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Background: Ribavirin is associated with haemolytic anaemia. Antioxidants have been reported to decrease severity of this anaemia. Aim: To determine effect of vitamin E supplementation on ribavirin-associated haemolysis in chronic hepatitis C treated with standard α-interferon and ribavirin. Methods: Fifty-one naive chronic hepatitis C patients were randomized to receive either α-interferon/ribavirin therapy (control) or therapy plus vitamin E 800 IU b.d. with 24-week follow-up. Alanine aminotransferase ALT, haemoglobin and reticulocyte percentage were monitored. Symptoms and health-related quality of life were also monitored at each visit. Results: Forty-seven subjects were treated (27 vitamin E /20 controls). Thirteen withdrew because of adverse effects or non-compliance. Groups were similar in demographics, genotype and baseline lab indices. Comparison with baseline, treatment and follow-up values showed a significant haemoglobin and ALT reduction in both groups. There was no significant difference in haemoglobin and reticulocyte percentage between groups. Sustained viral response was not significantly different between vitamin E (11/18) and control (6/16) groups. Three patients required ribavirin dose-reduction in the vitamin E group compared with two controls. Health-related quality of life during and end-of-treatment was not different between groups. Conclusions: Vitamin E supplementation alone during standard α-interferon and ribavirin therapy does not appear to diminish ribavirin-associated haemolysis. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the number of supervised gastrointestinal endoscopic procedures required to achieve initial competency using a simple objective grading system.Design: Prospective, cross-sectional study.Setting: A gastroenterology and surgical training program at a large, university-affiliated county hospital.Participants: Seven gastroenterology fellows and five fourth-year surgery residents.Interventions: Trainees were graded postprocedure using a microcomputer program. Grading criteria for esophagogastroduodenoscopy included entering the esophagus (esophageal intubation), traversing the pylorus into the duodenum, and recognizing whether the upper gastrointestinal tract was abnormal. Criteria for colonoscopy were traversing the splenic flexure, intubating the cecum, and recognizing whether the colon was abnormal.Results: When presented with a case mix representative of practice, esophageal intubation did not reach 90% until more than 100 procedures had been done. Cecal intubation remained at only 84% after 100 procedures.Conclusions: More than 100 supervised upper gastrointestinal endoscopies or colonoscopies are necessary to achieve technical competence in gastrointestinal endoscopy. [ABSTRACT FROM AUTHOR]

T helper 1 (T H 1) cell identity is defined by the expression of the lineage-specifying transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated T H 1 cells based on their quantitative expression of T-bet and interferon-γ. Heterogeneous T-bet expression states were regulated by virus-induced type I interferons and were stably maintained even after secondary viral infection. Exposed to alternative differentiation signals, the sorted subpopulations exhibited graded levels of plasticity, particularly toward the T H 2 lineage: T-bet quantities were inversely correlated with the ability to express the T H 2 lineage-specifying transcription factor GATA-3 and T H 2 cytokines. Reprogramed T H 1 cells acquired graded mixed T H 1 + T H 2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated T H 1 cells was essential to ensure T H 1 cell stability. Thus, innate cytokine signals regulate T H 1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges.

Background: Mobile applications (apps) are a resource for information on lifestyle and nutrition which are associated to improved outcomes in inflammatory arthritis., Objective: The aim of this study was to explore whether targeted lifestyle counselling via an app improves disease activity in arthritis patients., Methods: Patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA) were randomized to 12 weeks of lifestyle counselling via an app (Mida, Midaia GmbH, Germany) pertaining to a healthy Mediterranean Diet, physical activity, and mental health. Disease activity was measured with specific instruments by a blinded physician and categorized (remission, low, moderate, high). Dietary adherence was assessed by the Mediterranean Diet Adherence Screener (MEDAS). Mixed effects logistic regression adjusted to baseline disease activity, age, and sex were calculated., Results: Of 158 patients included (73% female, 53.3 ± 11.7 years), 74 were in the active counselling group (ACG). All showed improvement in low disease activity or remission. ACG patients had an odds ratio (OR) of 2.8 (95%-CI 1.1-7.2, p = 0.035), while OR in the control group was not significant OR = 2.1 (0.9-5.0, p = 0.097). The control group was less likely to reach a MEDAS >= 4 (OR = 0.16 (0.03-0.77), p = 0.02), while this was not seen in the ACG (OR = 0.54 (0.06-4.63), p = 0.6). Patients in the ACG showed a tendency towards improved adhesion to a Mediterranean Diet (MEDAS) (β = 0.35 (-0.05-0.74), p = 0.086). This tendency was not observed in the control group (β = 0.09 (-0.29-0.46), p = 0.64)., Conclusions: Individualized lifestyle and dietary counselling via app may help to improve disease control in inflammatory arthritis patients.

Introduction: Recently, diet has received considerable attention as an important factor in inflammatory arthritis. The objective of this study was to evaluate disease activity and fatigue in patients with rheumatoid arthritis and spondyloarthritis (including psoriatic arthritis) depending on their dietary preferences., Material and Methods: We retrospectively evaluated data of 774 patients collected by the Mida Rheuma App from January 2022 to December 2022. We assessed demographic parameters, major dietary patterns, and food groups (dairy products, fruits, vegetables, processed meat, meat, oily fish, white fish, and sugar) by each patient's consumption intensity. Disease activity was measured by Routine Assessment of Patient Index Data 3 (RAPID3), Patient's Global Assessment of Disease Activity (PtGADA), and Patient's Global Assessment of Pain Intensity (PPAIN). Fatigue was assessed by the Brief Fatigue Inventory (BFI). Depending on the food group, patients were divided into a high-consumption group (HCG; consuming the product 0-2 times per day/per week) and a lowconsumption group (LCG; consuming the product 3 and more times per day/per week). Patients on a specific diet which they followed before inclusion in the analysis were compared with the "eat all group" (EAG)., Results: The Mediterranean diet group had significantly lower ( p < 0.05) RAPID3, PtGADA, and PPAIN (by 9.22%, 8.98%, and 14.3%, respectively), compared with the EAG. In the processed meat HCG, RAPID3, PtGADA, PPAIN, and BFI were significantly higher (14.5%, 18.3%, 16.1%, and 11.8%, p < 0.05) vs. the LCG. The PtGADA, PPAIN, and RAPID3 were significantly lower ( p < 0.05) in the oily fish HCG vs. the LCG (18.9%, 18.1%, and 10.6%)., Conclusions: Our study results suggest that Mediterranean diet and oily fish have a potentially positive impact on patient-reported disease activity and fatigue in patients with inflammatory arthritis. In contrast, processed meat consumption has a negative effect., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie.)

Serological assays measuring antibodies against SARS-CoV-2 are key to describe the epidemiology, pathobiology or induction of immunity after infection or vaccination. Of those, multiplex assays targeting multiple antigens are especially helpful as closely related coronaviruses or other antigens can be analysed simultaneously from small sample volumes, hereby shedding light on patterns in the immune response that would otherwise remain undetected. We established a bead-based 17-plex assay detecting antibodies targeting antigens from all coronaviruses pathogenic for humans: SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV strains 229E, OC43, HKU1, and NL63. The assay was validated against five commercial serological immunoassays, a commercial surrogate virus neutralisation test, and a virus neutralisation assay, all targeting SARS-CoV-2. It was found to be highly versatile as shown by antibody detection from both serum and dried blot spots and as shown in three case studies. First, we followed seroconversion for all four endemic HCoV strains and SARS-CoV-2 in an outbreak study in day-care centres for children. Second, we were able to link a more severe clinical course to a stronger IgG response with this 17-plex-assay, which was IgG1 and IgG3 dominated. Finally, our assay was able to discriminate recent from previous SARS-CoV-2 infections by calculating the IgG/IgM ratio on the N antigen targeting antibodies. In conclusion, due to the comprehensive method comparison, thorough validation, and the proven versatility, our multiplex assay is a valuable tool for studies on coronavirus serology., (© 2023. The Author(s).)

Purpose: COViK, a prospective hospital-based multicenter case-control study in Germany, aims to assess the effectiveness of COVID-19 vaccines against severe disease. Here, we report vaccine effectiveness (VE) against COVID-19-caused hospitalization and intensive care treatment during the Omicron wave., Methods: We analyzed data from 276 cases with COVID-19 and 494 control patients recruited in 13 hospitals from 1 December 2021 to 5 September 2022. We calculated crude and confounder-adjusted VE estimates., Results: 21% of cases (57/276) were not vaccinated, compared to 5% of controls (26/494; p < 0.001). Confounder-adjusted VE against COVID-19-caused hospitalization was 55.4% (95% CI: 12-78%), 81.5% (95% CI: 68-90%) and 95.6% (95%CI: 88-99%) after two, three and four vaccine doses, respectively. VE against hospitalization due to COVID-19 remained stable up to one year after three vaccine doses., Conclusion: Three vaccine doses remained highly effective in preventing severe disease and this protection was sustained; a fourth dose further increased protection., (© 2023. The Author(s).)

Background/purpose: While current guidelines recommend the use of respiratory tract specimens for the direct detection of SARS-CoV-2 infection, saliva has recently been suggested as preferred sample type for the sensitive detection of SARS-CoV-2 B.1.1.529 (Omicron). By comparing saliva collected using buccal swabs and oro-/nasopharyngeal swabs from patients hospitalized due to COVID-19, we aimed at identifying potential differences in virus detection sensitivity between these sample types., Methods: We compare the clinical diagnostic sensitivity of paired buccal swabs and combined oro-/nasopharyngeal swabs from hospitalized, symptomatic COVID-19 patients collected at median six days after symptom onset by real-time polymerase chain reaction (PCR) and antigen test., Results: Of the tested SARS-CoV-2 positive sample pairs, 55.8% were identified as SARS-CoV-2 Omicron BA.1 and 44.2% as Omicron BA.2. Real-time PCR from buccal swabs generated significantly higher quantification cycle (Cq) values compared to those from matched combined oro-/nasopharyngeal swabs and resulted in an increased number of false-negative PCR results. Reduced diagnostic sensitivity of buccal swabs by real-time PCR was observed already at day one after symptom onset. Similarly, antigen test detection rates were reduced in buccal swabs compared to combined oro-/nasopharyngeal swabs., Conclusion: Our results suggest reduced clinical diagnostic sensitivity of saliva collected using buccal swabs when compared to combined oro-/nasopharyngeal swabs in the detection of SARS-CoV-2 Omicron in symptomatic individuals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

We included 852 patients in a prospectively recruiting multicenter matched case-control study in Germany to assess vaccine effectiveness (VE) in preventing COVID-19-associated hospitalization during the Delta-variant dominance. The two-dose VE was 89 % (95 % CI 84-93 %) overall, 79 % in patients with more than two comorbidities and 77 % in adults aged 60-75 years. A third dose increased the VE to more than 93 % in all patient-subgroups., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S. G. received payment/honoraria from Astra Zeneca, Boehringer Ingelheim, Roche Pharma and Berlin Chemie, this had no influence on this work; all other authors reported no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

EULAR highlighted the essential role of digital health in increasing self-management and improving clinical outcomes in patients with arthritis. The objective of this study was to evaluate the efficacy and safety of the digital health application (DHA) in patients with inflammatory arthritis. We assessed demographic parameters, treatment regimen, disease activity, and other patient-reported outcomes at baseline and after 4 weeks of DHA use added to standard care treatment. Of 17 patients, who completed the study, 7 (41.2%) patients were male, ranging from 19 to 63 (40.5 ± 12.2) years. No significant change in antirheumatic treatment was observed during the study. Statistically significant improvements (p < 0.05) were noted for health-related quality of life (increase in Physical Component Summary of Short Form-36 (SF-36) by 23.6%) and disease activity (decrease of Clinical Disease Activity Index and Simple Disease Activity Index by 38.4% and 39.9%, respectively). Clinically significant improvement was demonstrated for SF-36 Total Score (+ 14.4%), disease activity (Rheumatoid Arthritis Disease Activity Index- 5 to 15.9%), and depression (Patient Health Questionnaire- 9 to 13.5%). None of the efficacy parameters showed negative trends. No adverse events were reported throughout the study. The usability level was high i.e., the mean mHealth Application Usability Questionnaire Score of 5.96 (max.: 7.0) demonstrated a high level of application usability. This suggests that using a personalized disease management program based on DHA significantly improves several measures of patient-reported outcomes and disease activity in patients with inflammatory arthritis in a timely manner. These findings highlight the potential of complementary digital therapy in patients with inflammatory arthritis., (© 2022. The Author(s).)

Vaccines against COVID-19 have been available in Germany since December 2020. At the Robert Koch Institute (RKI), the Immunization Unit is responsible for monitoring vaccination coverage and assessment of vaccine effectiveness. This article provides an overview of the respective reporting structures, vaccination databases, and epidemiological studies established by the Immunization Unit during the COVID-19 pandemic. We describe the COVID-19 Digital Vaccination Coverage Monitoring (DIM), which provides daily updates on vaccination coverage by age group. We next describe how, based on the DIM data and COVID-19 case data, the assessment of vaccine effectiveness against different clinical endpoints (hospitalization, intensive care, death) is performed. While this method is used for a preliminary estimate of vaccine efficacy, population-based nonrandomized studies are able to provide more precise and detailed estimates under "real-world" conditions. In this context, we describe the hospital-based case-control study COViK, which is being conducted in collaboration with the Paul Ehrlich Institute (PEI). We discuss strengths and limitations of the abovementioned structures and tools. Finally, we provide an outlook on future challenges that may arise during the ongoing pandemic and during the transition phase into an endemic situation., (© 2022. The Author(s).)

Selective differentiation of CD4+ T helper (Th) cells into specialized subsets such as Th1 and Th2 cells is a key element of the adaptive immune system driving appropriate immune responses. Besides those canonical Th-cell lineages, hybrid phenotypes such as Th1/2 cells arise in vivo , and their generation could be reproduced in vitro . While master-regulator transcription factors like T-bet for Th1 and GATA-3 for Th2 cells drive and maintain differentiation into the canonical lineages, the transcriptional architecture of hybrid phenotypes is less well understood. In particular, it has remained unclear whether a hybrid phenotype implies a mixture of the effects of several canonical lineages for each gene, or rather a bimodal behavior across genes. Th-cell differentiation is a dynamic process in which the regulatory factors are modulated over time, but longitudinal studies of Th-cell differentiation are sparse. Here, we present a dynamic transcriptome analysis following Th-cell differentiation into Th1, Th2, and Th1/2 hybrid cells at 3-h time intervals in the first hours after stimulation. We identified an early bifurcation point in gene expression programs, and we found that only a minority of ~20% of Th cell-specific genes showed mixed effects from both Th1 and Th2 cells on Th1/2 hybrid cells. While most genes followed either Th1- or Th2-cell gene expression, another fraction of ~20% of genes followed a Th1 and Th2 cell-independent transcriptional program associated with the transcription factors STAT1 and STAT4. Overall, our results emphasize the key role of high-resolution longitudinal data for the characterization of cellular phenotypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Burt, Peine, Peine, Borek, Serve, Floßdorf, Hegazy, Höfer, Löhning and Thurley.)

The aim of this study was to compare the effect on HCV RNA levels of using induction dosing with 5 MU interferon-alpha2b (IFN) given daily for four weeks followed by 5 MU IFN given three times a week (TIW) for 44 weeks vs standard noninduction TIW dosing of 5 MU IFN for 48 weeks. We randomly assigned 135 patients with chronic hepatitis C to induction therapy or noninduction therapy. After four weeks of therapy 17/65 (26.1%) patients had undetectable HCV viral levels in the induction group compared with 16/64 (25.0%) patients in the noninduction group. The mean HCV viral levels were similar at four weeks in patients who received induction and noninduction therapy. Mean HCV viral titers in the induction group increased from 4 to 16 weeks, whereas the mean viral titers in the noninduction group decreased during this time (P < 0.0001). HCV RNA was undetectable at the end of therapy in 17/66 (25.8%) in the induction group and 21/68 (30.9%) in the noninduction group. The sustained virologic response rate 24 weeks after the end of therapy was 14/67 (20.9%) in the induction group compared with 13/68 (19.1%) in the noninduction group. These results indicate that an initial four week period of daily interferon confers no benefit in the treatment of patients with chronic hepatitis C.

Transjugular intrahepatic portosystemic shunts (TIPS) may worsen liver function and decrease survival in some patients. The Child-Pugh classification has several drawbacks when used to determine survival in such patients. The survival of 231 patients at 4 medical centers within the United States who underwent elective TIPS was studied to develop statistical models to (1) predict patient survival and (2) identify those patients whose liver-related mortality post-TIPS would be 3 months or less. Among these elective TIPS patients, 173 had the procedure for prevention of variceal rebleeding and 58 for treatment of refractory ascites. Death related to liver disease occurred in 110 patients, 70 within 3 months. Cox proportional-hazards regression identified serum concentrations of bilirubin and creatinine, international normalized ratio for prothrombin time (INR), and the cause of the underlying liver disease as predictors of survival in patients undergoing elective TIPS, either for prevention of variceal rebleeding or for treatment of refractory ascites. These variables can be used to calculate a risk score (R) for patients undergoing elective TIPS. Patients with R > 1.8 had a median survival of 3 months or less. This model was superior to both the Child-Pugh classification, as well as the Child-Pugh score, in predicting survival. Using logistic regression and the same variables, we also developed a nomogram that indicates which patients survive less than 3 months. Finally, the model was validated among an independent set of 71 patients from the Netherlands. This Mayo TIPS model may predict early death following elective TIPS for either prevention of variceal rebleeding or for treatment of refractory ascites.

Sepsis following the placement of a transjugular intrahepatic portosystemic shunt (TIPS) has been reported in up to 10% of cases. This report describes an unusual case of polymicrobial gram-negative sepsis after placement of TIPS associated with a cholangiographically documented fistulous connection between the biliary tree and shunt. The patient was treated with temporary biliary stent placement, endoscopic sphincterotomy, and broad-spectrum antibiotics with rapid closure of the fistula and resolution of sepsis. In the absence of hemobilia, it is hypothesized that flow through the fistula allowed bilious contamination of the systemic circulation and subsequent inoculation with enteric flora. The prevalence of biliary-vascular fistula after placement of TIPS is unknown. It may be a previously unsuspected source of sepsis after placement of TIPS and is likely to be overlooked unless endoscopic retrograde cholangiopancreatography is performed.

Non-bleeding visible vessel and sentinel clot are terms used interchangeably to describe protuberances in the base of ulcers that have recently bled, but a consensus as to their definition or natural history does not exist. In patients with severe ulcer hemorrhage, non-bleeding protuberances were classified as vessels, with or without a small attached clot, or as sentinel clots, according to a schema based on the appearance of the protuberance at endoscopy but not subjected to pathologic correlation. Endoscopic therapy was not performed at the index endoscopic evaluation, and natural evolution was prospectively documented with daily videoendoscopy. Eleven (46%) of 24 patients with non-bleeding protuberances had rebleeding. Independent classification by three authors concurred in 18 (75%) of 24 lesions. Ten (91%) of 11 vessels with or without attached clot rebled versus 0 (0%) of 7 sentinel clots and 1 (17%) of 6 lesions without unanimous classification (p < 0.01, vessels versus other groups). Rebleeding occurred in 5 (71%) of 7 nonpigmented (pale or white), 6 (38%) of 16 red or purple, and 0 (0%) of 1 black protuberances. In general, vessels persisted until rebleeding, whereas sentinel clots disappeared within 1 to 3 days. We conclude that nonbleeding protuberances in ulcer bases can be separated into vessels, which have a high risk of rebleeding, and sentinel clots, which have a low risk of rebleeding.

It can be anticipated that most new therapies will generate considerable excitement and optimism when introduced. This is usually tempered with time as additional clinical experience is gained and therapeutic limitations and adverse effects are realized. All areas in the nonsurgical management of gallstones have experienced this course--some, such as ESWL, rather meteorically. Perspective, however, is important and may allow the appropriate use of each of these modalities in the correct clinical setting. For example, ursodiol when given in sufficient dose to nonobese patients with small radiolucent stones, could be expected to effect partial or complete dissolution in as many as 75% of patients, with minimal or no adverse effects and in a cost-effective manner. Contact dissolution using MTBE has been shown to be safe and generally effective but requires diligent characterization of stones to avoid those that are pigmented or heavily calcified. Similarly, ESWL combined with oral bile acids may be consistently effective if treatment is restricted to patients with acceptable cholesterol stone burdens and if treatment can be safely continued until fragments are substantially reduced. Continued experience with each of these treatment options, along with advances in research providing new solvents and technologies or in preventing recurrence, is likely to establish this field in an appropriately optimistic light.

Passage of stone fragments after extracorporeal shock wave lithotripsy (ESWL) of gallstones has resulted in biliary colic, duct obstruction, and pancreatitis in some patients. Rapid dissolution of these fragments with methyl tert-butyl ether (MTBE) may prevent such side effects and achieve complete clearance of gallstones within hours rather than several months to a year or longer. This study examines the safety of same-day ESWL fragmentation and MTBE dissolution of surgically implanted human gallstones in 15 dogs. The animals were randomly assigned to one of four treatment groups to assess MTBE absorption from the gallbladder and to observe hematology and chemistry profiles after 0, 400, and 1,200 shock waves from a lithotriptor followed by MTBE dissolution therapy. They were sacrificed either immediately after treatment (12 dogs) or 2 weeks later (3 dogs). The results demonstrated that although ESWL causes moderate trauma to the gallbladder, this did not result in increased MTBE absorption or histologic evidence of mucosal disruption. Blood profiles demonstrated an increase in only the level of aspartate aminotransferase. The three dogs that were sacrificed 2 weeks after the combined treatment had no residual evidence of gallbladder injury or remaining stone material. In all animals, severe injury occurred where shock waves passed through lung or air-filled colon. This study suggests that same-day sequential fragmentation of gallstones by ESWL followed by dissolution of stone fragments with use of MTBE may be associated with only mild to moderate and reversible gallbladder trauma and can rapidly achieve clearance of gallstones.

A search was made for the presence of spontaneous auto-anti-idiotype in sera of three insulin-dependent diabetics when they converted from islet cell antibody positive to islet cell antibody negative states. Rabbit anti-idiotype specific for islet cell antibody was used as the positive control. Using an enzyme-linked immunoabsorbent assay, binding of the rabbit anti-idiotype to idiotype-coated plates could not be inhibited by islet cell antibody negative sera. Using this same assay, there was no significant difference in the binding of islet cell antibody positive or negative sera to either idiotype-coated or normal IgG-coated plates. Binding of islet cell antibody to pancreatic sections could not be inhibited by islet cell antibody negative sera in an immunofluorescent assay. Network regulation by auto-anti-idiotype does not seem to play a role in the decline or absence of islet cell antibody in the early phases of insulin-dependent diabetes mellitus.

Tissue obtained from young dogs was fixed in buffered aldehydes by vascular perfusion or direct immersion. Selected hearts were maintained in modified mammalian Ringer's solution for three to five minutes prior to fixation. The chambers of the heart and related valves were exposed by dissection and prepared by routine techniques for observation by scanning electron microscopy (SEM). Subsequent to SEM studies, selected specimens were embedded in Epon 812 and sectioned for transmission electron microscopy (TEM). The cardiac endothelium, when fixed immediately in buffered aldehydes, presents an essentially invariable surface throughout the interior of the heart. The predominant nuclear bulges and attenuated peripheral plasmatemma are consistently smooth, with occasional marginal ruffles, scattered microvilli and small blebs. Apart from the higher population of nuclear bulges on valvular surfaces, local variations in SEM of endocardium occur in response to the various stages of systole and diastole encountered. These physiological changes do not produce microappendages. Immersion for three to five minutes in (Chenoweth's) Ringer's solution, prior to fixation, produces a substantial population of microappendages. The cellular surface acquires a swirled appearance erupting in microvilli, blebs and ruffles. These exhibit considerable pleomorphism. There is great lability of the endocardial surface in response to a classic "holding solution" widely used in preparatory techniques. In preparing soft tissues for SEM caution must be used if physiological "holding solutions" are used prior to fixation.

We treated 75 patients with symptomatic cholesterol gallstones by dissolving the stones with methyl tert-butyl ether (MTBE) instilled into the gallbladder through a percutaneous transhepatic catheter. The MTBE was continuously infused and aspirated manually four to six times a minute, for an average of five hours per day for one to three days; the treatment was monitored by fluoroscopy. The placement of the catheter and the administration of MTBE caused few side effects or complications, and treatment did not have to be stopped in any patient for this reason. In 72 patients there was complete dissolution of stones or more than 95 percent dissolution. Among 21 patients who were completely free of stones after treatment, 4 had recurrence of stone formation 6 to 16 months later. The other 51 patients had residual debris, which spontaneously cleared completely in 15 patients within 6 to 35 months; only 7 with persisting debris have had symptoms. Five of the initial 6 patients treated, but only 1 of the next 69 patients, have required surgery during follow-up periods of 6 to 42 months. We conclude that the dissolution of gallstones by MTBE delivered through a percutaneous transhepatic catheter is a useful alternative to surgery in selected patients with symptomatic cholesterol stones. Further study will be necessary to establish the long-term effectiveness of this treatment and its appropriate role in the management of the various types of gallstones.

To explore the possibility that gallbladder stone fragments might be able to be safely dissolved using methyl tert-butyl ether immediately after extracorporeal shock-wave lithotripsy (ESWL), a feasibility study in 8 patients with one to four partially calcified gallbladder stones was performed. The gallstones averaged 2.2 cm in diameter (range 1.3-3 cm) and contained layered or diffuse calcium detectable by computed tomography scan only (7 patients) or plain film (1 patient). After a 5F (1.7 mm) pigtail catheter was placed percutaneously into the gallbladder, ESWL fragmentation was performed using a renal stone lithotriptor. The patients were under general anesthesia and in the prone position on a support gantry designed for gallbladder stone ESWL. Following ESWL, methyl tert-butyl ether was infused and aspirated via the gallbladder catheter until no further stone material was radiologically detectable or could be dissolved. After 8-26 h (mean = 13 h) of methyl tert-butyl ether therapy, no radiologically detectable gallstones remained in 6 of 8 patients. Shell fragments of three peripherally calcified stones in 1 patient and the densely calcified, predominantly pigment stone in a second patient were refractory to combined therapy. Both ESWL and treatment with methyl tert-butyl ether were well tolerated in all patients, although bile leakage after catheter removal occurred in 3 patients, one of whom was treated by cholecystectomy. Additional measures to prevent bile leakage may be advisable if these two modalities are to be used in tandem. We found no evidence, however, that predissolution stone fragmentation with ESWL predisposed the gallbladder to either mucosal damage by methyl tert-butyl ether or increased absorption of it.