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).     

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.     

Antigen specific serum antibody response to Chlamydia trachomatis in patients with acute pelvic inflammatory disease.

Sera from 35 patients with acute pelvic inflammatory disease (PID) with and without Chlamydia trachomatis confirmed by culture and sera from 19 control patients with neither evidence of pelvic infection nor C trachomatis infection were studied for the presence of serum IgG, IgA, and IgM antibodies to C trachomatis using enzyme immunoassay (EIA) and immunoblotting techniques. There was no correlation between the antibody concentrations in the EIA and the spread of chlamydial infection, as determined by cervical, endometrial, and laparoscopic sampling for chlamydia. The immunoblot analysis showed antibodies to the major outer membrane protein (MOMP) of C trachomatis elementary bodies in all patients who had had C trachomatis isolated. Reactivity was also frequently observed against the 68, 62, 60, 45, and 31 kilodalton antigens. About 20 antigenic polypeptides were identified. Differences in antibody prevalence to specific chlamydial antigens, however, were not related to the site of chlamydial isolation or serum antibody concentrations observed with the EIA. The results indicate that patients with PID with and without upper genital tract infection with C trachomatis cannot be differentiated by reactivity of sera to specific chlamydial polypeptide antigens. The determination of a specific serum IgA antibody response by EIA was the most effective single test to discriminate between patients with and without acute chlamydial infection.     

Interferon (IFN)-α, IFN-γ, interleukin (IL)-2, and arachidonic acid metabolites modulate IL-4-induced IgE synthesis similarly in healthy persons and in atopic dermatitis patients

The role of cytokines and arachidonic acid metabolites in the regulation of IgE production in healthy persons and in atopic dermatitis patients with elevated IgE levels was studied. Interleukin-4 (IL-4) induced IgE production in peripheral blood mononuclear cells (PBMCs) of all donors, and no significant difference was found between the amounts of IgE produced by healthy persons and atopic dermatitis patients. Similarly, recombinant interferon (IFN)-α and IFN-γ, as well as IL-2, inhibited IL-4-induced IgE production to a similar extent in both study groups. To evaluate the role of arachidonic acid (AA) metabolites in the regulation of IgE production, we added indomethacin, an inhibitor of the cyclooxygenase pathway, or nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase pathway, to IL-4-treated cultures. Both indomethacin and NDGA strongly inhibited IL-4-induced IgE production. They also inhibited IL-4-induced IgG4 synthesis. No significant difference in the amount of inhibition was found between the two study groups. We were unable to restore the NDGA-induced inhibition of IgE-production by adding leukotrienes B₄, C₄, D₄, or 5-HETE to the NDGA-treated cultures. PGE₂ also failed to restore the indomethacin-mediated inhibitory effect. Consequently, NDGA- and indomethacin-mediated inhibitory effects do not appear to be mediated by any single factor studied. Collectively, our results show IFNs and IL-2 to be similar in effect in the modulation of IL-4-induced IgE synthesis in healthy and atopic persons. In addition, our results show the importance of AA metabolites in the regulation of IgE and IgG4 synthesis in normal persons as well as in atopic dermatitis patients.     

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.     

The role of interleukin 2 in the regulation of proliferation and IgM synthesis of human newborn mononuclear cells.

The effect of interleukin 2 (IL-2) on cord blood mononuclear cells (CBMC) was studied, with special reference to B cell function. The study shows that CBMCs proliferate in response to recombinant interleukin 2 (rIL-2) without in-vitro preactivation. The response was also detected when whole blood cultures were used. CBMCs not preactivated in vitro proliferated in response to rIL-2 even after T cell and monocyte depletion. Thus, rIL-2 affects both non-T cells and T cells of newborns without preactivation in vitro. IL-2 receptors on unstimulated CBMCs appear to be distinct from Tac antigen, as the mean number of Tac antigen-positive cells among CBMCs was only 0.8%. Furthermore, rIL-2 inhibited PWM-induced proliferation and the response was more prominent in newborns than in adults. Thus, rIL-2 seems to cause a higher increase of suppressor cell function in CBMCs than in adult peripheral blood mononuclear cells. Neither rIL-2 nor Staphylococcus aureus Cowan 1 (SAC) stimulated any IgM synthesis, but a dose-dependent IgM synthesis was obtained by combining SAC and rIL-2. Alone, however, rIL-2 appears to be an insufficient factor to induce differentiation of SAC-activated cord blood B cells, as no IgM production in response to rIL-2 occurred in T cell and monocyte-depleted cell populations. The results of this study suggest both increased suppressor cell function and intrinsic B cell deficiency as causes of a weak humoral immune response in newborns.     

Low-FODMAP vs regular rye bread in irritable bowel syndrome:Randomized SmartPill~ study

AIM To compare the effects of regular vs low-FODMAP rye bread on irritable bowel syndrome(IBS) symptoms and to study gastrointestinal conditions with Smart Pill?.METHODS Our aim was to evaluate if rye bread low in FODMAPs would cause reduced hydrogen excretion,lower intraluminal pressure,higher colonic p H,different transit times,and fewer IBS symptoms than regular rye bread.The study was a randomized,double-blind,controlled cross-over meal study.Female IBS patients(n = 7) ate study breads at three consecutive meals during one day.The diet was similar for both study periods except for the FODMAP content of the bread consumed during the study day.Intraluminal p H,transit time,and pressure were measured by Smart Pill,an indigestible motility capsule.RESULTS Hydrogen excretion(a marker of colonic fermentation) expressed as area under the curve(AUC)(0-630 min) was [median(range)] 6300(1785-10800) ppm?min for low-FODMAP rye bread and 10 635(4215-13080) ppm?min for regular bread(P = 0.028).Mean scores of gastrointestinal symptoms showed no statistically significant differences but suggested less flatulence after low-FODMAP bread consumption(P = 0.063).Intraluminal pressure correlated significantly with total symptom score after regular rye bread(ρ = 0.786,P = 0.036) and nearly significantly after lowFODMAP bread consumption(ρ = 0.75,P = 0.052).We found no differences in p H,pressure,or transit times between the breads.Gastric residence of Smart Pill was slower than expected.Smart Pill left the stomach in less than 5 h only during one measurement(out of 14 measurements in total) and therefore did not follow on par with the rye bread bolus.CONCLUSION Low-FODMAP rye bread reduced colonic fermentation vs regular rye bread.No difference was found in median values of intraluminal conditions of the gastrointestinal tract.