An ingenious design for peptide vaccines

For humoral immunization, it may be possible to make effective and safe peptide vaccines for various diseases by selection of proper B-cell epitopes. However, a lack of T-cell epitopes on short peptides, such as those associated with major histocompatibility complex (MHC)-restriction, is a major problem for peptide vaccine development. We propose a solution for the design of peptide vaccines that involves induction of broadly reactive T-cell epitopes via agretopes. The strategy involves positioning multi-agretope type peptides on the N-terminal side of a di-lysine linker and B-cell epitopes on the C-terminal side. The addition of the arginine-glysine-aspartate (RGD)-motif to the N terminus of the peptide enhances its immunogenicity, and enables nasal immunization without adjuvants.     

Correlation between the pituitary size and function in patients with asthenia

To explore the relationship between pituitary morphology and function, we performed mid-sagittal MRI and endocrinological evaluation in 38 patients with asthenia. Six patients were diagnosed as having complete empty sella (ES) and 16 patients partial empty sella (PES). BMI, blood pressure, serum Na, ACTH, cortisol, TSH and T(4) were lower in ES group and PES group than in the group with normal pituitary size. Age in the patients with ES was oldest. Multiple regression analysis revealed that serum cortisol level was independently correlated with the size of the pituitary (beta = 0.586, p = 0.0069). Other variables, including age, BMI, blood pressure, serum Na, ACTH, TSH and T(4), were not correlated with the pituitary size when multivariate analysis was employed. In conclusion, there is a close relationship between the reduction of size of pituitary gland and the degree of adrenocortical dysfunction in asthenic patients. It is suggested that the pituitary-adrenal axis is especially vulnerable in empty sella syndrome, and therefore, meticulous evaluation of the hypophysial adrenal axis is recommended in subjects with reduced pituitary size even in elderly population.     

RNA expression analysis of a congenital intracranial teratoma

Congenital intracranial tumors are extremely rare and account only for 0.5%-1.5% of brain tumors in children. We report a large intrauterine congenital teratoma in a female fetus at gestation weeks 37, which was diagnosed by detecting the tumor and associated craniomegaly with ultrasonography (US) and magnetic resonance (MR) imaging. The tumor had replaced the cerebral hemispheres and produced prenatal manifestations. Pathologic examination showed an immature teratoma, which was differentiated from all three germ layers. Microarray analysis revealed upregulation of ten genes and downregulation of three genes, as well as upregulation of 41 genes of ribosomal proteins in teratoma cells, compared to normal brain tissue of the patient. The data from the microarray analysis offer not only the potential to help define disease pathogenesis but may also provide clues to identify potential molecular therapeutic targets.     

Choice and administration sequence of antiepileptic agents for status epilepticus and frequent seizures in children

We investigated the sequence of the administration, the efficacy and the safety of antiepileptic drugs (AED) given intravenously for the treatment of status epilepticus and frequent seizures in children. Our institute has a recommended sequence of AED administration for treatment of status epilepticus: the first-line agent is diazepam (0.3 - 0.5 mg/kg administered intravenously, once or twice). The second-line drugs include midazolam (0.15 - 0.4 mg/kg intravenously, once or twice, and if necessary, followed by continuous infusion at 0.06 - 0.18 mg/kg/hour), lidocaine (1 - 2 mg/kg intravenously, once or twice, and if necessary, followed by continuous infusion at 2 - 4 mg/kg/hour) and phenytoin (10 - 20 mg/kg, infused slowly). For those patients who previously experienced a seizure which was refractory to diazepam but responsive to the second-line agent, it was recommended to use the second-line agent as a first-line agent. When seizures were refractory to the first and second-line agents, thiopental was administered (3 - 10 mg/kg intravenously, and if necessary, followed by continuous infusion at 2 -5 mg/kg/hour). The etiologies of 177 occasions of status epilepticus and frequent seizures were categorized into two groups:epilepsy (n = 95) and situation-related seizures (n = 82). Situation-related seizures included febrile seizures (n = 44), acute encephalopathy/encephalitis (n = 31) and benign infantile convulsions (n = 7). The ages of the patients ranged from 0.1 to 18.4 years (average +/- SD:3.69 +/- 3.15 years). Diazepam was administered as the first-line drug on 157 of 177 occasions (88.7%). On 116 occasions the second-line agents were administered. Midazolam and lidocaine were injected as the second-line agent on 54 (46.6%), and on 33 (28.4%) occasions, respectively, although both midazolam and lidocaine injections were off-label use for seizure control in Japan. Thiopental was used as the third to fifth-line agent. Effective ratios (effective occasions/total occasions) of each drug were the following: thiopental 19/21 (90.4%), midazolam 57/99 (57.6%), lidocaine 25/60 (41.7%), phenytoin 16/41 (39.0%), diazepam 59/164 (36.0%). Thiopental was statistically more effective than midazolam, lidocaine, diazepam or phenytoin (p < 0.01), and midazolam was statistically more effective than diazepam (p < 0.01) or phenytoin (p < 0.05). Administration of thiopental caused complications more frequently than the other agents (p < 0.01): The complications by thiopental were severe in some cases requiring intratracheal intubations and artificial ventilation. From the viewpoint of both efficacy and safety, midazolam should be recommended as one of the first-line agents for status epilepticus.     

Wallerian degeneration of the middle cerebellar peduncle after pontine infarction: MR imaging

PURPOSE: To report magnetic resonance (MR) imaging findings of wallerian degeneration of the pontocerebellar tract secondary to a pontine infarction. MATERIALS AND METHODS: We retrospectively reviewed cranial MR images obtained during the past seven years in our institution and selected those from patients with a chronic stage of pontine infarction and a hyperintense lesion at the central portion of the middle cerebellar peduncle on T2-weighted images. RESULTS: In three patients with a ventromedial pontine infarction, we found a symmetrical hyperintense lesion at the central portion of the middle cerebellar peduncle bilaterally on T2-weighted MR images in the chronic stage. In another patient with a ventrolateral pontine infarction, we found such a lesion at the ipsilateral middle cerebellar peduncle. CONCLUSION: Because the middle cerebellar peduncle carries afferent fibers from the contralateral basis pontis to the cerebellar cortex, these middle cerebellar peduncular lesions are regarded as wallerian degeneration. This secondary degeneration should not be misinterpreted as a newly developed infarction or other disease.     

Role of PKC in the attenuation of the cGMP-mediated relaxation of skinned resistance artery smooth muscle seen in glyceryl-trinitrate-tolerant rabbit

We examined whether 10 days' in vivo treatment with glyceryl trinitrate (GTN) might reduce cGMP-induced relaxation in the smooth muscle of rabbit mesenteric resistance arteries and, if so, whether protein kinase C (PKC) plays a role in this downregulation. The relaxation responses to GTN and the nitric oxide donor NOC-7 were significantly reduced in endothelium-denuded strips from GTN-treated rabbits. In beta-escin-skinned smooth muscle, the ability of 8-bromoguanosine 3',5' cyclic monophosphate (8-Br-cGMP, a phosphodiesterase-resistant cGMP analogue) to relax the contraction induced by 0.3 microM Ca2+ was significantly reduced in GTN-treated rabbits. In beta-escin-skinned smooth muscle, an inhibitor of conventional and/or novel PKCs, GF109203X (0.6 microM), inhibited the Ca2+ -induced contraction and enhanced the 8-Br-cGMP-induced relaxation. However, since the relaxing ability of 8-Br-cGMP was found to be unchanged by GF109203X when contractions were amplitude-matched (0.2 microM Ca2+ alone vs 0.3 microm Ca2+ + GF109203X), the increase in the 8-Br-cGMP-response seen with GF109203X was probably due to its inhibitory action on the Ca2+ -induced contraction. Furthermore, although the PKC activator phorbol 12,13-dibutyrate (PDBu, 0.1 microM) decreased the 8-Br-cGMP-induced relaxation of the Ca2+ (0.3 microM) contraction, this was probably due to its enhancement of the Ca2+ -induced contraction since no such effect of PDBu was seen when the Ca2+ -induced contractions were amplitude-matched (0.2 microM Ca2+ + PDBu vs 0.3 microM Ca2+ alone). These results suggest that the relaxing response to cGMP is reduced in the smooth muscle of mesenteric resistance arteries in GTN-treated rabbits but that conventional and/or novel PKCs do not play a major role in maintaining this downregulation.British Journal of Pharmacology (2004) 141, 391-398. doi:10.1038/sj.bjp.0705625     

Association of the Neprilysin gene with susceptibility to late-onset Alzheimer's disease

Neprilysin (NEP), also known as neutral endopeptidase, enkephalinase, CD 10, and common acute lymphoblastic leukemia antigen, is a 97-kD protein. NEP can degrade amyloid beta peptides, and its mRNA and protein levels are known to be reduced in the brains of patients with Alzheimer's disease (AD), making the NEP gene a substantial candidate for an AD risk factor. We examined the genetic association of three NEP polymorphisms, a GT-repeat polymorphism and two single nucleotide polymorphisms (SNPs, -1075A>G and -1284G>C) in its promoter region, with AD in a Japanese case-control sample (240 patients and 163 controls). The GT-repeat polymorphism, but not the SNPs, was significantly associated with late-onset AD (p = 0.0007). Our findings suggest that the GT-repeat polymorphism in the promoter region of the NEP gene or some other unknown polymorphisms, which are in a linkage disequilibrium, confer a susceptibility to late-onset AD.     

Effect of egg yolk antibody on experimental Cryptosporidium parvum infection in scid mice

In this study the effect of chicken egg yolk antibody (IgY) against Cryptosporidium parvum infection was examined. IgY sample was prepared from eggs of chickens immunized with C. parvum oocyst antigens. In vitro, antibody-treated sporozoites showed reduced binding to Caco-2 cells and lost vitality. These phenomena were not observed with a control IgY sample prepared from eggs of non-immunized chickens. Scid mice orally administered with the antibody demonstrated partial reduction in oocyst shedding after challenge with 10(3) oocysts. IgY, however, could not eliminate the infection after 17 days of continuous treatment. The potentials of using specific IgY for treatment and prevention of cryptosporidiosis were discussed.     

Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome

BACKGROUND: Intravenous administration of magnesium sulphate (MgSO(4)) is a very effective and safe treatment for torsades de pointes (TdP) associated with acquired long QT syndrome (LQTS) in adults. Discussed here is the efficacy of MgSO(4) for TdP in children with congenital and acquired LQTS. METHODS: The optimal MgSO(4) dosage and serum magnesium (SMg) was determined in six consecutive children with TdP; four had congenital LQTS and two had acquired LQTS. A bolus injection of MgSO(4) was given intravenously over 1 to 2 minutes followed by continuous infusion for the next 2 to 7 days. RESULTS: Of the six patients, five responded completely to the initial bolus of 6.1 +/- 4.2 mg/kg (range, 2.3-12 mg/kg). One (a neonate with congenital LQTS) required a total of 30 mg/kg until complete TdP elimination. Continuous infusion was given at rates of 0.3 to 1.0 mg/kg/hr with no recurrence of TdP. SMg concentration was 3.9 +/- 1.0 mg/dL (2.9-5.4 mg/dL) immediately after bolus injection. CONCLUSION: Intravenous MgSO(4) infusion effectively treated TdP in children with LQTS. Optimal bolus dosage, infusion rates and SMg concentration were 3 to 12 mg/kg, 0.5 to 1.0 mg/kg/hr and 3 to 5 mg/dL, respectively.     

Cardiac failure caused by severe pre-eclampsia with placental abruption, and its treatment with anti-hypertensive drugs

Pre-eclampsia is the abnormality of blood circulation in late pregnancy, often caused by renal failure, hemolysis, elevated liver enzyme, low platelet syndrome, and eclampsia. We present a case of severe pre-eclampsia with placental abruption in a 24-year-old woman, pregnant for the first time. The patient was diagnosed with congestive heart failure, which came as a result of pre-eclampsia. Anti-hypertensive drugs were used for its treatment.