Therapeutic potential of ramipril, losartan, and spironolactone against sepsis-associated liver tissue injury induced by cecal ligation and puncture in rats.

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.

Prognostic significance of microRNA 17-92 cluster expression in Egyptian chronic lymphocytic leukemia patients.

BACKGROUND: Abnormal expression patterns of microRNAs (miRs) play an important role in the development and progression of malignancy. Identification of the clinical significance and prognostic value of these small molecules in chronic lymphocytic leukemia (CLL); a disease of heterogeneous biological landscape and clinical course, has always been of tremendous translational value. AIM: To evaluate the prognostic value of microRNA17-92 cluster members in Egyptian CLL patients. METHODS: The expression levels of miR17-92 cluster members were evaluated by qRT-PCR, including miR17, miR18a, miR19a, miR19b-1, miR20a, and miR92a-1. Other investigations included serum LDH, serum ß2 microglobulin (ß2M), CD38 and ZAP70 expression by flow cytometry, fluorescence in situ hybridization (FISH) for 17p deletion, and imaging studies (computerized tomography (CT) scans of neck, chest, abdomen, and pelvis or PET-CT scans). RESULTS: Overexpression of all members of the miRNA17-92 cluster was detected in CLL patients compared to controls (p = < 0.001 for all miRs while p = 0.01 for miR19b-1). A significant positive correlation between Hb and miR17 and a significant negative correlation between Hb and miR19b-1 were observed (p = 0.041, 0.017 respectively). A statistically significant positive correlation between miR19b-1 expression and each of the WBCs and absolute lymphocytic count (ALC) was detected (p = 0.023, 0.022 respectively). Moreover, a statistically significant relation between miR19b-1 expression and advanced Binet stages was also found (p = 0.05). Regarding miR18a, a statistically significant positive correlation with LDH level was found (p = 0.003). We also found a significant positive correlation between miR92a-1 and ß2M level (p = 0.005), as well as a significant relation between miR17 and negative CD38 expression (p = 0.034). However, no significant relationships between any of studied miRNA expression levels and 17p deletion or response to treatment were observed. Patients who expressed miR19b-1 were significantly indicated to start therapy at diagnosis (p = 0.05). The overall survival of CLL patients included in our study was 90.2% after 1 year from the time of diagnosis. Patients with high expression of miR19a had better OS than those with low expression (p = 0.04). CONCLUSIONS: Overexpression of all members of the miR17-92 cluster was detected in Egyptian CLL patients. MiR18a, miR19b-1, and miR92a-1 also have an adverse prognostic value while miR17 can be considered a good prognostic marker. High expression of miR19a is associated with better OS.

Insights in the mechanisms underlying the anti-ulcer activity of nicorandil.

This study was conducted to investigate possible mechanisms underlying the gastroprotective effect of nicorandil on experimentally-induced gastric lesions in rats. The rats were randomly assigned to vehicle (saline or tween 80), nicorandil (2 mg/kg), glibenclamide (2 mg/kg), nicorandil plus glibenclamide- and cimetidine (50 mg/kg)-pretreated groups, in addition to the non-stressed control group, to demonstrate whether the KATP channel opening activity contributed to nicorandil's gastroprotection. Gastric lesions were induced by water immersion-restraint stress (WIRS) and ulcer indices were determined. Gastric juice parameters (pH, free and total acid output, and pepsin and mucin concentrations) were determined for each group. Another group of rats was divided into control, saline-pretreated and nicorandil (2 mg/kg)-pretreated subgroups. The rats were subjected to 5 h of WIRS and the stomachs were used for determination of gastric mucosal levels of lipid peroxides, histamine, prostaglandin E2 (PGE2) and total nitrites. Nicorandil displayed significant protection against gastric lesions formation. Glibenclamide, when administered concomitantly with nicorandil, abolished its protective effects. Nicorandil significantly reduced gastric acid secretion and pepsin concentration, but upon co-administration with glibenclamide, these effects were blocked. Additionally, nicorandil significantly reduced gastric mucosal lipid peroxides and total nitrites back to near normal levels and significantly increased gastric mucosal PGE2, but did not alter significantly histamine levels. The results confirm a gastroprotective effect for nicorandil, the mechanism of which comprises KATP channel opening, free radical scavenging, PGE2 elevation, decrease of proteolytic activity and acid output and prevention of the detrimental increase of nitric oxide during WIRS, probably, by inhibiting iNOS activity.

Investigation of the mechanisms underlying the gastroprotective effect of nicorandil.

AIM: This study investigated possible mechanisms underlying the gastroprotective effect of nicorandil on experimentally-induced gastric lesions in rats. METHODS: Rats were randomly assigned to vehicle-, nicorandil (10 mg/kg)-, glibenclamide (6 mg/kg)-, nicorandil + glibenclamide- and cimetidine-pretreated groups, in addition to non-stressed control group, to demonstrate whether the K(ATP )channel opening contributed to nicorandil's gastroprotection. Lesions were induced by water immersion-restraint stress (WIRS) and ulcer indices were determined. Gastric juice parameters (pH, acid output, pepsin and mucin concentrations) were determined. Another set of rats was divided into control, saline-pretreated and nicorandil (10 mg/kg)-pretreated groups. Rats underwent WIRS and their stomachs were used for determination of gastric mucosal lipid peroxides, histamine, PGE(2), and total nitrites levels. RESULTS: Nicorandil displayed significant protection against gastric lesions formation, abolished by concomitant administration of glibenclamide. Nicorandil significantly reduced gastric acid and pepsin secretion, but upon coadministration with glibenclamide, these effects were blocked. Additionally, nicorandil significantly reduced gastric mucosal lipid peroxides and total nitrites, but did not affect PGE(2) and histamine levels. CONCLUSION: Results confirm a gastroprotective effect for nicorandil, the mechanism of which comprises K(ATP) channel opening, free radical scavenging, decrease of pepsin and acid secretion and prevention of the detrimental rise in nitric oxide during WIRS.

Klinefelter syndrome is a common cause for mental retardation of unknown etiology among prepubertal males.

Klinefelter syndrome (KS) has not typically been associated with mental retardation (MR), however, in recent years a growing body of evidence suggested that KS boys often experience language deficits and academic difficulties. In this study, we screened DNA samples from 1205 patients originally referred for fragile X syndrome (FRAX) testing, because of MR of unknown etiology and detected 8 KS patients. A similar number of males in the same age group were found to have FRAX; 3 of them had a family history of FRAX. Based on these findings, KS might be the most common cause of MR of unknown etiology among prepubertal males. Because of the significant benefits of early recognition and treatment of KS, we emphasize the importance of cytogenetic testing of all prepubertal males with cognitive impairment even without dysmorphic features.

New mental retardation syndrome associated with ocular colobomas, cleft palate, and genital, skeletal, and craniofacial abnormalities.

We describe three Canadian brothers of Cree origin, with a previously undescribed pattern of malformation including distinctive craniofacial abnormalities with triangular facies, hypertelorism, low-set and posteriorly rotated ears, ocular colobomas, ptosis, brachycephaly with widely separated sutures, cleft soft palate, undescended testes, bifid scrotum and hypospadius, wide webbed neck, webbed fingers, pectus excavatum and hypersegmented sternum, and severe psychomotor retardation. The presence of normal brain imaging and physical growth distinguishes them from other syndromes with overlapping abnormalities. This is either an X-linked or autosomal recessive condition.

Methylation of HpaII site at the human DXS16 locus on Xp22 as an assay for abnormal patterns of X inactivation.

The highly polymorphic human DXS16 locus on Xp22 contains a BglII restriction fragment length polymorphism with 33% heterozygosity. We report that methylation of the HpaII site, 3.1 kb away from this restriction fragment length polymorphism, correlates with X-inactivation. The BglII polymorphism distinguishes between the maternal and paternal alleles, and HpaII digestion identifies their methylation status. The accuracy of this assay was tested on more than 30 control females and some patients with known patterns of X-inactivation. The data obtained from this assay agree substantially with those obtained using the androgen receptor assay, which is widely used for detecting patterns of X-inactivation. This is the first marker on Xp22 found to be suitable for clonal analysis. Of additional significance is this marker's proximity to the pseudoautosomal boundary on the X chromosome and its potential use in identifying rare events occurring in this region, which lead to escape from normal X-inactivation.

Diencephalic neuronal hamartoma associated with congenital obstructive hydrocephalus, anophthalmia, cleft lip and palate and severe mental retardation: a possible new syndrome.

A male infant was born with severe hydrocephalus, bilateral cleft lip/palate, left anophthalmos and right microphthalmos, and an equino-varus foot deformity. Imaging studies showed enlarged lateral ventricles, apparent absence of the corpus callosum and a midline density in the third ventricular region. He had a normal male karyotype. He was severely mentally retarded and died suddenly at 7 years of age. Neuropathological examination of the brain revealed enlarged and polygyric cerebral hemispheres, due to congenital obstructive hydrocephalus, and secondary thinning of the corpus callosum. An unusually large neuronal hamartoma filled the interpeduncular fossa and third ventricle. It was continuous posteriorly with the left thalamus and so was classified as diencephalic rather than as hypothalamic. The right optic nerve merged with the hamartoma, whereas the left nerve was absent. Microscopically the hamartoma consisted of mature grey matter interspersed with narrow bands of white matter. No immature or non-neural elements were identified. This combination of diencephalic neuronal hamartoma, hydrocephalus, ocular and craniofacial abnormalities has not, to our knowledge, previously been described.

Interstitial 6q duplication in an adult male without growth delay or severe mental retardation.

We report on a 28 year-old male with peculiar facies, distal joint contractures and other multiple congenital anomalies. Cytogenetic analysis by G banding revealed a distal tandem interstitial duplication of the long arm of chromosome q6, dup.(6)(6q24.2-->q26). This chromosome abnormality was confirmed by fluorescence in situ hybridization with total chromosome 6 painting. This is probably the second documented case of 6q duplication without growth retardation or severe psychomotor retardation. The clinical findings in our patient are similar to that of whistling face syndrome (WFS) and, in fact, he was diagnosed with WFS as a child. The literature were reviewed and the phenotypic features of this patient were compared with those previously reported for both duplication 6q and whistling face syndromes. There is a significant overlap between the phenotypes of these two syndromes. Careful evaluation of the terminal end of the 6q in cases suggestive of WFS might be warranted.

Additional case of Keipert syndrome and review of the literature.

We report on a 7-year-old boy with unusual facial features, severe bilateral sensorineural hearing loss, and broad terminal phalanges. These findings are similar to those described by Keipert et al. in two brothers and by Balci and Dagli in two other male siblings. Our patient has, in addition, developmental delay and abnormal behaviour. To the best of our knowledge, this is only the third report of Keipert syndrome.

Parental origin of the isochromosome 12p in Pallister-Killian syndrome: molecular analysis of one patient and review of the reported cases.

Pallister-Killian syndrome (PKS) is characterized by multiple congenital anomalies including pigmentary skin changes, mental retardation, and the mosaic presence of a tissue-limited isochromosome 12p [i(12p)]. Mechanism(s) of formation and parental origin of the isochromosome are not well understood. In this study, microsatellite DNA markers of chromosome 12p were used to identify the parental origin of the extra chromosome in an 8-year-old previously reported patient with PKS. The i(12p) was found to be maternally inherited. Reported cases of PKS where the parental origin of the i(12p) was determined were also reviewed. In all the cases, with one exception, the errors were found to be maternal in origin. Premeiotic mitotic error may be the most likely mechanism for i(12p) formation in this syndrome.

Preventive aspects of genetic morbidity: experiences of the Canadian model.

Genetic disorders are emerging as a major health problem in industrialized countries, especially with greater control of environmental diseases. Of total admissions to major paediatric hospitals, 50% are due to genetic disorders, and at least 10% of all adult admissions to hospitals involve major genetic contributions. Several programmes aimed at preventing or ameliorating these genetic disorders are being implemented. Identifying people at risk of genetic disease has helped decrease the burden of such diseases on families and society. Early recognition also leads to greater success of treatment and improves outcome and prognosis. In Arab populations, genetic disorders are still not perceived as a major health problem, even though they are widely prevalent. Applying similar programmes of early detection, maternal screening, neonatal screening, carrier testing and susceptibility testing will significantly help reduce the impact of these disorders in our populations.

Preventive aspects of genetic morbidity: experiences of the Canadian model

Genetic disorders are emerging as a major health problem in industrialized countries, especially with greater control of environmental diseases. Of total admissions to major paediatric hospitals, 50% are due to genetic disorders, and at least 10% of all adult admissions to hospitals involve major genetic contributions. Several programmes aimed at preventing or ameliorating these genetic disorders are being implemented. Identifying people at risk of genetic disease has helped decrease the burden of such diseases on families and society. Early recognition also leads to greater success of treatment and improves outcome and prognosis. In Arab populations, genetic disorders are still not perceived as a major health problem, even though they are widely prevalent. Applying similar programmes of early detection, maternal screening, neonatal screening, carrier testing and susceptibility testing will significantly help reduce the impact of these disorders in our populations

Evidence that skewed X inactivation is not needed for the phenotypic expression of Aicardi syndrome.

Aicardi syndrome is a rare disorder characterized by absent corpus callosum, infantile spasms, and choriorentinal lacunae. It is sporadic in nature and affects only females, resulting in severe mental and physical handicap. It has been suggested that the disease is caused by a dominant X-linked mutation which occurs de novo in females, and is lethal in hemizygous male embryos. This mode of inheritance has been observed in a number of other rare syndromes. In these syndromes, when X inactivation is studied, a non-random pattern is usually found. We have studied the X inactivation pattern in ten female patients with Aicardi syndrome and their parents using the highly polymorphic, differentially methylated androgen receptor gene. The results showed an unexpected random X-inactivation pattern in these patients. Previous clinical and cytogenetic evidence suggests that Aicardi syndrome is caused by an X-linked dominant mutation, de novo in females and lethal in males. However, unlike most other known X-linked disorders inherited in this fashion, Aicardi syndrome patients have a normal (i.e., random) X-inactivation pattern. A number of possible explanations is proposed for this apparently contradictory evidence.

Adenosine for reversal of hemorrhagic shock in rabbits.

The potential use of adenosine in the treatment of hemorrhagic shock was evaluated in rabbits. Hemorrhagic shock was induced by bleeding the animals to a mean arterial blood pressure of 30-35 mmHg that was maintained for 2 hr. The intravenous infusion of 300 micrograms/kg/min adenosine for 1 hr, after reinfusion of the shed blood, was found to be capable of increasing the survival rate of rabbits subjected to hemorrhagic shock. In shocked rabbits, adenosine profoundly improved the postreinfusion depressed contractility of the heart, but it produced a decrease in the mean arterial blood pressure and heart rate. In the same animals, the plasma concentrations of glucose, lactate and inorganic phosphate, which were markedly elevated during shock, were returned back toward normal levels by the intravenous infusion of adenosine. Similarly the alteration that occurred in the plasma sodium, potassium and calcium levels during shock was corrected by adenosine. It is consequently concluded that the use of adenosine after shock improves tissue perfusion and enhances the functional recovery of cells by restoring their metabolic machinery and thereby improves the survival rate.

Pallister-Killian syndrome: a mild case diagnosed by fluorescence in situ hybridization. Review of the literature and expansion of the phenotype.

Pallister-Killian syndrome (PKS) is a rare disorder characterized by a specific combination of anomalies, mental retardation and mosaic presence of a supernumerary isochromosome 12p which is tissue-limited. We report an atypical case of PKS with a mild phenotype. Flourescence in situ hybridization (FISH) was used to demonstrate that the supernumerary marker chromosome identified in the patient's fibroblasts was an isochromosome 12p. This study broadens the spectrum of PKS phenotype. It also illustrates the usefulness of fluorescence in situ hybridization in diagnosis of patients with chromosomal abnormalities and mild or atypical clinical findings.

A female with monosomy 18 mosaicism: a previously undescribed chromosome abnormality.

We report on a patient with monosomy 18 mosaicism, a previously undescribed chromosome abnormality. The phenotype is reminiscent of chromosome 18 ring mosaicism. The reason that the patient survived may be attributed to low level mosaicism for the monosomy.

Enhancement of 5-fluoro-2'-deoxyuridine antitumor efficacy by the uridine phosphorylase inhibitor 5-(benzyloxybenzyl)barbituric acid acyclonucleoside.

5-(Benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA) was recently synthesized as a potent and specific inhibitor of uridine phosphorylase (EC 2.4.2.3), the enzyme responsible for the catabolism of 5-fluoro-2'-deoxyuridine (FdUrd) in many types of tumors that are deficient or have little thymidine phosphorylase (EC 2.4.2.4) activity. The effect of BBBA on modulating the antitumor efficacy of FdUrd was evaluated in vitro, against the human colon carcinomas DLD-1 and HCT-15 grown in culture, and in vivo, against DLD-1 grown as xenografts in anti-thymocyte serum immunosuppressed mice. The concentrations of FdUrd that produced 50% growth inhibition after a 3-h exposure were 88 and 340 nM for HCT-15 and DLD-1, respectively. BBBA alone, at all concentrations tested, had no significant effect on the growth of DLD-1 and HCT-15 in culture. However, BBBA at 5, 10, 20, and 40 nM potentiated (P < 0.05) the cytotoxicity of FdUrd (340 nM; 3 h) against DLD-1 in culture by 20, 33, 55, and 63%, respectively. Similarly, BBBA at 10 and 20 nM potentiated the cytotoxicity of FdUrd (88 nM; 3 h) against HCT-15 in culture by 37 and 45%, respectively. In soft agar, BBBA (10 nM) also enhanced the cytocidal effect of FdUrd (10 and 32 nM) against DLD-1 by 41 and 55%, respectively, and against HCT-15 by 6 and 31%, respectively. Increasing BBBA dose to 20 nM enhanced further the FdUrd (10 and 32 nM) cytotoxicity against DLD-1 by 76 and 77%, respectively, and HCT-15 by 31 and 48%, respectively. BBBA also potentiated the chemotherapeutic efficacy of FdUrd in anti-thymocyte serum immunosuppressed mice bearing DLD-1 xenografts with no apparent host toxicity. At a low tumor burden (2.5 x 10(6) cells/mouse), 2 days treatment with FdUrd alone (50 mg/kg/day x 2) did not result in significant reduction in tumor volume. Coadministration of BBBA at 5 and 10 mg/kg/day x 2 did not potentiate the efficacy of FdUrd over that achieved by FdUrd alone, but it significantly reduced the tumor volume by 27 and 32%, respectively, when compared with untreated controls. FdUrd alone at 150 mg/kg/day x 2 reduced the tumor volume by 29%. This reduction in tumor volume was enhanced 1.8-fold by coadministration of BBBA (10 mg/kg/day x 2). At a higher tumor burden (5 x 10(6) cells/mouse) and 4 days treatment, BBBA at 10 and 30 mg/kg/day x 4 reduced further the tumor volume produced by FdUrd alone (200 mg/kg/day x 4) by 1.2- and 1.4-fold, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

New dominant syndrome of pterygium colli, mental retardation, and digital anomalies.

We describe a proband and his mother who appear to have a new dominant syndrome of mental retardation: pterygium colli, unusual features, and digital anomalies. The craniofacial abnormalities include brachycephaly, epicanthus inversus, angulated eyebrows, upward slanting of the palpebral fissures, ptosis, hypertelorism, and prominent low set, posteriorly rotated ears. The digits are remarkable for proximally displaced small thumbs, widened interphalangeal joints, and broad terminal phalanges.