Review article: inhibition of methanogenic archaea by statins as a targeted management strategy for constipation and related disorders.

BACKGROUND: Observational studies show a strong association between delayed intestinal transit and the production of methane. Experimental data suggest a direct inhibitory activity of methane on the colonic and ileal smooth muscle and a possible role for methane as a gasotransmitter. Archaea are the only confirmed biological sources of methane in nature and Methanobrevibacter smithii is the predominant methanogen in the human intestine. AIM: To review the biosynthesis and composition of archaeal cell membranes, archaeal methanogenesis and the mechanism of action of statins in this context. METHODS: Narrative review of the literature. RESULTS: Statins can inhibit archaeal cell membrane biosynthesis without affecting bacterial numbers as demonstrated in livestock and humans. This opens the possibility of a therapeutic intervention that targets a specific aetiological factor of constipation while protecting the intestinal microbiome. While it is generally believed that statins inhibit methane production via their effect on cell membrane biosynthesis, mediated by inhibition of the HMG-CoA reductase, there is accumulating evidence for an alternative or additional mechanism of action where statins inhibit methanogenesis directly. It appears that this other mechanism may predominate when the lactone form of statins, particularly lovastatin lactone, is administered. CONCLUSIONS: Clinical development appears promising. A phase 2 clinical trial is currently in progress that evaluates the effect of lovastatin lactone on methanogenesis and symptoms in patients with irritable bowel syndrome with constipation. The review concludes with an outlook for the future and subsequent work that needs to be done.

Natural biology of polyomavirus middle T antigen.

"It has been commented by someone that 'polyoma' is an adjective composed of a prefix and suffix, with no root between--a meatless linguistic sandwich" (C. J. Dawe). The very name "polyomavirus" is a vague mantel: a name given before our understanding of these viral agents was clear but implying a clear tumor life-style, as noted by the late C. J. Dawe. However, polyomavirus are not by nature tumor-inducing agents. Since it is the purpose of this review to consider the natural function of middle T antigen (MT), encoded by one of the seemingly crucial transforming genes of polyomavirus, we will reconsider and redefine the virus and its MT gene in the context of its natural biology and function. This review was motivated by our recent in vivo analysis of MT function. Using intranasal inoculation of adult SCID mice, we have shown that polyomavirus can replicate with an MT lacking all functions associated with transformation to similar levels to wild-type virus. These observations, along with an almost indistinguishable replication of all MT mutants with respect to wild-type viruses in adult competent mice, illustrate that MT can have a play subtle role in acute replication and persistence. The most notable effect of MT mutants was in infections of newborns, indicating that polyomavirus may be highly adapted to replication in newborn lungs. It is from this context that our current understanding of this well-studied virus and gene is presented.

Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer.

BACKGROUND: In many institutions, computed tomography (CT)-guided percutaneous fine-needle aspiration (FNA) has become the procedure of choice for biopsies of pancreatic mass lesions. This method of biopsy and others, such as endoscopic retrograde cholangiopancreatography (ERCP) cytology, are problematic because of a substantial false-negative rate. OBJECTIVE: To investigate the yield of endoscopic ultrasonography-guided FNA biopsies in patients who had negative results on CT-guided biopsy or negative cytologic findings on ERCP sampling. DESIGN: Prospective cohort study. SETTING: Tertiary care university medical center. PATIENTS: 102 patients (median age, 65 years; 58 men and 44 women) with suspected pancreatic cancer who fulfilled the above criteria were prospectively identified and underwent endoscopic ultrasonography-guided FNA biopsy. MEASUREMENTS: The operating characteristics of endoscopic ultrasonography-guided FNA for diagnosing pancreatic masses were determined. Surgical pathology or long-term follow-up (median, 24 months) was used to identify false-positive or false-negative results. RESULTS: Median mass size was 3.5 cm x 2.7 cm. A median of 3.4 passes were performed. Cytologic results on endoscopic ultrasonography-guided FNA biopsy were positive in 57 patients, negative in 37, and inconclusive or nondiagnostic in 8. No false-positive results were observed. A diagnosis of pancreatic cancer was subsequently confirmed in 3 patients who had tested negative (false-negative results) and 1 of the 8 patients with nondiagnostic results. Of these 4 patients, 3 had cytologic evidence of chronic pancreatitis on endoscopic ultrasonography-guided FNA biopsy. The 95% CI for the likelihood ratio for a positive test result contained all values greater than or equal to 9.7. The likelihood ratio for a negative test result was 0.05 (CI, 0.02 to 0.15). The posterior probability of pancreatic cancer after a definitely positive result was at least 93.5% by a conservative lower 95% confidence limit; after a definitely negative test result, it was 6.9%. The prevalence of pancreatic cancer was 59.8% (61 of 102 patients). Self-limited complications occurred in 3 of the 102 patients (2.9% [CI, 0.6% to 8.4%]). CONCLUSION: Endoscopic ultrasonography-guided FNA biopsy may play a valuable role in the evaluation of a pancreatic mass when results on other biopsy methods are negative but pancreatic cancer is suspected.

A prospective evaluation of the incidence of bacteremia associated with EUS-guided fine-needle aspiration.

BACKGROUND: Endoscopic ultrasound (EUS)--guided fine-needle aspiration (FNA) is frequently performed for diagnostic evaluation of lesions in or near the gastrointestinal (GI) tract. Little data exist concerning possible infectious complications associated with EUS-guided FNA. This prospective evaluation was undertaken to determine the frequency of bacteremia and infectious complications associated with EUS-guided FNA. METHODS: All patients undergoing EUS-guided FNA for any indication were enrolled in this study. Patients who required antibiotic prophylaxis as per the American Heart Association or American Society for Gastrointestinal Endoscopy guidelines were excluded from the study as were patients with cystic lesions, patients with advanced liver disease/ascites and those with human immunodeficiency virus/acquired immune deficiency syndrome. Blood cultures were obtained 30 and 60 minutes after the EUS-FNA. Patients were monitored for evidence of infection after procedure including telephone follow-up of each subject 1 week after procedure. RESULTS: One hundred patients underwent EUS-FNA of 108 lesions. All blood cultures were negative except in 6 patients in whom 1 of 2 bottles were positive for coagulase negative Staphylococcus, which was considered a contaminant. There were no complications of acute febrile illness, abscess or other infections. CONCLUSION: EUS-guided FNA was not associated with bacteremia or infectious complications.

Endoscopic ultrasound characteristics of mucinous cystic neoplasms of the pancreas.

OBJECTIVE: Mucinous cystic neoplasms of the pancreas have a more favorable prognosis than ductal adenocarcinoma. Management of a subgroup, intraductal papillary-mucinous neoplasms, is controversial. Endoscopic ultrasound (EUS) with fine-needle aspiration biopsy may emerge as the imaging modality of choice. There are few studies describing the EUS features of these tumors. METHODS: A total of 35 consecutive cases of cystic tumors of the pancreas with an established pathological diagnosis were analyzed for characteristic EUS features. RESULTS: Mucinous cystadenocarcinomas (n = 14) were more likely to be characterized by hypoechoic cystic/solid mass or complex cyst and were frequently associated with a dilated main pancreatic duct. Benign mucinous duct ectasia (n = 6) were characterized by a dilated main pancreatic duct in conjunction with hyperechoic thickening of the duct wall. The two cases of intraductal mucinous hyperplasia additionally showed a hypoechoic mass. Intraductal papillary carcinoma (n = 11) had features in common with mucinous cystadenocarcinoma but also had echogenic foci in the mass and intraductal hyperechoic lesions. The two cases of microcystic cystadenoma showed either a mixed hypoechoic solid/cystic mass or a complex cyst without the additional features seen in mucinous cystadenocarcinoma. CONCLUSIONS: EUS features seem to exist that may help to differentiate cystic neoplasms from adenocarcinoma of the pancreas and, thus, to establish the preoperative diagnosis of cystic tumors of the pancreas.

Triple-tissue sampling at ERCP in malignant biliary obstruction.

BACKGROUND: Procurement of cytologic samples by brushing is common practice at endoscopic retrograde cholangiopancreatography (ERCP) but has low sensitivity for cancer detection. Limited data are available on other techniques, including endoluminal fine-needle aspiration and forceps biopsy. This series reviews the yield of these three stricture sampling methods. METHODS: In this prospective study, patients with biliary obstruction with a clinical suspicion of malignancy underwent triple-tissue sampling at one ERCP session. Final cancer diagnosis was based on all sampling methods plus surgery, autopsy, and clinical follow-up. Tissue specimens were reported as normal, atypia, or malignant. RESULTS: A total of 133 patients were evaluated: 104 had cancer and 29 had benign strictures. Tissue sampling sensitivity varied according to the type of cancer; the highest yield was seen in ampullary cancers (62% to 85%). The cumulative sensitivity of triple-tissue sampling in the cancer patients was as follows: sensitivity was 52% if atypia was considered benign and 77% if it was considered malignant. The addition of a second or third technique increased sensitivity rates in most instances. No serious complications occurred from the tissue sampling methods. CONCLUSIONS: Tissue sampling sensitivity varied according to the type of cancer. Combining a second or third method increased sensitivity; general use of at least two sampling methods is therefore recommended.

The distribution and kinetics of polyomavirus in lungs of intranasally infected newborn mice.

The primary cell types that sustain polyomavirus (Py) replication following intranasal infection as well as the nature of the host cellular response to Py were unknown. As this is an essential and specific site for virus entry, it seems likely that viral gene function must be adapted to these mucosal tissues. Using immunohistochemistry and in situ hybridization, we determined the cell types in the lung that support Py gene expression and replication following intranasal inoculation of newborn mice within 24 h of birth. Lungs were collected daily from days 1 to 10 postinfection for Py DNA and early T antigen analysis and for histological examination by H&E staining, using methods that preserve the delicate newborn lung architecture. Viral DNA was present in increasing quantities from 2 to 6 dpi in a subset of the Clara cells lining the inner lumen of the bronchi and bronchioles, while T antigen expression was present in a majority of the cells in the bronchi and bronchiole lumen. A distinct and transient pattern of hyperplasia was observed among the cells expressing T antigen and was present from 3 through 6 dpi. Py DNA-containing cells exfoliated into the bronchiole lumen and alveolar ducts, but Py T antigen was not detected in these cells. Py DNA was first detected at 2 dpi, increased through 6 dpi, and abruptly declined through 9 dpi at which time there was no sign of viral DNA in the lungs by in situ hybridization. An unusual infiltration of neutrophils began before the presence of exfoliated cells or Py replication and continued for 2-3 days and was followed by a lymphocytic infiltration at 8-10 dpi lasting 2-3 days. Neither the hyperplasia nor the neutrophil infiltration occurred following infection with the MOP1033 MT-Ag or RB1 LT-Ag mutants of Py. In addition, both the neutrophil infiltration and the transient hyperplasia are in stark contrast to the heavy macrophage infiltration that follows infection of lungs with mouse adenovirus. Thus it appears that Py elicits a distinct host response pattern not seen with other DNA viral infections.

Amylase normal, lipase elevated: is it pancreatitis? A case series and review of the literature.

OBJECTIVE: This study was undertaken to identify clinical scenarios in which the lipase is significantly elevated (three times above the upper limit of normal) but the amylase is normal, and to examine whether or not pancreatitis is the likely cause for this seemingly unusual constellation of laboratory results. METHODS: Twenty-five patients were retrospectively identified over a 2-yr period, which fulfilled the above criteria. A thorough review of their charts was conducted. In addition, a critical review of the literature was performed. RESULTS: It appears that isolated elevation of lipase in this case series was either related to renal insufficiency (two patients), to nonpancreatic sources of lipolytic enzymes due to malignant tumors (two), to acute cholecystitis (two) or esophagitis (one), to delayed blood withdrawal (at least five patients), to hypertriglyceridemia (two), or to subclinical pancreatitis in patients without abdominal pain (three). CONCLUSIONS: 1. An elevated lipase should not be equated with evidence for pancreatitis if the amylase is normal. 2. A simultaneous determination of both amylase and lipase is recommended for the evaluation of patients with abdominal pain.

Approaches to study interactions between small DNA viruses and differentiated tissue.

Polyomavirus (Py) derives its name from the early observation of multiple tumors that develop in newborn mice following inoculation with this family of viruses. In nature, however, tumor development is rare in the virus life cycle, rather a two-phase infection occurs, acute and persistent, resulting in a final latent infection in the kidneys. The acute phase induces an antiviral immune response, although no recognizable inflammation, which can last the lifetime of the mouse, even passing on antibodies to its offspring. The structure, replication, and expression of the Py viral genome in permissive and nonpermissive infections has been studied extensively in various cell culture systems. However, the nature of Py expression, replication, and immunopathogenesis in mice has not been thoroughly researched.

Is telemedicine justifiable?

A three-year experience in urban telemedicine is presented. The digital technology linking a community teaching hospital to a nearby clinic is described, as is the typical protocol for the consultations. The medical advantages and disadvantages, the security implications, and the cost-effectiveness of this project are analyzed.

ERCP and biliary endoscopic sphincterotomy-induced pancreatitis.

The magnitude of post-ERCP pancreatitis as a clinical and economic problem has increased, and with it the need to find ways of decreasing its incidence and severity. Furthermore, the study of post-ERCP pancreatitis is interesting as a unique model for acute pancreatitis in general. Current thinking and results of recent promising studies are reviewed.

Designing a home health care system for Alaska Natives in Anchorage.

PURPOSE: To design a health care program that allows Alaska Natives to receive culturally appropriate health services in their homes, thus avoiding the trauma of institutionalization and significantly increasing the quality of the patient's life during the course of the treated illness. METHOD: Utilizing the culturally appropriate sensitivity that is found within Tribal Health Corporations, Southcentral Foundation is designing a federally based community health care model to bring health support services into the patient's home. Health Aides and Community Health Representatives play an important role in extending this model into an urban community setting. The cost of care is significantly reduced, as it is more cost-effective to keep patients in their own home environments rather than in institutions. RESULTS: Major outcomes for patients are increased cultural sensitivity to their needs, personal comfort, dignity, and care in their own home surroundings. Outcomes for the federal care system are significant savings and more efficient personalized health care.

Median arcuate ligament syndrome with multivessel involvement: diagnosis with spiral CT angiography.

Intestinal angina may be caused by compression of the celiac artery by the median arcuate ligament of the diaphragm. Aortography can suggest the diagnosis, but the diaphragm cannot be visualized by this examination. We report a symptomatic woman in whom spiral computed tomography-guided angiography demonstrated stenosis of the celiac artery, superior mesenteric artery, and both renal arteries due to diaphragmatic compression. Surgery was beneficial.

5-year incidence of adenomas after negative colonoscopy in asymptomatic average-risk persons [see comment].

BACKGROUND & AIMS: Cost-effectiveness of colorectal cancer screening will be maximized by selecting the widest screening intervals that effectively prevent cancer mortality. However, data on the incidence of neoplasia in persons with no abnormal findings on initial examination are limited. The aim of this study was to describe the incidence of colonic neoplasia 5 years after negative screening colonoscopy in asymptomatic average-risk persons. METHODS: We previously reported the results of screening colonoscopy in 496 asymptomatic average-risk persons, 368 of whom had no neoplasia identified. Colonoscopy to the cecum was performed in 154 of these persons at a mean of 66 months after the initial negative colonoscopy. RESULTS: Forty-one (27%) had at least one adenoma, but only 1 person had an adenoma > or = 1 cm and none had cancer, severe dysplasia, or villous or tubulovillous histology. Hyperplastic polyps at the initial examination did not predict incident adenomas. Regular nonsteroidal anti-inflammatory drug use was associated with a decreased rate of incident adenomas. CONCLUSIONS: In average-risk persons, the interval between screening examinations can be safely expanded beyond 5 years, provided the initial examination is a carefully performed complete colonoscopy that is negative for colonic adenomas or cancer.

Effects of meperidine on the pancreatic and biliary sphincter.

BACKGROUND: Opioids are traditionally avoided during sphincter of Oddi manometry because of indirect evidence suggesting that these agents cause sphincter of Oddi spasm. This study was undertaken to determine the direct effects of meperidine on the biliary and pancreatic sphincter. METHODS: Forty-seven patients were prospectively evaluated by sphincter of Oddi manometry in the conventional retrograde fashion. Manometry was initially performed with intravenous diazepam sedation alone. The manometry was repeated 3 to 5 minutes after meperidine was administered. RESULTS: The basal sphincter pressure of the biliary sphincter, pancreatic sphincter, and the combined sphincter group were not significantly altered by meperidine. Concordance (normal versus abnormal) between the basal sphincter pressure before and after meperidine was seen in 44 of 47 patients (94%). Meperidine produced a significant increase in the pancreatic, biliary, and combined sphincter phasic frequency and a significant decrease in the phasic duration. The pancreatic and combined sphincter phasic pressures were significantly reduced following meperidine administration. Seventeen manometry tracings (36%) were believed to be qualitatively better after meperidine, while only four (8.5%; p < .001) were qualitatively better with diazepam alone. CONCLUSION: Meperidine can be used for additional analgesia during sphincter of Oddi manometry if the basal sphincter pressure is the parameter used to determine therapy.

Early recognition of post-ERCP pancreatitis by clinical assessment and serum pancreatic enzymes.

BACKGROUND: This study evaluates the relative value of clinical assessment and serum pancreatic enzymes in the discharge management of outpatients undergoing ERCP. METHODS: Two hundred thirty-one patients who underwent ERCP had a detailed clinical assessment performed 2 h after the procedure and blood drawn for amylase and lipase. RESULTS: One-third of the patients who later developed pancreatitis had no pain 2 h after the end of the procedure, whereas an equal number who had no pancreatitis did complain of pain. Values below 276 U/L for amylase and 1000 U/L for lipase were useful in ruling out pancreatitis with negative predictive values of 0.97 and 0.98, respectively. Based on the data of this study a discharge algorithm for outpatients undergoing ERCP is proposed. CONCLUSIONS: In contrast to clinical assessment, which is unreliable, it is possible to stratify patients according to their risk of developing pancreatitis according to their 2-h serum amylase and lipase values. This helps to rationalize the discharge management of outpatients undergoing ERCP at a time when careful utilization of resources, especially the avoidance of unnecessary hospital admissions, becomes increasingly more important.