Oxathiazinane derivatives display both antineoplastic and antibacterial activity: a structure activity study.

PURPOSE: The Oxathiazinane substance class is characterized by a high diversity of chemical structures yet to be fully investigated. Our research group recently proved that the 1.4.5-oxathiazine-4.4-dioxide, known as substance GP-2250, possesses antineoplastic properties as shown on pancreatic carcinoma. This current study aims to gain insights into the structure and activity relationship of a series of different Oxathiazinanes regarding their antineoplastic activity and the potential correlation with antibacterial activity. We investigated the newly synthesized Oxathiazinane derivatives: 2255, 2256, 2287, 2289, 2293 and 2296 in comparison to GP-2250. METHODS: The antineoplastic effect was evaluated in different cancer entities (breast, skin, pancreas and colon cancer cell lines) by viability, proliferation, and cell migration assays in vitro. Disc diffusion tests were performed on various bacteria strains to examine the antibacterial potential. Additionally, reactive oxygen species (ROS) assays were conducted to investigate mechanistic aspects. RESULTS: The substances GP-2250, 2293, 2289 and 2296 not only showed antineoplastic activity in four different cancer entities but also antibacterial effects, as tested on multiple bacteria strains including MRSA (Methicillin-resistant Staphylococcus aureus). Furthermore, these substances also induced high ROS levels up to 110% in the treated cancer cell lines compared to untreated control cells. These results indicate a correlation between an antineoplastic capacity and antibacterial properties of these derivatives. Both activities appear to be ROS driven. The Oxathiazinane derivatives 2255, 2256 and 2287 lacked both, antineoplastic and antibacterial activity. CONCLUSION: Thus, a comparable structure activity relationship became apparent for both the antineoplastic and antibacterial activity.

Effects of momentary self-monitoring on empowerment in a randomized controlled trial in patients with depression.

BACKGROUND: Interventions based on the experience sampling method (ESM) are ideally suited to provide insight into personal, contextualized affective patterns in the flow of daily life. Recently, we showed that an ESM-intervention focusing on positive affect was associated with a decrease in symptoms in patients with depression. The aim of the present study was to examine whether ESM-intervention increased patient empowerment. METHODS: Depressed out-patients (n=102) receiving psychopharmacological treatment who had participated in a randomized controlled trial with three arms: (i) an experimental group receiving six weeks of ESM self-monitoring combined with weekly feedback sessions, (ii) a pseudo-experimental group participating in six weeks of ESM self-monitoring without feedback, and (iii) a control group (treatment as usual only). Patients were recruited in the Netherlands between January 2010 and February 2012. Self-report empowerment scores were obtained pre- and post-intervention. RESULTS: There was an effect of group×assessment period, indicating that the experimental (B=7.26, P=0.061, d=0.44, statistically imprecise) and pseudo-experimental group (B=11.19, P=0.003, d=0.76) increased more in reported empowerment compared to the control group. In the pseudo-experimental group, 29% of the participants showed a statistically reliable increase in empowerment score and 0% reliable decrease compared to 17% reliable increase and 21% reliable decrease in the control group. The experimental group showed 19% reliable increase and 4% reliable decrease. CONCLUSIONS: These findings tentatively suggest that self-monitoring to complement standard antidepressant treatment may increase patients' feelings of empowerment. Further research is necessary to investigate long-term empowering effects of self-monitoring in combination with person-tailored feedback.

[Reactive hemophagocytosis syndrome as a rare cause of fatal pancytopenia]. / Reaktives Hämophagozytosesyndrom als seltene Ursache einer fatalen Panzytopenie.

CASE REPORT: We present the case of a feverish 36-year-old female patient with unspecific pain and weight loss. After initial diagnosis of an unclear infection with Candida esophagitis, unspecific duodenitis, proctitis and liver damage there was a further clinical deterioration during antibiotic and symptomatic therapy. A newly developed pancytopenia could be identified as caused by reactive hemophagocytosis using bone marrow analysis. The patient died despite maximal supportive and specific therapy. Cause of death was a retroperitoneal hematoma and an invasive aspergillosis, the latter not identified premortem. CONCLUSION: The reactive infect-associated hemophagocytosis is a rare differential diagnosis in feverish pancytopenia. The prognosis is poor. In absence of a proven causal therapy supportive therapy and maximal diagnostics for detection of curable underlying diseases are essential. Antimycotic therapy should be considered generally.

[Endometrial metastasis of a "balloon" cell melanoma mimicking a "xanthomatous endometritis"]. / Endometrial metastasiertes "Balloon"-Zell-Melanom unter dem Bild einer "xanthomatösen Endometritis".

Xanthomatous changes are unusual lesions of the corpus endometrium that may mask endometrial carcinoma. The term "xanthomatous endometritis" refers to morphological changes frequently induced by estrogen stimulation. We report for the first time a case of uterine metastasis of balloon-cell melanoma mimicking xanthomatous endometritis. Light microscopic, immunohistological, and ultrastructural results are presented and discussed in connection with our ideas on the pathogenesis of this peculiar tumor. The findings favor the hypothesis of a regressive phenomenon in the balloon-cell transformation of melanoma cells. The melan-A immunohistology seems to be more important in the diagnosis of balloon cell melanoma than the classic melanoma antibody HMB 45.

Crystal Structure, Electrical Transport, and Magnetic Properties of Niobium Monophosphide.

Large single crystals of NbP have been prepared. A single-crystal X-ray diffraction study shows that it crystallizes in tetragonal symmetry with space group I4(1)md (No. 109) and lattice parameters a = 3.3324(2) Å, c = 11.3705(7) Å, and Z = 4. A full matrix least-squares refinement based on a unique data set of 285 reflections (I> 2sigma(I)) yielded R(F) = 0.017 and R(w)(F(2)) = 0.046 for nine variables. The unit cell consists of one unique Nb and one P, each in trigonal prismatic coordination with the other element. There are two short and four long bond distances of Nb-P. The Nb-Nb bond distances are significantly shorter than R(c) = 4.09 Å, the critical distance required for good Nb-Nb 4d orbital overlap for niobium metal-metal bonds. NbP shows metallic behavior with rho = 4.5 x 10(-)(5) Omega cm at room temperature. Magnetic susceptibility measurements on a collection of randomly oriented single crystals indicate very weak Pauli paramagnetism ( approximately 10(-)(5) emu/mol). A discussion of the structure as well as the physical properties of NbP compared with those of previous results are presented. The band structure of NbP based on the extended Hückel (tight-binding) calculations is presented along with an analysis that reveals that the valence band is built up from three center bonds localized within Nb(3) triangles.

A cluster of hematopoietic serine protease genes is found on the same chromosomal band as the human alpha/delta T-cell receptor locus.

The chymotrypsin-like family of serine protease genes includes several members that are expressed exclusively in subsets of hematopoietic cells. For example, human neutrophil elastase and cathepsin G are expressed only in myelomonocytic precursors, and cytotoxic-T-cell serine proteases are found only in cytotoxic lymphocytes. We have used a cathepsin G cDNA probe to clone two cathepsin G-like genes (designated CGL-1 and CGL-2) from a human genomic library. We have determined that CGL-1 is identical to a previously identified gene (known as CCPI, CTLA I, or cytotoxic serine protease B) that is expressed only in activated cytotoxic T lymphocytes. We show here that cathepsin G, CGL-1, and CGL-2 are linked on an approximately 50-kilobase locus found on human chromosome 14 at band q11.2. This gene cluster maps to the same chromosomal band as the alpha and delta T-cell receptor genes; this region is involved in most chromosomal translocations and inversions that are specifically associated with T-cell malignancies.

Genomic organization and chromosomal localization of the human cathepsin G gene.

Cathepsin G is a 26,000-Da serine protease that is found in the azurophil granules of neutrophils and monocytes. The cathepsin G gene is expressed at high levels in U937 promonocytic cells, but is down-regulated with phorbol-induced differentiation. To characterize the genomic sequences responsible for the regulated expression of this gene, we screened a human genomic fibroblast library using cathepsin G cDNA, and obtained two lambda clones that contained the cathepsin G locus. The cathepsin G gene spans 2.7 kilobase pairs of genomic DNA and consists of 5 exons and 4 introns. The genomic organization of cathepsin G is similar to that of human neutrophil elastase, rat mast cell protease II, murine adipsin, and murine cytotoxic T-cell serine proteases, with protease catalytic residues located near the borders of exons 2, 3, and 5. Using in situ hybridization techniques, we localized cathepsin G to chromosome 14q11.2, a site that is near the alpha/delta T-cell receptor complex. Cathepsin G transcription is abolished in U937 nuclei with 2 micrograms/ml alpha-amanitin, indicating that this gene is probably transcribed by RNA polymerase II. The 5' end of the cathepsin G gene was defined by primer extension and S1 nuclease protection assays. A TATA box is found at position -29, and a CAAT box is found at -69 with respect to the transcription initiation site. Having defined the genomic structure and chromosomal location of cathepsin G, we are now attempting to identify the DNA elements in or near this gene that mediate its tissue and development-specific pattern of expression.

Hereditary stomatocytosis: consistent association with an integral membrane protein deficiency.

We studied the RBC membrane proteins of four patients, including a mother and daughter, with hereditary stomatocytosis. One- and two-dimensional gel electrophoresis revealed that a 28 kDa integral protein, present in normal RBC membranes, was absent in all four patients. This abnormality, reported once previously (Lande et al, 1982), appears to be a characteristic feature of hereditary stomatocytosis, and may be related to the underlying permeability defect in this disorder.

The relation between tumor cell proliferation and vascularization in differentiated and undifferentiated colon carcinomas in the rat.

Tumor cell proliferation and tumor vascularization were investigated in differentiated and undifferentiated colon carcinomas of the rat. The following results were found: 1, in both tumor types, vascularization is developed equally well; 2, both in the differentiated and in the undifferentiated carcinomas, the number of proliferating tumor cells decreases with increasing distance from the capillaries; at a distance of about 80 microns, there is no longer any noteworthy tumor cell proliferation; 3, the differentiated and undifferentiated carcinomas differ both in the level of the mitosis index and 3H-thymidine labeling index as well as in their local proliferation pattern despite equal vascularization; 4, these differences must be based on factors which are independent of vascularization; they are attributed to proliferation properties which are inherent in the differently differentiated tumor cell populations. It is concluded from this that the actual proliferation behavior of a carcinoma is primarily dependent on the proliferation properties of the tumor cell population.

Does uremic enterocolitis exist? A morphological and functional investigation of rat intestine in chronic renal insufficiency.

In rats a severe but compensated chronic renal insufficiency was induced by stepwise 9/10 nephrectomy. Despite this severe chronic renal insufficiency we observed no relevant pathological changes in the intestinal mucosa. In particular, we found no evidence of mucosal erosions, ulceration or pseudomembranous colitis, findings which are traditionally thought to be characteristic of the uremic state. This was also true of those animals dying prematurely from uremia. Thus serious doubts arise about the existence of "uremic enterocolitis", doubts which also proved justified after a critical review of the literature on human pathology.

Myxoid lipoadenoma of the parathyroid gland.

A myxoid lipoadenoma of the parathyroid gland causing primary hyperparathyroidism is reported. The very rare and histologically unusual tumor consists of an epithelial component which is combined with a stromal component in a characteristic way. Slender, irregularly branched trabeculae which mainly consist of chief cells as well as a few oxyphil cells are found as epithelial component. The predominantly myxomatous and only focally lipomatous stromal component is interpreted as an integrated tumor component of the lipoadenoma which is derived from the parathyroid adipose tissue.

Grades of atypia in tubular and villous adenomas of the human colon. An electron microscopic study.

Of a total of 544 tubular, villous and tubulo-villous adenomas of the human colon which were investigated by light microscopy, six tubular and six villous adenomas were examined under the electron microscope. It was shown that the two types of adenoma differ in their tissue architecture, but not in their cytological appearance. Different grades of epithelial atypia occur in both types of adenoma. These are designated as grades I to III, correspond to mild, moderate and severe atypia respectively. Whereas adenoma cells with atypia grade I clearly show a cytological relationship with crypt epithelia of the normal colonic mucosa under the electron microscope, adenoma cells with atypia grade III have largely lost the differentiation characteristics of the parent cells and there is no longer intracytoplasmic organization. In the cytoplasm of adenoma cells with atypia grade II, glycogen storage is found as a special feature which does not occur in normal colonic epithelium. A similar finding has been described in the course of malignant transformation of the liver and kidney and thus can be regarded as a further indication of the precancerous nature of the adenomas.

The mechanism of epithelial shedding after ischemic damage to the small intestinal mucosa. A light and electron microscopic investigation.

The intestinal mucosa of the rat was examined by light and electron microscopy 15, 30, 60 and 120 min after complete ligation of the vessel arcades of the proximal jejunum. The characteristic sign of ischemic damage to the small intestinal mucosa and the reason for epithelial shedding is the appearance of membrane enclosed cytoplasmic blebs which arise at the cell base of the enterocytes and detach the epithelium from the basement membrane. This process begins at the tip of the villi before the enterocytes display signs of irreversible damage and progress to the base of the villi with continuation of the ischemia.

Differentiation and aging of the rat intestinal mucosa. II. Morphological, enzyme histochemical and disc electrophoretic aspects of the aging of the small intestinal mucosa.

At different times of day (08.00, 12.00, 16.00 and 24.00) the small intestinal mucosa of four month (adult) and 30 month (senile) old rats was examined histologically, by scanning electron microscopy, autoradiography, enzyme histochemistry and disc electrophoresis. In senile rats a villous atrophy is found histologically and an irregular architecture is found in scanning electron microscopy. The changes are essentially restricted to the proximal small intestine. The enterocytes of adult and senile rats show an identical enzyme histochemical picture. In the proximal small intestine of adult and senile rats, synchronous statistically significant fluctuations of the activity of alkaline and acid phosphatase were revealed in the disc electropherograms. Likewise statistically significant are the at all times of day low enzyme activities in the intestinal mucosa of senile rats as compared to the findings in adult rats. The fall in activity of alkaline and acid phosphatase in old rats is attributed to the numerical reduction of the enterocytes which is caused by the age atrophy of the intestinal mucosa. These findings are discussed in connection with results of our own studies of proliferation kinetics and those of other authors.

[Retrograde pancreatic phlebography with simultaneous balloon occlusion of portal and arterial flow. An experimental study (author's transl)]. / Retrograde Pankreasphlebographie bei simultaner portaler und arterieller Ballonokklusion--Eine experimentelle Studie.

The possibility of demonstrating the venous system of the entire pancreas by retrograde portal contrast injection with simultaneous balloon occlusion of the portal vein, coeliac axis and superior mesenteric artery was investigated in 12 dogs. In seven cases good filling of the larger pancreatic veins was obtained. Portal and arterial pressure relationships altered considerably during various experimental conditions. A rise in serum transaminases was observed only once when there was thrombosis of the portal vein and branches of the hepatic veins. Apart from this, there was no rise in transaminases or alphaamylase. Histologically there were only minor changes in the liver after total occlusion of 40 minutes, the occlusion having been performed over periods of six minutes with two to five minutes of flow alternating. The application of this method to man is discussed.

Ischemia and post-ischemic regeneration of the small intestinal mucosa. An enzyme-histochemical investigation.

After ligation of the vascular arcades of the upper jejunum in rats, the ischemic damage to the intestinal mucosa and its regenerative behavior after ischemia lasting 120 minutes were investigated with histological and enzyme-histochemical methods. During the ischemic injury of the jejunal mucosa, there is rejection of hydropically swollen epithelial cells into the intestinal lumen advancing from the tip to the base of the villi without a previously detectable loss of activity of the enzymes investigated. At the end of ischemia lasting 120 minutes, there is complete destruction of the villi as well as the upper portions of the crypts. After rapid re-epithelialization of the mucosal surface by a flat epithelium, reformation of villi begins already after a 24 h period of regeneration. On the third day of regeneration, the intestinal mucosa has plump villi again. Their epithelia already show the morphological characteristics of mature enterocytes. On the other hand, enzymatic maturation of the enterocytes is only concluded between the first and second week of regeneration. An altered proliferation kinetics of the crypt epithelia due to the repair process is discussed as cause of this delayed enzymatic maturation of the enterocytes relative to the morphological differentiation. Although the intestinal mucosa has a regular villous structure again after regeneration lasting 8 days, enzyme histochemical finding in the lamina propria indicate that the process of repair is only complete here in the sixth week of regeneration.