A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

Echovirus type 9 epidemic in Kagoshima, southern Japan: seroepidemiology and clinical observation of aseptic meningitis.

An outbreak of aseptic meningitis caused by echovirus type 9 occurred between March and October, 1990, in Kagoshima, Southern Japan. Clinical manifestations and laboratory data of 259 children with aseptic meningitis who were admitted to the outpatient clinic of pediatrics in the Kagoshima City Hospital were analyzed (other diseases caused by echovirus type 9 were not investigated). The patients' age ranged from 1 month to 15 years and the highest incidence was in 4-year-old children. The male:female ratio was 1.3:1. Frequencies of headache (69%), vomiting (64%), neck stiffness (36%) and rash (195%) were lower than those in the previous reports in the United States or in the Europe. Pleocytosis in the cerebrospinal fluid increased with increasing age in the younger children. A predominance of neutrophils in cerebrospinal fluid lasted for 3 days or more after onset in 16% of the patients. Seroepidemiologic study suggested that the accumulation of susceptible children < 5 years of age had predisposed to the epidemic.

A magnetoencephalographic study on development of the somatosensory cortex in infants.

In order to examine the sensori-motor correlation in infants, we recorded the somatosensory evoked magnetic fields to tactile stimulation by using a 37-channel magnetoencephalograph. Twelve healthy infants were examined at palmar grasp stage and pincers grasp stage. Air-tapping stimulation of the right thumb was performed. Three distinct components (W1-3) emerged, W3, with a latency of approximately 100 ms, being the most prominent. As infants grew up, the correlation coefficient and the amplitude of the equivalent current dipole of W3 for the thumb increased. These developmental changes may be attributable to increases in the stability and reproducibility of the cortex in response to somesthetic inputs. Moreover, this change along with motor development supports the presence of a sensori-motor correlation in infants.

High prevalence of anticardiolipin antibodies in hepatitis C virus infection: lack of effects on thrombocytopenia and thrombotic complications.

Hepatitis C virus (HCV) causes various extrahepatic immunologic abnormalities. Recently, an association between HCV infection and antiphospholipid syndrome, including thrombocytopenia, has been reported. However, the precise relationship between thrombocytopenia and anticardiolipin antibodies in patients with chronic HCV infection is not fully understood; likewise, the association of antiphospholipid syndrome and various liver diseases is not well understood. To evaluate the prevalence and importance of antiphospholipid antibodies in various chronic liver diseases, we determined the levels of anticardiolipin antibodies, platelet numbers, and levels of platelet-associated immunoglobulin G (PA-IgG) and thrombin-antithrombin III complex (TAT) in patients with chronic HCV infection, chronic hepatitis B virus (HBV) infection, and primary biliary cirrhosis (PBC). The prevalence of anticardiolipin antibodies in patients with HCV infection was significantly higher than that in control subjects or individuals with the other liver diseases examined. However, there was no significant correlation between anticardiolipin antibodies and platelet counts or TAT. The frequency of thrombotic complications was similar in anticardiolipin antibody-positive and -negative patients with chronic HCV infection. Further, sera from all but one anticardiolipin antibody-positive HCV patient were negative for phospholipid-dependent anti-beta2 glycoprotein I antibodies. Our results suggest that anticardiolipin antibodies are frequently found in patients with chronic HCV infection, but they do not appear to be of clinical importance. Immunologic disturbances induced by HCV or prolonged tissue damage in systemic organs as a result of the extrahepatic manifestations of HCV infection may induce the production of antibodies to various cardiolipin-binding proteins or phospholipids.

Effects of lisinopril and low-dose trichlormethiazide on lipoprotein metabolism in patients with mild to moderate hypertension.

Fifty-six hypertensive patients were recruited to participate in a 12 week, randomised, multicentre trial to compare the effects of lisinopril (n = 31) and low-dose trichlormethiazide (n = 25) administration on blood pressure and lipoprotein metabolism. Both systolic and diastolic BPs decreased significantly after administration of lisinopril (5-40mg/day, mean dose 11 mg/day) and trichlormethiazide (2.0-4.0 mg/day, mean dose 2.2 mg/day). There were no significant changes in lipids, lipoproteins or apolipoproteins with either drug for 12 weeks and no significant differences between the two drugs for these parameters. It is concluded that lisinopril and low-dose trichlormethiazide administration are effective antihypertensive measures without any adverse effects after 12 weeks on lipoprotein metabolism in patients with mild to moderate essential hypertension.

Surgical management of intractable epilepsy associated with cerebral neurocytoma.

Neuronal neoplasms of the CNS constitute a rarely encountered group of tumors. This report concerns the surgical management of seizures encountered in four cases (ranging from 2 to 10 years-of-age at onset; consisting of two males and two females) of a recently recognized morphologically unique tumor, called 'cerebral neurocytoma'. All patients were associated solely with intractable complex partial seizures. The tumor involved the temporal lobe in two cases, and the frontal in two. Magnetoencephalography (MEG) clearly demonstrated an accumulation of equivalent current dipoles originating from the interictal spikes on the cortex around the tumor. On intra-operative electrocorticography (ECoG), the epileptogenic zone was topographically distinct from the region of the tumor. No definite ECoG activities were observed at the tumor site, although this tumor did consist of small mature neuronal cells. Either a complete or a subtotal resection of the tumor and the epileptogenic cortex was performed and, post-operatively, universal freedom from seizures was demonstrated in all patients. A histological examination of the epileptogenic cortex revealed the presence of minute cortical dysplasia or tumor involvement in the hippocampus. A resection of the epileptogenic cortex along with the tumor was thus found to improve the seizure outcome in patients with neurocytoma-associated epilepsy without inducing any identifiable neurological deficits attributable to the incremental resection.

Cortical somatosensory evoked potentials to posterior tibial nerve stimulation in newborn infants.

Successful cortical recordings of somatosensory-evoked potentials (SEPs) to posterior tibial nerve (PTN) stimulation were obtained in 21 (87.5%) for P1 and 22 (91.7%) for N1 of 24 infants who were followed up for at least 3 years and had a normal outcome. There were linear decreases with increasing post menstrual age in both P1 and N1 peak latency. Of the four cases with diplegia later, three showed definite abnormalities, no responses and delayed latency in PTN SEPs respectively, however, the other case showed normal responses. Of the three cases with mental retardation, two showed relatively long latency and borderline responses respectively, and the other case showed normal responses. As the pathway of PTN SEPs traverses the periventricular area of the brain likely to be affected by ischemic lesions in premature infants, abnormalities in the responses might indicate a later motor disorder.

Diagnostic usefulness of diffusion-weighted magnetic resonance imaging in influenza-associated acute encephalopathy or encephalitis.

A magnetic resonance imaging (MRI) study was performed for a 20-month-old girl with an influenza type A infection who presented acute encephalopathy. Conventional MRI performed 8 days after the onset of encephalopathy, including T1-weighted, T2-weighted, and fluid-attenuated inversion recovery imaging, revealed only vague lesions in the right frontal, temporal, and parietal lobes. In contrast, diffusion-weighted imaging (DWI) then demonstrated the lesions much more intensively. On the 26th day, the lesions previously observed on DWI had become less discernible. The hyperintensity observed on DWI might reflect cytotoxic edema. Thus, DWI may be useful for evaluation of acute influenzal encephalopathy/encephalitis.

Acute disseminated encephalomyelitis in a female with hereditary neuropathy with susceptibility to pressure palsy.

A 7-year-old female presented with fever, urinary incontinence, mental regression, gait disturbance, and lethargy after diarrhea. Magnetic resonance imaging revealed multifocal T(2)-weighted hypersignal lesions supportive of acute disseminated encephalomyelitis. Her mother had been diagnosed with hereditary neuropathy with susceptibility to pressure palsy. The girl was also determined to have hereditary neuropathy with liability to pressure palsy, with a 1.5-Mb deletion in chromosome 17p11.2 encompassing the gene for peripheral myelin protein 22 detected by fluorescent in situ hybridization. Hereditary peripheral neuropathies may be a factor in triggering the autoimmune demyelinating disorder of the central nervous system.

Asymmetric sweating in a child with multiple sclerosis.

A 10-year-old male with multiple sclerosis complained of excessive sweating on the right side of the forehead and shoulder on relapse 3 months after the onset of multiple sclerosis. Because the neurologic evaluation revealed no abnormalities in the sudomotor function, it is likely that the hyperhidrosis resulted from a lesion in the central or preganglionic sympathetic nervous system. Magnetic resonance imaging demonstrated a high-intensity lesion involving the left hypothalamus on T(2)-weighted imaging. Thus hypothalamic involvement might be the reason for the hyperhidrosis in this patient.

[An evaluation of automated hematology analyzers in detecting abnormal blood cells].

We report the usefulness and capability of two hematology analyzers with different principles in characterization of abnormal cells such as immature granulocytes and blasts. We studied a total 1635 specimens which included 69 cases with hematopoietic malignancies. THMS H-1 (Technicon Instruments) and NE-8000 (Toa Instruments) were used as analyzers. An effort was made to determine the sensitivity and specificity of positive abnormal cell flag in comparison with the presence of abnormal cells seen on a manual differential. True positive rate for immature granulocytes in H-1 and NE were 43% and 30%, respectively. False positive rate for immature granulocytes in H-1 and NE were 0.01% and 0.03%, respectively. With both analysers, cases with low percentage of immature granulocytes generated negative flag for abnormal cells. True positive rate for blasts in H-1 and NE were 74% and 65%, respectively. False positive rate for blasts in H-1 and NE were 1.8% and 0.2%, respectively. With both instruments, in all cases with blast count over 100/microliters, blasts were detected. Only H-1 detected the cases with blast counts less than 100/microliters. In H-1 all cases with ATL, one case with AMMoL and another with ALL generated negative blast flag. Upon morphologic examination, these blasts were found to be large and peroxidase negative with convoluted and irregularly shaped nuclei. On the other hand, NE detected blasts regardless of those morphology. In conclusion, Both instruments are useful in screening abnormal blood cells, while their unique capability must be considered.

[Blood coagulation and fibrinolysis in patients with Behçet's disease].

In patients with Behçet's disease, venous thrombosis has often been described as a complication. The pathogenesis of this complication, however, has not been fully understood. In this work, various parameters of blood coagulation and fibrinolysis were studied in 20 patients with Behçet's disease and 13 sex-matched healthy volunteers. Patients were classified into three subgroups according to the number of clinical signs involved; group I (no sign): 4 patients; group II (one or two signs): 11 patients; group III (more than three signs): 5 patients. Patients with Behçet's disease, showed an activation of blood coagulation, such as the shortening of prothrombin time (p less than 0.001), decreases in concentrations and activities of plasma antithrombin III (AT-III) (p less than 0.01) and elevated levels of plasma thrombin-antithrombin-III complex (TAT) (p less than 0.01), compared to the control group. Plasma levels (p less than 0.01) and activities (p less than 0.01) of protein C (PC) and total protein S (PS) levels (p less than 0.05) were increased in the patients. Decreased levels of alpha 2-plasmin inhibitor (p less than 0.001) also indicated an activation of fibrinolysis in the patients. When analyzed among the subgroups, patients belong to group II and III showed higher levels of plasma FDP D-dimer (p less than 0.05) and lower levels of plasminogen (p less than 0.05), as compared with patients in group I or control group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Estimation of megakaryothrombopoiesis by mean platelet volume in leukemia patients during the course of chemotherapy and patients undergoing bone marrow transplantation].

The mean platelet volume (MPV) was measured in 14 patients with acute leukemia during the course of chemotherapy for remission induction and 21 patients undergoing bone marrow transplantation, in order to assess its usefulness as an indicator for megakaryothrombopoiesis at bone marrow suppression and recovery. In patients with acute leukemia, the MPV fell from 9.7 +/- 0.8 fl to 9.2 +/- 0.4 fl during the myelosuppression, and then it rose transiently to 10.2 +/- 0.5 fl and fell to 9.3 +/- 0.5 fl during recovery of platelet count. Similarly, in patients undergoing bone marrow transplantation, the MPV elevation was followed by the recovery of platelet count. Thus, when engraftment was defined as this MPV elevation, engraftment was confirmed significantly earlier by MPV (19.9 +/- 5.8 days) than by platelet count (24.8 +/- 6.7 days). MPV should be a useful indicator for engraftment or recovery from marrow aplasia in cases of acute leukemia and those of bone marrow transplantation.

[Frequency of the development of RNA-rich reticulocytes in allogeneic bone marrow transplant recipients].

We measured appearance rates of RNA-rich reticulocytes in 8 patients undergoing allogeneic bone marrow transplantation, using a Sysmex R-1000 reticulocyte counter which utilizes laser flow cytometry. The changes in proportion of RNA-rich reticulocytes (high fluorescence ratio: HFR) and maturation index (MI: HFR + middle fluorescence ratio/low fluorescence ratio) were compared with those of WBC, neutrophil or reticulocyte counts. Engraftment was defined as an HFR of greater than or equal to 5% or a MI of greater than or equal to 15%. Engraftment was confirmed significantly earlier by HFR (13.5 +/- 2.4 days) and MI (13.1 +/- 2.9 days) than by neutrophils (17.1 +/- 3.2 days) or reticulocytes (20.4 +/- 6.2 days). The maturation of reticulocytes would be a useful indicator for engraftment or recovery from marrow aplasia in cases of bone marrow transplantation.

[Long survival in a case of metastatic brain tumor].

A 45-year-old man was admitted after resection of a metastatic brain tumor (papillary adenomatous adenocarcinoma, well differentiated) for both therapy and a search for the primary and any other metastatic lesions. An extensive general examination revealed no evidence of malignant lesion except for fibrous change in the right lung apex by roentgenography and CT scan. Histological examination of the right upper lobe and group II lymph nodes revealed a scar cancer presenting the same histology but no evidence of metastasis. The patient, who received CAP and FVM alternately, is currently healthy with no recurrence after 4 years.