Loss of heterozygosity on chromosome 17p predicts neoplastic progression in Barrett's esophagus

BACKGROUND AND AIM: Endoscopic surveillance for adenocarcinoma in patients with Barrett's esophagus is costly, with one cancer detected every 48-441 patient years of follow up. Genetic abnormalities, including loss of heterozygosity at sites of tumor suppressor genes, have been detected in malignant and premalignant Barrett's esophagus. The aim of this prospective study was to determine if loss of heterozygosity analysis could identify patients with Barrett's esophagus at greatest risk of adenocarcinoma, for whom endoscopic surveillance is most appropriate. METHODS: Loss of heterozygosity analysis was performed on endoscopic biopsies from 48 patients as part of a Barrett's surveillance program using 14 microsatellite markers shown previously to detect loss of heterozygosity in more than 30% of esophageal adenocarcinomas. Patients were followed up endoscopically for a median of 5 years. RESULTS: Loss of heterozygosity was detected in nine patients. Three patients with loss of heterozygosity on chromosome 5q or 9p did not progress beyond metaplasia. Loss of heterozygosity at 17p11.1-p13 was detected in six patients, all of whom demonstrated dysplasia and/or carcinoma during follow up (four low-grade dysplasia, one high-grade dysplasia and one adenocarcinoma). CONCLUSION: Loss of heterozygosity at 17p11.1-p13 on chromosome 17p identifies patients with Barrett's esophagus at risk of neoplastic progression and can supplement histology in determining the frequency of endoscopy during surveillance.     

Bacterial cholangitis causing secondary sclerosing cholangitis: A case report

Background  

Although bacterial cholangitis is frequently mentioned as a cause of secondary sclerosing cholangitis, it appears to be extremely rare, with only one documented case ever reported.     

Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF

Recombinant human interleukin-5 (rhIL-5), in either liquid or semi- solid cultures, selectively induced eosinophil production from normal human bone marrow, with no activity on other cell lineages. The time course of eosinophil production induced by murine IL-5, rhIL-3, and rh granulocyte-macrophage colony stimulating factor (GMCSF) was similar to rhIL-5. The rate of eosinophil maturation in vitro was independent of the stimulating cytokine, mature eosinophils being produced after 4 to 5 weeks in liquid culture with each of these cytokines. The eosinophils produced in response to each cytokine were morphologically indistinguishable, and had the ultrastructural features of maturity except that the electron-dense material in the granules had not formed into crystalline cores. Neither rhIL-1 nor rhIL-6 alone, or in combination with rhIL-5 or rhIL-3, induced eosinophil differentiation or proliferation under the conditions used. rhIL-3 and rhGMCSF induced more eosinophil colonies than rhIL-5, rhIL-5 had an additive, not synergistic, effect on eosinophil colony production when combined with either rhIL-3 or rhGMCSF, suggesting that rhIL-5 stimulates a smaller and possibly different population of eosinophil progenitors. However, rhIL-5 induced the greatest eosinophil production in liquid cultures, suggesting that although it may act on a smaller population of precursors, it is able to stimulate more proliferative steps than either rhIL-3 or rhGMCSF.     

The diagnostic value of the fibrinogen/fibrin fragment E antigen assay in clinically suspected deep vein thrombosis

We have evaluated the fibrinogen/fibrin fragment E antigen assay as a diagnostic test in patients with clinically suspected venous thrombosis by comparing the results of this assay with venography in 272 patients. The result of the fragment E antigen assay was elevated in 79 of 80 patients with positive venograms for recent venous thrombosis (sensitivity 99%) and within the normal range in 161 of 192 patients with normal venograms (specificity 84%). The fragment E assay was also evaluated in 130 medical and surgical controls without evidence of venous thrombosis by leg scanning and the test was found to be relatively nonspecific. However, in the patient group under study, a correct clinical diagnosis of no thrombosis, based on a normal fragment E result, was made in 161 of 162 cases (negative predictive value of 99%). Therefore, a normal test result effectively excludes a diagnosis of venous thrombosis in clinically symptomatic patients. The assay, as currently performed, is technically demanding and takes 24 hr to complete. Therefore, it will have to be simplified before it can be applied to clinical practice.     

Dual role of tumor necrosis factor-alpha in hepatic ischemia-reperfusion injury: studies in tumor necrosis factor-alpha gene knockout mice

Although hepatic ischemia-reperfusion (IR) injury is partially mediated by tumor necrosis factor-alpha (TNF), we recently found that low-dose TNF before IR is hepatoprotective. We examined the seemingly conflicting roles of TNF in mediating liver injury in a partial hepatic IR model using TNF gene knockout (TNF ko) mice to allow TNF replacement at specified times. Compared with wild-type mice, TNF ko mice exhibit minimal alanine aminotransferase release and few hepatonecrotic lesions during the early (time, 2 hours) and late (time, 24 hours) phases of IR. TNF ko mice differed from wild-type mice in that TNF ko mice exhibited no activation or induction of nuclear factor-kappa B, p38, cyclin D1, or proliferating cell nuclear antigen after IR. A single low-dose TNF injection 1 minute before the onset of hepatic ischemia restored hepatic IR injury in TNF ko mice. To clarify the importance of TNF for hepatoprotection, preconditioning (10 minutes of ischemia and 10 minutes of reperfusion) was performed before the onset of IR for TNF ko mice whose capacity to undergo IR injury had been restored by TNF replacement. Ischemic preconditioning failed to protect these mice from TNF-augmented IR injury; however, following the administration of intravenous TNF (1 microg per kg body weight, which mimics the early increase in hepatic and plasma TNF levels that is mobilized by ischemic preconditioning), significant hepatoprotection against both the early and late phases of TNF-augmented IR injury was observed. In conclusion, TNF appears to mediate both the early and late phases of liver injury in hepatic IR, but it also is an essential mediator of hepatoprotective effects brought about by ischemic preconditioning.     

LCZ696: a new paradigm for the treatment of heart failure?

Introduction: Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. Currently, blockade of the renin–angiotensin–aldosterone system (RAAS) is the cornerstone of treatment; however, the combination of RAAS blockade with inhibition of neprilysin (NEP), an enzyme that degrades natriuretic peptides, has recently emerged as a potentially superior treatment strategy.

Areas covered: Following the results of the recent Phase III Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure clinical trial in patients with chronic HF with reduced ejection fraction (HF-REF), this review focuses on LCZ696, a first-in-class angiotensin receptor NEP inhibitor. This drug consists of a supramolecular complex containing the angiotensin receptor inhibitor valsartan in combination with the NEP inhibitor prodrug, AHU377. Following oral administration, the LCZ696 complex dissociates and the NEP inhibitor component is metabolized to the active form (LBQ657). Aspects of the trial that might be relevant to clinical practice are also discussed.

Expert opinion: Speculation that LCZ696 will pass the scrutiny of regulatory agencies for HF-REF appears to be justified, and it is likely to become a core therapeutic component in the near future. Replication of the eligibility criteria and titration protocol used in the PARADIGM-HF trial would be valuable in clinical practice and may minimize the risk of adverse events. Although long-term data remain to be generated, the promising results regarding hypertension are likely to expedite acceptance of the drug for HF-REF.     

Corticotropin-releasing factor decreases plasma luteinizing hormone levels in female rats by inhibiting gonadotropin-releasing hormone release into hypophysial-portal circulation

To evaluate whether the hypothalamus is the site of action of CRF in inhibiting LH levels in female rats, we measured hypophysial-portal blood concentrations of immunoreactive GnRH (irGnRH) after the central injection of CRF. Ovine CRF (0.1, 1.0, 2.0, and 5.0 nmol) was injected intracerebroventricularly to intact rats on the afternoon of proestrus and in long term ovariectomized (OVX) rats in the presence or in absence of estradiol benzoate (OVX + EB). CRF injection decreased the amplitude of the proestrous irGnRH surge without affecting presurge levels. CRF (0.1 nmol) attenuated the afternoon irGnRH surge in OVX + EB rats; higher doses of CRF blocked this surge and decreased nonsurge irGnRH levels. No dose-related alterations of irGnRH levels were observed in OVX rats; only the highest dose of CRF was active. For comparison, plasma LH concentrations were measured after a single dose of CRF (2 nmol) in rats under the same experimental conditions. While CRF decreased LH concentrations in anesthetized proestrous and OVX + EB rats, it was inactive in OVX rats. In contrast, CRF injection in awake rats did decrease LH concentrations in all experimental conditions, suggesting that in OVX rats, the anesthetic (Saffan) used during portal blood collection affected CRF action on LH secretion. Indeed, the observation that the LH response to opiate receptor blockade with naloxone (2.5 mg/kg) in anesthetized OVX rats was different compared to that in awake rats suggested that the ineffectiveness of CRF to decrease irGnRH and LH in OVX anesthetized rats was related to the action of the anesthetic on the opioid system. The existence of a putative CRF-opioid interaction in the inhibitory control of LH secretion was supported by the effectiveness of naloxone to reverse the CRF-induced decrease in LH levels in EB-treated and untreated OVX rats. These results indicate that CRF attenuates LH secretion by a central action to inhibit irGnRH release into the hypophysial-portal circulation and that this action is independent of basal concentrations of irGnRH and/or LH. Moreover, the present results support the involvement of endogenous opioids in mediating the effect of CRF on LH secretion.     

Crohn's disease and myasthenia gravis: a possible role for thymectomy.

A female patient with a three year history of Crohn's disease of the colon developed myasthenia gravis. Despite diversion of the faecal stream by an ileostomy, and total colectomy, the patient had continuing problems with perineal and perianal abscesses and fistulas. Her myasthenia gravis became unresponsive to anti-cholinergics so a thymectomy was performed. The perineal and perianal disease improved subsequently. This case supports the theory that functional disturbances of the thymus may have a role in the pathogenesis of inflammatory bowel disease.