Mortality and complications after percutaneous endoscopic gastrostomy: a retrospective multicentre study.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is the method of choice for patients in need of long-term nutritional support or gastric decompression. Although it is considered safe, complications and relatively high mortality rates have been reported. We aimed to identify risk factors for complications and mortality after PEG in routine healthcare. METHODS: This retrospective study included all adult patients who received a PEG between 2013 and 2019 in Region Norrbotten, Sweden. RESULTS: 389 patients were included. The median age was 72 years, 176 (45%) were women and 281 (72%) patients received their PEG due to neurological disease. All-cause mortality was 15% at 30 days and 28% at 90 days. Malignancy as the indication for PEG was associated with increased mortality at 90 days (OR 4.41, 95% CI 2.20-8.88). Other factors significantly associated with increased mortality were older age, female sex, diabetes mellitus, heart failure, lower body mass index and higher C-reactive protein levels. Minor and major complications within 30 days occurred in 11% and 15% of the patients, respectively. Diabetes increased the risk of minor complications (OR 2.61, 95% CI 1.04-6.55), while those aged 75 + years were at an increased risk of major complications, compared to those younger than 65 years (OR 2.23, 95% CI 1.02-4.85). CONCLUSIONS: The increased risk of death among women and patients with malignancy indicate that these patients could benefit from earlier referral for PEG. Additionally, we found that age, diabetes, heart failure, C-reactive protein and body mass index all impact the risk of adverse outcomes.

Trisodium phosphonoformate, a new antiviral compound.

Trisodium phosphonoformate selectively inhibits cell-free DNA polymerase activity induced by herpesvirus. The new inhibitor has an antiviral effect on herpes simplex virus types 1 and 2, pseudorables virus, and infectious bovine rhinotracheitis virus in cell culture. It has a good therapeutic activity against cutaneous herpes simplex virus infection in guinea pigs.

Conjunctival polyploid cells and donor-derived myofibroblasts in ocular GvHD.

After allogeneic hematopoietic stem cell transplantation (allo-SCT), ocular GvHD is a common complication, typical symptoms being dry eye syndrome with features of fibrosis. In this study, we have identified and quantified two cell types-myofibroblasts (MFB) and polyploid (PP) cells-in the conjunctival surface of allo-SCT patients (pts) and have explored their kinetics and association with local and systemic GvHD. Results are compared with control groups of (a) pretransplant samples from allo-SCT patients, (b) recipients of autologous transplantation (auto-SCT) and (c) healthy controls. Imprint cytologies were obtained by pressing the conjunctival surface with a sterile, non-abrasive cellulose acetate filter (Millipore). After retraction, typically a monolayer of the outermost cells of the epithelium were retrieved. MFB were identified by immunofluorescent (IF) staining for alpha-smooth muscle protein. PP cells were detected by aberrant chromosome content analyzed via X/Y-FISH (X/Y fluorescence in situ hybridization). In female pts with a male donor (MF group), donor genotype were identified by sex chromosome detection using FISH methodology. IF and FISH methods were applied in situ on the same filter, and amounts of MFB and PP cells are expressed as the percentage of all cells on the filter. In all, 70 samples from 46 pts were obtained 1-122 months after allo-SCT. The total MFB density (MFB(TOT)) was higher in allo-SCT pts compared with healthy individuals and auto-SCT pts and increased by time after transplantation (P<0.001). In MF recipients, this increase proved to be due to a significant (P<0.001) and gradual elevation of donor-derived MFB (MFB(XY)), whereas recipient-derived MFB (MFB(XX)) did not vary over time. Clinical ocular GvHD correlated with MFB(XY)/MFB(TOT) ratio (P=0.034), whereas no association between MFB(TOT) or MFB(XY) systemic GvHD was observed. In the MF group (n=25), both MFB(XY) and MFB(XX) were detected on 28 of the 37 imprints (76%). In pts >36 months post transplant, on 11/12 imprints, a median of 9.4% (1.4-39%) MFB(XY) and 3.6% (0-11%) MFB(XX) was found. In one patient, 1.6% MFB(XY) were detected at 3 weeks post transplant. PP cells (6-24n), exclusively of recipient origin, were found to a median of 0.6% (0-37%). The PP cell density differed significantly (P<0.001) between time intervals, with a maximum 8.9% (0-35%) of all cells at 3-12 months. No correlation between PP cells and GvHD (ocular or systemic) was observed. The MFB has been indicated as a culprit in chronic inflammation and fibrosis. The observation that MFB(XY)/MFB(TOT) ratio correlated with ocular GvHD suggests a role of donor MFB in GvHD pathogenesis. The constant finding of recipient-derived MFB(XX) cells many years after transplant in pts with 100% donor hematopoiesis indicates that there is a non-hematopoietic differentiation route to MFB. The origin and role of PP cells after allo-SCT remains obscure.

Effects of foscarnet on the cell kinetics of Madin-Darby canine kidney cells.

The antiherpes compound, foscarnet (trisodium phosphonoformate), showed concentration-dependent effects on the cell kinetics of Madin-Darby canine kidney cells. At 1 mM, only minor effects could be seen on cell proliferation and cell cycle distribution, as measured by flow cytometry DNA analysis. Treatment with 5 mM foscarnet resulted in an accumulation of cells in the S-phase although no complete cell cycle block was evident. At 10 mM foscarnet, cells accumulated earlier in the S phase, probably at the G1/S border. However, at both 5 and 10 mM foscarnet the block was not established until after 15 h incubation. Upon removing 10 mM foscarnet after 24 h incubation, G1 cells rapidly entered the S phase, whereas the progression through S and G2 + M was delayed considerably. The DNA synthesizing S phase seems, therefore, to be the main cell cycle phase affected by foscarnet.

Precipitation of nucleotides by calcium phosphate.

Earlier it has been shown that nucleic acids of high molecular weight can be be introduced into cells by coprecipitation with calcium phosphate. We have studied the requirements for calcium phosphate coprecipitation of shorter nucleotides. The degree of coprecipitation of dodecanucleotides lacking terminal phosphate varied between 25 and 72%. Tetramers with a 5'-monophosphate were coprecipitated to 29-87% by calcium phosphate. A high content of guanosine residues and an increased number of terminal phosphate groups increased the degree of coprecipitation of nucleotides. The trinucleotide pppA2'p5'A2'p5'A was effectively precipitated by calcium phosphate but the monophosphate and the core structure were not.

Three-dimensional structures of glycolate oxidase with bound active-site inhibitors.

A key step in plant photorespiration, the oxidation of glycolate to glyoxylate, is carried out by the peroxisomal flavoprotein glycolate oxidase (EC 1.1.3.15). The three-dimensional structure of this alpha/beta barrel protein has been refined to 2 A resolution (Lindqvist Y. 1989. J Mol Biol 209:151-166). FMN dependent glycolate oxidase is a member of the family of alpha-hydroxy acid oxidases. Here we describe the crystallization and structure determination of two inhibitor complexes of the enzyme, TKP (3-Decyl-2,5-dioxo-4-hydroxy-3-pyrroline) and TACA (4-Carboxy-5-(1-pentyl)hexylsulfanyl-1,2,3-triazole). The structure of the TACA complex has been refined to 2.6 A resolution and the TKP complex, solved with molecular replacement, to 2.2 A resolution. The Rfree for the TACA and TKP complexes are 24.2 and 25.1%, respectively. The overall structures are very similar to the unliganded holoenzyme, but a closer examination of the active site reveals differences in the positioning of the flavin isoalloxazine ring and a displaced flexible loop in the TKP complex. The two inhibitors differ in binding mode and hydrophobic interactions, and these differences are reflected by the very different Ki values for the inhibitors, 16 nM for TACA and 4.8 microM for TKP. Implications of the structures of these enzyme-inhibitor complexes for the model for substrate binding and catalysis proposed from the holo-enzyme structure are discussed.

Incorporation into nucleic acids of the antiherpes guanosine analog buciclovir, and effects on DNA and protein synthesis.

Using cells expressing herpes simplex virus (HSV) thymidine kinase, we investigated the metabolism of the acyclic antiherpes guanosine analog buciclovir, in relation to the effects of the drug on viral DNA and protein synthesis. In these cells the predominant metabolite of buciclovir was its triphosphate, as in the HSV-1 infected Vero cells investigated in parallel. Further metabolism of buciclovir led to incorporation into RNA and DNA. Buciclovir inhibited DNA synthesis, not RNA synthesis, and prevented an increase in the size of newly synthesized DNA. To study the relative effects of BCV on cellular and viral DNA synthesis, human TK-cells transformed to a TK+ phenotype with HSV-2 DNA, were infected with HSV-1. In these HSV-1 infected cells buciclovir-triphosphate caused a preferential inhibition of viral DNA synthesis. Despite incorporation of buciclovir into RNA, and the presence of buciclovir-triphosphate from the time of infection onwards, no effect was observed on the synthesis of the beta proteins ICP-6 and ICP-8. Presumably as a consequence of inhibition of viral DNA synthesis, the synthesis of a beta gamma protein (gD) and a gamma protein (gC) were inhibited, and synthesis of the beta proteins (ICP-6 and ICP-8) was not shut-off. Glycosylation of gC that was still synthesized, was not inhibited. Thus, the biological effects of buciclovir can be explained by its inhibition of DNA synthesis.

Immune response in chlamydial conjunctivitis among neonates and adults with special reference to tear IgA.

Tear and serum samples from 128 neonates and 122 adults with conjunctivitis were examined for antibodies to Chlamydia trachomatis with a micro-immunofluorescence (MIF) technique and the results compared to antigen detection by culture, enzyme immunoassay (EIA) (Chlamydiazyme, Abbott) and direct immunofluorescence (IF) (MicroTrak, Syva and Chlamyset, Orion) tests. From the 52 culture-positive adults, chlamydial IgA (titre greater than or equal to 1:8) antibodies were detected in 81% of the tear and in 62% of the serum samples, while 88% had such serum IgG antibodies (titre greater than or equal to 1:32). The persistence of chlamydial IgA in tears and sera was related to the duration of symptoms of conjunctivitis and the antibody titres declined after institution of antibiotic treatment. In the adults, the sensitivity of the MIF tear IgA antibody test (81%) was higher than that of the EIA (71%) and the IF (MicroTrak 71% and Chlamyset 62%) tests. The specificity for the MIF test was 79%, while it was 100% for the EIA and the two IF tests. Of the 67 chlamydia-infected neonates, 36% had chlamydial tear IgA antibodies, while such antibodies were only found in 15% of the sera. No neonates with chlamydia-negative conjunctivitis had chlamydial IgA antibodies. The MIF test may be used as a diagnostic method complementary to culture, EIA and IF tests in the diagnosis of chlamydial conjunctivitis in adults, but is not applicable in neonates.

Haemophilus influenzae causing conjunctivitis in day-care children.

The role of Haemophilus influenzae in acute purulent conjunctivitis was studied during an outbreak among children in day care. Five day-care centers contributed 20 cases and 35 controls. All the children were subjected to culture of the nasopharynx and the eyes. H. influenzae was carried in the nasopharynx of 53% of the children (range between day care centers, 20 to 91%). Of the 20 children with acute conjunctivitis 8 had eye cultures positive for H. influenzae, 2 had Moraxella and the remaining were culture-negative. Ten colonies of H. influenzae were isolated from each positive culture and identified by capsular type, biotype and multi-locus enzyme electrophoresis. All but one of the isolates were nonencapsulated. They belonged to 4 biotypes and 8 electrophoretic types. The same strain was recovered from the eyes and nasopharynx of the symptomatic children, suggesting that the H. influenzae in the eyes originated from the nasopharynx. There was no evidence for spread of the same H. influenzae strains between day-care centers. Even within each center the Haemophilus strains recovered from the eyes varied among the symptomatic children. The in vitro capacity to attach to oropharyngeal epithelial cells was not increased among the H. influenzae recovered from the eyes. The results question if the majority of conjunctivitis cases were caused by H. influenzae and suggested that eyes were colonized with the nasopharyngeal carrier strain rather than infected by an isolate with special virulence for the eye.

Culture, ELISA and immunofluorescence tests for the diagnosis of conjunctivitis caused by Chlamydia trachomatis in neonates and adults.

The relative value of culture, direct specimen antigen detection tests, i.e., enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) tests in the diagnosis of Chlamydia trachomatis infection was studied in 125 newborns and 121 adults with signs of conjunctivitis. Eye and nasopharyngeal samples were tested by culture using cycloheximide-treated or irradiated McCoy cells, ELISA (i.e., Chlamydiazyme, Abbott) and IF tests (i.e., Chlamyset, Orion and MicroTrak, Syva). Of the neonates, 70 (35 boys and 35 girls) and 54 (33 males and 21 females) of the adults were positive in one or both eyes in one or more tests: 191 (39%) in cultures, 173 (35%) in ELISA and 160 (33%), 176 (36%) in each of the IF tests. Using culture as standard reference, the sensitivities of ELISA and the IF tests were 88%, 81% and 87%, while the corresponding specificities were 99%, 98% and 97%, respectively. The predictive values for a negative test (PVN) were 93%, 89% and 92% and for a positive test (PVP) 98%, 96% and 94%. Of the 124 cases chlamydia-positive in the eyes, 67 (54%), 76 (61%), 64 (52%) and 70 (57%) were positive in nasopharyngeal samples in one or more of culture, ELISA and the two IF tests, respectively. The sensitivities of ELISA and the IF tests in nasopharyngeal samples were 87%, 78% and 81%, while the corresponding specificities were 90%, 93% and 91%, respectively. The predictive values for a negative (PVN) test were 95%, 92% and 93%, and for a positive test (PVP) 76%, 81%, and 77%. Nasopharyngeal swabs were more often positive in cases with 2 or more weeks' duration of symptoms than in those with shorter duration.

Critical determinants of antiherpes efficacy of buciclovir and related acyclic guanosine analogs.

Buciclovir is an example of an antiherpes, acyclic guanosine analog activated by the viral thymidine kinase and inhibiting viral DNA synthesis in infected cells. An investigation of closely related buciclovir-analogs with similar antiherpes activities in cell cultures and similar, or identical, modes of action but with disparate effects in vivo, revealed the following critical determinants of antiherpes efficacy. (1) The accumulation of guanosine analog-triphosphates in infected cells, which is cell-type-specific and analog-dependent. (2) The potencies of the triphosphates as inhibitors of the viral DNA polymerase. (3) The plasma kinetics of the analogs, which are widely different despite the similar structures. (4) The penetration into nervous tissue relative to penetration into non-nervous tissues, of importance in connection with the neurotropic behavior of the virus. (5) The concentration of the antagonist thymidine in certain tissues. (6) The difference in pathogenesis between primary infections and recurrent infections, exemplified in the different efficacies of topically applied drugs in cutaneous and genital HSV-2 infections in guinea pigs.

Toxic effects of some xanthine derivatives with special emphasis on adverse effects on rat testes.

Testicular toxicity and effects on thymus and body weights of 4 xanthine derivatives (D4026: 1,8-dimethyl-3-phenylxanthine, D4152: 8-methyl-3-phenylxanthine, D4160: 1,8-dimethyl-3-(2-methylbutyl)-xanthine, D4173: 8-methyl-3-(2-methylbutyl)-xanthine) were studied in Sprague-Dawley rats and cellular toxicity in human embryonal cells. The effect on toxicity by variation of substituent at positions 1 and 3 was tested. The compounds were administered orally to the rats once a day for 1 month. Mortalities were noted only with D4160. Dose related decreases in body weight gain were found for all substances, but only marginally with D4152. A significant decrease in thymus weight relative to control was observed with all substances, D4152 being the least potent. No effects on testes weights were found with any treatment but histological examination disclosed degeneration of germ producing epithelium of all rats given 100 mumol/kg of D4026 but not at 25 mumol/kg. One rat out of 5 showed testicular damage at 400 mumol/kg of D4173 or D4152. Plasma analysis for unchanged compounds showed significantly higher plasma concentrations at the high dose compared with the low dose with the exception for D4152 showing unexpectedly low levels. In the cellular toxicity test, D4160 was the most potent while D4152 was the least potent. D4026 had a steeper dose-response curve than the others but was less potent than D4160. The 1-methylated xanthine derivatives seemed to be more toxic than the two in position 1 unsubstituted analogues. Mechanisms for testicular toxicity of xanthine derivatives in the rat and clinical relevance of animal data are discussed.

Preliminary results from the Scandinavian multicentre evaluation of in vitro cytotoxicity (MEIC).

The multicentre evaluation study of in vitro cytotoxicity tests (MEIC) is organized by the Scandinavian Society of Cell Toxicology. All interested laboratories are invited to test a published list of 50 reference chemicals in their various in vitro assays with a bearing on general toxicity. Submitted results will be centrally evaluated for their relevance to human toxicity, including a comparison with the efficiency of conventional animal tests. This brief communication presents the very first preliminary results of the study, that is, prediction of human acute lethal toxicity for the first 10 MEIC chemicals by all the results submitted to date, that is, five in vitro cytotoxicity assays. As a baseline for judging the efficiency of the cytotoxicity tests, rat and mouse LD(50) values were compared with human acute lethal dosage of the chemicals. Rat LD(50) prediction was relatively poor, but mouse LD(50) values correctly predicted the human lethal dose for six out of the 10 substances. A multivariate method of comparison including all cytotoxicity test results, predicted human lethal blood concentrations as well as the mouse LD(50) prediction of dosage. Since the blood concentrations used in the comparison were derived from human lethal dosage with the help of two simple pharmacokinetic factors (absorbed fraction in the intestine and distribution volume of chemicals), the cytotoxicity assays were found also to be able to predict human dosage, as well as did the mouse LD(50) prediction.

Effect of lumbar sympathetic blockade and chlorpromazine-induced adrenergic alpha-receptor blockade on skin temperature in peripheral arterial diseases.

The post-cooling toe temperature changes after lumbar sympathetic blockade and after intramuscular administration of an adrenergic alpha-receptor blocking substance (chlorpromazine) were studied in 14 patients with impending gangrene because of peripheral arterial insufficiency. The post-cooling temperature rise was similar after sympathetic blockage and chlorpromazine administration and significantly different from the basal toe temperature changes after cooling. It is concluded that administration of an adrenergic alpha-receptor blocking substance is as good as the lumbar sympathetic blockage for evaluation of a remaining sympathetic vasomotor tone in arterial disease patients.

Recycling of process streams in ethanol production from softwoods based on enzymatic hydrolysis.

In ethanol production from lignocellulose by enzymatic hydrolysis and fermentation, it is desirable to minimize addition of fresh-water and waste-water streams, which leads to an accumulation of substances in the process. This study shows that the amount of fresh water used and the amount of waste water thereby produced in the production of fuel ethanol from softwood, can be reduced to a large extent by recycling of either the stillage stream or part of the liquid stream from the fermenter. A reduction in fresh-water demand of more than 50%, from 3 kg/kg dry raw material to 1.5 kg/kg dry raw material was obtained without any negative effects on either hydrolysis or fermentation. A further decrease in the amount of fresh water, to one-fourth of what was used without recycling of process streams, resulted in a considerable decrease in the ethanol productivity and a slight decrease in the ethanol yield.

Application of the Bayesian approach for derivation of PDFs for concentration ratio values.

Concentration ratios (CRs) are used to derive activity concentrations in wild plants and animals. Usually, compilations of CR values encompass a wide range of element-organism combinations, extracted from different studies with statistical information reported at varying degrees of detail. To produce a more robust estimation of distribution parameters, data from different studies are normally pooled using classical statistical methods. However, there is inherent subjectivity involved in pooling CR data in the sense that there is a tacit assumption that the CRs under any arbitrarily defined biota category belong to the same population. Here, Bayesian inference has been introduced as an alternative way of making estimates of distribution parameters of CRs. This approach, in contrast to classical methods, is more flexible and also allows us to define the various assumptions required, when combining data, in a more explicit manner. Taking selected data from the recently compiled wildlife transfer database (http://www.wildlifetransferdatabase.org/) as a working example, attempts are made to refine the pooling approaches previously used and to consider situations when empirical data are limited.