The Crystal and Molecular Structures of N4-(5-Bromosalicylidene)-N1-(3,4-dimethyl-5-isoxazolyl)sulfanilamide

The structure of the title compound was determined by X-ray analysis. Medicinal compounds with Schiff base structure have been widely synthesized and investigated in recent years. The functional group-CH?N- of the Schiffbases has been shown to have considerable biological importance¹⁾ . Many compounds with such a structure have important analgesic, anti-inflammatory, antibiotic, antimicrobial and especi ally anticancer activities^2-8). Medicinal sulphonamides, having a primary amino group in their molecule, react very easily with salicylaldehyde or its derivatives⁹⁾. Information about the exact structure of the reac tion products is rather scanty, however, even though the formation reaction of the base has been utilized in many analytical pr ocedures for medicinal sulphonamides^9-12) and many such Schiff bases have been found to possess good bac teriostatic properties^13-14).     

A short luteal phase in cycles stimulated with clomiphene and human menopausal gonadotropin for in vitro fertilization

Of 70 cycles stimulated with clomiphene and human menopausal gonadotropin (hMG) for an in vitro fertilization-embryo transfer (IVF-ET) program, a short luteal phase of 11 days or less was found in 18. In this group the mean estradiol and progesterone levels were elevated in the early luteal phase. Despite the elevated initial values, progesterone levels fell rapidly at the mid luteal phase as a sign of premature luteolysis. The mean total amount of gonadotropin administered and the mean number of follicles punctured and of oocytes recovered did not show any significant difference between the groups of normal and short luteal phases. The present findings support the theory that hyperestrogenism in the early luteal phase may initiate the premature luteolysis observed in clomiphene-menopausal gonadotropin-stimulated cycles.     

Immune response against P815X2 mastocytoma growing in syngeneic DBA/2 mice. V. Spleen immunoreactivity and cell mediated cytotoxicity

The in vitro cytotoxicity assay and the histological in vivo analysis were used to study cell-mediated immunity in the spleen of DBA/2 mice bearing subcutaneously developing P815X2 mastocytoma. Mononuclear cells separated from the spleen showed P815X2 specific cytotoxic activity between days 10 (12) and 16 following tumor inoculation. Maximal cytotoxicity was detected on days 13 and 14. In the T cell area of the spleen white pulp (C-PALS), an increase in the proportions of T lymphocytes and mononuclear phagocytes was observed on days 10 and 12 after the injection of P815X2 cells. On day 14, the T cell level in C-PALS dropped below control values, and the cellular density in the T cell area was reduced. Tumor metastases were seen in the spleen from day 14 onwards. The results indicate, that the T cell reaction in vivo was detectable in C-PALS one to two days earlier than the in vitro cytotoxicity of the spleen cells. By the time of maximal cytotoxic activity, the in vivo reaction had disappeared.     

Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability

The colorectum and uterine endometrium are the two most commonly affected organs in hereditary nonpolyposis colon cancer (HNPCC), but the genetic basis of organ selection is poorly understood. As tumorigenesis in HNPCC is driven by deficient DNA mismatch repair (MMR), we compared its typical consequence, instability at microsatellite sequences, in colorectal and endometrial cancers from patients with identical predisposing mutations in the MMR genes MLH1 or MSH2. Analysis of non-coding (BAT25, BAT26, and BAT40) and coding mononucleotide repeats (MSH6, MSH3, MLH3, BAX, IGF2R, TGF beta RII, and PTEN), as well as MLH1- and MSH2-linked dinucleotide repeats (D3S1611 and CA7) revealed significant differences, both quantitative and qualitative, between the two tumor types. Whereas colorectal cancers displayed a predominant pattern consisting of instability at the BAT loci (in 89% of tumors), TGF beta RII (73%), dinucleotide repeats (70%), MSH3 (43%), and BAX (30%), no such single pattern was discernible in endometrial cancers. Instead, the pattern was more heterogeneous and involved a lower proportion of unstable markers per tumor (mean 0.27 for endometrial cancers versus 0.45 for colorectal cancers, P < 0.001) and shorter allelic shifts for BAT markers (average 5.1 bp for unstable endometrial cancers versus 9.3 bp for colorectal cancers, P < 0.001). Among the individual putative "target" loci, PTEN instability was associated with endometrial cancers and TGF beta RII instability with colon cancers. The different instability profiles in endometrial and colorectal cancers despite identical genetic predisposition underlines organ-specific differences that may be important determinants of the HNPCC tumor spectrum.     

PTEN mutational spectra,expression levels,and subcellular localization in microsatellite stable and unstable colorectal cancers

PTEN on 10q23.3 encodes a dual-specificity phosphatase that negatively regulates the phosphoinositol-3-kinase/Akt pathway and mediates cell-cycle arrest and apoptosis. Germline PTEN mutations cause Cowden syndrome and a range of several different hamartoma-tumor syndromes. Hereditary nonpolyposis colon cancer (HNPCC) syndrome is characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors. Although both colorectal carcinoma and endometrial carcinoma are the most frequent component cancers in HNPCC, only endometrial cancer has been shown to be a minor component of Cowden syndrome. We have demonstrated that somatic inactivation of PTEN is involved in both sporadic endometrial cancers and HNPCC-related endometrial cancers but with different mutational spectra and different relationships to MSI. In the current study, we sought to determine the relationship of PTEN mutation, 10q23 loss of heterozygosity, PTEN expression, and MSI status in colorectal cancers (CRCs). Among 11 HNPCC CRCs, 32 MSI+ sporadic cancers, and 39 MSI- tumors, loss of heterozygosity at 10q23.3 was found in 0%, 8%, and 19%, respectively. Somatic mutations were found in 18% (2 of 11) of the HNPCC CRCs and 13% (4 of 32) of the MSI+ sporadic tumors, but not in MSI- cancers (P = 0.015). All somatic mutations occurred in the two 6(A) coding mononucleotide tracts in PTEN, suggestive of the etiological role of the deficient MMR. Immunohistochemical analysis revealed 31% (14 of 45) of the HNPCC CRCs and 41% (9 of 22) of the MSI+ sporadic tumors with absent or depressed PTEN expression. Approximately 17% (4 of 23) of the MSI- CRCs had decreased PTEN expression, and no MSI- tumor had complete loss of PTEN expression. Among the five HNPCC or MSI+ sporadic CRCs carrying frameshift somatic mutations with immunohistochemistry data, three had lost all PTEN expression, one showed weak PTEN expression levels, and one had mixed tumor cell populations with weak and moderate expression levels. These results suggest that PTEN frameshift mutations in HNPCC and sporadic MSI+ tumors are a consequence of mismatch repair deficiency. Further, hemizygous deletions in MSI- CRCs lead to loss or reduction of PTEN protein levels and contribute to tumor progression. Finally, our data also suggest that epigenetic inactivation of PTEN, including differential subcellular compartmentalization, occurs in CRCs.     

The hydrolethalus syndrome: delineation of a "new", lethal malformation syndrome based on 28 patients

We describe a lethal malformation syndrome in 28 newborn infants from 18 families. The main manifestations were hydrocephalus (often with an unusual structure of the brain and the occipital bone), very small mandible, Polydactyly, congenital heart defect, abnormalities of the respiratory organs, and (different from the Meckel syndrome) normal kidneys. Polyhydramnios and stillbirth or neonatal death were the rule. Autosomal recessive inheritance is evident. This syndrome is another in the group of rare recessive disorders which are found in Finland. Because of the 25 % recurrence risk and possibilities for prenatal diagnosis, this syndrome should be recognized by paediatricians and, because of the frequent stillbirths, also by obstetricians and pathologists. The name hydrolethalus syndrome (hydramnios, hydrocephalus, lethality) may be of help in this.     

Estrogen receptor genotype modulates myocardial perfusion in young men

Most of the effects of estrogens are mediated by estrogen receptors. Vascular endothelial cells and smooth muscle cells express estrogen receptor (ESR1) in both genders. A long genotype group of a common thymine-adenine (TA) dinucleotide repeat polymorphism in the regulatory region of this gene has previously been related to coronary artery disease. The present study examined whether coronary blood flow is affected by this genotype. A total of 49 healthy men were genotyped by PCR and divided into three groups according to median number of the ESR1 promoter TA repeat (=19), i.e., in the short allele genotype group both alleles were of fewer than 19 repeats whereas in the long allele group both alleles were 19 repeats or more. The intermediate group comprised men who had one short and one long allele. Myocardial blood flow was measured by positron emission tomography using [¹⁵O]water, performed at rest and during adenosine stimulation. Men with long alleles had lower adenosine-stimulated coronary flow than those with short alleles and those with one short and one long allelle. Our results suggest that adenosine-stimulated myocardial perfusion is lower in subjects with ESR1 long alleles than the other TA repeat genotypes.     

A controlled study of the influence of continuous subcutaneous insulin infusion treatment on diabetic retinopathy during pregnancy

Forty consecutive pregnant patients with insulin-dependent (Type I) diabetes mellitus were randomized at the end of the first trimester for treatment with conventional insulin therapy (CIT) or continuous subcutaneous insulin infusion therapy (CSII). Nine patients randomized into the CSII group declined the pump treatment. The mean glycosylated haemoglobin (Hb AIc) decreased (p less than 0.001) both in the CIT and the CSII groups with no difference between the groups. Some deterioration in retinopathy was found in 2/18 patients in the CIT group, in 5/13 in the CSII group, and in 3/9 of those who declined the pump treatment. The proportion of patients whose retinopathy progressed did not differ significantly between the groups, and in the majority the deterioration was mild. However, two patients in the CSII group developed acute ischaemic retinopathy, which progressed to proliferative stage in spite of laser treatment. In these two cases the decrease in the Hb AIc level was among the greatest and fastest in the study. These data suggest that a rapid near normalization of glycaemic control by CSII during pregnancy can accelerate the progress of retinopathy in poorly controlled diabetic patients.     

Periodontitis is associated with a low concentration of vitamin C in plasma

This study aimed to clarify how concentrations of vitamin C in plasma relate to the serology of periodontitis. The random sample used comprised 431 men, 194 from Finland and 237 from Russia. The plasma vitamin C concentration was determined by o-phtaldialdehyde-fluorometry, and serum immunoglobulin G antibodies to Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis were determined by a multiserotype enzyme-linked immunosorbent assay (ELISA). The mean plasma vitamin C concentration was higher (P < 0.001) in Finnish subjects (mean +/- standard deviation, 4.5 +/- 2.8 mg/liter) than in Russian subjects (1.4 +/- 1.8 mg/liter). Mean antibody levels to both A. actinomycetemcomitans (4.7 +/- 3.6 versus 5.2 +/- 3.1 ELISA units [P = 0.05]) and P. gingivalis (5.7 +/- 2.5 versus 7.6 +/- 2.9 ELISA units [P < 0.001]) were lower in Finnish men than in Russian men. In the combined Finnish and Russian population, the antibody levels to P. gingivalis were negatively correlated with vitamin C concentrations (r = -0.22; P < 0.001); this association remained statistically significant (P = 0.010) in a linear regression model after adjustment for confounding factors. The proportion of P. gingivalis-seropositive subjects decreased with increasing vitamin C concentrations (P for trend, <0.01), but no trend was seen among A. actinomycetemcomitans-seropositive subjects. In conclusion, P. gingivalis infection is associated with low concentrations of vitamin C in plasma, which may increase colonization of P. gingivalis or disturb the healing of the infected periodontium.