Frequent loss of heterozygosity for loci on chromosome 8p in hepatocellular carcinoma, colorectal cancer, and lung cancer.

Frequent loss of heterozygosity at chromosomal loci in a specific tumor type may indicate the presence of a tumor suppressor gene. We have examined loss of heterozygosity on chromosome 8p in paired tumor and constitutional DNA from 346 patients representing seven different types of human cancer. Frequent allelic losses were observed in hepatocellular carcinoma (22 of 46 cases, 47.8%), in colorectal cancer (12 of 26, 46.2%), and in non-small cell lung cancer (14 of 35, 40.0%), in contrast to low frequencies detected in breast cancer (5 of 56, 8.9%) and renal cell carcinoma (2 of 27, 7.4%). Ovarian cancer and gastric cancer showed intermediate frequencies of 33.3% and 22.2%. Subsequent analysis of 120 hepatocellular carcinomas and 94 colorectal cancers with five polymorphic markers along the short arm of chromosome 8 defined commonly deleted regions within the same chromosomal interval, 8p23. 1-8p21.3, suggesting that one or more tumor suppressor genes for both cancers may be present in that region.     

Neurochemical Findings in the Cerebrospinal Fluid of Schizophrenic Patients with Tardive Dyskinesia and Neuroleptic-Induced Parkinsonism

Abstract: Monoamine and their acid metabolites were determined in the CSF of 18 drug-treated chronic schizophrenic patients with the symptoms of tardive dyskinesia and neuroleptic-induced Parkinsonism (Parkinsonism). Six healthy volunteers were used as the control group.
The norepinephrine (NE) levels were found to be significantly higher in the patients with tardive dyskinesia than in the controls. Furthermore, elevated CSF NE levels were also observed in the patients with Parkinsonism. Epinephrine (E) and Dopamine (DA) were not present in the CSF of the control group, whereas measurable levels of DA could be detected in 4 out of 9 and E was found in 8 out of 9 patients with tardive dyskinesia. The mean concentration of HVA was slightly but not significantly elevated in the patients with tardive dyskinesia and Parkinsonism. The mean values of CSF 5-HIAA were all within the normal range in both patient groups. From the above results, it was suggested that abnormal adrenergic activity rather than abnormal dopaminergic activity may play an important role as a mechanism in the etiopathogenesis of extrapyramidal disorders. Furthermore, in the patients with Parkinsonism, CSF neurochemical observations were similar to those of the patients with tardive dyskinesia in this study. It may help to explain the clinical coexistence of tardive dyskinesia and neuroleptic-induced Parkinsonism.     

Synthesis of 1-N-(D-threo- and racemic erythro-3-amino-2-hydroxybutanoyl)-2',3'-dideoxykanamycin A

1-N-(D-Threo-3-amino-2-hydroxybutanoyl)-2',3'-dideoxykanamycin+ ++ A has been prepared by coupling of 3,6'-bis(N-benzyloxycarbonyl)-2',3'-dideoxy-3"-N-(trifluoroacetyl)kanamy cin A with D-threo-3-azido-2-hydroxybutanoic acid. A diastereomeric mixture of the erythro analog has also been prepared by use of racemic erythro-3-azido-2-hydroxybutanoic acid. Synthesis of the D-threo- and racemic erythro-3-amino-2-hydroxybutanoic acids has been described.     

Benign brainstem encephalopathy with truncal ataxia--a clinical study of 3 cases]

Three cases (case 1, female, aged 30; case 2, male, aged 32; case 3, male, aged 34) of benign brainstem encephalopathy with truncal ataxia were reported. Two patients had prodromal symptoms Neurological examination revealed truncal ataxia in all cases. As additional neurological signs, anisocoria, mydriasis, nystagmus, ptosis, transient opsoclonus, and facial palsy were seen. There was neither drowsiness nor myoclonus in the three cases. On laboratory examinations, cold agglutination test revealed significant elevation in two cases. The examination of cerebrospinal fluid showed a moderate rise of proteins in one case, but did not revealed pleocytosis in any of the cases. Magnetic resonance imaging of one patient revealed an area of high intensity in the left pontine tegmentum by T2-weighed imaging. The prognosis for all these cases was good, and the reappearance of neurological signs was not present until now. Our cases were different from brainstem encephalitis (Bickerstaff's encephalitis) because of an absence of disturbed consciousness and no pleocytosis in the cerebrospinal fluid. Our cases were also different from "myoclonus-opsoclonus syndrome" because of an absence of myoclonus. We discussed a possibility of a new clinical syndrome which we call "benign brainstem encephalopathy with truncal ataxia".     

Amyotrophic lateral sclerosis with ophthalmoplegia and multisystem degeneration in patients on long-term use of respirators

Summary We describe two patients with sporadic amyotrophic lateral sclerosis (ALS), who had developed progressive external ophthalmoplegia of a predominantly supranuclear type while they survived on respirators, and displayed histopathological abnormalities both typical and atypical of ALS. Patient 1 was a 43-year-old man with ALS of 5-year duration, who had initially exhibited fulminant ALS, and remained on a respirator for 4 years. Patient 2 was a 51-year-old man with ALS of 13-year duration, who remained on a respirator for 8 years. Both patients died in a totally locked-in state. Autopsy of both patients revealed not only histopathological abnormalities consistent with ALS, but also multisystem degeneration which involved the pontine tegmentum, substantia nigra, Clarke's dorsal nuclei and spinocerebellar tracts. In addition, Patient 2 displayed intracyto-plasmic neuronal basophilic inclusion bodies which exhibited marked immunoreactivity to anti-ubiquitin antibodies. Our case reports indicate that the longer survival which is possible through the use of respirators may make one subgroup of ALS patients prone to develop atypical clinical and neuropathological features which are not observed during the natural cours of ALS.Supported by a Grant-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health and Welfare of Japan, and by a Grant from Nihon University School of Medicine, Tokyo     

Effects of multipurpose solutions (MPS) for hydrogel contact lenses on gap-junctional intercellular communication (GJIC) in rabbit corneal keratocytes

To ensure the effects of multipurpose solutions (MPS) for hydrogel contact lenses on the cornea, the inhibitory activity of three types of MPS on corneal cells has been evaluated with the use of scrape loading and dye transfer assay (SLDT assay) and Western blotting on rabbit corneal keratocytes (RC4). In SLDT assay, MPS-A and poloxamine showed dose-dependent inhibitory activity, suggesting the inhibitory action of MPS-A and poloxamine to gap junctional intercellular communication (GJIC) in the tested cells. Moreover, after treatment with MPS-A, the GJIC was initially inhibited within 4 h, and thereafter gradually turned to an approximately 60% level of the initial value. When MPS-A was removed from the incubation media after exposure of the cells, the recovery of GJIC was time dependent and returned to approximately initial levels at 8 h. Complete recovery was established after approximately 24 h. These findings suggested that the inhibitory action of MPS-A on corneal keratocytes was reversible. This inhibition was accompanied by a decrease in the quantity of connexin-43, which is a major protein constituting the gap junctional channel of these cells, and its change in the phosphorylation state. Taken together, it was suggested that MPS-A interacts with connexin-43, inducing an inhibitory action on GJIC.     

Parental death and bipolar disorder: a robust association was found in early maternal suicide

BACKGROUND: Previous studies have suggested that early parental death may be associated with the emergence of bipolar disorder in later life. However, it remains unknown whether this association applies specifically to parental death due to suicide or only to early parental death. The present study aimed to explore whether suicide as well as the non-suicidal death of father, mother, or siblings are associated with an increased risk for bipolar disorder, and whether the possible association is modified by the age at which the subject experiences such a death in the family. METHODS: The subjects were born in 1960 or later and were first admitted to or had first contact with Danish psychiatric facilities between 1981 and 1998 with a diagnosis of bipolar disorder, and fifty age-matched controls per case were extracted. The effects of the deaths of relatives were estimated by means of a conditional logistic regression analysis. RESULTS: Among 947 subjects with bipolar disorder and 47,350 controls, those having experienced the parental suicide were significantly associated with an increased risk for BPD (incidence rate ratios: 1.83 [95% confidence interval: 1.07 to 3.12] for paternal suicide, 3.44 [1.97 to 6.00] for maternal suicide), whereas the non-suicidal death of parents showed no such association. Those having experienced maternal suicide at some point before reaching 10 years of age were seven times as likely to develop bipolar disorder. LIMITATIONS: The cohort members were followed until, but not exceeding, the age of 38. CONCLUSION: Early parental, particularly maternal, suicide increases the risk for bipolar disorder in the offspring. Possible explanations include a family history of mental disorders as well as psychosocial factors.     

alpha 2-macroglobulin stimulation of protein tyrosine phosphorylation in macrophages via the mannose receptor for Fc gamma receptor-mediated phagocytosis activation.

Macrophage phagocytic activity has previously been shown to be increased by binding of modified alpha 2-macroglobulin (alpha 2M) with mannose residues at termini of sugar chains to mannose receptors on macrophages, with a subsequent increase in the number of Fc gamma receptors at the cell surface. In the present study, an examination was made of the association of protein tyrosine kinase with the increase in number of Fc gamma receptors following binding of modified alpha 2M to mannose receptors. The phagocytosis of IgG-opsonized sheep red blood cells through the action of the Fc gamma receptor by modified alpha 2M was inhibited by mannose and herbimycin A and slightly so by genistein. The mannose receptor would thus appear to be associated with tyrosine kinase activity. By Western blotting, tyrosine phosphorylated proteins with molecular weights of 32000, 34000, 36000, 65000, 85000 and 110000 appeared or increased upon treating macrophages with modified alpha 2M. The degree of tyrosine phosphorylated proteins was the same for control macrophages following incubation in the presence of mannose and herbimycin A. Genistein treatment affected only tyrosine phosphorylated proteins of 65000 and 110000. The binding of modified alpha 2M to mannose receptors was demonstrated by the inducement of tyrosine kinase activation that was sensitive to herbimycin A, followed by an increase in Fc gamma receptors and consequently greater phagocytosis.     

Antibody Response to Bacterial Antigens: Characteristics of Antibody Response to Somatic Antigens of Salmonella typhimurium

The character of the antibody response in the rabbit to Salmonella typhimurium somatic (O) antigen was similar to the response to each of several serotypes of Shigella flexneri O antigens, namely a predominance of production of immunoglobulin M (IgM) antibody. Lipopolysaccharide protein (LPSP) and lipopolysaccharide (LPS) fractions of Salmonella O antigen differed significantly in both quantitative and qualitative aspects of their immunogenicity. LPSP elicited high levels of agglutinins and also induced the production of a significant amount of immunoglobulin G (IgG) antibody at a late period. LPS antigen elicited low levels of agglutinins which were exclusively IgM antibody. These results suggested that the chemical nature of the antigen is one important factor in the determination of the character of the antibody response. Further, it is suggested that the protein moiety of the O antigen complex is a carrier active in allowing induction of early IgM and of late IgG antibodies; in contrast, the lipid moiety may compete with this action of the carrier protein, thereby suppressing IgG antibody in the primary stage of the antibody-forming process.