The Saudi Project for Assessment of Coronary Events (SPACE) registry: Design and results of a phase I pilot study

OBJECTIVE:

The delay between the availability of clinical evidence and its application to the care of patients with acute coronary syndrome (ACS) in the Kingdom of Saudi Arabia remains undefined. The Saudi Project for Assessment of Coronary Events (SPACE) registry provides a comprehensive view of the current diagnostic and treatment strategies for patients with ACS; thus, the registry may be used to identify opportunities to improve the care of these patients.

METHODS:

Eight hospitals in different regions of Saudi Arabia were involved in the pilot phase of the registry, from December 2005 to July 2006. The study patients included individuals with ST segment elevation myocardial infarction (STEMI), non-STEMI and unstable angina.

RESULTS:

A total of 435 patients (77% men and 80% Saudis) with a mean age of 57.1 years were enrolled. Medical history included previously diagnosed ischemic heart disease (32%), percutaneous coronary intervention (12%), diabetes mellitus (53%), hypertension (48%), current smoking (39%), hyperlipidemia (31%) and family history of premature coronary artery disease (11%). The median door-to-needle time for fibrinolytic therapy received by patients with STEMIs was 90 min. Inhospital medications included acetylsalicylic acid (98%), clopidogrel (73%), angiotensin-converting enzyme inhibitors (74%), beta-blockers (73%), statins (88%), unfractionated heparin (80%), low-molecular weight heparin (22%) and glycoprotein IIb/IIIa inhibitors (9%). The inhospital mortality rate was 5%.

CONCLUSION:

The first nationwide registry of patients with ACS in the Kingdom of Saudi Arabia is presented. In contrast to registries from developed countries, our cohort is characterized by a younger age at presentation and a much higher prevalence of diabetes mellitus. Most patients with STEMIs did not receive fibrinolytic therapy within the time recommended in the American College of Cardiology/American Heart Association guidelines. The results of the present pilot study show potential targets for improvement in care.     

A Synthetic Analogue of 20‐HETE, 5,14‐HEDGE,Reverses Endotoxin‐Induced Hypotension via Increased 20‐HETE Levels Associated with Decreased iNOS Protein Expression and Vasodilator Prostanoid Production in Rats

Abstract: Nitric oxide (NO) produced by inducible NO synthase (iNOS) is responsible for endotoxin (ET)‐induced hypotension and vascular hyporeactivity and plays a major contributory role in the multiorgan failure. Endotoxic shock is also associated with an increase in vasodilator prostanoids as well as a decrease in endothelial NO synthase (eNOS) and cytochrome P450 4A protein expression, and production of a vasoconstrictor arachidonic acid product, 20‐hydroxyeicosatetraenoic acid (20‐HETE). The aim of this study was to investigate the effects of a synthetic analogue of 20‐HETE, N‐[20‐hydroxyeicosa‐5(Z),14(Z)‐dienoyl]glycine (5,14‐HEDGE), on the ET‐induced changes in eNOS, iNOS and heat shock protein 90 (hsp90) expression as well as 20‐HETE and vasodilator prostanoid (6‐keto‐PGF_1α and PGE₂) production. ET‐induced fall in blood pressure and rise in heart rate were associated with an increase in iNOS protein expression and a decrease in eNOS protein expression in heart, thoracic aorta, kidney and superior mesenteric artery. ET did not change hsp90 protein expression in the tissues. ET‐induced changes in eNOS and iNOS protein expression were associated with increased 6‐keto‐PGF_1α and PGE₂ levels and a decrease in 20‐HETE levels, in the serum and kidney. These effects of ET on the iNOS protein expression and 6‐keto‐PGF_1α, PGE₂ and 20‐HETE levels were prevented by 5,14‐HEDGE. Furthermore, a competitive antagonist of vasoconstrictor effects of 20‐HETE, 20‐hydroxyeicosa‐6(Z),15(Z)‐dienoic acid, prevented the effects of 5,14‐HEDGE on the ET‐induced changes in systemic and renal levels of these prostanoids and 20‐HETE. These data are consistent with the view that an increase in systemic and renal 20‐HETE levels associated with a decrease in iNOS protein expression and vasodilator prostanoid production contributes to the effect of 5,14‐HEDGE to prevent the hypotension during rat endotoxemia.     

Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan

Malik S, Kakar N, Hasnain S, Ahmad J, Wilcox ER, Naz S. Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan. Mutations in IRF6 cause Van der Woude syndrome (VWS), one of the most common syndromes associated with cleft lip (CL) with or without cleft palate (CP). The presence of pits on the lower lip of patients is the most characteristic feature of the syndrome. We have identified three novel and seven previously reported IRF6 mutations in 12 of 16 unrelated families segregating VWS from Pakistan. The three newly identified mutations include a frameshift (c.568delG) and two missense mutations c.295G>A (p.G99S) and c.1219T>C (p.S407P). Recent functional studies on IRF6 and the three‐dimensional structure of IRF5 carboxy (C) terminus, a protein encoded by a paralog of IRF6, shed light on the p.S407P substitution. Additionally, the identification of the same mutations responsible for VWS in Pakistan, as reported in other global populations worldwide, marks these residues as mutational hotspots and indicates their essential role in structural stability or function of IRF6. This is the first study of VWS in Pakistan and we estimate that 1 in 100 patients with CL with or without CP (CL/P) are affected in the Pakistani population predominantly from the Punjab area.     

In Vitro Susceptibility of the Yeast Pathogen Cryptococcus to Fluconazole and Other Azoles Varies with Molecular Genotype

Cryptococcosis is primarily caused by Cryptococcus neoformans and Cryptococcus gattii. These two pathogenic species each divide into four distinct molecular genotypes. In this study, we examined whether genotype influenced susceptibility to antifungal drugs used to treat cryptococcosis using the broth microdilution method described by the Clinical and Laboratory Standards Institute. C. gattii isolates belonging to molecular genotype VGII had significantly higher MIC values for flucytosine and all azole antifungal agents tested, particularly fluconazole, than isolates of other C. gattii genotypes. In an extended analysis of fluconazole susceptibility, VGII isolates from the north and west of Australia required higher drug levels for inhibition than those from Vancouver Island, Canada. Within C. neoformans, genotype VNII had significantly lower geometric mean MICs for fluconazole than genotype VNI. These results indicate that cryptococcal species, molecular genotype, and region of origin may be important when deciding treatment options for cryptococcosis.Cryptococcosis, caused by the encapsulated yeasts Cryptococcus neoformans and Cryptococcus gattii, is a fungal disease of humans and animals (10). C. neoformans is a worldwide, usually opportunistic pathogen that typically infects immunosuppressed patients, including those with HIV/AIDS (38, 41). In contrast, C. gattii is a primary pathogen that affects immunocompetent people and has caused significant outbreaks in animals in Australia and in humans and animals in Canada (18, 40).The two pathogenic Cryptococcus species divide into eight major molecular types: VNI to VNIV for C. neoformans and VGI to VGIV for C. gattii. There is increasing evidence that these molecular types may represent cryptic species (4, 36), with differences found in important traits, including virulence, geographic range, epidemiology, and population genetics (3, 8). VNI and VGI molecular types are widespread and cause most of the disease attributed to C. neoformans and C. gattii, respectively. C. neoformans VNII to VNIV and C. gattii VGIII and VGIV are less common, and VGIII, VGIV, and VNIV appear to be geographically restricted (15, 21). C. gattii VGII, until recently considered to be rare, has received increasing attention due to its link with a large, ongoing outbreak of cryptococcosis that originated on Vancouver Island, Canada, and has now extended into the Pacific Northwest of the United States (5, 7, 21). VGII also predominates in some parts of Australia and South America and has likely been endemic in these regions for a substantial period (31, 45).Clinical data suggest that the response to antifungal therapy is slower in C. gattii infection than in C. neoformans infection (41, 42) and that more prolonged treatment may be required (13). This is corroborated by various in vitro studies that have found that C. gattii may be less susceptible than C. neoformans to antifungal agents, in particular, fluconazole (13, 17, 44); however, other studies report no significant differences in susceptibility (9, 43). A possible reason for these contradictory findings is that most studies have not considered genetic or geographic differences within the two Cryptococcus species. Iqbal et al. (19) found significant differences in susceptibility between VGII subgenotypes VGIIa, VGIIb, and VGIIc that occur in the Pacific Northwest of Canada and the United States, suggesting that genotype and origin may influence MICs to antifungal agents.The aim of the present study was to determine whether the most common genotypes of C. gattii and C. neoformans differ in their in vitro susceptibility to common antifungal agents. Reduced susceptibility to fluconazole was evident in C. gattii VGII, and this was further explored in an extended set of isolates from Australia and Vancouver Island, Canada, where C. gattii VGII accounts for a substantial proportion of infection.     

Hepatitis B virus BCP,precore/core,X gene mutations/genotypes and the risk of hepatocellular carcinoma in India

The study aims to characterize mutations of the HBV genome involving BCP, Precore/core and X regions and also defines HBV genotypes in patients of hepatocellular carcinoma (HCC). The study involved 150 HBV‐related HCC cases and 136 HBV‐related chronic liver disease patients without HCC as controls. HBV DNA was subjected to mutational analysis using SSCP technique, genotyping by RFLP, and direct nucleotide sequencing. HBV DNA was found in 58.7% (88/150) of the HCC cases and 74.3% (101/136) of controls. HBV mutants were observed in 44.3% of HCC cases and 43.2% of controls. HBV/D was prevalent amongst the patients and controls, followed by HBV/A. The prevalence of the TT1504 mutation in the X gene, the V1753 and T1762/A1764 mutations in the BCP region, and G1914 mutation in the core gene were significantly higher in the HCC group than in the non‐HCC group. Multivariate analyses showed that the TT1504, V1753, A1762T/G1764A, and the G1914 mutations and the patient's age, sex, and HBeAg status increased the risk of HCC development significantly. Also, patients with HCC had lower levels of serum albumin, viral load, and platelet counts but higher values of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, and Alpha feto‐protein than those of controls (P < 0.001 for all comparisons). HBV/D was the predominant genotype associated with HCC cases seen in India. The presence of different types of HBV mutations, age, sex, HBeAg status, and viral load was found to increase significantly the risk of HCC development in India. J. Med. Virol. 82: 1115–1125, 2010. © 2010 Wiley‐Liss, Inc.     

Spectrum of anemia in pregnant Indian women and importance of antenatal screening

Anemia is a common health problem but control of anemia in pregnant women is less well studied. The purpose was to study prevalence of anemia in young pregnant women, correlate with indices and study significance of identification of hemoglobinopathies. Of the 120 pregnant women, Hb was less than 8 g% in 58 (44.2%). Seventy-eight (65%) had iron deficiency, 22 (18.3%) had dimorphic anemia, and 14 (11.6%) had hemolytic anemia. Megaloblastic anemia was present in 6 (5%). Of hemolytic anemia, 50% were thalassemia trait. MCV< 76 fl was observed in 88 (73.3 %) cases. MCV<76 fl and MCH < 27 pg had 100 % sensitivity and 28.7 % specificity for screening of beta-thalassemia trait. NESTROFT had comparable sensitivity but lower specificity (14.9%). Sixty-three percent (60/78) of IDA had increased RDW whereas 78 % (11/14) of hemolytic anemia had RDW value in normal range (p value< 0.05). MCV/RBC of <14 was more specific parameter (96.8%) for beta-thalassemia trait. Four high-risk couples were identified. Thus, moderate to severe anemia was observed in most pregnant women. Hemoglobinopathies should be screened in antenatal clinics to identify the couples that would need a prenatal test. A lower MCV/RBC with RDWin the normal range may be useful in screening for thalassemia trait in pregnant women.     

Skeletal stability after correction of maxillary hypoplasia by the Glasgow extra-oral distraction (GED) device

Maxillary distraction osteogenesis delivers excellent results, particularly in patients with clefts. In the past, devices such as the conventional facemask and the rigid external distraction device have been used to correct maxillary hypoplasia after a Le Fort I osteotomy. We describe a new device, the Glasgow extra-oral distraction device. The extent of skeletal and dental stability of corrections achieved in 10 patients with maxillary hypoplasia associated with clefts was satisfactory. This device costs little, can be produced in developing countries, and provides effective treatment for severe secondary deformity associated with clefts.     

Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury

Recovery of endothelial integrity after vascular injury is vital for endothelial barrier function and vascular homeostasis. However, little is known about the molecular mechanisms of endothelial barrier repair following injury. To investigate the functional role of forkhead box M1 (FoxM1) in the mechanism of endothelial repair, we generated endothelial cell-restricted FoxM1-deficient mice (FoxM1 CKO mice). These mutant mice were viable and exhibited no overt phenotype. However, in response to the inflammatory mediator LPS, FoxM1 CKO mice displayed significantly protracted increase in lung vascular permeability and markedly increased mortality. Following LPS-induced vascular injury, FoxM1 CKO lungs demonstrated impaired cell proliferation in association with sustained expression of p27(Kip1) and decreased expression of cyclin B1 and Cdc25C. Endothelial cells isolated from FoxM1 CKO lungs failed to proliferate, and siRNA-mediated suppression of FoxM1 expression in human endothelial cells resulted in defective cell cycle progression. Deletion of FoxM1 in endothelial cells induced decreased expression of cyclins, Cdc2, and Cdc25C, increased p27(Kip1) expression, and decreased Cdk activities. Thus, FoxM1 plays a critical role in the mechanism of the restoration of endothelial barrier function following vascular injury. These data suggest that impairment in FoxM1 activation may be an important determinant of the persistent vascular barrier leakiness and edema formation associated with inflammatory diseases.