Polymorphisms of platelet adhesive receptors: do they play a role in primary intracerebral hemorrhage?

BACKGROUND: Several reports suggested that polymorphisms affecting the structure or level of the main adhesive platelet glycoproteins (GPs) could behave as genetic risk factors for arterial thrombotic disorders. However, very few reports analyzed the significance of these polymorphisms in bleeding disorders. Interestingly, one study suggested a role of the 807 C/T polymorphism of the collagen receptor GP Ia in the severity of the bleeding manifestations in von Willebrand disease. The aim of this study was to evaluate the role of frequent polymorphisms affecting platelet GPs in primary intracerebral hemorrhage (PIH), the third most frequent cause of cerebrovascular disorder. METHODS: We evaluated the role of four putative prothrombotic polymorphisms: GP Ia [807 C/T, and human platelet alloantigen system 5 (HPA-5)], GP Ibalpha (variable number of tandem repeats), and GP IIIa (HPA-1) in 141 Caucasian patients diagnosed of PIH, 141 race-, age-, sex- and risk factor-matched controls, and 446 subjects from the general population. RESULTS: The frequency of genotypes and alleles were similar between patients and controls. CONCLUSIONS: Our results suggest that these polymorphisms play a minor role in PIH.     

Adamantylamide dipeptide as effective immunoadjuvant in rabbits and mice

In the search for more potent and less toxic immunomodulators, adamantylamide dipeptide (AdDP) was synthesized by the covalent union of amantadine with the L-alanyl-D-isoglutamine residue of muramyldipeptide (MDP). The present experiments demonstrate the ability of AdDP, co-administered with a protein immunogen, to raise or enhance a humoral response in immunized animals. BALB/c mice were immunized either by the intraperitoneal (ip) or oral route with ovalbumin (Ova) alone or combined with either AdDP or CpG oligonucleotide (ODN-CpG), a proved adjuvant. A clear adjuvant dose-response relationship was observed on the increment of Ova-specific serum antibody titers when AdDP was used as adjuvant, irrespectively of the administration route. The IgG isotype analysis showed that AdDP promotes a consistent increment in IgG1 antibodies associated with a dominant Th2 response pattern. When administered by the oral route, AdDP was at least as efficient as ODN-CpG as adjuvant. Similar results were obtained in rabbits immunized by the oral route, suggesting that the adjuvanticity of AdDP is not restricted to the murine system. In conclusion, AdDP was shown to be a powerful and non-toxic adjuvant at both systemic and mucosal levels, which makes it a promising tool for vaccine development.     

Synthesis, characterisation, and antineoplastic cytotoxicity of hybrid naphthohydroquinone–nucleic base mimic derivatives

From a partially degraded Diels–Alder adduct of α-myrcene and 1,4-benzoquinone, several model compounds belonging to a new series of 1,4-naphthohydroquinone derivatives have been prepared. Phenyl, pyridyl, imidazolyl and some nucleic base mimic heterocycles have been attached to the naphthohydroquinone system through linkers of different size and type, leading to potentially antineoplastic hybrid structures. The new compounds have been evaluated in vitro for their cytotoxicity against cultured human cancer cells of A-549 lung carcinoma, HT-29 colon adenocarcinoma and MDA-MB-231 breast carcinoma. GI₅₀ values ranged in the μM level.     

Cut‐off score of the Mattis Dementia Rating Scale for screening dementia in Parkinson's disease

The prevalence of dementia in Parkinson's disease (PD) is close to 30%, and its incidence is 4 to 6 times higher than in age‐matched general population. PD with dementia (PDD) is mainly characterized by a predominant and progressive frontal‐subcortical impairment. The Mattis Dementia Rating Scale (MDRS) is a commonly used screening test that sensitively measures the degree of frontal‐subcortical defects. Although the MDRS has been validated as a screening test of cognitive dysfunction in nondemented PD patients (PD‐ND), its utility for screening dementia in PD is unknown. In order to validate the MDRS for diagnosis of PDD it was prospectively administered to 92 PD patients (57 PD‐ND, 35 PDD) fulfilling UK‐PDSBB criteria. Dementia was diagnosed according to DSM‐IV‐TR and a Clinical Dementia Rating (CDR) scale score ≥1. Univariate, logistic regression, and ROC curve analysis were carried out to measure the discriminative power of MDRS in PDD. Regression analysis showed MDRS total scores to independently differentiate PD‐ND from PDD (P < 0.001). Age and education did not predict the presence of dementia. ROC curve analysis showed a cut‐off score of ≤123 on the MDRS total scores to yield high sensitivity (92.65%), specificity (91.4%), positive and negative predictive values (PPV 83.3%, NPV 96.4%). A brief version of the MDRS obtained by the addition of the memory, initiation/perseveration, and conceptualization subscores yielded similar discriminant properties. The MDRS has an excellent discriminant ability to diagnose dementia in PD and provides an objective measure to distinguish PD‐ND from PDD. © 2008 Movement Disorder Society     

Improvement in organ blood flow by inhibition of thromboxane synthetase during experimental endotoxic shock in the rat

Endotoxic shock is associated with increased metabolism of arachidonic acid to thromboxane (Tx) and prostaglandins. This investigation examined the effects of two structurally dissimilar inhibitors of (Tx) synthetase on Salmonella enteritidis endotoxin (LPS) (15 mg/kg)-induced alterations in cardiac output and organ blood flow in Long-Evans rats. An imidazole derivative, 7(1-imidazolyl) heptanoic acid (7-IHA), and sodium -(E)-3-[4-(3-pyridyl-methyl)phenyl]-2-methacrylate (OKY-1581) were injected intravenously at 30 and 5 mg/kg, respectively, 30 min before injection with endotoxin. Cardiovascular function was assessed 30 min post-LPS with Sr-85 labeled microspheres under light ether anesthesia. Injection of endotoxin caused a 60% decrease in cardiac output (34.0 +/- 2.7 ml/min/100 g body weight in control rats) and a 38.9% decrease in systolic arterial pressure. Both Tx synthetase inhibitors significantly (p less than 0.05) attenuated the decrease in cardiac output, although only 7-IHA improved blood pressure. Pretreatment with 7-IHA or OKY-1581 significantly (p less than 0.05) attenuated the LPS-induced decrease in renal perfusion. Lung nutrient blood flow (1.1 +/- 0.2 ml/min/g lung) decreased nearly 70% in shock. Both Tx synthetase inhibitors prevented this reduction. LPS shock resulted in approximately a 30% decrease in brain blood flow. 7-IHA significantly (p less than 0.05) improved flow, while OKY-1581 was without apparent effect. Splanchnic blood flow was likewise improved by 7-IHA and OKY-1581. Liver blood flow, 55% less than values of the control group in shock (p less than 0.05), was returned to values of the controls by both inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)     

The number of platelet glycoprotein Ia molecules is associated with the genetically linked 807 C/T and HPA-5 polymorphisms

BACKGROUND: The neutral 807 C/T (Phe224) polymorphism (807 C/T polymorphism) of the glycoprotein (GP)Ia gene has been recently associated with the number of GPIa molecules on the platelet surface. The association of the number of GPIa molecules with other GPIa polymorphisms, such as HPA-5 (Glu/Lys505) (HPA-5 polymorphism), involved in alloimmune thrombocytopenias is unknown. STUDY DESIGN AND METHODS: The association of the HPA-5 polymorphism with the number of GPIa molecules on the platelet surface in 159 white blood donors was investigated. The genetic linkage between the HPA-5 and the 807 C/T polymorphisms in 316 individuals was also determined. RESULTS: Both the 807 C/T and HPA-5 polymorphisms correlate with the number of GPIa molecules on the platelet surface. The 807 T and HPA-5b alleles are associated with increased numbers of GPIa molecules on the platelet surface. Moreover, the HPA-5b allele is genetically linked to 15.8 percent of the 807 C alleles. Therefore, the number of GPIa molecules on the platelet surface is dependent on both GPIa polymorphisms as follows: 807 T/T, HPA-5 a/a > 807 C/T, HPA-5 a/b > 807 C/T, HPA-5 a/a > 807 C/C, HPA-5 a/b > 807 C/C, HPA-5 a/a. CONCLUSION: Two GPIa polymorphisms (807 C/T and HPA-5) responsible for the variability in the numbers of GPIa/IIa molecules on the platelet surface in whites have been identified. Despite the genetic linkage between the two polymorphisms, their influence on the number of GPIa molecules on the platelet surface may occur through different mechanisms.     

Ruptured gastrointestinal stromal tumors: radiologic findings in six cases

Background Gastrointestinal stromal tumors (GISTs) are characterized by the expression of c-KIT (antigen CD 117) and are the most common mesenchymal tumors of the digestive tract. An important complication, although infrequently described in the literature, is the rupture of these tumors with accompanying hemoperitoneum. Methods We performed a retrospective evaluation of the clinical history and radiologic records of 23 patients with a diagnosis of GIST and anatomopathologic and immunohistochemical confirmation at our hospital between 1999 and 2004. Results In five cases there was rupture of the primary tumor (four gastric and one jejunal). In all five cases ultrasonographic and computed tomographic examinations showed a heterogenic tumor of laminated or whirled appearance, associated with echogenic or dense ascites. No relation was found between histologic criteria of malignancy and the rupture. Four patients underwent surgical intervention, three of them urgently. Two of five patients died. There was a sixth case with rupture of a hepatic metastasis, with accompanying hemoperitoneum and subcapsular hematoma. This patient died at 3 months, after recurrence of bleeding. Conclusions The finding of a heterogeneous tumor of laminated or whirled appearance associated with ascites with characteristics compatible with hemoperitoneum in an appropriate context must lead to a suspicion of the existence of a ruptured GIST.