The use of mesenchymal (skeletal) stem cells for treatment of degenerative diseases: current status and future perspectives

Human bone marrow derived-mesenchymal (skeletal) stem (MSC) cells are a group of non-hematopoietic stem cells residing in the perivascular niches in bone marrow. These cells have the capacity to differentiate mainly into mesoderm-type cells such as osteoblasts, chondrocytes and adipocytes and possibly but not proven to non-mesodermal cell types. Recently, there has been an increased interest in understanding the biology of MSC due to their potential use in cell-based therapy for multiple degenerative diseases. Here, we will provide an update on the current status of these novel therapeutic opportunities. J. Cell. Physiol. 218: 9-12, 2009. (c) 2008 Wiley-Liss, Inc.     

Nanoemulsion as a Potential Ophthalmic Delivery System for Dorzolamide Hydrochloride

Dilutable nanoemulsions are potent drug delivery vehicles for ophthalmic use due to their numerous advantages as sustained effect and high ability of drug penetration into the deeper layers of the ocular structure and the aqueous humor. The aim of this article was to formulate the antiglaucoma drug dorzolamide hydrochloride as ocular nanoemulsion of high therapeutic efficacy and prolonged effect. Thirty-six systems consisting of different oils, surfactants, and cosurfactants were prepared and their pseudoternary-phase diagrams were constructed by water titration method. Seventeen dorzolamide hydrochloride nanoemulsions were prepared and evaluated for their physicochemical and drug release properties. These nanoemulsions showed acceptable physicochemical properties and exhibited slow drug release. Draize rabbit eye irritation test and histological examination were carried out for those preparations exhibiting superior properties and revealed that they were nonirritant. Biological evaluation of dorzolamide hydrochloride nanoemulsions on normotensive albino rabbits indicated that these products had higher therapeutic efficacy, faster onset of action, and prolonged effect relative to either drug solution or the market product. Formulation of dorzolamide hydrochloride in a nanoemulsion form offers, thus, a more intensive treatment of glaucoma, a decrease in the number of applications per day, and a better patient compliance compared to conventional eye drops.     

Synthesis and preliminary chemotherapeutic evaluation of the fully C-linked glucuronide of N-(4-hydroxyphenyl)retinamide

All-trans retinoic acid analogues such as N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive and chemotherapeutic agents but their utility has been hampered by dose-limiting side effects. The glucuronide derivatives of 4-HPR, the oxygen-linked 4-HPROG and the carbon-linked 4-HPRCG, have been found to be more effective agents. The synthetic route to the fully C-linked analogue of 4-HPROG (4-HBRCG), which employs Suzuki coupling and Umpolung chemistries as key methodologies, is shown. The results of this study show 4-HBRCG to be an effective chemotherapeutic agent in a rat mammary tumor model while being devoid of classical retinoid toxicities.     

Synthesis and anticancer activity of new [(Indolyl)pyrazolyl]-1,3,4-oxadiazole thioglycosides and acyclic nucleoside analogs

New [(Indolyl)pyrazolyl]-1,3,4-oxadiazole compounds and their derived thioglycosides as well as the corresponding sugar hydrazones were synthesized. The acyclo C-nucleoside analogs of the oxadiazoline base system were also prepared by reaction of acid hydrazides with aldehydo sugars followed by one pot process encompassing acetylation and cyclization of the synthesized hydrazones. The anticancer activity of the newly synthesized compounds was studied against colorectal carcinoma (HCT116), breast adenocarcinoma (MCF7) and prostate cancer (PC3) human tumor cell lines and a number of compounds showed moderate to high activities.     

Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.     

Identification of QTL for increased fibrous roots in soybean

Drought stress adversely affects soybean at various developmental stages, which collectively results in yield reduction. Unpredictable rainfall has been reported to contribute about 36% to variation of yield difference between the rain-fed and irrigated fields. Among the drought resistance mechanisms, drought avoidance in genotypes with fibrous roots was recognized to be associated with drought resistance in soybean. Plant introduction PI416937 was shown to possess fibrous roots and has been used as a parent in breeding programs to improve soybean productivity. Little information is available on relative contribution and chromosomal location of quantitative trait loci (QTL) conditioning fibrous roots in soybean. To identify the genomic locations and genetic bases of this trait, a recombinant inbred line population was derived from a cross between PI416937 and ‘Benning’. To detect associated QTLs, phenotypic data were collected and analyzed for 2 years under rain-fed field conditions. The selective genotyping approach was used to reduce the costs and work associated with conducting the QTL analysis. A total of five QTLs were identified on chromosomes Gm01 (Satt383), Gm03 (Satt339), Gm04 (Sct_191), Gm08 (Satt429), and Gm20 (Sat_299), and together explained 51% of the variation in root score. Detected QTLs were co-localized with QTLs related to root morphology, suggesting that fibrous roots QTL may be associated with other morpho-physiological traits and seed yield in soybean. Genetic dissection of the fibrous roots trait at the individual marker loci will allow for marker-assisted selection to develop soybean genotypes with enhanced levels of fibrous roots.     

Efficiency of diagnostic biomarkers among colonic schistosomiasis Egyptian patients

The schistosomal parasite plays a critical role in the development of malignant lesions in different organs. The pathogenesis of cancer is currently under intense investigation to identify reliable prognostic indices for disease detection. The objective of this paper is to evaluate certain biochemical parameters as diagnostic tools to efficiently differentiate between colonic carcinoma and colonic carcinoma associated with schistosomal infection among Egyptian patients. The parameters under investigation are interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-α), carcinoembryonic antigen (CEA) levels, tissue telomerase, pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G-6-PD) and lactate dehydrogenase (LDH) enzyme activities. The results revealed a significant elevation in the level of the tumour markers IL-2, TNF-α and CEA as well as the activities of LDH, telomerase and G-6-PD among non-bilharzial and bilharzial colonic cancer groups, with a more potent effect in bilharzial infection-associated colonic cancer. A significant inhibition in PK activity was recorded in the same manner as compared to normal tissues. The efficacy of this biomarker was also evaluated through detecting sensitivity, specificity, negative and positive predictive values. In conclusion, schistosomal colonic carcinoma patients displayed more drastic changes in all parameters under investigation. The combination of the selected parameters succeeded in serving as biomarkers to differentiate between the two malignant types.     

Creatine phosphokinase and aspartate aminotransverase profiles and its relation to the severity of uterine torsion in Egyptian buffalo

Thirty-five female buffalo suffering from uterine torsion were brought to the veterinary clinic and were clinically examined as well as monitored using trans-rectal and trans-abdominal ultrasonography. Three blood samples were taken from each animal (before re-torsion, 1h and 24h after delivery) to investigate the relationship between the serum concentrations of creatine phosphokinase (CPK), aspartate aminotransverase (AST) and the severity of uterine torsion. The incidence of uterine torsion was greater in multiparous than young buffalo. The concentration of CPK and AST showed a significant (P<0.05) increase with increased duration and severity of uterine torsion. However, the concentration of CPK was less in the cases delivering a live foetus than a dead one. Animals with CPK above 450 IU usually had uterine rupture during labour (85.7%) and CPK level above 500 U/l did not respond to treatment. After labour, the AST concentration reached normal in some cases (1-6 and 24-48h). Animals with AST above 100 U/l may be either not respond to the re-torsion procedures or respond but exposed to uterine rupture during vaginal delivery. Occurrence of the uterine torsion is usually accompanied by an elevation (P<0.05) of AST concentration regardless the degree, position and viability of the foetus (76.47-100.25 U/l vs. 59.43 U/l). Animals with severe torsion or carrying a dead foetus had greater (P<0.05) AST compared to those having a mild degree or carrying live foetus. After labour, the concentration of AST decreased (P<0.05) but never reached normal concentrations up to 24h except in animals having a live foetus. In conclusion, concentration of CPK and AST can be used as a prognostic indicator for the occurrence of uterine torsion in Egyptian buffalo.     

Cytology and clinical spectrum of sexually transmitted infections in Lebanese women as revealed by Pap smear: a cross-sectional study from 2002-2006

To study the cytology profile of cervical smears and the respective prevalence and incidence of certain cervico-vaginal infections detectable by routine Pap smear cytology in Lebanese women from 2002 to 2006. Pap smear cytology results were compiled from the archives of the Institut National de Pathologie for the period extending from 2002 until 2006. This study covered 118,230 cervical specimens obtained from Lebanese women attending clinics and hospitals in all the five districts of Lebanon; prevalence and incidence rates for infections detectable by routine Pap smear examination were determined. A rise in prevalence of these infections by 2.1 percent (2,555) from 2002 to 2006 was revealed. A doubling of Pap smears showing HPV-associated changes was detected (1.4 percent in 2002 to 2.9 percent in 2006), and a simultaneous almost 7-fold increase of Atypical Squamous Cells of Undetermined Significance (ASCUS) cytology was detected during this period; the rise in ASCUS cytology was age-dependent. Moreover, a 60 percent increase in prevalence of bacterial vaginosis (2.3 percent in 2002 to 3.7 percent in 2006) and a more than 3-fold decline in Trichomonas vaginalis infection (1 percent in 2002 to 0.3 percent in 2006) were also noted in this population during this period. An increase in the prevalence and incidence of cervico-vaginal infections detectable by Pap smear cytology in Lebanese women was revealed from 2002 to 2006. Such changes could point to recent modifications of sexual and health behaviours in the Lebanese community.