Factor VIII efficient and specific non-covalent binding to PEGylated liposomes enables prolongation of its circulation time and haemostatic efficacy

Haemophilia A is a bleeding disorder caused by the lack of factor VIII (FVIII). We report the prolongation of exogenous FVIII circulation time and haemostatic efficacy by its formulation with PEGylated liposomes (PEGLip). FVIII binds non-covalently but with high affinity in a specific mode with the external surface of PEGLip neither losing its activity nor its binding to von Willebrand Factor. Experiments in haemophilic and non-haemophilic mice indicate that the circulation time and clotting efficacy of PEGLip-formulated exogenous FVIII (PEGLip-FVIII) are significantly enhanced over those of free FVIII. The data support the feasibility of using PEGLip-FVIII to extend the duration of haemostatic efficacy in the treatment of haemophilia A.     

Intracerebral HIV-1 glycoprotein 120 produces sickness behavior and pituitary-adrenal activation in rats: role of prostaglandins

HIV infection is associated with profound neurobehavioral and neuroendocrine impairments. Previous studies demonstrated that HIV causes neuropathological alterations indirectly, via shedding of glycoprotein 120 (gp120) within the brain. To extend these findings, we examined the neurobehavioral and neuroendocrine effects of central administration of gp120, as well as the role of brain prostaglandins in mediating these effects. Intracerebroventricular (i.c.v.) injection of gp120 in rats produced a marked sickness behavior syndrome, consisting of reduced exploratory behavior, suppressed consumption of food and saccharin solution, and reduced body weight. Gp120 also induced a significant febrile response and increased serum levels of ACTH and corticosterone. Following i.c.v. gp120 administration, the ex vivo production of PGE2 by the hypothalamus, frontal cortex, and hippocampus was significantly elevated, and indomethacin, a prostaglandin synthesis inhibitor, attenuated this elevation. Pre-treatment with indomethacin reduced the fever and adrenocortical activation induced by gp120 administration, but not its behavioral effects. These findings indicate that gp120 may be responsible for some of the behavioral and endocrine abnormalities seen in HIV-infected patients. Prostaglandins are important mediators of the physiological, but not the behavioral effects of brain gp120.     

The emergence and treatment of anorexia and bulimia nervosa. A comprehensive and practical model

The objective was to propose and describe a new bio-psycho-social model of emergence and maintenance of anorexia nervosa and bulimia nervosa, and demonstrate its application to treatment. An original model, based on literature review and our own clinical experience, was created. Therapeutic guidelines were derived from the theoretical model and applied in the treatment of 97 anorexia and bulimia nervosa patients presented at the eating disorders unit at Kaplan Hospital in Israel over 18 months. A team comprising a pediatrician, a child psychiatrist, a dietician, and trained nurses collaborated in a comprehensive systemic therapeutic approach involving parents, schools, and community agents. RESULTS: Ninety-one girls and six boys were treated in the eating disorder unit (55 had AN, 29 had BN and 13 had EDNOS). Thirty-seven patients were hospitalized and sixty were treated in the outpatient clinic. Mean hospitalization time of the first five patients was 108 days. Mean hospitalization time of the remaining 32 patients was reduced to 32 days. The mean number of outpatient clinic interventions was 12. At the one-year follow up, 74 patients were doing well in all respects. Fourteen patients still needed a lot of supervision in eating. Five are still hospitalized and four were lost to follow up. CONCLUSIONS: The proposed model proves to be more than just another theory in that it is successfully applied in treatment. Short systemic therapy is very effective. The longer the delay in drastic, aggressive treatment, the worse the prognosis. Extended hospitalization periods worsen the prognosis. Weakness of the parental unit is a strong indication for inpatient care. The longer the experience in treating eating disorders, the shorter the hospitalization and number of interventions.     

Prospective Study To Determine Clinical Relevance of Detection of Pneumococcal DNA in Sera of Children by PCR

We undertook a prospective study to evaluate the accuracy of PCR of serum (aimed at the pneumococcal pneumolysin gene) at detecting pneumococcal infections in infants and children. The assay was positive for all blood and cerebrospinal fluid culture-positive samples and for 38 and 44% of patients with lobar pneumonia and acute otitis media, respectively. It was positive for 17% of healthy controls. There was a marked effect of age on the rate of positivity among healthy controls, with the highest rate (33%) being in 2-year-old children, the age group with the highest rate of nasopharyngeal (NP) carriage; the lowest rate was found among infants <2 months of age (13%) and adults ages 18 to 50 years (0%), age groups with the lowest NP pneumococcal carriage rates. Carriers of pneumococci in the nasopharynges had a higher rate of positivity than noncarriers of pneumococci in the nasopharynges for all groups. Our results suggest that although PCR of serum is a sensitive test for the detection of Streptococcus pneumoniae in sterile fluids, its high rate of positivity for healthy controls, related to NP pneumococcal carriage, might exclude it from being useful in detecting deep-seated pneumococcal infections.     

Prevalence of circulating procoagulant microparticles in women with recurrent miscarriage: a case-controlled study

BACKGROUND: Circulating microparticles are markers of cell activation associated with various prothrombotic states. As hypoxia due to uteroplacental thrombosis is considered to be one of the causes of pregnancy loss, microparticles may be associated with pregnancy loss, in addition to, or as part of, other procoagulant states such as antiphospholipid syndrome or hereditary thrombophilias. The objective of this study was to examine the prevalence of circulating microparticles in women with recurrent pregnancy loss. METHODS: A total of 96 women with recurrent pregnancy losses were enrolled in a case-control study and compared with 90 parous women. Microparticles were measured by flow cytometry using fluorescent anti-CD51/CD31 antibodies. RESULTS: Microparticle levels >2 SD above the mean of controls (57,700/ml) were detected in 12 out of 96 women with recurrent miscarriages (12.5%), compared with two of the 90 control women (2.2%), P<0.008. The titre of microparticles did not correlate with age, number of pregnancy losses, primary secondary or tertiary aborters status, or with pregnancy losses in the 1st or 2nd trimesters. CONCLUSIONS: A proportion of women with pregnancy loss have elevated endothelial microparticles suggesting that endothelial damage or activation might be associated with the pathogenesis of pregnancy loss.     

Aspects of a Theory of Mind and Self-Reports of Quality of Life by Persons with Mental Retardation

The present study examined the assumption that individual differences on aspects of the cognitive development of a Theory of Mind (TOM) may account for differences in the capacity of persons who are mentally retarded (MR) to provide accurate, reliable, and valid self-reports of their quality of life (QOL). Seventy-five adults with mild to moderate levels of mental retardation and basic communication skills filled out a multifaceted measure of QOL which included a measure of acquiescence. In addition, they were asked to perform four TOM tasks, two related to the ability to attribute ignorance and two related to the ability to attribute false belief. As expected, TOM development was found to be negatively related to acquiescence. However, no relation was found between TOM development and the reliabilities of self-reported QOL. In addition, relations between TOM and these self-reports were in the opposite direction to what was predicted on the basis of the assumed association between the validity of the self-reports and TOM development. The self-reported QOL of persons with less developed TOM tended to differentiate between different degrees of inclusion, whereas those of persons with more developed TOM did not. Furthermore, TOM was shown to be positively related to self-reported QOL.     

Negative impact of 'old-to-old' donations on success of cadaveric renal transplants

The effect of 'old-to-old' cadaveric renal transplants on operative complications and graft survival was assessed in all 325 patients undergoing solitary cadaveric renal transplantations in Israel during a 3-yr period. Preoperative information and hospital course data were abstracted from the charts. Results were analyzed using Kaplan-Meyer survival curves, univariate and multivariate Cox models. Overall, 62 (19.1%) grafts failed within a year. Failure rate was 46.2% for 'old-to-old' transplants compared with 15.5% for all other donor/recipient age combinations (p < 0.0001). 'Old-to-old' transplants remained independently associated with graft failure in a multivariate Cox model after controlling the effect of other risk factors. 'Old-to-old' transplants were also associated with increased operative complications relative to other age combinations. The decision to use 'old-to-old' transplants, even when donors are scarce, is problematic and should be reconsidered.     

Further development of reconstructive and cell tissue-engineering technology for treatment of complete peripheral nerve injury in rats

In this work we evaluated the efficacy of biodegradable composite co-polymer guiding neurotube, based on tissue-engineering technology, for the treatment of complete peripheral nerve injury where the nerve defect is significant. The right sciatic nerve of 12 three-month-old rats was completely transected and peripheral nerve segment was removed. A 2.2-cm biodegradable co-polymer neurotube containing viscous gel (NVR-N-Gel) with survival factors, neuroprotective agents and Schwann cells was placed between the proximal and the distal parts of the transected nerve for reconnection a 2-cm nerve defect. The proximal and distal parts of the nerve were fixed into the neurotube using 10-0 sutures. Ultrasound observation showed growth of the axons into the composite neurotube 2 months after the surgery. Electrophysiological study indicated compound muscle action potentials in nine out of 12 rats, 2-4 months after peripheral nerve reconstructive surgery. The postoperative follow-up (up to 4 months) on the operated rats that underwent peripheral nerve reconstruction using composite co-polymer neurotube, showed beginning of re-establishment of active foot movements. The tube was dissolved and nerve showed complete reconnection. Histological observation of the nerve showed growth of myelinated axons into the site where a 2-cm nerve defect replaced by composite co-polymer neurotube and into the distal part of the nerve. In CONCLUSION: (1) an innovative composite neurotube for reconstruction of significant loss of peripheral nerve segment is described; (2) a viscous gel, containing survival factors, neuroprotective agents and Schwann cells served as a regenerative environment for repair. Further investigations of this reconstructive procedure are being conducted.