Randomised controlled trials of homeopathy in hyperactive children: treatment procedure leads to an unconventional study design. Experience with open-label homeopathic treatment preceding the Swiss ADHD placebo controlled, randomised, double-blind, cross-over trial

BACKGROUND: Treatment of patients with attention deficit hyperactivity disorder (ADHD) with homeopathy is difficult. The Swiss randomised, placebo controlled, cross-over trial in ADHD patients (Swiss ADHD trial) was designed with an open-label screening phase prior to the randomised controlled phase. During the screening phase, the response of each child to successive homeopathic medications was observed until the optimal medication was identified. Only children who reached a predefined level of improvement participated in the randomised, cross-over phase. Although the randomised phase revealed a significant beneficial effect of homeopathy, the cross-over caused a strong carryover effect diminishing the apparent difference between placebo and verum treatment. METHODS: This retrospective analysis explores the screening phase data with respect to the risk of failure to demonstrate a specific effect of a randomised controlled trial (RCT) with randomisation at the start of the treatment. RESULTS: During the screening phase, 84% (70/83) of the children responded to treatment and reached eligibility for the randomised trial after a median time of 5 months (range 1-18), with a median of 3 different medications (range 1-9). Thirteen children (16%) did not reach eligibility. Five months after treatment start, the difference in Conners Global Index (CGI) rating between responders and non-responders became highly significant (p = 0.0006). Improvement in CGI was much greater following the identification of the optimal medication than in the preceding suboptimal treatment period (p < 0.0001). CONCLUSIONS: Because of the necessity of identifying an optimal medication before response to treatment can be expected, randomisation at the start of treatment in an RCT of homeopathy in ADHD children has a high risk of failure to demonstrate a specific treatment effect, if the observation time is shorter than 12 months.

Anteroposterior pelvic radiographs to assess acetabular retroversion: high validity of the "cross-over-sign"

Acetabular retroversion has been proposed to contribute to the development of osteoarthritis of the hip. For the diagnosis of this condition, conventional AP pelvic radiographs may represent a reliable, easily available diagnostic modality as they can be obtained with a reproducible technique allowing the anterior and posterior acetabular rims to be visible for assessment. This study was designed to: (i) determine cranial, central, and caudal anatomic acetabular version (AV) from cadaveric specimens; (ii) establish the validity and reliability of the radiographic measurements of central acetabular anteversion; and (iii) determine the validity and reliability of the radiographic "cross-over-sign" to detect acetabular retroversion. Using 43 desiccated pelvises (86 acetabuli) the anatomic AVs were measured at three different transverse planes (cranially, centrally, and caudally). From these pelvises, standardized AP pelvic radiographs were obtained. To directly measure central AV, a modified radiographic method is introduced for the use of AP pelvic radiographs. The validity and reliability of this radiographic method and of the radiographic cross-over-sign to detect cranial acetabular retroversion were determined. The mean central and caudal anatomic AVs were approximately 20 degrees , and the mean cranial AV was 8 degrees . Cranial retroversion (AV < 0 degrees ) was present in 19 of 86 hips (22%). A linear correlation was found between the central and cranial AV. Below 10 degrees of central AV, all acetabuli were cranially retroverted. Between 10 degrees and 20 degrees , 30% of the acetabuli were cranially retroverted, and above 20 degrees , only 1 of 45 acetabuli was cranially retroverted. The radiographic measurement of the central AV (20.3 +/- 6.5 degrees ) correlated strongly with the anatomic AV (20.1 +/- 6.4 degrees ). The sensitivity of the cross-over-sign to detect a cranial acetabular anteversion of less than 4 degrees was 96%, its specificity 95%, and the positive predictive and negative predictive values 90% and 98%, respectively. Both the modified radiographic anteversion measurements and the cross-over-sign demonstrated substantial inter- and intraobserver reliability. Retroversion is almost exclusively a problem of the cranial acetabulum. The cranial AV is on average 12 degrees lower than the central AV, with the latter directly measurable from AP pelvic radiographs. A central AV of less than 10 degrees was associated with cranial retroversion. The presence of a positive cross-over-sign is a highly reliable indicator of cranial AV of <4 degrees.

A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus--effects on slowphase eye velocity, postural stability, locomotion and symptoms

Objective The effects of 4-aminopyridine (4-AP) on downbeat nystagmus (DBN) were analysed in terms of slow-phase velocity (SPV), stance, locomotion, visual acuity (VA), patient satisfaction and side effects using standardised questionnaires. Methods Twenty-seven patients with DBN received 5 mg 4-AP four times a day or placebo for 3 days and 10 mg 4-AP four times a day or placebo for 4 days. Recordings were done before the first, 60 min after the first and 60 min after the last drug administration. Results SPV decreased from 2.42 deg/s at baseline to 1.38 deg/s with 5 mg 4-AP and to 2.03 deg/s with 10 mg 4-AP (p<0.05; post hoc: 5 mg 4-AP: p=0.04). The rate of responders was 57%. Increasing age correlated with a 4-AP-related decrease in SPV (p<0.05). Patients improved in the ‘get-up-and-go test’ with 4-AP (p<0.001; post hoc: 5 mg: p=0.025; 10 mg: p<0.001). Tandem-walk time (both p<0.01) and tandem-walk error (4-AP: p=0.054; placebo: p=0.059) improved under 4-AP and placebo. Posturography showed that some patients improved with the 5 mg 4-AP dose, particularly older patients. Near VA increased from 0.59 at baseline to 0.66 with 5 mg 4-AP (p<0.05). Patients with idiopathic DBN had the greatest benefit from 4-AP. There were no differences between 4-AP and placebo regarding patient satisfaction and side effects. Conclusions 4-AP reduced SPV of DBN, improved near VA and some locomotor parameters. 4-AP is a useful medication for DBN syndrome, older patients in particular benefit from the effects of 5 mg 4-AP on nystagmus and postural stability.

Standard model cross-over on the lattice

With the physical Higgs mass the standard model symmetry restoration phase transition is a smooth cross-over. We study the thermodynamics of the cross-over using numerical lattice Monte Carlo simulations of an effective SU(2)×U(1) gauge+Higgs theory, significantly improving on previously published results. We measure the Higgs field expectation value, thermodynamic quantities like pressure, energy density, speed of sound and heat capacity, and screening masses associated with the Higgs and Z fields. While the cross-over is smooth, it is very well defined with a width of only ∼5  GeV. We measure the cross-over temperature from the maximum of the susceptibility of the Higgs condensate, with the result Tc=159.5±1.5  GeV. Outside of the narrow cross-over region the perturbative results agree well with nonperturbative ones.

Efficacy of a Nasal Spray from Citrus limon and Cydonia oblonga for the Treatment of Hay Fever Symptoms - A Randomized, Placebo Controlled Cross-Over Study

Nasal spray from lemon and quince (LQNS) is used to treat hay fever symptoms and has been shown to inhibit histamine release from mast cells in vitro. Forty-three patients with grass pollen allergy (GPA) were randomized to be treated either with placebo or LQNS for one week, respectively, in a cross-over study. At baseline and after the respective treatments patients were provoked with grass pollen allergen. Outcome parameters were nasal flow measured with rhinomanometry (primary), a nasal symptom score, histamine in the nasal mucus and tolerability. In the per protocol population absolute inspiratory nasal flow 10 and 20 min after provocation was higher with LQNS compared to placebo (-37 ± 87 mL/s; p = 0.027 and -44 ± 85 mL/s; p = 0.022). The nasal symptom score showed a trend (3.3 ± 1.8 in the placebo and 2.8 ± 1.5 in the LQNS group; p = 0.070) in favor of LQNS; the histamine concentration was not significantly different between the groups. Tolerability of both, LQNS and placebo, was rated as very good. LQNS seems to have an anti-allergic effect in patients with GPA. Copyright © 2016 John Wiley & Sons, Ltd.

Postprandial serum endotoxin in healthy humans is modulated by dietary fat in a randomized, controlled, cross-over study

Background: High-fat diets may contribute to metabolic disease via postprandial changes in serum endotoxin and inflammation. It is unclear how dietary fat composition may alter these parameters. We hypothesized that a meal rich in n-3 (ω3) fatty acids would reduce endotoxemia and associated inflammation but a saturated or n-6 (ω6) fatty acid-rich meal would increase postprandial serum endotoxin concentrations and systemic inflammation in healthy adults. Methods: Healthy adults (n = 20; mean age 25 ± 3.2 S.D. years) were enrolled in this single-blind, randomized, cross-over study. Participants were randomized to treatment and reported to the laboratory, after an overnight fast, on four occasions separated by at least one week. Participants were blinded to treatment meal and consumed one of four isoenergetic meals that provided: 1) 20 % fat (control; olive oil) or 35 % fat provided from 2) n-3 (ω3) (DHA = 500 mg; fish oil); 3) n-6 (ω6) (7.4 g; grapeseed oil) or 4) saturated fat (16 g; coconut oil). Baseline and postprandial blood samples were collected. Primary outcome was defined as the effect of treatment meal on postprandial endotoxemia. Serum was analyzed for metabolites, inflammatory markers, and endotoxin. Data from all 20 participants were analyzed using repeated-measures ANCOVA. Results: Participant serum endotoxin concentration was increased during the postprandial period after the consumption of the saturated fat meal but decreased after the n-3 meal (p < 0.05). The n-6 meal did not effect a different outcome in participant postprandial serum endotoxin concentration from that of the control meal (p > 0.05). There was no treatment meal effect on participant postprandial serum biomarkers of inflammation. Postprandial serum triacylglycerols were significantly elevated following the n-6 meal compared to the n-3 meal. Non-esterified fatty acids were significantly increased after consumption of the saturated fat meal compared to other treatment meals. Conclusions: Meal fatty acid composition modulates postprandial serum endotoxin concentration in healthy adults. However, postprandial endotoxin was not associated with systemic inflammation in vivo. Trial registration: This study was retrospectively registered at clinicaltrials.gov as NCT02521779 on July 28, 2015.

One-step synthesis of 2-pentanone from ethanol over K-Pd/MnOx-ZrO2-ZnO catalyst

A highly active and selective K-Pd/MnOx-ZrO2-ZnO catalyst for the one-step synthesis of 2-pentanone from ethanol is described. The possible reaction pathways for ethanol reaction over K-Pd/MnOx-ZrO2-ZnO catalyst were investigated by means of TPSR, CO2- and NH3-TPD techniques. The reactions were performed in a fixed bed continuous flow reactor. Complete conversion with high selectivity for 2-pentanone, was observed under 370 similar to 390degreesC, 2 similar to 4 MPa, GHSV = 8000 similar to 10,000 h(-1) and LHSV < 1.25 h(-1) conditions. Ethanol reactions over K-Pd/MnOx-ZrO2-ZnO catalyst showed that the catalyst could catalyze dehydrogenation. aldol. dehydration and hydrogenation reactions. Both acidic and basic properties are found on the surface of K-Pd/MnOx-ZrO2-ZnO catalyst, whose multifunctionality with the combination of basic, acid and metal sites may be responsible for the efficiency of the K-PdMnOx-ZrO2-ZnO catalyst. (C) 2004 Elsevier B.V. All rights reserved.

Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats

BACKGROUND: There has been some difficulty getting standard laboratory rats to voluntarily consume large amounts of ethanol without the use of initiation procedures. It has previously been shown that standard laboratory rats will voluntarily consume high levels of ethanol if given intermittent-access to 20% ethanol in a 2-bottle-choice setting [Wise, Psychopharmacologia 29 (1973), 203]. In this study, we have further characterized this drinking model. METHODS: Ethanol-naïve Long-Evans rats were given intermittent-access to 20% ethanol (three 24-hour sessions per week). No sucrose fading was needed and water was always available ad libitum. Ethanol consumption, preference, and long-term drinking behaviors were investigated. Furthermore, to pharmacologically validate the intermittent-access 20% ethanol drinking paradigm, the efficacy of acamprosate and naltrexone in decreasing ethanol consumption were compared with those of groups given continuous-access to 10 or 20% ethanol, respectively. Additionally, ethanol consumption was investigated in Wistar and out-bred alcohol preferring (P) rats following intermittent-access to 20% ethanol. RESULTS: The intermittent-access 20% ethanol 2-bottle-choice drinking paradigm led standard laboratory rats to escalate their ethanol intake over the first 5 to 6 drinking sessions, reaching stable baseline consumption of high amounts of ethanol (Long-Evans: 5.1 +/- 0.6; Wistar: 5.8 +/- 0.8 g/kg/24 h, respectively). Furthermore, the cycles of excessive drinking and abstinence led to an increase in ethanol preference and increased efficacy of both acamprosate and naltrexone in Long-Evans rats. P-rats initiate drinking at a higher level than both Long-Evans and Wistar rats using the intermittent-access 20% ethanol paradigm and showed a trend toward a further escalation in ethanol intake over time (mean ethanol intake: 6.3 +/- 0.8 g/kg/24 h). CONCLUSION: Standard laboratory rats will voluntarily consume ethanol using the intermittent-access 20% ethanol drinking paradigm without the use of any initiation procedures. This model promises to be a valuable tool in the alcohol research field.

Evaluation of the adverse effects of subcutaneous carprofen over six days in healthy cats

This study evaluated the adverse effects of carprofen in seven healthy cats. Values for CBC, biochemical profiles and platelet aggregation were measured before and at seven days after SID treatment with subcutaneous carprofen: 4 mg/kg (day 1), 2 mg/kg (day 2 and 3) and 1 mg/kg (day 4 and 6) (CG) or 0.35 ml of saline (SG) for six days in a randomized, blinded, cross-over study with a four-week washout period. No treatment was given on day 5. Endoscopy of the GI tract was performed pre-treatment and on day 7 post-treatment. There were no significant changes in hematological profiles, biochemical profiles and endoscopy grading scores within nor between groups, except for lower albumin values at baseline than on day 7 (CG), and globulin and ALP values were higher at baseline than on day 7 in CG and SG. SC administration of carprofen over six days did not cause any adverse effects on gastrointestinal, hematological, or serum biochemical variables. (c) 2008 Elsevier Ltd. All rights reserved.

Assessment of the astrogliotic responses of three human astrocytoma cell lines to ethanol, trimethyltin chloride and acrylamide

The astrogliotic responses of the CCF-STTG1, U251-MG, and U373-MG human astrocytoma lines were determined after exposure to ethanol, trimethyltin chloride (TMTC), and acrylamide over 4, 16, and 24 h. Basal glial fibrillary acidic protein (GFAP) expression in the U-251MG and U373-MG cells was 10-fold greater than the CCF-STGG1 line. Ethanol treatment over 24 h, but not at 4 and 16 h, resulted in significant increases in GFAP in all three glioma lines at sub-cytotoxic levels; the GFAP responses in the CCF-STTG1 line were the most sensitive, as concentrations of 0.1 and 1 mM led to increases in GFAP expression compared with control of 56.8 ± 15.7 and 58.9 ± 11.5%, respectively (P < 0.05). Treatment with TMTC (1 μM) over 4 h showed elevated GFAP expression in the U251-MG cell line to 28.0 ± 15.7% above control levels (P < 0.01), but not in the other U373-MG or CCF-STTG1 cells. At 4 h, MTT turnover was markedly increased compared with control, particularly in the U373-MG line at concentrations as low as 1 μM (17.1 ± 2.3%; P < 0.01). TMTC exposure over 16 and 24 h resulted in reduction in GFAP expression in all three lines at concentrations; at 24 h incubation, the reduction was >50% (P < 0.01). There were no changes in GFAP expression or MTT turnover in response to acrylamide except at the highest concentration ranges of 10-100 mM. This study underlines the significance of period of exposure, as well as toxin concentration in astrocytoma cellular response to toxic pressure. © 2007 Elsevier Ireland Ltd. All rights reserved.

Kava Anxiety Depression Spectrum Study (KADSS): a mixed methods RCT using an aqueous extract of Piper methysticum

Objectives: To report on the design, significance and potential impacts of the first documented human clinical trial assessing the anxiolytic and thymoleptic efficacy of an aqueous monoextract of Piper methysticum (kava). The significance of the qualitative element of our clinical trial is also explored. The Kava Anxiety Depression Spectrum Study (KADSS) is a 3-week placebocontrolled, double-blind, cross-over trial involving 60 adult participants (18—65) with elevated stable anxiety and varying levels of depressive symptoms. Aims: The aims of KADSS are: (1) to determine whether an aqueous standardised extract of kava is effective for the treatment of anxiety; (2) to assess the effects of kava on differing levels of depression; and (3) to explore participants’ experience of taking kava via qualitative research. The study also provides preliminary assessment of the safety of an aqueous extract of kava in humans. Conclusion: If results reveal that the aqueous kava preparation exerts significant anxiolytic effects and appears safe, potentially beneficial impacts may occur. Data supporting a safe and effective kava extract may encourage a re-introduction of kava to Europe, UK and Canada. This may provide a major socioeconomic benefit to Pacific Island nations, and to sufferers of anxiety disorders.

Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects

Recombinant glucagon-like peptide-1 (7–36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1 was given for 5d by prandial subcutaneous injections (PSI) (76nmol 30min before meals, four times daily; a total of 302·4nmol/24h) or by continuous subcutaneous infusion (CSI) (12·7nmol/h; a total of 304·8nmol/24h). This was performed in nineteen healthy obese subjects (mean age 44·2 (sem 2·5) years; BMI 39·0 (sem 1·2)kg/m2) in a prospective randomised, double-blind, placebo-controlled, cross-over study. Compared with the placebo, rGLP-1 administered as PSI and by CSI generated a 15% reduction in mean food intake per meal (P=0·02) after 5d treatment. A weight loss of 0·55 (sem 0·2) kg (P<0·05) was registered after 5d with PSI of rGLP-1. Gastric emptying rate was reduced during both PSI (P<0·001) and CSI (P<0·05) treatment, but more rapidly and to a greater extent with PSI of rGLP-1. To conclude, a 5d treatment of rGLP-1 at high doses by PSI, but not CSI, promptly slowed gastric emptying as a probable mechanism of action of increased satiety, decreased hunger and, hence, reduced food intake with an ensuing weight loss.