Prognostic significance of gamma-glutamyltransferase in patients with endometrial cancer: a multi-centre trial.

BACKGROUND: Gamma-glutamyltransferase (GTT), a known marker for apoptotic balance, seems to promote tumour progression, invasion and drug resistance. Recently, high GGT serum levels were shown to be associated with impaired prognosis in patients with cervical cancer. The aim of this study was to investigate the value of pre-therapeutic serum GGT levels as prognostic parameter in patients with endometrial cancer. METHODS: Within the present multi-centre trial, clinical-pathological parameters and pre-therapeutic serum GGT levels were evaluated in 874 consecutive patients with endometrial cancer. Patients were stratified in GGT risk groups, and univariate and multivariable survival analyses were performed. RESULTS: Mean pre-therapeutic serum GGT level was 30.8 (41.5) U l(-1). Elevated and highly elevated serum GGT levels (P=0.03 and P=0.005), tumour stage (P<0.001 and P<0.001), grade (P<0.001 and P=0.02) and age (P<0.001 and P<0.001) were independently associated with progression-free survival in univariate and multivariable survival analyses. Pre-therapeutic GGT was not associated with advanced tumour stage (P=0.6), higher histological grade (P=0.6) or unfavourable histological subtype (P=0.3). CONCLUSION: Pre-therapeutic serum GGT is a novel and independent prognostic parameter for progression-free survival of patients with endometrial cancer. Stratifying patients into prognostic subgroups could be used for patient counselling and individualised treatment planning.

Accuracy of Fetal Weight Estimation in Women with Diet Controlled Gestational Diabetes.

Purpose: To evaluate whether ultrasound accuracy of estimated fetal weight (EFW) differs in women with diet controlled gestational diabetes mellitus (GDM) compared to nondiabetic pregnant women. Material and Methods: We included 363 patients, 121 patients with diet controlled GDM and 242 patients with a normal oral glucose tolerance test (oGTT). Each case of diet controlled GDM was matched with 2 unaffected controls. All patients were screened/diagnosed for GDM by means of an oGTT. Both groups received ultrasound examination including fetal biometry, using Hadlock's Formula, within 7 days to delivery. After birth, gestational age, birthweight and Apgar scores were collected from each newborn. Results: There was a good correlation between EFW and birth weight (coefficient = 0.747, p < 0.001 by Pearson correlation, even after adjustment for glucose status). Regression analyses, including noGDM/GDM, maternal age, maternal body mass index, birth weight and time interval between ultrasound and delivery revealed that only fetal birth weight significantly influences weight difference between ultrasound EFW and actual birth weight at term. Conclusion: Our data suggests that ultrasound accuracy of EFW using Hadlock's Formula at term does not differ in women with diet controlled GDM compared to women with normal glucose tolerance.

[Tonsillotomy and adenotonsillectomy in childhood. Study on postoperative pain therapy]. / Tonsillotomien und Adenotomien im Kindesalter. Studie zu postoperativen Schmerztherapie.

BACKGROUND: The primary aim of this study was to determine whether the combination of i.v. ketoprofen and i.v. paracetamol provides superior postoperative analgesia in children undergoing adenoidectomy or tonsillotomy compared to either drug alone. The secondary goal was to assess the time until rescue analgesia was needed, propofol requirements and the incidence of vomiting and time of discharge from the postanaesthesia recovery unit (PARU). METHODS: This double-blinded study included 120 children (aged 3-13 years) scheduled for elective tonsillectomy, adenoidectomy or adenotonsillectomy. The children were randomly assigned to one of 3 groups of 40 children each, using the sealed envelope method. The children received i.v. ketoprofen 2 mg/kgBW (group 1) or paracetamol 15 mg/kgBW (group 2) or the combination of these 2 drugs (group 3) after induction of anaesthesia. Standardized general anaesthesia consisted of sevoflurane and fentanyl at a dose of 2-3 µg/kgBW. Pain was assessed using a 5-point scoring system based on the Smiley scale. The Smiley scale shows various faces from a laughing face which corresponds to the state of no pain to a very unhappy face which corresponds to the situation of worst pain (1: no pain, 2: mild pain, 3: moderate pain, 4: severe pain, 5: worst pain). Pain was assessed at 30 min, 1 h, 2 h, 3 h and 4 h after arriving in the PACU. If the pain score exceeded 2 an i.v. dose of 0.1 mg/kgBW morphine was administered as rescue analgesia. RESULTS: During the stay in the PACU the children in the combination group required significantly less supplementary rescue analgesia than children in the ketoprofen and paracetamol groups (17.5% versus 30.8% versus 45%, respectively, χ(2) analysis <0.05). Pain scoring was highest after paracetamol, however, this difference was only significant when compared to the group receiving the combination of paracetamol and ketoprofen (U-test p<0.05). Rescue analgesia was administered earliest in group 2 (paracetamol) reaching statistical significance, however, only when compared to group 3 (logrank test p<0.05). Propofol requirements and time to discharge from the PACU did not differ significantly between the 3 groups (χ(2) analysis; U-test; p>0.05). The overall incidence of vomiting was very low in this study with 6.4% (9/139). Significantly more children in the paracetamol group compared to ketoprofen group and combination group suffered from vomiting (17.5% versus 2.6% versus 2.5%; χ(2) analysis; p<0.05). The time to discharge from PACU did not differ significantly between the 3 groups (U-test: p>0.05). CONCLUSION: The combination of i.v. paracetamol and i.v. ketoprofen provides superior postoperative analgesia compared to the single use of paracetamol.

The prognostic value of plasma fibrinogen levels in patients with endometrial cancer: a multi-centre trial.

BACKGROUND: To analyse the correlation between pre-treatment plasma fibrinogen levels and clinical-pathological parameters in patients with endometrial cancer and to assess the value of plasma fibrinogen as a prognostic parameter. METHODS: Within a retrospective multi-centre study, the records of 436 patients with endometrial cancer were reviewed and pre-treatment plasma fibrinogen levels were correlated with clinical-pathological parameters and patients' survival. RESULTS: The mean (s.d.) pre-treatment plasma fibrinogen level was 388.9 (102.4) mg per 100 ml. Higher plasma fibrinogen levels were associated with advanced tumour stage (FIGO I vs II vs III and IV, P=0.002), unfavourable histological subtype (endometrioid vs non-endometrioid histology, P=0.03), and higher patients' age (< or =67 years vs >67 years, P=0.04), but not with higher histological grade (G1 vs G2 vs G3, P=0.2). In a multivariate analysis, tumour stage (P<0.001 and P<0.001), histological grade (P=0.009 and P=0.002), patients' age (P=0.001 and P<0.001), and pre-treatment plasma fibrinogen levels (P=0.04 and P=0.02) were associated with disease-free and overall survival, respectively. CONCLUSION: Plasma fibrinogen levels can be used as an independent prognostic parameter for the disease-free and overall survival of patients with endometrial cancer.

Gestational diabetes mellitus is associated with increased C-reactive protein concentrations in the third but not second trimester.

OBJECTIVE: Serum C-reactive protein (CRP) concentrations were measured longitudinally throughout pregnancy to test the hypothesis that CRP could relate more closely to glucose tolerance than to adiposity. METHODS: The CRP concentrations in pregnant women with normal glucose tolerance (NGT) and those with gestational diabetes mellitus (GDM) were measured at the same time as the oral glucose tolerance test (OGTT), at the 24th and 28th weeks of gestation and between the 37th and 38th weeks of gestation. RESULTS: At the end of the third trimester, women with GDM had significantly higher CRP levels than women with NGT [median (interquartile range), 9.7 mg L(-1) (5.4-16.0) and 5.7 mg L(-1) (5.1-7.2); P < 0.001, respectively], but at the time of the diagnostic OGTT no significant difference between the two groups was observed. This was owing to a significant increase of CRP in women with GDM between the time of the OGTT and the 37th-38th gestational weeks [median (interquartile range), 1.9 mg L(-1) (-2.2, 6.7); P = 0.01]; whereas, no change in CRP was found in women with NGT [median (interquartile range), -0.1 mg L(-1) (-2.4, 3.1); P = 0.76]. Multiple linear regression analysis showed only a significant independent influence of GDM (P < 0.001) on maternal CRP concentrations in the 37th-38th gestational weeks and a significant influence of body mass index (P < 0.007), but no influence of GDM at the time of the OGTT. CONCLUSION: These data suggest that in women with gestational diabetes the CRP concentration is primarily related to the degree of adiposity until the second trimester and that thereafter impaired glucose metabolism appears to be the predominant predictor of changes in CRP.

A mechanistic analysis of carrier-mediated oral delivery of protein therapeutics.

This article summarizes the results of a theoretical analysis of protein absorption into the systemic circulation from the small intestine, with and without molecular 'carriers' designed to enhance absorption. The predictions are compared with experimental systemic protein concentrations following intraduodenal delivery of insulin, interferon alpha-2b, and human growth hormone. The results show that, from the standpoint of improving oral absorption, the primary consequence of carrier molecules is to increase epithelial membrane permeability, thereby leading to higher bioavailability. Several possible mechanisms of this permeability enhancement are discussed.

Alkaline heating of canola and rapeseed meals reduces toxicity for chicks.

A simple method for improving the nutritive quality of canola and high glucosinolate rapeseed meals for monogastric animals (chicks) was developed; the meals were mixed with NaHCO3 and NH4HCO3, then heated in a conventional oven. Chicks fed untreated canola or rapeseed meals gained less weight than those fed a soybean meal diet, whereas chicks fed the alkaline-heated meals had weight gains not significantly different than those fed the soybean diet. The antithyroid effect of the untreated rapeseed meal was reduced by alkaline treatment of the meals, as shown by improved T4 and free T4 levels in chicks fed the processed products. In chicks fed untreated or alkaline-treated canola or alkaline heated rapeseed meal, all thyroid hormone levels were similar to those of birds fed the soybean meal diet. However, heart tissue of chicks fed diets containing rapeseed or canola meals showed muscle fiber degeneration, although relative heart weights were the same in all groups. Liver tissue from most of the chicks in all dietary groups appeared normal or only slightly abnormal. The nutritive value of both rapeseed and canola meals was improved by this simple processing technique.

Partially unfolded proteins efficiently penetrate cell membranes--implications for oral drug delivery.

We have previously reported on the biological activity of members of a library of low molecular weight compounds (carriers) that enable the oral delivery of proteins (Milstein, Proceedings of the 1995 Miami Bio/Technology Winter Symposium on Protein Engineering and Structural Biology, IRL Press at Oxford University Press, 1995, p. 13; Leone-Bay et al., J. Med. Chem. 38 (1995) 4263-4269; Leone-Bay et al., J. Med. Chem. 39 (1996) 2571-2578; [1-3]). When rats or primates are orally administered a solution of carrier and either recombinant human alpha-interferon (rhIFN), insulin or recombinant human growth hormone (rhGH) significant serum concentrations of the proteins are detectable. The transport activity of these compounds is positively correlated with their structural effects on the protein molecules. Direct measurement of the interaction of these carrier molecules with the proteins indicates that they reversibly destabilize the native state of the molecule favoring a partially unfolded conformation. Apparently these intermediate protein conformations are transport competent and are able to be absorbed through the intestinal tissue and into the bloodstream. Since the measured binding of the carriers to the partially unfolded proteins is relatively weak (Kb = 100 M(-1)) and the systemic activity of the proteins appears to be unaffected, the changes in the structure of the proteins are manifestly reversible.

Acylated non-alpha-amino acids as novel agents for the oral delivery of heparin sodium, USP.

Ten N-acylated, non-alpha-amino acids have been prepared as oral delivery agents and used to demonstrate the oral delivery of heparin in vivo in rats and primates. Following the oral administration of solutions containing a combination of heparin and a delivery agent to rats or primates, significant plasma heparin concentrations were evidenced by APTT and anti-Factor Xa assays. The estimated pharmacodynamic equivalence for an oral dosing solution containing heparin and a delivery agent is 39% in primates. In vitro experiments based on heparin affinity chromatography or heparin/methylene blue complexation were also performed to begin investigation of the mechanism by which these compounds facilitate heparin oral delivery. Results of in vitro studies suggest that absorption of the drug across the gastrointestinal membrane is the result of a non-covalent interaction between heparin and the delivery agent.

Hereditary syndactyly in Angus cattle.

Twenty-five syndactylous Angus cattle, characterized pathologically, were reported from 16 herds in 10 states from 1979 to 1994. Twenty-one (84%) had all 4 legs syndactylous, 3 (12%) had 3 legs syndactylous, and 1 (4%) had 2 legs syndactylous. All syndactylous cattle walked with considerable difficulty. Hooves of aged animals became curled and bent laterally or medially. Affected hooves had the appearance of a truncated cone, the base of which was located at the coronary band. Most hooves were fused completely with no indication of dual anlage. An occasional hoof had a distal notch, and other hooves had a dorsally located groove indicating dual embryonic origin. Lateral dewclaws were enlarged in most cases. Radiographs and dissections of limbs of 19 animals revealed a consistent pattern of fusion in most affected calves. Lesions included 1 or more of the following: disappearance of the large metacarpal and metatarsal intertrochlear notches, horizontal fusion of 1 or more carpals and tarsals, fusion of proximal sesamoids, 1 distal sesamoid, and fusion of paired phalanges. Evidence of a genetic cause consisted of 11 syndactylous calves among 70 offspring of 4 3/4 sib families, 8 preterm syndactylous fetuses among 148 preterm fetuses and 13 calves in progenies of 19 animals tested for possible heterozygosity, and 5 syndactylous calves from matings of an Angus syndactylous bull with 1 Angus and 4 Holstein syndactylous cows. Data were consistent with recessive inheritance at a single locus. Angus cattle with sydactytly had a larger number of affected limbs than did syndactylous Holsteins and their Angus crosses, suggesting existence of 2 recessive alleles. The allele of Holsteins (syH) appeared to influence phenotypic expression in a dominant pattern over the Angus allele (syA). Both syA and syH alleles acted as recessives to the normal SY allele. Phenotypic effects on limb development were most dramatic in calves with the syA/syA genotype.

Protective effects of cruciferous seed meals and hulls against colon cancer in mice.

Protective effects of diets containing cruciferous seed meals or hulls against chemically-induced colon tumors were examined in male CF1 mice. When commercial crambe meal, autolyzed crambe meal, crambe hulls, high glucosinolate rapeseed meal, or canola meal were fed as 12% of the diets of mice injected with 1,2-dimethylhydrazine, 25-80% of the animals developed colon tumors. Animals fed a soybean meal control diet had a 100% tumor rate. Data suggest that cruciferous seed meals may contain a number of compounds that can exert protective effects against tumor formation and growth.

Synthesis and evaluation of compounds that facilitate the gastrointestinal absorption of heparin.

A family of novel compounds (delivery agents) that promote the gastrointestinal absorption of USP heparin in rats and primates has been discovered. The delivery agents in combination with heparin were administered either orally or intracolonically in an aqueous propylene glycol solution and caused dramatic increases in both plasma heparin concentrations (anti-Factor Xa) and clotting times (APTT). Using one of the most effective delivery agents in this series, an estimated relative bioavailability of 8% can be achieved following oral administration to cynomolgus monkeys. To establish a correlation between the in vivo data and an in vitro parameter, immobilized artificial membrane (IAM) chromatography was performed. Log relative k' values were correlated to the efficiency of oral heparin delivery.

An ovarian teratoma in a cat.

A 5-month-old, intact female, domestic shorthaired cat was presented for evaluation of abdominal distension. Abdominal radiographs revealed a midabdominal mass that contained multiple, irregular, mineralized opacities. The mass was surgically removed, and an ovariohysterectomy performed. The mass was located at the tip of the left uterine horn and was covered partially by haired skin. Histologically, the mass was diagnosed as a mature ovarian teratoma based on the presence of well-differentiated somatic structures derived from three primary embryonal germ-cell layers. Germ-cell tumor classification and feline ovarian teratomas are reviewed.

Heparin absorption across the intestine: effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate in rat in situ intestinal instillations and in Caco-2 monolayers.

PURPOSE: The effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) on heparin intestinal absorption were studied using rat in situ ileal and colonic instillations and Caco-2 monolayers. METHODS: The flux of heparin was tested in the following groups: i) heparin alone, ii) heparin in the presence of SNAC, iii) heparin in the presence of propylene glycol (PG), and iv) heparin in the presence of SNAC and PG. Heparin absorption was measured by the APTT assay in the in situ models and by the anti-Factor Xa assay in Caco-2. SNAC and [3H]-SNAC fluxes were assessed by HPLC and by scintillation counting respectively. RESULTS: In the rat ileal and colonic in situ instillations SNAC (17-35 mg) promoted heparin absorption in the presence and absence of PG without damaging the tissue. PG alone did not alter heparin absorption in situ, but it amplified the effect of SNAC. In Caco-2, enhanced heparin fluxes were variable in the presence of non-cytotoxic concentrations of SNAC (< 10 mg/ml) and these effects could not be discriminated from those of PG. Papp values for SNAC alone were 2.2 x 10(-5) cm/s and 2.0 x 10(-5) cm/s in the mucosal-to-serosal and serosal-to-mucosal directions respectively, suggesting a substantial passive transcellular flux. Transport of SNAC was significantly reduced in the presence of heparin and/or PG, perhaps indicating physical association between the agents. CONCLUSIONS: SNAC augmented heparin absorption alone and in combination with PG in the rat in situ models without causing toxicity. Caco-2 had limitations for testing increased heparin absorption due to cytotoxic effects of high concentrations of SNAC and PG. However, SNAC itself was well absorbed across Caco-2 and its mechanism of permeation was determined.

Oral delivery of sodium cromolyn: preliminary studies in vivo and in vitro.

PURPOSE: Herein we report the discovery of a group of derivatized alpha-amino acids that increase the oral bioavailability of sodium cromolyn. METHODS: We prepared three N-acylated alpha-amino acids and used these compounds to demonstrate the oral delivery of cromolyn in an in vivo rat model. In vitro experiments, including permeation studies and near infrared spectroscopy, were also performed to initiate an understanding of the mechanism by which these compounds facilitate cromolyn oral delivery. RESULTS: Following oral administration to rats of solutions containing a combination of cromolyn and the delivery agent, significant systemic plasma concentrations of the drug were detected. In vitro studies suggest that absorption of the drug across the gastrointestinal membrane is a passive process. CONCLUSION: The absolute oral bioavailability of sodium cromolyn in the rat model is estimated to be approximately 5%. Preliminary mechanistic studies suggest that a complex of the cromolyn/delivery agent facilitates permeation across/through the membrane.

Gross and light-microscopic features of ovine pulmonary hydatidosis and verminous pneumonias in Morocco.

Verminous pneumonias appear to be common in sheep in Morocco, therefore, a systematic study was undertaken to classify the pulmonary changes induced by various parasites in Morocco. A total of 613 pairs of lungs with parasitic pneumonias were diagnosed in 1152 young and adult sheep either slaughtered at two abattoirs in Morocco (487 out of 1152 sheep) or received at necropsy services (126 out of 1152 sheep) over a 15-month period. Based on gross and microscopic findings, four types of pulmonary changes were classified. Included were those associated with: 1. The larvae of Taenia echinococcus (Echinococcus granulosus (canine tapeworm); 520 out of 613 lungs (84.8%)); 2. Muellerius capillaris (450 out of 613 lungs (79.9%)); 3. Protostrongylus rufescens (375 out of 613 lungs (61.1%)); and 4. Dictyocaulus filaria (285 out of 613 lungs (46.4%)). Mixed infestations, involving the presence of two, three, or four species of parasites in the same lung, were encountered in 325 out of 613 (53%) lungs studied. Red-to-brownish consolidated areas, confined to the cranial parts of the lung, were observed frequently in some lungs affected with M. capillaris and P. rufescens. In most of the lungs, co-existent emphysematous, atelectatic, and abscessed areas were seen.

N-acylated alpha-amino acids as novel oral delivery agents for proteins.

A series of N-acylated alpha-amino acids were synthesized and shown to improve the oral delivery of two protein drugs, salmon calcitonin (sCT) and interferon-alpha. Forty-five compounds in this series were tested in vivo in rats and primates. A significant positive correlation was found between the log P of the acylated amino acids and the decrease in serum calcium following oral dosage of sCT in rats. Such a correlation was not found for interferon-alpha. These derivatized amino acids only weakly inhibited the activity of trypsin or leucine aminopeptidase. Histological examinations of rat intestinal tissue after oral dosing of acylated amino acid/protein combinations revealed no detectable pathology.

Septicemic salmonellosis in two llamas.

At necropsy, Salmonella choleraesuis var kunzendorf was recovered from the lungs of a 6-year-old female llama that died within a few days of onset of illness. The llama had had fence-line contact with 40 sows at a farm. Salmonella typhimurium was isolated from a blood sample of a 6-day-old male cria that also died after a short illness.