Coherent and Incoherent Tunneling into Yu-Shiba-Rusinov States Revealed by Atomic Scale Shot-Noise Spectroscopy.

The pair breaking potential of individual magnetic impurities in s-wave superconductors generates localized states inside the superconducting gap commonly referred to as Yu-Shiba-Rusinov (YSR) states whose isolated nature makes them promising building blocks for artificial structures that may host Majorana fermions. One of the challenges in this endeavor is to understand their intrinsic lifetime, ℏ/Λ, which is expected to be limited by the inelastic coupling with the continuum thus leading to decoherence. Here we use shot-noise scanning tunneling microscopy to reveal that electron tunneling into superconducting 2H-NbSe_{2} mediated by YSR states is not Poissonian, but ordered as a function of time, as evidenced by a reduction of the noise. Moreover, our data show the concomitant transfer of charges e and 2e, indicating that incoherent single particle and coherent Andreev processes operate simultaneously. From the quantitative agreement between experiment and theory we obtain Λ=1 µeV≪k_{B}T demonstrating that shot noise can probe energy scales and timescales inaccessible by conventional spectroscopy whose resolution is thermally limited.

Inflammatory bowel disease and risk of adenocarcinoma and neuroendocrine tumors in the small bowel.

BACKGROUND: Uncertainty prevails about the magnitude of excess risk of small bowel cancer in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: To quantify the risk of small bowel adenocarcinoma and neuroendocrine tumors in patients with ulcerative colitis (UC) and Crohn's disease (CD), we undertook a population-based cohort study of all patients with IBD diagnosed in Norway and Sweden from 1987 to 2016. Patients were followed through linkage to national registers. We calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) of small bowel adenocarcinomas and neuroendocrine tumors for patients with CD and UC. We excluded the first year of follow-up to reduce reverse causality. RESULTS: Among 142 008 patients with a median follow-up of 10.0 years, we identified 66 adenocarcinomas and 57 neuroendocrine tumors in the small bowel. The SIR of small bowel adenocarcinoma was 8.3 (95% CI 5.9-11.3) in CD and 2.0 (95% CI 1.2-3.1) in UC. The incidence rates of adenocarcinomas were highest in CD with stricturing disease and extent limited to the small bowel, at 14.7 (95% CI 8.2-24.2) and 15.8 (95% CI 8.4-27.0) per 100 000 person-years, respectively. The SIR of neuroendocrine tumors was 2.5 (95% CI 1.5-3.9) in CD and 2.0 (95% CI 1.4-2.8) in UC. CONCLUSIONS: Patients with CD experienced an eightfold increased risk of small bowel adenocarcinomas, patients with both UC and CD experienced an about twofold increased risk of neuroendocrine tumors, and patients with UC experienced a twofold increased risk of small bowel adenocarcinoma. The small absolute excess cancer risk suggests that active surveillance to diagnose small intestinal cancer early is unlikely to be cost-effective.

Implication of the JNK pathway in a rat model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder resulting from the expansion of a glutamine repeat (polyQ) in the N-terminus of the huntingtin (htt) protein. Expression of polyQ-containing proteins has been previously shown to induce various cellular stress responses. Among these, activation of the c-Jun N-terminal kinase (JNK) cascade has been observed in cellular models of HD. However, the implication of the JNK pathway has not previously been evaluated in the striatum of HD animal models. Here we report that the JNK pathway participates in HD pathology in a rat model of the disease. Increased phosphorylation of the JNK target c-Jun was observed as early as 4 weeks and persisted for 13 weeks after lentiviral-mediated expression of htt171-82Q. In order to assess the importance of this pathway in HD pathology, JNK inhibitors including dominant-negative mutants of upstream kinases (ASK1(K709R), MEKK1(D1369A)), a c-Jun mutant (Delta169c-Jun) and the active domain of the scaffold protein JIP-1/IBI (IBI-JBD) were tested for their ability to mitigate the effect of htt171-82Q. The overexpression of MEKK1(D1369A) and JIP-1/IBI reduced the polyQ-related loss of DARPP-32 expression, while the other inhibitors had no effect. In all cases, the formation of EM48-positive htt inclusions and P-c-Jun immunoreactivity were unaltered. These results suggest that JNK activation is involved in HD and that blockade of this pathway may be of benefit in counteracting HD-related neurotoxicity.

Bronchodilating effects of salbutamol from a novel inhaler Airmax.

This randomized, placebo-controlled, evaluator-blind, five-way crossover study compared the equivalence in terms of FEV1 response to single ascending cumulative doses of salbutamol (100-400 micrograms) from Airmax, a new multidose dry powder inhaler, in comparison with placebo, the same dose from a standard pressurized metered dose inhaler (Ventolin) or at double the dose from the dry powder inhalers Diskhaler and Accuhaler. Sixty-one adult asthmatic subjects with FEV150-80% predicted and > or = 15% increase in FEV1 to salbutamol took part. Equivalence was declared if the 95% CI for the ratio of the FEV1 responses to the two treatments was within the range 90-111%. Following the cumulative four doses, FEV1 (1) changes pre-dose to the highest dose were: 2.53-3.31, 2.47-3.30, 2.51-3.35, 2.52-3.31 and 2.57-2.55 for Airmax salbutamol, salbutamol Ventolin, salbutamol Diskhaler, salbutamol Accuhaler and placebo, respectively. The 95% CIs for the ratio of Airmax salbutamol to each of the active devices were within +/- 5% demonstrating a 1:1 dose equivalence between Airmax salbutamol and Ventolin and a 1:2 dose equivalence between each of the other two salbutamol dry powder devices. Adverse events profiles were similar for all treatments. In conclusion, the novel multidose inhaler Airmax salbutamol is as efficacious and safe as the pressurized metered dose inhaler without the need for co-ordinating actuation and inhalation and with the added benefit of a dose counter.

Effects of 4-week treatment with low-dose budesonide (100 micrograms BID) from a novel inhaler Airmax and from a conventional inhaler on bronchial hyper-responsiveness, lung function and symptoms in patients with mild asthma.

This study investigated the effect of low dose of budesonide 100 micrograms b.d from a new multi-dose dry powder inhaler (Airmax) and from a conventional inhaler (Turbuhaler) on bronchial hyper-responsiveness, lung function and asthma symptoms in mild stable asthmatics. Twenty-five patients were enrolled into a double-blind double-dummy crossover study with two 4-week treatment periods separated by a 4-week washout. Patients had a mean forced expiratory volume in 1 s (FEV1) of 91 +/- 13% predicted, had previously received inhaled short-acting beta 2-agonists only and had a PC20 to adenosine 5' monophosphate (AMP) < 40 mg/ml. PC20 AMP was assessed at baseline, and at the start and end of each treatment period. Patients recorded peak expiratory flow and symptoms throughout the study. There was a mean increase in PC20AMP from start to end of 3.49 doubling dilutions (DD) in the Airmax group and 2.90 DD in the Turbuhaler group. The difference was 0.60 DD (95% CI--0.47, 1.69) favouring Airmax and the upper limit exceeded the equivalence limit of +/- 1 DD. There were similar improvements in FEV1, daily PEF and symptoms in both groups. The majority of patients preferred treatment with Airmax to Turbuhaler (64 vs. 23%). Both treatments were equally well tolerated. In conclusion, 100 micrograms budesonide bid during 4 weeks from Airmax effectively attenuates the response to AMP in mild asthmatics. Overall Airmax offers equal clinical benefit to Turbuhaler.

Multiple access to sterile syringes for injection drug users: vending machines, needle exchange programs and legal pharmacy sales in Marseille, France.

OBJECTIVE: In Marseille, southeastern France, HIV prevention programs for injection drug users (IDUs) simultaneously include access to sterile syringes through needle exchange programs (NEPs), legal pharmacy sales and, since 1996, vending machines that mechanically exchange new syringes for used ones. The purpose of this study was to compare the characteristics of IDUs according to the site where they last obtained new syringes. METHODS: During 3 days in September 1997, all IDUs who obtained syringes from 32 pharmacies, four NEPs and three vending machines were offered the opportunity to complete a self-administered questionnaire on demographics, drug use characteristics and program utilization. RESULTS: Of 485 individuals approached, the number who completed the questionnaire was 141 in pharmacies, 114 in NEPs and 88 at vending machines (response rate = 70.7%). Compared to NEP users, vending machine users were younger and less likely to be enrolled in a methadone program or to report being HIV infected, but more likely to misuse buprenorphine. They also had lower financial resources and were less likely to be heroin injectors than both pharmacy and NEP users. CONCLUSIONS: Our results suggest that vending machines attract a very different group of IDUs than NEPs, and that both programs are useful adjuncts to legal pharmacy sales for covering the needs of IDUs for sterile syringes in a single city. Assessment of the effectiveness and cost-effectiveness of combining such programs for the prevention of HIV and other infectious diseases among IDUs requires further comparative research.

Injecting misuse of buprenorphine among French drug users.

AIMS: To evaluate the extent to which the introduction (February 1996) of ambulatory prescriptions of buprenorphine for drug maintenance treatment (DMT) has been associated with its intravenous illicit use by French injecting drug users (IDUs). DESIGN: Cross-sectional survey (September 1997), using self-administered questionnaires, in a sample of IDUs recruited at 32 pharmacies, four needle exchange programmes and three syringe vending machines. SETTING: Thirty-nine sites where IDUs have access to sterile syringes in the city of Marseille (South-Eastern France). PARTICIPANTS: Sample of IDUs attending community pharmacies, vending machines and needle exchange programs to obtain equipment. MEASUREMENT: To compare characteristics of IDUs who declared that they only injected buprenorphine in the prior 6 months versus the rest of the sample. FINDINGS: Among the 343 respondents (response rate = 70.7%), 33.8% were polydrug users who occasionally injected buprenorphine in parallel to heroin and/or cocaine, while 23.9% only injected buprenorphine in the previous 6 months. IDUs in this latter group were younger, injected more frequently, and were more frequently on buprenorphine DMT, but they were less likely to be HIV-infected and to declare HIV-related injecting risky behaviours. CONCLUSIONS: Substantial risk of injecting misuse is associated with large-scale diffusion of buprenorphine DMT. A more stringent regulation for medical dispensation of buprenorphine than the current French general freedom of prescription for all physicians, including general practiioners in ambulatory care, may be necessary in other countries which are considering the diffusion of buprenorphine DMT.

Identification and synthesis of a trisaccharide produced from lactose by transgalactosylation.

Enzymatic transgalactosylation of lactose by means of Streptococcus thermophilus, subspecies DN-001065, led to a mixture of D-galactose (approximately 4%), D-glucose (approximately 15%), lactose (approximately 51%), minor disaccharides (6%), trisaccharides (approximately 20%) and tetrasaccharides (3%). The major trisaccharide (approximately 16%) was identified by NMR spectroscopy and chemical synthesis as being the known beta-D-galactopyranosyl-(1-->3)-beta-D-galactopyranosyl-(1-->4)-D-glucos e (3'-beta-D-galactopyranosyl-lactose). It was purified from a mixture of peracetylated oligosaccharides by column chromatography followed by deacetylation. For the first time, 3'-beta-D-galactopyranosyl-lactose has been obtained on the 1 g scale, by resorting to simple techniques and equipment. NMR spectra have been unambiguously assigned.

Characterization of the mechanical nonlinear behavior of piezoelectric ceramics.

A characterization of the nonlinear behavior with high signal excitation in piezoceramic resonators was carried out. The behavior of power devices working at resonance, in which high strains are involved, is explained. A theoretical model previously described is used to explain the motional impedance variation proportional to the square of the motional current. This impedance increase DeltaZ is independent of the frequency and explains: the nonlinear elasticity that produces the A-F effect, the nonlinear mechanical losses that increase greatly close to the resonance, and the hysteresis phenomenon produced with frequency sweeps. Different methods for measuring the mechanical nonlinear coefficients of piezoceramics with high signal excitation are presented. An experimental method is proposed to measure the mechanical loss tangent and the compliance variations as a function of the mean square strain in the piezoceramic. This consists in measuring the maximum admittance and the series resonance frequency for downward frequencies. At this jumping point, the phase angle remains zero whatever the amplitude of the excitation. Two main coefficients characterizing the material mechanical nonlinearity are deduced. Experimental measurements were carried out to compare the nonlinearity of different ceramic materials in longitudinal and transverse mode.

Variability of attitudes toward early initiation of HAART for HIV infection: a study of French prescribing physicians.

This study assessed prescribing physicians' attitudes toward early initiation of HAART, three months after the dissemination of the first French official treatment guideline. Telephone interviews have been made in a national random sample of physicians with full- or part-time practice in hospital departments delivering care for HIV-infected patients. Questionnaires included hypothetical clinical cases. Logistic regression compared characteristics of respondents according to attitudes toward HAART. Among the 483 respondents (response rate = 87.0%), agreement was high with official recommendations to systematically initiate HAART with protease inhibitors (PIs) for patients with CD4+ cell counts < or = 300/mm3, following a diagnosis of acute primary HIV infection, or for HIV sexual risk post-exposure prophylaxis. Confronted with a case of a naive asymptomatic patient with stable 450 CD4+/mm3, 34.6% would prescribe HAART with PIs in any case, and 29.8% only if the patient has plasma viral load < or = 10,000 HIV RNA copies/ml. The remaining 35.6% would not prescribe PIs and were older, had limited activity in HIV care and expressed more interest in alternative medicines. To avoid a confusing impact of variability of clinical attitudes toward uncertainties associated with antiretroviral treatments among HIV-infected patients, shared decision-making between patient and physician should be promoted for initiation of HAART.

Syringe vending machines for injection drug users: an experiment in Marseille, France.

OBJECTIVES: This study evaluated the usefulness of vending machines in providing injection drug users with access to sterile syringes in Marseille, France. METHODS: Self-administered questionnaires were offered to 485 injection drug users obtaining syringes from 32 pharmacies, 4 needle exchange programs, and 3 vending machines. RESULTS: Of the 343 respondents (response rate = 70.7%), 21.3% used the vending machines as their primary source of syringes. Primary users of vending machines were more likely than primary users of other sources to be younger than 30 years, to report no history of drug maintenance treatment, and to report no sharing of needles or injection paraphernalia. CONCLUSIONS: Vending machines may be an appropriate strategy for providing access to syringes for younger injection drug users, who have typically avoided needle exchange programs and pharmacies.

Inhaled beclomethasone (BDP) with non-CFC propellant (HFA 134a) is equivalent to BDP-CFC for the treatment of asthma.

As part of a development programme for a range of new CFC-free beclomethasone dipropionate (BDP) inhalers, two multicentre double-blind studies have been conducted to compare the therapeutic equivalence of a new HFA-134a propellant-formulated BDP metered-dose inhaler (Norton Healthcare Ltd, London, U.K.) with a CFC counterpart for the management of adult patients with all grades of asthma. Doses of 100 micrograms qds for 6 weeks were administered in a low dose study and in a high dose study 500 micrograms qds doses were given for 12 weeks. Efficacy assessments included lung function (FEV1) in the clinic and asthma symptoms, peak flow rates and bronchodilator use by patients on diary cards. Safety parameters measured included routine haematology and biochemistry (including serum cortisols), clinical adverse events and throat swabs for Candida spp. Both CFC and HFA-formulations of inhaled BDP produced similar and significant improvements in lung function and asthma symptoms. In the low dose study, baseline to endpoint FEV1 increased from 2.2 +/- 0.51 to 2.5 +/- 0.81 (P = 0.0001) with BDP-CFC and from 2.2 +/- 0.51 to 2.6 +/- 0.81 with BDP-HFA (P = 0.0001), with no significant difference between treatments. In the high dose study, corresponding increases were 2.1 +/- 0.71 to 2.4 +/- 0.91 (P = 0.0002) for BDP-CFC and 2.1 +/- 0.71 to 2.3 +/- 0.71 (P = 0.017) for BDP-HFA. PEF also improved similarly on both treatments in both studies. Both formulations were well tolerated with no difference in the pattern of adverse events, effect on serum cortisol or Candida colonization. These studies showed that, in the management of asthma, the new HFA-formulated BDP metered dose inhaler is equivalent to, and directly substitutable for, the older CFC-formulated product at the same dose, making change-over for patients straightforward.

[Therapeutic attitude to HIV infection: uncertain and variable scientific attitudes. 1998 national survey of physicians prescribing antiretroviral drugs]. / Attitudes thérapeutiques pour l'infection à VIH: incertitudes scientifiques et variabilités. Enquête nationale 1998 auprès des médecins prescripteurs d'antirétroviraux. Groupe PAMPA. Pratiques et Attitudes des Médecins Prescriteurs d'Antirétroviraux.

OBJECTIVES: Analyze the attitudes of French practitioners managing HIV infected patients towards multidrug antiretroviral therapies with protease inhibitors, open issues, and the official guidelines (Dormont report). METHODS: A telephone survey was conducted in February-March 1998 on a random sample of the nation file of hospital physicians prescribing antiretroviral drugs (response rate 87%, n = 483). RESULTS: The responding clinicians were in general agreement on defining virological efficacy at three months treatment as an undetectable viral load (86.5%). There was a general concensus on multidrug therapy with a protease inhibitor in case of primary infection (83.2%) or sexual exposure with risk of HIV transmission (83.2%). Inversely, only 43.7% abandoned PCP and toxoplasmosis prophylaxis in patients with CD4 counts above 350/mm3 taking tritherapy antiretroviral regimens. When asked to state their approach to a hypothetical case of an asymptomatic patient with a CD4 count of 450, 35.6% would not propose multidrug therapy with an antiprotease, 29.8% would only envisage such a regimen if the viral load was above 10,000 copies/ml, and finally 34.6% would prescribe a multidrug regimen with a protease inhibitor whatever the viral load. CONCLUSION: The variability observed in routine clinical practices would appear to be justified in light of the uncertainty about the long-term effects of the new antiretroviral drugs for HIV/AIDS.

Overview of initial clinical studies with intravenous and oral GR43175 in acute migraine.

The novel 5-HT 1-like receptor agonist GR43175 has been evaluated as a treatment for acute migraine in a series of open, dose-ranging and controlled clinical trials. Patients with severe attacks of migraine have attended special pain or headache clinics for treatment and assessment. Given intravenously as a bolus, GR43175 is capable of aborting all migraine symptoms within 10-30 min in over 90% of cases at a dose of 64 micrograms/kg. Characteristic transient and reversible side effects with such a regimen include feelings of heaviness, pressure and occasionally warmth or tingling which can be diminished by extending the duration of drug administration to a short infusion. Initial dose-ranging studies with a dispersible tablet formulation of GR43175 have revealed an efficacy of 70-85% within 2 h with doses of 70-280 mg. Furthermore, tolerability is excellent. These encouraging early results warrant larger-scale controlled studies of GR43175 in acute migraine.

Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine.

GR43175, a selective 5-HT1-like agonist, was given as an intravenous infusion in an open dose-ranging study to treat 46 attacks of severe migraine in 34 patients. The highest dose, 2 mg infused over 10 min in 24 severe attacks, resulted in rapid and complete relief of symptoms in 17 attacks (71%) and in improvement to a non-migrainous residual headache in 7 attacks. Treatment was well tolerated, the only adverse effects being transient feelings of heaviness and pressure, predominantly in the head. GR43175 may represent an important advance in the treatment of acute migraine.

Clinical pharmacokinetics of ergotamine in migraine and cluster headache.

Ergotamine has been in use for the treatment of migraine for a century and is still considered to be the most effective therapeutic agent for acute attacks. Only during the last few years have assays been developed, enabling its pharmacokinetics to be studied. Appropriate assays for determining ergotamine concentrations in plasma are radioimmunoassay and high-performance liquid chromatography. There is great interindividual variation in absorption of ergotamine in both patients and normal volunteers. Bioavailability is of the order of 5% or less by oral or rectal administration. After intramuscular or intravenous administration, plasma concentrations decay in a biexponential fashion. The elimination of half-life is 2 to 2.5 hours and clearance is about 0.68 L/h/kg. As yet, formal pharmacokinetics following oral dosing have not been determined. There is some evidence that ergotamine enters the cerebrospinal fluid. Metabolism occurs in the liver, and the primary route of excretion is biliary. Up to 90% of migraine patients experience complete or partial symptom relief after ergotamine, providing the drug is given as early in their attack as possible. Efficacy is greatest after parenteral administration, although adverse effects may make the rectal or inhaled routes preferable. There is some evidence to suggest that good responses are associated with plasma concentrations of 0.2 ng/ml or above within one hour of administration. The mode of action of ergotamine in migraine may be by means of selective arterial vasoconstriction on certain cranial vessel beds or, alternatively, by depression of central serotonergic neurons mediating pain transmission or circulatory regulation. Principal adverse effects of ergotamine include nausea, vomiting, weakness, muscle pains, paraesthesiae and coldness of the extremities. Ergotamine dependence is not uncommon, resulting in an exacerbation of the above symptoms. Dosage must therefore be limited to no more than 10mg per week to minimise toxicity.

Gastric ulcer healing with ranitidine and cimetidine. A multicentre study.

A single-blind study of 339 patients in 19 centres compared the efficacy and tolerance of ranitidine in treating endoscopically confirmed gastric ulcers. Ranitidine (150 mg twice daily) was compared with cimetidine (1 g daily in divided doses) over 4 weeks, followed by a second 4-week treatment for any patient whose ulcer was not healed. In 292 patients who completed the study, endoscopy showed healing in 69% of patients receiving ranitidine and 59% receiving cimetidine after 4 weeks, and 90% and 88%, respectively, by 8 weeks. These results were not significantly different, and, similarly, healing rates for different ulcer sites did not differ. There were no serious adverse drug reactions during the study. Ranitidine is an effective and safe treatment for healing gastric ulcers, with a tendency to produce a faster healing rate than cimetidine during the first 4 weeks of treatment.