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Pancreatic anastomotic leakage remains a persistent problem after pancreaticoduodenectomy (PD), especially in the presence of a soft, nonfibrotic pancreas. A modified technique for pancreatogastrostomy was devised, which combines one binding purse-string and two transfixing mattress sutures between the pancreatic stump and the posterior gastric wall. This technique was applied in 35 patients after PD for malignant and benign diseases of whom 10 (28.6%) had a soft pancreas. Median time for the anastomosis was 18 minutes. Operative mortality was zero, and morbidity was 34.3%. Three (8.6%) patients developed a pancreatic fistula (2 type A, 1 type B) as classified according to the International Study Group on pancreatic fistula. All fistulas resolved without further intervention. The described technique is a simple and safe reconstruction procedure after PD that warrants further evaluation. [ABSTRACT FROM AUTHOR]

In view of evidence in animals that enterohepatic recirculation of non- steroidal anti-inflammatory drugs contributes to small intestinal mucosal damage we have investigated the extent of biliary elimination of three nonsteroidals. Ibuprofen (n = 3), diclofenac (n = 2) and indomethacin (n = 3) were given to six patients with a percutaneous transhepatic cholangiodrainage placed in the bile duct system. One patient received all three drugs. The mean biliary elimination of ibuprofen was 0.82% of the given dose compared with 50.41% urinary excretion. When diclofenac or indomethacin was administered 4.62% and 6.40% of the dose were found in bile, whereas 34.73% and 32.22% (means) were recovered from urine, respectively. The mean percentage eliminated in bile as unchanged drug and active phase II metabolites was 0.15% for ibuprofen, 1.09% for diclofenac and 5.02% for indomethacin. [ABSTRACT FROM AUTHOR]

Abstract Background The SNF3 gene in the yeast Saccharomyces cerevisiae encodes a low glucose sensor that regulates expression of an important subset of the hexose transporter (HXT) superfamily. Null mutations of snf3 result in a defect in growth on low glucose concentrations due to the inability to relieve repression of a subset of the HXT genes. The snf3 null mutation phenotype is suppressed by the loss of either one of the downstream co-repressor proteins Rgt1p or Mth1p. The relief of repression allows expression of HXT transporter proteins, the resumption of glucose uptake and therefore of growth in the absence of a functional Snf3 sensor. Results Strains heterozygous for both the RGT1 and MTH1 genes (RGT1/rgt1Δ MTH1/mth1Δ snf3Δ/snf3Δ) but homozygous for the snf3∆ were found to grow on low glucose. Since null alleles in the heterozygous state lead to suppression, MTH1 and RGT1 display the phenomenon of combined haploinsufficiency. This observed haploinsufficiency is consistent with the finding of repressor titration as a mechanism of suppression of snf3. Mutants of the STD1 homolog of MTH1 did not display haploinsufficiency singly or in combination with mutations in RGT1. HXT gene reporter fusion assays indicated that the presence of heterozygosity at the MTH1 and RGT1 alleles leads to increased expression of the HXT2 gene. Deletion of the HXT2 gene in a heterozygous diploid, RGT1/rgt1Δ MTH1/mth1Δ snf3Δ/snf3Δ hxt2Δ/hxt2Δ, prevented the suppression of snf3Δ. Conclusions These findings support the model of relief of repression as the mechanism of restoration of growth on low glucose concentrations in the absence of functional Snf3p. Further, the observation that HXT2 is the gene responsible for restoration of growth under these conditions suggests that the numbers of repressor binding domains found in the regulatory regions of members of the HXT family may have biological relevance and enable differential regulation.

Background/aims: Pancreatic head resection is performed with low mortality, but morbidity remains high. Extensive preparation, long operating times, intraoperative blood loss and the need for blood transfusions are risk factors for postoperative morbidity. The aim of our study was to evaluate the feasibility and safety of the ultrasonic dissection device in pylorus-preserving duodenopancreatectomy (PPPD)., Methods: Fifty consecutive patients who underwent PPPD with an ultrasonic dissection device (group 1) were compared with a match-controlled group of 50 consecutive patients who underwent PPPD with conventional dissection techniques (group 2). Duration of surgery, intraoperative blood loss, blood units, complications, mortality and duration of hospital stay were analyzed., Results: There was no difference in age, gender or BMI between groups. In group 1, mean blood loss (446 ± 281.8 ml, p = 0.008) and number of blood units (0.32 ± 0.86, p = 0.001) were significantly lower than in group 2 (819 ± 915.4 ml; 1.36 ± 2.83 units). Duration of surgery was shorter in group 1 (345.6 vs. 373 min, p = 0.28). The rate of postoperative complications, mortality and hospital stay were not significantly different., Conclusions: Use of an ultrasonic dissection device in PPPD might significantly reduce intraoperative blood loss and the need for blood transfusions. These results should be verified in a prospective randomized controlled trial., (Copyright © 2012 S. Karger AG, Basel.)

Background: Postoperative pancreatic fistula (PF) is still regarded as a major complication in pancreatic surgery. In the present study, we evaluated the risk of PF in a large study population of patients with neuroendocrine pancreatic tumors (NPT), pancreatic cancer (PC), and chronic pancreatitis (CP)., Methods: Patients who underwent pancreatic surgery between 1989 and 2008 at our institution were retrospectively evaluated. Patients were analyzed regarding age, gender, BMI, alcohol, smoking, preoperative diabetes, reason for operation, operative procedure, and PF. Three different grades of PF (grades A, B, C) were defined., Results: 133 patients with NPT, 212 patients with PC, 52 patients with CP, and 76 patients with other reasons were evaluated. Patients with a NPT had a significant higher risk of developing a PF than patients with PC, CP, or other reasons (p = 0.0001). Enucleation of the tumor was associated with the highest rate of PF (p = 0.001). In a multivariate analysis, BMI >26, and preoperative diabetes were associated with a higher rate of PF (p = 0.042 and p = 0.02, respectively)., Conclusion: We demonstrated that after excluding factors like different definitions of PF, or different peri- or postoperative management, patients with NPT have a significantly higher risk of postoperative PF than patients with other pancreatic diseases., (Copyright © 2011 S. Karger AG, Basel.)

A vineyard isolate of the yeast Saccharomyces cerevisiae, UCD932, was identified as a strain producing little or no detectable hydrogen sulfide during wine fermentation. Genetic analysis revealed that this trait segregated as a single genetic determinant. The gene also conferred a white colony phenotype on BiGGY agar (bismuth-glucose-glycine-yeast agar), which is thought to indicate low basal levels of sulfite reductase activity. However, this isolate does not display a requirement for S-containing amino acids, indicating that the sulfate reduction pathway is fully operational. Genetic crosses against known mutations conferring white colony color on BiGGY agar identified the gene leading to reduced H(2)S formation as an allele of MET10 (MET10-932), which encodes a catalytic subunit of sulfite reductase. Sequence analysis of MET10-932 revealed several corresponding amino acid differences in relation to laboratory strain S288C. Allele differences for other genes of the sulfate reduction pathway were also detected in UCD932. The MET10 allele of UCD932 was found to be unique in comparison to the sequences of several other vineyard isolates with differing levels of production of H(2)S. Replacing the MET10 allele of high-H(2)S-producing strains with MET10-932 prevented H(2)S formation by those strains. A single mutative change, corresponding to T662K, in MET10-932 resulted in a loss of H(2)S production. The role of site 662 in sulfide reduction was further analyzed by changing the encoded amino acid at this position. A change back to threonine or to the conservative serine fully restored the H(2)S formation conferred by this allele. In addition to T662K, arginine, tryptophan, and glutamic acid substitutions similarly reduced sulfide formation.

Processive versus distributive methyl group transfer was assessed for pea Rubisco large subunit methyltransferase, a SET domain protein lysine methyltransferase catalyzing the formation of trimethyllysine-14 in the large subunit of Rubisco. Catalytically competent complexes between an immobilized form of des(methyl) Rubisco and Rubisco large subunit methyltransferase were used to demonstrate enzyme release that was co-incident with and dependent on formation of trimethyllysine. Catalytic rate constants determined for formation of trimethyllysine were considerably lower ( approximately 10-fold) than rate constants determined for total radiolabel incorporation from [3H-methyl]-S-adenosylmethionine. Double-reciprocal velocity plots under catalytic conditions favoring monomethyllysine indicated a random or ordered reaction mechanism, while conditions favoring trimethyllysine suggested a hybrid ping-pong mechanism. These results were compared with double-reciprocal velocity plots and product analyses obtained for HsSET7/9 (a monomethyltransferase) and SpCLR4 (a dimethyltransferase) and suggest a predictive ability of double-reciprocal velocity plots for single versus multiple methyl group transfers by SET domain protein lysine methyltransferases. A model is proposed for SET domain protein lysine methyltransferases in which initial binding of polypeptide substrate and S-adenosylmethionine is random, with polypeptide binding followed by deprotonation of the epsilon-amine of the target lysyl residue and subsequent methylation. Following methyl group transfer, S-adenosylhomocysteine and monomethylated polypeptide dissociate from monomethyltransferases, but di- and trimethyltransferases begin a successive and catalytically obligatory deprotonation of enzyme-bound methylated lysyl intermediates, which along with binding and release of S-adenosylmethionine and S-adenosylhomocysteine is manifested as a hybrid ping-pong-like reaction mechanism.

The disposition of a chemical delivery system for estradiol (E2-CDS) which is based on a redox dihydropyridine-pyridinium salt conversion was investigated in rats. Tissue and plasma concentrations of E2-CDS and the oxidized metabolite (E2-Q+) were evaluated at times ranging from 1 to 14 days after intravenous administration of E2-CDS formulated as a modified cyclodextrin inclusion complex. While E2-CDS levels were below HPLC assay detection limits for all samples by 1 day postdosing, E2-Q+ was readily quantified. The calculated half-life of E2-Q+ was longest in brain tissue, significantly shorter in heart, lung, and kidney tissues, and shortest in plasma. There was a linear relationship between administered E2-CDS dose and oxidized metabolite measured in brain as well as in other tissues collected 24 hr after drug administration. Coadministration of high doses of a similarly oxidizable dihydropyridine, 1-methyl-1,4-dihydronicotinamide (NMN), in a dimethylsulfoxide (DMSO) vehicle decreased E2-Q+ measured in brain and other tissues without significantly affecting the relative patterns of distribution in these tissues. Brain tissue E2Q+ levels were not detected after dosing with the oxidized metabolite.

We investigated the effects of sodium salicylate on the elimination kinetics of indomethacin in bile duct-cannulated beagles. Indomethacin and metabolites were quantified by HPLC in plasma, bile, and urine. Indomethacin was administered as iv bolus injection and iv infusion to yield a steady-state plasma concentration of approximately 1 microgram/ml. Following sodium salicylate, given either iv (25 mg/kg) or via duodenal fistula (50 mg/kg), the indomethacin plasma level dropped instantaneously by 60-70%. Concomitantly, total systemic clearance from the plasma and biliary clearance were increased significantly. In addition, a reduced plasma protein binding of indomethacin and a significant increase in the volume of distribution were observed. The amount of indomethacin, excreted as free and conjugated drug in bile, was significantly increased temporarily by sodium salicylate. The total amount eliminated in bile (approximately 70% of the dose), however, was not changed by sodium salicylate co-administration. The bile flow was significantly enhanced for at least 4 hr. Both phase 1 metabolism and renal excretion of indomethacin remained practically unaffected by sodium salicylate treatment.

The pharmacokinetics of a dihydropyridine-pyridinium salt-type chemical delivery system (CDS) for brain-targeted delivery of estradiol (E2) were examined in dogs. Parameters evaluated in vitro included stability in buffers and biological fluids and plasma protein binding. In vivo studies examined drug and metabolite concentrations in plasma, urine, and cerebrospinal fluid as well as in selected brain regions. The administered lipophilic E2-CDS disappeared very quickly from plasma and was not detected in urine. The oxidized drug form, E2-Q+, was excreted unchanged or as a conjugate in the urine for as long as 2 weeks. Plasma levels were below assay detection limits at later times. Pharmacokinetic analysis of urine E2-Q+ levels allowed estimation of a half-life of 2.2 days. Amounts of E2-Q+ excreted into the urine were proportional to the dose but averaged only 13.9% of the dose, indicating that other routes of excretion must be considered. CSF levels were below the limit of detection for both E2-CDS and E2-Q+, however, brain tissue concentrations of E2-Q+ were similar in several brain regions of individual animals examined 1 or 3 days after drug dosing.

The biliary and urinary excretion of ibuprofen and its metabolites were determined in rats after intravenous and peroral administration of 25 and 100 mg/kg of the drug. Within 24 hours 48% of the low i.v. dose and 59% of the high i.v. dose were eliminated via bile as ibuprofen and its metabolites. Following oral administration 40 to 41% of the dose were recovered in bile, whereas 16 to 32% of the dose were eliminated in urine, resulting in an overall drug recovery of 66 to 79% within 24 hours. Upon infusion of bile containing ibuprofen and its metabolites into the duodenum substantial enterohepatic cycling of the drug occurred in the rat.

The mediastinoscopy is a routine method in cases with suspect changes of the mediastinum. The instruments for endolaryngeal microsurgery (KLEINSASSER) are usefully in this examinations. With this method no complications were observed in 50 patients.

2908 persons were investigated by mass chest x-ray combined with mass x-ray of the paranasal sinuses to find respiratory tract diseases. In 412 persons a sinusitis was diagnosed. 212 persons had a positive history, that is headache, cough and/or bronchial secretions, the other 200 persons had a negative history. 91 persons with a negative history and 21 persons with apositive history showed spontaneous remissions. The results of the bacteriological tests and antibiogramms corresponded with the preceding reports. In the investigated population groups a high percentage of new undetected cases of sinusitis was found one year after their previous treatment needing a new treatment. The frequency of undetected sinusitis in adults is often underestimated. Mass chest x-ray examinations should be combined with x-ray examinations of the paranasal sinuses.

Radiographs of the mastoids and the petrous pyramids of ear-healthy adults were investigated to ascertain the normal appearance of the temporal bone pneumatisation. The radiographs included those of patients with skull trauma, provided that these subjects had had no signs or symptoms of middle ear disease or hearing loss before the trauma. The extent of pneumatisation of the mastoid and petrous pyramid ranged from small cell groups around the mastoid antrum to extensive cell formations in the squamous temporal bone, in the apex of the petrous pyramid and in the retrosinus area. The planimetric measurements did not correspond to a normal distribution. It was also striking that ears could be found among these healthy individuals with irregular, asymmetric or indistinct pneumatisation, probably as a residual of sub-clinical middle ear disorders during the development of the cell system. After eliminating these irregular findings the ears with exclusively regular, symmetric and clear cell pictures also did not follow a normal distribution. Rather, they resulted in a typical curve with a steep ascent rising from a functionally-necessary minimum of about 4 cm2 to mean values of 8-12 cm2, and then a wide distribution reaching a value of 26 cm2. All these can be taken as genetically-determined "normal variants". The irregular cell-formations were seen mainly in the smaller pneumatised mastoids, so that it can be concluded that exogenous influences have at some time disturbed the pneumatisation process.(ABSTRACT TRUNCATED AT 250 WORDS)

According to results obtained on the topographical studies of the anatomy of the recessus aorticus pericardii the authors stress the possibility of the vulnerability of the pericard due to mediastinoscopy, since its retroaortal fold reaches up to the truncus brachio-cephalicus and its broad-assertion up to the a. pulmonalis.

The pharmacokinetic properties of ibuprofen p.o. given either as a lysine salt or as acid to eight young, healthy male volunteers was investigated. Ibuprofen lysinate, administered after overnight fasting, produced peak plasma concentrations significantly earlier and higher than ibuprofen acid. A similar difference was observed when the drugs were given following a standardized breakfast. Under these conditions the lat-time was significantly shorter for the lysine salt than for the acid. The pharmacokinetic differences are likely to result from the faster dissolution rate of ibuprofen lysinate. They indicate that the administration of ibuprofen as lysine salt before meals may be advantageous if rapid and reliable onset of pain relief is required.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their gastrotoxic and duodenotoxic effects. A few years ago the introduction of a sustained release form of indomethacin led to an apparently high incidence of jejunal and ileal perforations. Recently, Langman in England was able to demonstrate that the intake of some NSAIDs is related to an enhanced incidence of ileal and jejunal perforations in rats and dogs, even after parenteral or rectal administration. We have been able to show that: 1. There is a correlation between biliary excretion of NSAIDs or ester conjugates of these drugs and ileal perforations in rats. 2. In contrast to dogs there is no (ibuprofen) or little enterohepatic circulation (diclofenac and diflunisal) in man. This agrees with the low incidence of ileal and jejunal ulcers reported with these drugs in contrast to indomethacin or piroxicam. 3. Reduction of enterohepatic circulation of indomethacin in rats by dietary means reduces the degree of small intestinal erosions and ulcerations in parallel with the reduced biliary excretion of the drug. It may be safely assumed that the enterohepatic circulation of some NSAIDs, particularly indomethacin and piroxicam, may contribute to the reported incidence of ileal and jejunal damage caused by these drugs. These drugs may, on the other hand, have clear-cut advantages as well.