino-6-purinethiol (I(1)) and 5-amino-1, 3, 4-thiadiazole-2-thiol (I(2)) were described. Ion selectivities were tested for various plasticizers, which were used as solvent mediators to incorporate the ionophores into the membrane. Effects of experimental parameters such as membrane composition, nature and amount of plasticizers and additives, pH and concentration of internal solution on the potential response of Hg(2+) electrodes were investigated. The best performance was obtained with the electrode having a membrane composition (w/w) of (I(1)) (3.17%): PVC (31.7%): DOP (dioctylpthalate) (63.4%): NaTPB (sodium tetraphenylborate) (1.58%). The proposed electrode reveals a Nernstian response over Hg(2+) ion in the concentration range of 7.0 x 10(-8)-1.0 x 10(-1) M with limit of detection 4.4 x 10(-8) M. The electrode shows good discrimination toward Hg(2+) ion with respect to most common cations. It shows a short response time (10s) for whole concentration range and can be used for 2 months without any considerable divergence in potentials. For evaluation of the analytical applicability, the electrode was used in the determination of Hg(2+) ion in different environmental and biological samples. The practical utility of the membrane electrode has also been observed in the presence of surfactants.

Research ethics: challenges in the Eastern Mediterranean Region.

The foundations of ethical principles in the Eastern Mediterranean Region can be found within the 3 major religions of the Region; Judaism, Christianity and Islam. Today, there are numerous ethical issues that have emerged as result of the technological advances of the 20th century and this paper addresses some of those related to biomedical research. The Islamic principles in relation to medicine and biomedical research are described, and in particular research involving human subjects. The paper also outlines the endeavours being made by the Islamic Organization for Medical Sciences to address such issues and draw up recommendations and rulings.

Human cloning: Eastern Mediterranean Region perspective.

Recent advances in genomics and biotechnology have ushered in a new era in health development. Therapeutic cloning possesses enormous potential for revolutionizing medical and therapeutic techniques. Cloning technology, however, is perceived as having the potential for reproductive cloning, which raises serious ethical and moral concerns. It is important that the Islamic countries come to a consensus on this vital issue. Developing science and technology for better health is a religious and moral obligation. There is an urgent need for Muslim scholars to discuss the issue of stem cell research and cloning rationally; such dialogue will not only consider the scientific merits but also the moral, ethical and legal implications.

A new Zn(II)-selective potentiometric sensor based on 4-tert-butylcalix[4]arene in PVC matrix.

Poly(vinyl chloride) (PVC) based membranes containing 4-tert-butylcalix[4]arene (I) as an electroactive material along with anion excluder sodiumtetraphenylborate (NaTPB) and plasticizer tri-butylphosphate (TBP) have been developed to fabricate a new zinc-selective sensor. Out of various compositions, the best performance was exhibited by the membrane having I, NaTPB, TBP and PVC in the ratio 8:5:100:200 (w/w). The sensor works well in the concentration range 9.8 x 10(-6) to 1.0 x 10(-1) mol dm(-3) with a near-Nernstian slope of 28.0+/-1.0 mV/decade of activity. The detection limit is down to 5.0 x 10(-7) mol dm(-3). The working pH range of this sensor is 2.5-4.3 and it works well in partially non-aqueous medium up to 15% (v/v) (methanol, ethanol and acetone). It exhibits a fast response time of 30s and could be used for more than four months without any considerable change in response characteristics. It has excellent selectivity for Zn(II) over other mono-, bi- and trivalent cations which have been reported to cause interference in the working of other sensors. It has been successfully used as an indicator electrode in the potentiometric titration of Zn(II) against EDTA and also to estimate zinc ions in industrial waste waters.

Inhibition of de novo synthesis of a jelly layer precursor protein by crustacean hyperglycemic hormone family peptides and posttranscriptional regulation by sinus gland extracts in Penaeus semisulcatus ovaries.

Mature penaeid oocytes possess extracellular cortical rods (CR) that contain precursor proteins of the jelly layer (JL) that forms a protective layer around eggs immediately after spawning and dissipates following the assembly of the hatching envelope. The temporal pattern of protein synthesis and mRNA expression of a jelly layer precursor protein in Penaeus semisulcatus ovaries was followed during vitellogenesis, and the regulation by sinus gland extracts (SGE) and crustacean hyperglycemic hormone (CHH) family peptides was evaluated. An approximately 33-kDa jelly layer precursor protein was previously identified in ovaries, CR, and JL and was named shrimp ovarian peritrophin-like protein (SOP), because its deduced amino acid sequence shows structural similarities to insect peritrophins. SOP was synthesized in ovarian explant fragments that were removed from vitellogenic ovaries and incubated in vitro, but synthesis was not detected in explants that were collected from previtellogenic ovaries. SOP transcripts were detected in all stages of ovarian development, but were more abundant in previtellogenic ovaries than in other stages. De novo synthesis of SOP was inhibited by P. semisulcatus SGE and by CHH family peptides that were purified from P. japonicus sinus glands. Sinus gland extracts, however, did not affect the steady state levels of SOP transcripts at any stage of ovarian development. These results suggest that SGE regulate SOP synthesis at the posttranscriptional level.

Molecular characterization and high expression during oocyte development of a shrimp ovarian cortical rod protein homologous to insect intestinal peritrophins.

Penaeoid shrimp oocytes nearing the completion of oogenesis are enveloped in an acellular vitelline envelope and possess extracellular cortical rods (CRs) that extended into the cortical cytoplasm. These cortical specializations are precursors of the jelly layer (JL) of the egg. In searching for highly expressed mRNAs during oogenesis in the marine shrimp (Penaeus semisulcatus), two related cDNAs have been isolated that encode a mature protein of 250 amino acid residues. The deduced amino acid sequences revealed the presence of repeated cysteine-rich domains that are related to the chitin-binding domains of insect intestinal peritrophins. Similar cysteine-rich domains were reported in insect intestinal mucin, crustacean tachycitin, and invertebrate chitinases. The shrimp ovarian peritrophin (SOP) is glycosylated and can bind chitin when extracted from CRs. Its apparent molecular mass in SDS-PAGE is 29-35 kDa and 33-36 kDa, under nonreducing or reducing conditions, respectively. SOP is a major protein of CRs and the JL, and was immunodetected in ovaries; purified CRs; fertilized eggs that were surrounded by a JL matrix; and in the cloudy, whitish flocculent material appearing in sea water immediately after spawning. Immunolocalization in tissue sections determined that SOP was present in oocyte cytoplasm and in extraoocytic CRs. Shrimp expressed SOP mRNA in ovaries at all oocyte developmental stages, whereas expression in the hepatopancreas was restricted to vitellogenic stages. SOP mRNA was abundant in the shrimp ovary and was detected before the presence of the corresponding protein. This is the first demonstration that a protein with similar features to insect intestinal peritrophins is a component of CRs and is therefore a main precursor of the JL of spawned shrimp eggs.