Headache service quality evaluation: implementation of quality indicators in primary care in Europe.

BACKGROUND: Lifting The Burden (LTB) and European Headache Federation (EHF) have developed a set of headache service quality indicators, successfully tested in specialist headache centres. Their intended application includes all levels of care. Here we assess their implementation in primary care. METHODS: We included 28 primary-care clinics in Germany (4), Turkey (4), Latvia (5) and Portugal (15). To implement the indicators, we interviewed 111 doctors, 92 nurses and medical assistants, 70 secretaries, 27 service managers and 493 patients, using the questionnaires developed by LTB and EHF. In addition, we evaluated 675 patients' records. Enquiries were in nine domains: diagnosis, individualized management, referral pathways, patient education and reassurance, convenience and comfort, patient satisfaction, equity and efficiency of headache care, outcome assessment and safety. RESULTS: The principal finding was that Implementation proved feasible and practical in primary care. In the process, we identified significant quality deficits. Almost everywhere, histories of headache, especially temporal profiles, were captured and/or assessed inaccurately. A substantial proportion (20%) of patients received non-specific ICD codes such as R51 ("headache") rather than specific headache diagnoses. Headache-related disability and quality of life were not part of routine clinical enquiry. Headache diaries and calendars were not in use. Waiting times were long (e.g., about 60 min in Germany). Nevertheless, most patients (> 85%) expressed satisfaction with their care. Almost all the participating clinics provided equitable and easy access to treatment, and follow-up for most headache patients, without unnecessary barriers. CONCLUSIONS: The study demonstrated that headache service quality indicators can be used in primary care, proving both practical and fit for purpose. It also uncovered quality deficits leading to suboptimal treatment, often due to a lack of knowledge among the general practitioners. There were failures of process also. These findings signal the need for additional training in headache diagnosis and management in primary care, where most headache patients are necessarily treated. More generally, they underline the importance of headache service quality evaluation in primary care, not only to identify-quality failings but also to guide improvements. This study also demonstrated that patients' satisfaction is not, on its own, a good indicator of service quality.

Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop.

Lysosomes have a central role in cellular catabolism, trafficking, and processing of foreign particles. Accumulation of endogenous and exogenous materials in lysosomes represents a common finding in nonclinical toxicity studies. Histologically, these accumulations often lack distinctive features indicative of lysosomal or cellular dysfunction, making it difficult to consistently interpret and assign adverse dose levels. To help address this issue, the European Society of Toxicologic Pathology organized a workshop where representative types of lysosomal accumulation induced by pharmaceuticals and environmental chemicals were presented and discussed. The expert working group agreed that the diversity of lysosomal accumulations requires a case-by-case weight-of-evidence approach and outlined several factors to consider in the adversity assessment, including location and type of cell affected, lysosomal contents, severity of the accumulation, and related pathological effects as evidence of cellular or organ dysfunction. Lysosomal accumulations associated with cytotoxicity, inflammation, or fibrosis were generally considered to be adverse, while those found in isolation (without morphologic or functional consequences) were not. Workshop examples highlighted the importance of thoroughly characterizing the biological context of lysosomal effects, including mechanistic data and functional in vitro readouts if available. The information provided here should facilitate greater consistency and transparency in the interpretation of lysosomal effects.

Prenatal and adult androgen activities in alcohol dependence.

OBJECTIVE: Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. METHOD: We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). RESULTS: The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P < 0.001) and alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P < 0.005). Moreover, stress levels (P = 0.002), alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). CONCLUSION: Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence.

The modulating effect of the androgen receptor on craving in alcohol withdrawal of men is partially mediated by leptin.

We reported recently that a functional relevant CAG trinucleotide repeat of the androgen receptor influences craving of men in alcohol withdrawal. It is known to modulate serum concentrations of leptin, which affects hypothalamic appetite regulation. Its plasma levels are elevated during chronic alcohol consumption, normalize within periods of abstinence and are associated with craving. The aim of this study was to further elucidate the role of leptin in mediating the effects of the mentioned polymorphism on craving in men undergoing alcohol withdrawal. We included 110 male in-patients who were admitted for detoxification treatment. Each one had an established diagnosis of alcohol dependence according to the DSM-IV. Our results show on the one hand negative associations between the number of CAG repeats and (i) leptin serum levels (P<0.01) and (ii) craving (P<0.05), and on the other hand, a positive association between leptin and craving of man in alcohol withdrawal (P<0.001). The path analysis revealed direct and mediated effects of the number of CAG repeats on alcohol craving, direct effects (r=-0.144) accounting for 60% and indirect, leptin-mediated effects (r=-0.096) accounting for 40% of the total effect. Dysregulation of sexual hormones influences human metabolism and seems to affect leptin homeostasis. This report suggests that the investigated polymorphism mediates its effect on craving of men in alcohol withdrawal mostly through the regulation of leptin. Nevertheless future studies are needed to further explore the functionality of the androgen receptor gene in terms of craving.

[Frontotemporal dementia: neurotransmitter and clinical symptoms with focus on therapeutic targets]. / Frontotemporale Demenz: Neurotransmitter und klinische Symptomatik im Fokus therapeutischer Uberlegungen.

Frontotemporal dementia is more frequently diagnosed because of revised diagnostic procedures. Due to the lack of pharmacological trials it is a disease that is difficult to manage in the way of evidence based medicine. Deficits in serotonergic and dopaminergic signal-transmission are well known. The cholinergic system does not seem to be affected. Case reports and clinical trials show a benefit by using antidepressants, neuroleptics and mood stabilizers. Nevertheless only paroxetine, trazodone and rivastigmine are tested by double-blind, placebo-controlled studies. While paroxetine shows inconsistent data, trazodone improves behavioural symptoms. Patients report a treatment-emergent adverse effect including fatigue, dizziness and hypotension. Rivastigmine leads to a significant decrease in the Neuropsychiatric Inventory Score. Finally, we present a two-cases-report that shows improve of disease symptoms under treatment with repetitive transcranial magnet stimulation.

Spectral functions of Sr2IrO4: theory versus experiment.

The spin-orbit Mott insulator Sr2IrO4 has attracted a lot of interest in recent years from theory and experiment due to its close connection to isostructural high-temperature copper oxide superconductors. Despite not being superconductive, its spectral features closely resemble those of the cuprates, including Fermi surface and pseudogap properties. In this article, we review and extend recent work in the theoretical description of the spectral function of pure and electron-doped Sr2IrO4 based on a cluster extension of dynamical mean-field theory ('oriented-cluster DMFT') and compare it to available angle-resolved photoemission data. Current theories provide surprisingly good agreement for pure and electron-doped Sr2IrO4, both in the paramagnetic and antiferromagnetic phases. Most notably, one obtains simple explanations for the experimentally observed steep feature around the M point and the pseudo-gap-like spectral feature in electron-doped Sr2IrO4.

Engaging adolescents with LD in higher order thinking about history concepts using integrated content enhancement routines.

The understanding and use of historical concepts specified in national history standards pose many challenges to students. These challenges include both the acquisition of content knowledge and the use of that knowledge in ways that require higher order thinking. All students, including adolescents with learning disabilities (LD), are expected to understand and use concepts of history to pass high-stakes assessments and to participate meaningfully in a democratic society. This article describes Content Enhancement Routines (CERs) to illustrate instructional planning, teaching, and assessing for higher order thinking with examples from an American history unit. Research on the individual components of Content Enhancement Routines will be illustrated with data from 1 of the routines. The potential use of integrated sets of materials and procedures across grade levels and content areas will be discussed.

Dissociation of therapeutic and toxic effects of polyinosinic-polycytidylic acid admixed with poly-L-lysine and solubilized with carboxymethyl cellulose in tumor-bearing mice.

In this paper, we describe a study of the therapeutic parameters (dose and schedule) and immunomodulatory activity (macrophage, natural killer cell, and T-cell number and function) of polyinosinic-polycytidylic acid admixed with poly-L-lysine and solubilized with carboxymethyl cellulose [poly(I,C)-LC] in the treatment of MBL-2 tumor ascites. Tumor-bearing mice received an optimal therapeutic protocol [100 micrograms poly(I,C)-LC administered twice a wk], a maximum tolerated dose [50 micrograms poly(I,C)-LC administered daily], or the optimal immunomodulatory protocol for normal mice [10 micrograms poly(I,C)-LC administered daily]. The percentage of tumor-associated macrophages and their cytotoxic activity correlated with host survival. In addition, splenic T-cell activity correlated with host survival, and splenic natural killer cell function had a near significant correlation with host survival. These results indicate that the optimal dose and schedule of poly(I,C)-LC for immunomodulation in tumor-bearing animals are also the optimal therapeutic protocol but have less toxicity than the maximum tolerated dose.

Immunomodulatory properties of recombinant murine and human tumor necrosis factor.

Tumor necrosis factor has traditionally been thought to have direct cytostatic and cytotoxic properties with little or no direct immunomodulatory activity. We report here that tumor necrosis factor is able to activate macrophages both in vitro and in vivo and can increase a mixed lymphocyte response and act as an adjuvant for both T- and B-cells in vivo. Adjuvant activity in T-cells occurred in conjunction with the administration of a suboptimal syngeneic tumor cell vaccine. In addition, tumor necrosis factor demonstrated a potent dose-dependent effect on bone marrow stem cell number, dramatically depressing cellularity and thus total stem cell number. An appreciable interval is required for recovery from such stem cell depletion. Therefore, the study of the therapeutic activity of tumor necrosis factor must include a consideration of its immunomodulatory properties.

Immunomodulatory and therapeutic properties of bestatin in mice.

In this report, we describe the immunomodulatory properties and therapeutic efficacy of bestatin. Macrophage activation, but not natural killer cell augmentation, was observed both in vitro and in vivo. Immunostimulation of T-cell activity was observed in assays of allogeneic mixed lymphocyte response, but cytotoxic effector cells did not develop after an allogeneic mixed lymphocyte-tumor cell culture. Bestatin also had T-cell adjuvant activity when it was admixed with a suboptimal vaccine composed of irradiated tumor cells. We observed significant therapeutic activity against preexisting experimental and spontaneous metastases when bestatin was administered at high doses per animal for 4 weeks.

Immunotherapeutic potential in murine tumor models of polyinosinic-polycytidylic acid and poly-L-lysine solubilized by carboxymethylcellulose.

The systemic administration of multiple, nontoxic doses of polyinosinic-polycytidylic acid and poly-L-lysine solubilized by carboxymethylcellulose [poly(I,C)-LC] eradicated established experimental and spontaneous pulmonary metastases. Optimal immunotherapy was schedule dependent, requiring three to five injections of poly(I,C)-LC per week for a minimum of 4 weeks; in addition, therapeutic efficiency was partially dosage independent. Immunotherapy by poly(I,C)-LC was found to be limited by tumor burden, although when combined with chemotherapy as a debulking regimen it resulted in increased survival with protocols in which poly(I,C)-LC alone was insufficient. These data suggest that the systemic administration of poly(I,C)-LC may provide a successful adjuvant therapeutic modality against cancer metastasis.

Therapy of autochthonous skin cancers in mice with intravenously injected liposomes containing muramyltripeptide.

Liposomes containing the immunomodulator muramyltripeptide phosphatidylethanolamine (MTP-PE) or free saline were injected i.v. into BALB/c mice with autochthonous skin cancers induced by chronic exposure to ultraviolet irradiation. Treatment with liposomes containing MTP-PE produced significant retardation in the growth of the primary autochthonous skin cancers and significantly prolonged survival of the treated mice as compared with the saline-treated controls. Since ultraviolet-irradiated mice have a defect in immunological recognition of their autochthonous tumors, the therapeutic effects of liposomes containing MTP-PE are very encouraging. These results suggest that liposomes containing MTP-PE could be used for the treatment of patients with skin cancer or other malignant diseases.

Immunomodulatory effects in mice of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose.

In this report, we describe the immunomodulatory characteristics of poly(I,C)-LC, a synthetic, double-stranded nucleic acid polymer, polyinosinic-polycytidylic acid, that is complexed with poly-L-lysine and solubilized by the addition of carboxymethylcellulose. We consistently observed, both in vitro and in vivo, stimulation of macrophage cytotoxicity and augmentation of natural killer-cell activity by poly(I,C)-LC. This immunomodulator also increased the allogeneic mixed-lymphocyte response, without any blastogenic effect on responder cells cultured in the absence of allogeneic stimulator cells. Further, the addition of poly(I,C)-LC to an allogeneic mixed-lymphocyte tumor reaction did not stimulate the development of cytotoxic effector T-cells. Poly(I,C)-LC did, however, have adjuvant activity when admixed with irradiated tumor cells in the immunization of syngeneic mice. Unlike classic adjuvants, poly(I,C)-LC also enhanced the development of specific cytotoxic T-lymphocytes when it was injected either i.v. or i.p. in conjunction with a vaccine delivered at an intradermal site. The results indicate that poly(I,C)-LC has considerable potential as an immunotherapeutic agent, with the ability not only to induce macrophage and NK cell activation but also to stimulate specific cytotoxic T-lymphocytes.

Rickettsial and serologic evidence for prevalent spotted fever rickettsiosis in inner Mongolia.

A field study in northeastern Inner Mongolia, People's Republic of China, in June of 1985 demonstrated a spotted fever group rickettsiosis. Two strains of spotted fever group rickettsiae were isolated. One strain was obtained from the blood of a patient with an eschar, regional lymphadenopathy, and history of a recent tick bite. The other strain originated from ova of ticks, Dermacentor nuttalli. These represent the second isolate of a spotted fever group rickettsia from a human and the first isolate from tick ova in the People's Republic of China. Antibodies to these rickettsiae were demonstrated by indirect immunofluorescence in the sera of 4% of healthy children and 34% of healthy human adults, in 58% of sheep, and in 76% of cattle in the same location. Hemolymph test revealed rickettsiae in 6 of 36 D. nuttalli examined.

Changing patterns of arterial injuries associated with fractures and dislocations.

BACKGROUND: Significant changes occurred over a 4.5-year period in the causes, diagnosis, and treatment of arterial injuries associated with skeletal fractures of the extremities. STUDY DESIGN: The trauma registry data of 1,091 consecutive patients with fractures, dislocations, or both, were reviewed for the diagnosis of associated arterial injury documented by arteriography or an exploratory operation. The decision to perform a vascular repair was based solely on the presence of definitive signs of arterial injury found during physical examination. RESULTS: Arterial injuries occurred in 41 patients (3.8 percent). Of these, 29 (71 percent) had penetrating injuries, and 12 (29 percent) had blunt trauma. Twenty-six patients (63 percent) had definitive signs of arterial injury and all required arterial repairs. Only three patients (7.3 percent), all with blunt injuries, required amputations because of massive soft tissue trauma. Fifteen patients had intimal flaps, irregularities, or localized narrowings shown on the arteriogram. No patient's condition had deteriorated by the time of a repeat arteriogram (n = 6) or physical examination (n = 9), and no injury required delayed repair (mean follow-up of 6.5 months). No patient without definitive signs of vascular injury at the time of initial examination required surgical repair. CONCLUSIONS: Arterial injuries associated with fractures increasingly result from penetrating trauma and carry a much lower risk of amputation than injuries from blunt trauma. Physical examination can accurately detect 100 percent of the arterial injuries requiring repair. Minimal arterial abnormalities seen on arteriograms may be safely followed up by observation.

Comparison of azelastine eye drops with levocabastine eye drops in the treatment of seasonal allergic conjunctivitis.

A randomised, multicentre parallel group study was undertaken to compare the efficacy and safety of 0.05% azelastine eye drops (101 patients) in an open manner with 0.05% levocabastine eye drops (103 patients) and in a double-blind manner with placebo (103 patients) during a 14-day treatment period involving patients with seasonal allergic conjunctivitis. The three main eye symptoms, scored on a four-point scale, were itching, lacrimation and conjunctival redness; the primary efficacy variable was the responder rate on day 3. Responders were patients whose sum score of the three main eye symptoms decreased by at least three points from a baseline score of at least six points. In addition to these main symptoms, five other symptoms were recorded on days 0, 3, 7 and 14, and patients kept daily diaries of the three main eye symptoms and swollen eyelids. The responder rate after 3 days of treatment was 69% in patients treated with azelastine, 59% in patients treated with levocabastine and 51% in the placebo group. Only the difference in responder rates between azelastine and placebo eye drops was statistically significant (p = 0.02). The improvements in other ocular symptoms and entries in the patients' diaries closely reflected the changes reported by the investigators. No serious adverse events occurred throughout the study. Nine patients (three in the azelastine, five in the levocabastine and one in the placebo group) terminated the study prematurely due to poor tolerability. Adverse drug reactions, mainly a mild, transient irritation and a bitter or unpleasant taste, were reported in 37% of patients receiving azelastine eye drops, 31% of patients receiving levocabastine and 9% of placebo patients. Overall tolerability was assessed as very good or good in 86% of azelastine- and levocabastine-treated patients, and in 95% of the patients receiving placebo. The results of this study indicate that azelastine possesses a tolerability profile at least comparable to that of levocabastine eye drops, but additionally appears to have a slightly quicker onset of effect, and confirm the therapeutic potential of azelastine eye drops in the treatment of allergic conjunctivitis.

Topical azelastine in perennial allergic conjunctivitis.

OBJECTIVE: Azelastine is a selective H(1)-receptor antagonist that inhibits histamine release and interferes with activation of several other mediators of allergic inflammation. Together with demonstrated efficacy in seasonal allergic conjunctivitis, azelastine indicated a therapeutic potential for perennial allergic conjunctivitis (PAC). The present study aimed to evaluate azelastine eye drops in patients with PAC compared to placebo. RESEARCH DESIGN AND METHODS: A multinational trial in 22 centres randomised 139 patients to twice-daily treatment for 6 weeks with masked 0.05% azelastine eye drops, matching masked placebo, or open-label levocabastine. Randomisation required a sum itching and conjunctival redness score of at least 3 (0-6 scale) after 1 week of placebo. The change in sum score was evaluated during treatment. RESULTS: Azelastine significantly improved itching and conjunctival redness compared to placebo (p < 0.001) with global tolerability that was not substantially different from placebo. On day 7, the mean symptoms sum score improved with azelastine by 1.9 +/- 1.1 and with levocabastine by 1.5 +/- 1.2 compared to placebo (0.6 +/- 1.1) from baseline values of 3.7-3.8. The sum scores continued to improve up to day 42. Daily patient logs confirmed the clinically assessed scores. Most frequent adverse events following azelastine were bitter taste and application site reaction. CONCLUSIONS: Topical azelastine progressively improved itching and conjunctival redness in PAC patients compared to placebo and was at least as effective as levocabastine. Rapid relief is consistent with H(1)-receptor antagonist action, while continued improvement up to 6 weeks may be consistent with mechanisms involving other mediators of allergic inflammation.

Comparison of the efficacy and tolerability of topically administered azelastine, sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis and rhino-conjunctivitis.

OBJECTIVE AND SETTING: Azelastine (AZE) in a novel, eye drop, formulation, was compared with topically applied sodium cromoglycate (SCG) and placebo (PLA) in the treatment of seasonal allergic conjunctivitis or rhino-conjunctivitis in a multicentre, parallel group study. RESEARCH DESIGN: 144 subjects ranging in age from 16 to 65 years participated. All had at least a 2-year history of seasonal allergic conjunctivitis and were symptomatic at the time of inclusion. Medications were administered topically either twice daily (AZE/PLA) or four times daily (SCG) over a 2-week treatment period. Method and outcome measures: Azelastine and placebo were compared double-blind; the comparison versus SCG was carried out in an open manner. Itching, redness, flow of tears, eyelid swelling, foreign-body sensation, photophobia, soreness and discharge were scored on a 4-point severity scale. RESULTS: Results for the decrease of main conjunctivitis symptoms (itching, tearing and conjunctival redness) showed a marked effect for both active treatments on day 3 with a sustained improvement on days 7 and 14. A clear response to treatment (an improvement of sum scores for day 3 of >/=3 points compared to baseline) occurred in 85.4% of azelastine-treated patients, 83.0% of sodium cromoglycate patients and 56.3% of placebo patients. Response rates for both active treatments were statistically superior to those for placebo (azelastine p = 0.005; sodium cromoglycate p = 0.007). Global assessment of efficacy was at least 'satisfactory' for 90.0% of azelastine patients, 81.3% of sodium cromoglycate patients and 66.3% of placebo-treated patients. The most frequent adverse effects were transient application site reactions which tended to disappear with increasing duration of treatment, and, less frequently, taste perversion. CONCLUSION: The results of this study indicate that the therapeutic use of azelastine eye drops in patients with seasonal allergic conjunctivitis or rhino-conjunctivitis can be recommended.

Reproducibility of circadian retinal and optic nerve head blood flow measurements by Heidelberg retina flowmetry.

BACKGROUND/AIM: The Heidelberg retina flowmeter (HRF) is designed to measure retinal capillary blood flow. Previous studies however showed weak reproducibility of data. The intraindividual reproducibility of circadian HRF measurements was examined in healthy subjects in three locations of the retina. METHODS: 36 healthy volunteers (27.3 (SD 4.3) years) were examined by HRF seven times a day (t0-t6). Using a default window of 10 x 10 pixels, three consecutive measurements were performed in three precise focusing planes: superficial, intermediate and deep layer, peripapillary retina, neuroretinal rim and cup, respectively. Images of identical tissue locations identified by capillary landmarks of each layer were selected to quantify the retinal microcirculation of each volunteer. Means and standard deviations of all flow results of a given subject were calculated, at t0-t6 and the coefficients of variation as a measure of reproducibility. RESULTS: The coefficients of variation ranged between 8.4% and 41.0% in the superficial layer (mean 19.8% (SD 8.4%)), 10.6%, and 43.0% in the intermediate layer (mean 24.0% (SD 8.4%)), and 9.9% and 84.0% (mean 29.6% (SD 15.8%)) in the deep layer. CONCLUSIONS: These data show the best reproducibility of measurements in the superficial layer followed by the intermediate and the deep layer. Clinically, this is an unsatisfactory intraindividual reproducibility of flow values in each studied layer.

Clinical evaluation of the peak inspiratory flow generated by asthmatic children through the Novolizer.

STUDY OBJECTIVE: To assess whether asthmatic children may generate sufficient peak inspiratory flow through the Novolizer, a novel multiple dose dry powder inhaler with acoustic and optical feedback mechanisms for correct inhalation. PATIENTS AND METHODS: 137 children (median age 7 years, range 4-2) with mild to moderate persistent asthma (FEV1 < 90% predicted or pre-treated with low-dose steroids) participated in this open, multi-centre study. After assessment of FEV1 and peak inspiratory flow (without inhalator device, PIF), the children were instructed to inhale with the Novolizer (PIF through inhaler, PIF-N). All assessments were done in triplicate and the mean out of three attempts analysed. RESULTS: Mean PIF was 128 +/- 61 l/min and mean PIF-N was 69 +/- 18 l/min. This is distinctly above the rate necessary to overcome the Novolizer's trigger threshold. PIF performance through the Novolizer was linear in the age interval of 4-8 years, no further increase was observed beyond 8 years. CONCLUSIONS: The medium to low intrinsic resistance of the Novolizer permits a relatively high PIF through this device. Together with the feedback mechanisms, this makes the Novolizer particularly valuable for inhalation therapy in asthmatic children with drugs such as salbutamol, formoterol, or budesonide.