T cell cytokine polarity as a determinant of immunoglobulin A (IgA) glycosylation and the severity of experimental IgA nephropathy.

Immunoglobulin A (IgA) glycosylation, recognized as an important pathogenic factor in IgA nephropathy (IgAN), is apparently controlled by the polarity of T helper (Th) cytokine responses. To examine the role of cytokine polarity in IgAN, inbred mice were immunized by intraperitoneal priming with inactivated Sendai virus (SeV) emulsified in either complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA), which promote Th1- or Th2-immune response, respectively, and then boosted identically twice orally with aqueous suspensions of inactivated virus. Next, some mice were challenged intranasally with infectious SeV. Mice primed with CFA or IFA had equal reductions in nasal viral titre relative to non-immune controls, and equally increased serum levels of SeV-specific IgA antibody. Mice primed with CFA showed higher SeV-specific IgG than those with IFA. Splenocytes from mice primed with IFA produced copious amounts of interleukin (IL)-4 and IL-5, but little interferon-gamma and IL-2; those primed with CFA had reciprocal cytokine recall responses. Total serum IgA and especially SeV-specific IgA from mice primed with IFA showed a selective defect in sialylation and galactosylation. Although the frequency and intensity of glomerular deposits and haematuria did not differ, glomerulonephritis in mice primed with IFA and challenged with infectious virus was more severe than in those given CFA, as judged by serum creatinine level. We conclude that the polarity of T cell cytokines controls the pattern of IgA glycosylation and exerts direct or indirect effects on functional glomerular responses to immune complex deposition.

Measurement of the nucleon strange-antistrange asymmetry at next-to-leading order in QCD from NuTeV Dimuon data.

We present a new measurement of the difference between the nucleon strange and antistrange quark distributions from dimuon events recorded by the NuTeV experiment at Fermilab. This analysis is the first to use a complete next to leading order QCD description of charm production from neutrino scattering. Dimuon events in neutrino deep inelastic scattering allow direct and independent study of the strange and antistrange content of the nucleon. We find a positive strange asymmetry with a significance of 1.6sigma. We also report a new measurement of the charm mass.

Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial.

BACKGROUND: The impact of long-term acid suppression on the gastric mucosa remains controversial. AIM: To report further observations on an established cohort of patients with gastro-oesophageal reflux disease, after 7 years of follow-up. METHODS: Of the original cohort randomized to either antireflux surgery or omeprazole, 117 and 98 patients remained in the medical and surgical arms, respectively. Gastric biopsies were taken at baseline and throughout the study. RESULTS: Fifty-three antireflux surgery and 39 omeprazole-treated patients had Helicobacter pylori infection at randomization. Eighty-three omeprazole-treated and 60 antireflux surgery patients remained H. pylori negative over the 7 years, and no change was observed in mucosal morphology except for a change in endocrine cell population (linear and diffuse hyperplasia, P = 0.03). During the 7-year study many patients, who were initially H. pylori infected, had the infection eradicated leaving only 13 omeprazole and 12 antireflux surgery patients still infected. In these patients, omeprazole induced a deterioration of the mucosal inflammation scores (P = 0.01) with a numerical increase of glandular atrophy. CONCLUSIONS: Long-term omeprazole therapy does not alter the exocrine oxyntic mucosal morphology in H. pylori-negative patients, but mucosal endocrine cells appear to be under proliferative stimulation; in H. pylori-positive patients there are changes in mucosal inflammation and atrophy.

The role of nasal tolerance in a model of IgA nephropathy induced in mice by Sendai virus.

Mucosal antigenic exposure is implicated in pathogenesis of IgA nephropathy. Although IgG and/or IgM codeposits may promote disease, protracted mucosal antigenic exposure reduces IgG and IgM antibody, a process termed mucosal tolerance. We immunized mice intranasally with infectious or inactivated Sendai virus for 6 or 14 weeks. Anti-virus IgG remained high in mice given infectious virus for 14 weeks, but decreased after 6 weeks in mice given inactivated virus; IgA antibody remained high in both groups. Upon viral challenge, glomerular IgG and complement deposits and the frequency of hematuria, all equal after 6 weeks of immunization, were lower in mice immunized with inactivated virus for 14 weeks but remained high in mice given infectious virus; glomerular IgA increased over time in both immunized groups. Viremia in a non-tolerized immune host can promote glomerulonephritis with IgG and complement codeposits and glomerular dysfunction. These preliminary experiments may guide future, more mechanistic, investigation.

Cure of Helicobacter pylori infection in patients with reflux oesophagitis treated with long term omeprazole reverses gastritis without exacerbation of reflux disease: results of a randomised controlled trial.

BACKGROUND: Helicobacter pylori gastritis may progress to glandular atrophy and intestinal metaplasia, conditions that predispose to gastric cancer. Profound suppression of gastric acid is associated with increased severity of H pylori gastritis. This prospective randomised study aimed to investigate whether H pylori eradication can influence gastritis and its sequelae during long term omeprazole therapy for gastro-oesophageal reflux disease (GORD). METHODS: A total of 231 H pylori positive GORD patients who had been treated for > or =12 months with omeprazole maintenance therapy (OM) were randomised to either continuation of OM (OM only; n = 120) or OM plus a one week course of omeprazole, amoxycillin, and clarithromycin (OM triple; n = 111). Endoscopy with standardised biopsy sampling as well as symptom evaluation were performed at baseline and after one and two years. Gastritis was assessed according to the Sydney classification system for activity, inflammation, atrophy, intestinal metaplasia, and H pylori density. RESULTS: Corpus gastritis activity at entry was moderate or severe in 50% and 55% of the OM only and OM triple groups, respectively. In the OM triple group, H pylori was eradicated in 90 (88%) patients, and activity and inflammation decreased substantially in both the antrum and corpus (p<0.001, baseline v two years). Atrophic gastritis also improved in the corpus (p<0.001) but not in the antrum. In the 83 OM only patients with continuing infection, there was no change in antral and corpus gastritis activity or atrophy, but inflammation increased (p<0.01). H pylori eradication did not alter the dose of omeprazole required, or reflux symptoms. CONCLUSIONS: Most H pylori positive GORD patients have a corpus predominant pangastritis during omeprazole maintenance therapy. Eradication of H pylori eliminates gastric mucosal inflammation and induces regression of corpus glandular atrophy. H pylori eradication did not worsen reflux disease or lead to a need for increased omeprazole maintenance dose. We therefore recommend eradication of H pylori in GORD patients receiving long term acid suppression.

Search for nu(mu)-->nu(e) and nu(mu)-->nu(e) oscillations at NuTeV.

Limits on nu(mu)-->nu(e) and nu(mu)-->nu(e) oscillations are extracted using the NuTeV detector with sign-selected nu(mu) and nu(mu) beams. In nu(mu) mode, for the case of sin(2)2alpha = 1, Delta(m)(2)>2.6 eV(2) is excluded, and for Delta(m)(2)>>1000 eV(2), sin(2)2alpha>1.1 x 10(-3). The NuTeV data exclude the high Delta(m)(2) end of nu(mu)-->nu(e) oscillation parameters favored by the LSND experiment without the need to assume that the oscillation parameters for nu and nu are the same. We present the most stringent experimental limits for nu(mu)(nu(mu))-->nu(e)(nu(e)) oscillations in the large Delta(m)(2) region.

Precise determination of electroweak parameters in neutrino-nucleon scattering.

The NuTeV Collaboration has extracted the electroweak parameter sin(2)theta(W) from the measurement of the ratios of neutral current to charged current nu and (-)nu cross sections. Our value, sin(2)theta((on-shell))(W) = 0.2277 +/- 0.0013(stat) +/- 0.0009(syst), is 3 standard deviations above the standard model prediction. We also present a model independent analysis of the same data in terms of neutral-current quark couplings.

Extraction of R = sigma(L)/sigma(T) from CCFR nu(mu)-Fe and nu(mu)-Fe differential cross sections.

We report on the extraction of R = sigma(L)/sigma(T) from CCFR nu(mu)-Fe and nu(mu)-Fe differential cross sections. The CCFR differential cross sections do not show the deviations from the QCD expectations that are seen in the CDHSW data at very low and very high x. R as measured in nu(mu) scattering is in agreement with R as measured in muon and electron scattering. All data on R for Q(2)>1 GeV(2) are in agreement with a NNLO QCD calculation which uses NNLO parton distribution functions and includes target mass effects. We report on the first measurements of R in the low x and Q(2)<1 GeV(2) region (where an anomalous large rise in R for nuclear targets has been observed by the HERMES Collaboration).

The cost of long term therapy for gastro-oesophageal reflux disease: a randomised trial comparing omeprazole and open antireflux surgery.

BACKGROUND AND AIM: To comprehensively assess the relative merits of medical and surgical therapy for gastro-oesophageal reflux disease (GORD), health economic aspects have to be incorporated. We have studied the direct and indirect costs of medical and surgical therapy within the framework of a prospective randomised multicentre trial. METHODS: After initial treatment of reflux oesophagitis with omeprazole to control symptoms and to heal oesophagitis, 154 patients were randomised to continue treatment with omeprazole (20 or 40 mg daily) and 144 patients to have an open antireflux operation (ARS). In case of GORD relapse, patients allocated to omeprazole were offered ARS and those initially operated on had either a reoperation or were treated with omeprazole. The costs were assessed over five years from randomisation. RESULTS: Differences in cumulative direct medical costs per patient between the two therapeutic strategies diminished with time. However, five year direct medical costs per patient when given omeprazole were still significantly lower than for those having ARS in Denmark, Norway, and Sweden (differences were DKK 8703 (US$1475), NOK 32 992 (US$ 5155), and SEK 13 036 (US$ 1946), respectively). However, in Finland the reverse was true (the difference in favour of ARS amounted to FMK 7354 (US$ 1599)). When indirect costs (loss of production due to GORD related sick leave) were also included, the cost of surgical treatment increased substantially and exceeded the cost of medical treatment in all countries. CONCLUSIONS: The total costs of medical therapy for chronic GORD were lower than those of open ARS when prospectively assessed over a five year period, although significant differences in cost estimates were revealed between countries.

Search for the lepton family number violating process nu(mu)e(-) --> mu(-)nu(e).

The NuTeV experiment at Fermilab has used a sign-selected neutrino beam to perform a search for the lepton number violating process nu(mu)e(-)-->mu(-)nu(e), and to measure the cross section of the standard model inverse muon decay process nu(mu)e(-)-->mu(-)nu(e). NuTeV measures the inverse muon decay asymptotic cross-section slope sigma/E to be (13.8 +/- 1.2 +/- 1.4) x 10(-42) cm(2)/GeV. The experiment also observes no evidence for lepton number violation and places one of the most restrictive limits on the cross-section ratio sigma(nu(mu)e(-)-->mu(-)nu(e))/sigma(nu(mu)e(-)-->mu(-)nu(e)) < or = 1.7% at 90% C.L. for V-A couplings and < or = 0.6% for scalar couplings.

Activation of the luteinizing hormone/choriogonadotropin hormone receptor promotes ADP ribosylation factor 6 activation in porcine ovarian follicular membranes.

Previously we demonstrated in a cell-free ovarian follicular plasma membrane model that agonist-dependent desensitization of the luteinizing hormone/choriogonadotropin receptor (LH/CG R) is GTP-dependent, mimicked by the addition of ADP-ribosylation factor (ARF) nucleotide binding site opener, which acts as a guanine nucleotide exchange factor for ARFs 1 and 6, and selectively inhibited by synthetic N-terminal ARF6 peptides. We therefore sought direct evidence that activation of the LH/CG R promotes activation of ARF1 and/or ARF6. Using a classic ARF activation assay, the cholera toxin-catalyzed ADP-ribosylation of G alpha(s), results show that LH/CG R activation stimulates an ARF protein by a brefeldin A-independent mechanism. Synthetic N-terminal inhibitory ARF6 but not ARF1 peptide blocks LH/CG R-stimulated ARF activity. LH/CG R activation also promotes the binding of a photoaffinity GTP analog to a protein that migrates on one- and two-dimensional polyacrylamide gel electrophoresis with ARF6. These results suggest that ARF6 is the predominant ARF activated by the LH/CG R. To activate ARF6, the LH/CG R does not appear to signal through the C-terminal regions of G alpha(i) or G alpha(q) or through the second or third intracellular loops or the N terminus of the cytoplasmic tail of the LH/CG R. Although exogenous recombinant ARNO promotes only a small increase in ARF6 activation in the presence of activated LH/CG R, hCG-stimulated ARF6 activation is reduced to basal levels by catalytically inactive ARF nucleotide binding-site opener. These results provide direct evidence that LH/CG R activation leads to the activation of membrane-delimited ARF6.

Observation of an anomalous number of dimuon events in a high energy neutrino beam.

A search for long-lived neutral particles ( N0's) with masses above 2.2 GeV/c(2) that decay into at least one muon has been performed using an instrumented decay channel at the NuTeV experiment at Fermilab. Data were examined for particles decaying into the final states mumu, mu(e), and mu(pi). Three mumu events were observed over an expected standard model background of 0.069+/-0.010 events; no events were observed in the other modes.

Mesenchymal factor bone morphogenetic protein 4 restricts ductal budding and branching morphogenesis in the developing prostate.

The budding of the urogenital sinus epithelium into the surrounding mesenchyme signals the onset of prostate morphogenesis. The epithelial and mesenchymal factors that regulate ductal budding and the ensuing process of ductal growth and branching are not fully known. We provide evidence that bone morphogenetic protein 4 (BMP4) is a mesenchymal factor that regulates ductal morphogenesis. The Bmp4 gene was most highly expressed in the male urogenital sinus from embryonic day 14 through birth, a period marked by formation of main prostatic ducts and initiation of ductal branching. From an initial wide distribution throughout the prostatic anlage of the urogenital sinus, Bmp4 expression became progressively restricted to the mesenchyme immediately surrounding the nascent prostatic ducts and branches. Exogenous BMP4 inhibited epithelial cell proliferation and exhibited a dose-dependent inhibition of ductal budding in urogenital sinus tissues cultured in vitro. Adult Bmp4 haploinsufficient mice exhibited an increased number of duct tips in both the ventral prostate and coagulating gland. Taken together, our data indicate that BMP4 is a urogenital sinus mesenchymal factor that restricts prostate ductal budding and branching morphogenesis.

First measurement of the low- x, low- Q(2) structure function F(2) in neutrino scattering.

A new structure function analysis of CCFR deep inelastic nu-N and nu-N scattering data is presented for previously unexplored kinematic regions down to Bjorken x = 0.0045 and Q(2) = 0.3 GeV(2). Comparisons to charged lepton scattering data from NMC and E665 experiments are made and the behavior of the structure function F(2)(nu)2 is studied in the limit Q(2)-->0.

Measurements of F2 and xF(nu)(3) - xF(nu;)(3) from CCFR nu(mu)-Fe and nu;(mu)-Fe Data in a Physics Model-Independent Way.

We report on the extraction of the structure functions F2 and DeltaxF(3) = xF(nu)(3)-xF(nu;)(3) from CCFR nu(mu)-Fe and nu;(mu)-Fe differential cross sections. The extraction is performed in a physics model-independent (PMI) way. This first measurement of DeltaxF(3), which is useful in testing models of heavy charm production, is higher than current theoretical predictions. The ratio of the F2 (PMI) values measured in nu(mu) and mu scattering is in agreement (within 5%) with the predictions of next-to-leading-order parton distribution functions using massive charm production schemes, thus resolving the long-standing discrepancy between the two sets of data.

A mucosal IgA-mediated excretory immune system in vivo.

The capacity of mucosal IgA Abs to serve as an excretory immune system in vivo was investigated. Mice expressing a transgenic TCR were immunized intragastrically with the cognate Ag to elicit a vigorous mucosal IgA Ab response. Soon after i.v. challenge, Ag was detected within the epithelial cells of the small intestinal crypts and to a lesser degree within the epithelial cells higher up the villi, paralleling the gradient in expression of the polymeric Ig receptor and the transport of its ligand, oligomeric IgA. Uptake of Ag into the epithelial cells occurred only from the basolateral aspect and only when Ag complexed to IgA Ab could be present in the lamina propria. The results support the concept that local IgA Abs can excrete Ags from the body by transporting them directly through mucosal epithelial cells, using the same mechanism that transports free IgA into the mucosal secretions.

Continued (5-year) followup of a randomized clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease.

BACKGROUND: The efficacy of antireflux surgery (ARS) and proton pump inhibitor therapy in the control of gastroesophageal reflux disease is well established. A direct comparison between these therapies is warranted to assess the benefits of respective therapies. STUDY DESIGN: There were 310 patients with erosive esophagitis enrolled in the trial. There were 155 patients randomized to continuous omeprazole therapy and 155 to open antireflux surgery, of whom 144 later had an operation. Because of various withdrawals during the study course, 122 patients originally having an antireflux operation completed the 5-year followup; the corresponding figure in the omeprazole group was 133. Symptoms, endoscopy, and quality-of-life questionnaires were used to document clinical outcomes. Treatment failure was defined to occur if at least one of the following criteria were fulfilled: Moderate or severe heartburn or acid regurgitation during the last 7 days before the respective visit; Esophagitis of at least grade 2; Moderate or severe dysphagia or odynophagia symptoms reported in combination with mild heartburn or regurgitation; If randomized to surgery and subsequently required omeprazole for more than 8 weeks to control symptoms, or having a reoperation; If randomized to omeprazole and considered by the responsible physician to require antireflux surgery to control symptoms; If randomized to omeprazole and the patient, for any reason, preferred antireflux surgery during the course of the study. Treatment failure was the primary outcomes variable. RESULTS: When the time to treatment failure was analyzed by use of the intention to treat approach, applying the life table analysis technique, a highly significant difference between the two strategies was revealed (p < 0.001), with more treatment failures in patients who originally were randomized to omeprazole treatment. The protocol also allowed dose adjustment in patients allocated to omeprazole therapy to either 40 or 60 mg daily in case of symptom recurrence. The curves subsequently describing the failure rates still remained separated in favor of surgery, although the difference did not reach statistical significance (p = 0.088). Quality of life assessment revealed values within normal ranges in both therapy arms during the 5 years. CONCLUSIONS: In this randomized multicenter trial with a 5-year followup, we found antireflux surgery to be more effective than omeprazole in controlling gastroesophageal reflux disease as measured by the treatment failure rates. But if the dose of omeprazole was adjusted in case of relapse, the two therapeutic strategies reached levels of efficacy that were not statistically different.

Methylphenidate affects striatal dopamine differently in an animal model for attention-deficit/hyperactivity disorder--the spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) is used as a model for attention-deficit/hyperactivity disorder (ADHD) because it has behavioural characteristics (hyperactivity, impulsiveness, poorly sustained attention) similar to those of ADHD. ADHD children have been shown to have reduced striatal activation in certain tasks. SHR have reduced striatal dopamine release in response to electrical stimulation. The present study set out to investigate possible long-term effects of methylphenidate treatment on dopaminergic function in striatal slices of SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. Methylphenidate treatment (3 mg/kg daily for 14 days) did not normalize the decreased electrically-stimulated release of [(3)H]dopamine from SHR caudate-putamen slices nor did it affect postsynaptic D(2) receptor function. However, the second electrical stimulus caused a relatively greater release of [(3)H]dopamine from caudate-putamen slices of methylphenidate-treated SHR than from vehicle-treated SHR, suggesting that presynaptic mechanisms controlling dopamine release had been altered. Interestingly, [(3)H]dopamine release from WKY caudate-putamen slices in response to D(2) autoreceptor blockade by the antagonist, sulpiride, was selectively increased by methylphenidate treatment. This effect was not seen in SHR possibly because D(2) autoreceptor function had already been up-regulated. The results show that methylphenidate is unable to enhance D(2) autoreceptor function in SHR.

The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells.

The polymeric immunoglobulin receptor (pIgR) plays a crucial role in mucosal immunity against microbial infection by transporting polymeric immunoglobulins (pIg) across the mucosal epithelium. We report here that the human pIgR (hpIgR) can bind to a major pneumococcal adhesin, CbpA. Expression of hpIgR in human nasopharyngeal cells and MDCK cells greatly enhanced pneumococcal adherence and invasion. The hpIgR-mediated bacterial adherence and invasion were abolished by either insertional knockout of cbpA or antibodies against either hpIgR or CbpA. In contrast, rabbit pIgR (rpIgR) did not bind to CbpA and its expression in MDCK cells did not enhance pneumococcal adherence and invasion. These results suggest that pneumococci are a novel example of a pathogen co-opting the pIg transcytosis machinery to promote translocation across a mucosal barrier.

Long-term management of gastro-oesophageal reflux disease with omeprazole or open antireflux surgery: results of a prospective, randomized clinical trial. The Nordic GORD Study Group.

BACKGROUND AND AIM: The efficacy of antireflux surgery (ARS) and omeprazole treatment in the control of gastrooesophageal reflux disease (GORD) are well established. We have compared these two therapeutic options in a randomized, clinical trial. PATIENTS AND METHODS: Three hundred and ten patients with erosive oesophagitis were enrolled into the trial. After a run-in period when all patients had < or = 40 mg of omeprazole daily to heal the oesophagitis and relieve symptoms, 155 patients were randomized to continuous omeprazole therapy and 155 to open antireflux surgery, of whom 144 later had an operation. One hundred and thirty-nine and 129 in the omeprazole and antireflux surgery groups, respectively, completed the 3-year follow-up. Symptoms, 24-h pH monitoring and endoscopy were used to document the outcome. Quality of life was evaluated by the psychological general well-being (PGWB) index and the gastrointestinal symptom rating scale (GSRS). RESULTS: Analysis of time to treatment failure (defined as moderate to severe GORD symptoms for > or = 3 days during the last 7 days, oesophagitis or changed therapy) revealed a significant difference in favour of antireflux surgery (P = 0.0016). Seventeen patients originally submitted to antireflux surgery experienced symptom relapse alone, 14 had oesophagitis at endoscopy and another six had omeprazole for different reasons, leaving 97 patients in clinical remission after 3 years. The corresponding figures in the omeprazole arm were 50 relapses, 18 with oesophagitis, two had surgery, leaving 77 patients in remission. Allowing a dose adjustment in the case of relapse in those on omeprazole therapy to either 40 or 60 mg, the curves describing the failure rates were not significantly different from each other. Quality of life assessment showed a comparable outcome in the two study groups. CONCLUSION: In this randomized multicentre trial we found antireflux surgery to be very efficacious in controlling GORD, a level of control which could also be achieved by omeprazole provided that advantage was taken of the opportunity of adjusting the dose.