M-F: Bipolar and probably multidimensional

Scores on the MMPI MF scale and the WAIS M-F index were found not to be correlated highly with each other, but to be correlated significantly with self-rated sexual orientation in a mixed-sex group of Ss. Only when the implicit bipolarity of each of the test scales was taken into account were the scales significantly related to sexual orientation. The combination of the two M-F indices accounted for significantly more of the variance in sexual orientation than either scale alone. The results suggest that M-F may be considered accurately to be both a bipolar and a multidimensional construct.     

Further evidence that stress hyperthermia is a fever

Exposure of rats to an open-field results in a rapid rise in body temperature. Fifty-four percent of this rise in body temperature was blocked by intracerebroventricular administration of the antipyretic drug sodium salicylate. Intraperitoneal administration of indomethacin, a potent blocker of prostaglandin production, also attenuated the stress-induced hyperthermia to the same degree. Based on the data presented in this and an earlier study, we conclude that a major component of the rise in body temperature induced by psychological stress in rats is mediated by prostaglandins released by the central nervous system, and may therefore be a fever.     

Further evidence that "malignant angioendotheliomatosis" is an angiotropic large-cell lymphoma

Malignant angioendotheliomatosis is a rare, generally fatal disease characterized by a multifocal proliferation of neoplastic mononuclear cells within the lumens of small blood vessels. Although the disease primarily involves the vasculature of the skin and central nervous system, vascular involvement of other organs may occur and may produce a variety of clinical findings. Some early investigators concluded that malignant angioendotheliomatosis was a neoplasm of endothelial cells, but recently others have suggested that it is of hematopoietic origin. We have studied three patients with the disease and have characterized the immunophenotype of the neoplasm on cryostat-cut fresh-frozen tissues. A detailed antigenic phenotyping of neoplastic lymphoid cells showed that one patient had the immunophenotype T11+, Leu-1+, Leu-3+, Leu-2+, B1-, B2-, SIg-, LN1-, LN2-, the predominant phenotype for peripheral T-cell lymphoma; the others had T11-, Leu-1-, Leu-3-, Leu-2-, B1+, B2+, SIg+, LN1+, LN2+, consistent with a B-cell-derived lymphoma. On the basis of our results, we suggest that angiotropic (intravascular) large-cell lymphoma would be more appropriate than malignant angioendotheliomatosis as a name for this disease.     

Further evidence showing that neurotoxin-acetylcholine receptor dissociation is accelerated by monoclonal neurotoxin-specific immunoglobulin

We have demonstrated that the dissociation of Naja nigricollis alpha-toxin from the two acetylcholine receptor sites [Weber and Changeux, Molec. Pharmac. 10, 1-14 (1974); Rousselet et al., Eur. J. Biochem. 140, 31-37 (1984)], is markedly accelerated by a monoclonal neurotoxin-specific antibody. The dissociation of the toxin occurs in a biphasic manner in the presence of a 900 molar excess of immunoglobulin (with respect to toxin concn). The progress curves are characterized by first-order kinetics. Under these conditions the maximal dissociation rate is achieved as further rate enhancement cannot be induced by exposure to an increased immunoglobulin level. In contrast when a toxin-immunoglobulin complex is incubated with a large excess of receptor, the dissociation kinetics of the complex are not enhanced. The data fit a kinetic model which implicates the existence of a transient ternary complex involving the receptor, the toxin and the antibody.     

Further evidence of MAO-A gene variants associated with bipolar disorder.

The aim of this study was to investigate MAOA gene variants in bipolar disorder by using a family-based association approach. The first sample included 331 nuclear families from Western and Central Canada with at least 1 offspring affected with bipolar disorder comprising a total of 1,044 individuals. All subjects were genotyped for MAOA-941T > G and -uVNTR gene variants using PCR techniques. Haplotype TDT was statistically significant (LRS = 12.17; df = 3; P = 0.0068; permutation global significance = 0.00098), with the T-4 haplotype significantly associated with bipolar disorder (OR = 1.63, 95% CI = 1.11-2.37). Single marker analysis evidenced a borderline association for MAOA-941T > G (P = 0.04), but not for the uVNTR. Pooling the Canadian sample with a second previously reported Italian sample genotyped for the uVNTR variant, negative results were obtained as well. No different results were detected when analyzing female subjects separately. In conclusion, our family-based association study gives mild but further support of the involvement of MAOA variants in bipolar disorder.     

Further evidence that androgen aromatization is essential for the activation of copulation in male quail

In Experiment 1 male quail (Coturnix coturnix japonica) with photically regressed testes were implanted intraperitoneally with Silastic tubing containing either testosterone propionate (TP), testosterone (T), androstenedione (AE), 17α-methyltestosterone (MT), estradiol benzoate (EB), dihydrotestosterone propionate (DHTP), 6α-fluorotestosterone propionate (FTP), fluoxymesterone (FM), or cholesterol (CHOL), or were implanted subcutaneously with pellets of FTP. All steroids except EB and FM stimulated proctodeal gland development, and all except MT, EB, and FM stimulated crowing to a significant extent. When administered as Silastic implants, the only androgens that activated copulation were TP, T, and AE. Subcutaneous pellets of FTP also activated copulation. In Experiment 2 male quail with photically regressed testes were injected with TP, TP + ATD (1,4,6-androstatrien-3,17-dione, an aromatase inhibitor), EB, EB + ATD, or oil. ATD completely blocked TP-stimulated copulation, but had no effect on EB-stimulated copulation. These experiments provide further evidence for an aromatization theory of quail copulation.     

Infectious diseases: Further evidence that infection is an infrequent cause of first trimester spontaneous abortion

A previous cohort study found no clinical evidence that infectionoccurred more often in subjects experiencing pregnancy losscompared with those experiencing success ful pregnancy [Simpsonet al (1996) Hum. Reprod., 11, 668—672]. Given these surprisingfindings, we conducted a similar analysis on another cohortalso followed prospectively. Using couples practising naturalfamily planning for conception or contraception, Informationon clinical evidence of infection was gathered beginning withweek 5 of gestation. Information on fever and signs of overtinfection was specilically sought by interview and physicalexamination. Frequencies of urinary, vaginal and other Infectionsin subjects experiencing pregnancy loss were 11.1, 9.5 and 8.7%respectively, not significantly different from rates in subjectshaving liveborns (10.1, 10.2 and 10.3% respectively). Thus,no association between clinical infection and early pregnancyloss (16 weeks) was observed. Cohort studies utilizing biologicallybased assays are awaited because extant data do not provideevidence that clinically evident infections play major rolesin first trimester pregnancy losses.     

In vivo evidence that retinal bipolar cells generate spikes modulated by light

Retinal bipolar cells have been assumed to generate purely graded responses to light. To test this idea we imaged the presynaptic calcium transient in live zebrafish. We found that ON, OFF, transient and sustained bipolar cells are all capable of generating fast 'all-or-none' calcium transients modulated by visual stimulation.     

Further evidence for association of GRK3 to bipolar disorder suggests a second disease mutation

OBJECTIVES: Two genome-wide linkage surveys suggest chromosome 22q12 may contain a susceptibility locus for bipolar disorder (BPD) in the immediate region of the gene G protein receptor kinase-3 (GRK3). We previously published evidence that a single nucleotide polymorphism (SNP) in the promoter region of GRK3, designated P5, was associated with BPD. This SNP, however, was too rare (allele frequency 0.007) to explain the evidence for linkage. METHODS: To identify other SNPs or haplotypes associated with illness, we have now sequenced an additional 28-kb genomic segment of GRK3 and tested an additional 35 SNPs for association with BPD in 181 Caucasian nuclear families. RESULTS: Transmission disequilibrium test analyses identified two closely related disease-associated haplotypes defined by four SNPs located upstream of the promoter region: transmission to nontransmission ratios=54:22 and 20:9, odds ratios=2.50 and 2.36, and P values=0.0009 and 0.05. The best P value remained significant after correction for multiple testing. These two haplotypes were found on an entirely different set of chromosomes from the previously identified SNP P5. They had a combined frequency of approximately 0.10 and, therefore, a much greater population attributable risk for disease than the previously identified P5 haplotype. CONCLUSIONS: These data provide evidence that at least two distinct haplotypes, and possibly two or more different underlying mutations, in GRK3 might be associated with BPD. These new findings add support for the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization and thereby predisposes to the development of BPD.     

Further evidence from two families that craniofrontonasal dysplasia maps to Xp22

Craniofrontonasal dysplasia (CFND) is a rare X-linked disorder that maps to a 13-cM region on Xp22. Phenotypic features include craniosynostosis, hypertelorism and a broad nasal root with or without a bifid nasal tip. Multiple examples have been reported of males having a less severe phenotype than females. We report haplotype analyses in two CFND families over the critical region to which the gene has been mapped. In pedigree 1, a clinically unaffected male inherited the affected marker haplotype spanning the critical region. We suggest that this individual does have the CFND mutation, but has an extremely mild phenotype that is not detectable with clinical examination. Under the assumption that he is an unknown phenotype, a combined two-point LOD score of 1.68 at zero recombination was obtained, increasing the previously reported total to 5.61 (DXS8022). The data do not narrow down the critical region. This result stresses the importance of subjecting fathers of apparently sporadic cases to a highly critical medical examination and may also explain the unequal ratio of reported female-to-male cases.     

Further evidence that hepatic sources confer biliary antibody in the rat.

The notion that bile-dedicated antibody is made within the liver by migratory antibody-forming cells (AFC) was examined further in rats. Livers from immunized animals were removed to perfusion in isolation so that plasma influences on bile antibody would be obviated. Antibody was secreted for at least 5 hr by the livers of rats that had received intravenous (i.v.) or intra-Peyer's patch (IPP) immunization with horse erythrocytes. After initially declining, the titres stabilized at 5-8% of the starting value for IPP-immunized rats and at 0.8% for i.v.-immunized animals, levels that were then sustained. In other experiments, the biliary antibody output was measured in immunized rats in the period immediately following splenectomy, an expedient that would deny the liver any newly formed AFC. Splenectomy during spleen-based, IgM antibody responses led to bile titres falling, over about 12 hr, to 21% of initial values. This level was then maintained for at least another 12 hr. Serum titres over this period remained static. Lastly, the bile ducts of immunized rats were ligated to test whether locally made antibody that was destined for bile could be forced instead to reflux to blood. Biliary obstruction during IgM responses to horse erythrocytes and pneumococcal polysaccharide, type 3, was found to raise significantly serum antibody titres. For pneumococcal polysaccharide, the serum response was also noticeably prolonged. These findings are consistent with the biliary antibody of immunized rats being constituted, in part, from local sources and not from plasma alone.     

Further evidence reveals that okra mottle virus arose from a double recombination event

As a result of surveys of okra begomoviruses (genus Begomovirus, family Geminiviridae) conducted over the last five years in Central Brazil, we report the complete genome sequence of an isolate of okra mottle virus (OMoV). The DNA-A and DNA-B components were 2660 and 2653 nucleotides (nt) long, respectively, and they were most closely related to the DNA-A (~99 % nt identity) and DNA-B (~98 % nt identity) components of an OMoV isolate from a soybean plant. A phylogenetic tree was generated based on these sequences, and it was shown that both of the OMoV DNA components were grouped in a branch with Brazilian begomoviruses known to infect weeds. By recombination analysis, strong evidence was observed that the OMoV genome may have been the product of a double inter-species recombination event.     

Further evidence that histamine in hippocampus affects the exploratory behavior in the rat

The effect of histamine (HA) and 3-methyl-histamine (3-MHA) in the hippocampus on hole-board behavior was studied. Male rats were microinjected stereotaxically into the hippocampus with 1 μl of saline solution containing 9, 45 or 90 nMol of HA or 3-MHA. Five min later, all rats were tested for 5 min in a hole-board and locomotor, rearing, grooming and head-dipping activities were measured by direct observation. HA inhibited rearing and grooming at all the doses used but it affected locomotor activity only at 45 and 90 nMol doses. There was no effect on head-dipping behavior. 3-MHA instead increased locomotor and head-dipping activities at all the doses used and it did not change rearing and grooming. The present results give a further support for a physiological participation of HA in the hippocampus.     

Further evidence that carbohydrates are the immunodeterminant structures of blood group M and N specificities

Terminal beta-D-galactopyranosyl (Gal) groups are implied in blood group N but not M specificity by the following findings: (a) Rabbit anti-asialoganglioside sera specific for terminal beta-Gal-(1 leads to 3)-GalNac agglutinate human group 0 M and N erythrocytes, the latter to a significantly higher titer, while rabbit anti-ganglioside GMl sera, whereas sialic acid modifies the antibody specificity, do not. The agglutination score with N erythrocytes was about twice that with M red blood cells. The asialoganglioside antibodies were readily absorbed by group 0 N erythrocytes, which were up to 10 times more efficient than group 0 M erythrocytes. Erythrocyte agglutination by the anti-asialoganglioside sera was inhibited by M and N antigen preparations isolated from group 0 red cells ghosts. N antigen was a better inhibitor. Asialoganglioside effectively inhibited the red cell agglutinations by anti-asialoganglioside serum. Ganglioside GMl did not inhibit. (b) Horse anti-pneumococcus Type XIV serum, which has anti-beta-Gal specificity, precipitated highly active N but not M substances. This precipitation was specifically inhibitable by oligosaccharides with terminal beta-Gal. (c) Beta galactosidase specifically inactivated native N and "acid-produced' N substances with the release of about three moles Gal per subunit of N antigen. It did not affect M antigen.     

Further evidence that one of the earliest alterations in colorectal carcinogenesis involves APC.

Colorectal cancer is hypothesized to arise after the accumulation of multiple mutations in critical oncogenes or tumor suppressor genes. The relative timing of each mutation is unknown because the exact number and types of mutations differ between tumors. However, for every mutation except the first, tumor heterogeneity must exist until clonal dominance is reestablished. This principle was applied to mutant APC genes in eight colorectal adenomas. The APC mutations were homogeneously present throughout the adenomas, including those less than 1 cm in size, but absent from the normal polyp stalks. In one adenoma with APC and c-K-ras mutations, both mutations were simultaneously present in only a small discrete portion, suggesting that the c-K-ras mutation was acquired after the APC mutation. These findings suggest that when mutations in APC occur, they are usually one of the first events in colorectal carcinogenesis or provide such a strong selective advantage that intratumor heterogeneity is seldom observed.