The headache under-response to treatment (HURT) questionnaire, an outcome measure to guide follow-up in primary care: development, psychometric evaluation and assessment of utility.

BACKGROUND: Headache disorders are both common and burdensome but, given the many people affected, provision of health care to all is challenging. Structured headache services based in primary care are the most efficient, equitable and cost-effective solution but place responsibility for managing most patients on health-care providers with limited training in headache care. The development of practical management aids for primary care is therefore a purpose of the Global Campaign against Headache. This manuscript presents an outcome measure, the Headache Under-Response to Treatment (HURT) questionnaire, describing its purpose, development, psychometric evaluation and assessment for clinical utility. The objective was a simple-to-use instrument that would both assess outcome and provide guidance to improving outcome, having utility across the range of headache disorders, across clinical settings and across countries and cultures. METHODS: After literature review, an expert consensus group drawn from all six world regions formulated HURT through item development and item reduction using item-response theory. Using the American Migraine Prevalence and Prevention Study's general-population respondent panel, two mailed surveys assessed the psychometric properties of HURT, comparing it with other instruments as external validators. Reliability was assessed in patients in two culturally-contrasting clinical settings: headache specialist centres in Europe (n = 159) and primary-care centres in Saudi Arabia (n = 40). Clinical utility was assessed in similar settings (Europe n = 201; Saudi Arabia n = 342). RESULTS: The final instrument, an 8-item self-administered questionnaire, addressed headache frequency, disability, medication use and effect, patients' perceptions of headache "control" and their understanding of their diagnoses. Psychometric evaluation revealed a two-factor model (headache frequency, disability and medication use; and medication efficacy and headache control), with scale properties apparently stable across disorders and correlating well and in the expected directions with external validators. The literature review found few instruments linking assessment to clinical advice or suggested actions: HURT appeared to fill this gap. In European specialist care, it showed utility as an outcome measure across headache disorders. In Saudi Arabian primary care, HURT (translated into Arabic) was reliable and responsive to clinical change. CONCLUSIONS: With demonstrated validity and clinical utility across disorders, cultures and settings, HURT is available for clinical and research purposes.

Maternal imprinting of human SNRPN, a gene deleted in Prader-Willi syndrome.

Prader-Willi syndrome (PWS), a human neuroendocrine disorder, is associated with deficiencies of paternal chromosome 15q12. Small nuclear ribonucleoprotein polypeptide N (SNRPN) is the first expressed gene identified in the PWS critically deleted region. Following our demonstration that the murine homologue of SNRPN is imprinted, we have characterized a sequence polymorphism within expressed portions of human SNRPN and show that human SNRPN is monoallelically expressed in fetal brain and heart and in adult brain. Analysis of maternal DNA and SNRPN cDNA confirmed that the maternal allele of SNRPN is not expressed in fetal brain and heart. Maternal imprinting of SNRPN supports the hypothesis that paternal absence of SNRPN is responsible for the PWS phenotype.

Maternal imprinting of the mouse Snrpn gene and conserved linkage homology with the human Prader-Willi syndrome region.

Prader-Willi syndrome (PWS) is associated with paternal gene deficiencies in human chromosome 15q11-13, suggesting that PWS is caused by a deficiency in one or more maternally imprinted genes. We have now mapped a gene, Snrpn, encoding a brain-enriched small nuclear ribonucleoprotein (snRNP)-associated polypeptide SmN, to mouse chromosome 7 in a region of homology with human chromosome 15q11-13 and demonstrated that Snrpn is a maternally imprinted gene in mouse. These studies, in combination with the accompanying human mapping studies showing that SNRPN maps in the Prader-Willi critical region, identify SNRPN as a candidate gene involved in PWS and suggest that PWS may be caused, in part, by defects in mRNA processing.

Rate and risk predictors for development of self-reported type-2 diabetes mellitus over a 5-year period: the SHIELD study.

AIMS: This investigation determined the proportion of adults newly diagnosed as having type-2 diabetes mellitus (T2DM), and ascertained risk predictors for development of self-reported T2DM. METHODS: The US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) survey was a 5-year longitudinal study of adults with and without diabetes mellitus. Adults completed a baseline health questionnaire in 2004 and ≥1 annual follow-up survey through 2009. Respondents with no self-reported diagnosis of diabetes at baseline were followed to measure rate of and assess risk factors for development of T2DM over 5 years. RESULTS: Among 8582 respondents without diabetes at baseline, 622 (7.2%) reported a diagnosis of T2DM over the subsequent 5 years. Increasing age, family history of T2DM, body mass index ≥30 kg/m(2), abdominal obesity, excessive thirst, asthma, gestational diabetes and 'high blood sugar without diabetes' significantly increased the risk of developing T2DM (p < 0.05 for each). Good to excellent health status and self-reported circulatory problems decreased the risk (p < 0.05 for each). CONCLUSIONS: Among this representative US adult population, the rate of developing T2DM was 7.2% over 5 years. Predictors of T2DM diagnosis identified in this analysis were readily obtainable via self-report.

Cumulative lifetime migraine incidence in women and men.

The aim was to estimate lifetime sex and age-specific incidence of migraine. Data are from the American Migraine Prevalence and Prevention study, a mailed survey sent to 120,000 US households. Age-specific incidence was estimated using self-reported data relevant to identification of migraine cases, age of onset of migraine and age at interview. Migraine incidence peaked between the ages of 20 and 24 years in women (18.2/1000 person-years) and the ages of 15 and 19 years in men (6.2/1000 person-years). Cumulative incidence was 43% in women and 18% in men. Median age of onset was 25 years among women and 24 years among men. Onset in 50% of cases occurred before age 25 and in 75% before age 35 years. Four of every 10 women and two of every 10 men will contract migraine in their lifetime, most before age 35 years. The incidence estimates from this analysis are consistent with those reported in previous longitudinal studies.

A heterologous maize rpoB editing site is recognized by transgenic tobacco chloroplasts.

Single nucleotides in plant chloroplast transcripts are edited from the genomically encoded C to U, often resulting in changes of the encoded protein sequence. Site-specific trans-acting factors are postulated to direct the selection of edited residues. In order to further define cis sequences required for RNA editing, we investigated whether two editing sites present in maize rpoB mRNA would be recognized by the editing machinery of transformed tobacco chloroplasts. A 93-nucleotide (nt) segment surrounding site I is sufficient to direct editing of the maize sequence in tobacco chloroplasts. However, an 86-nt segment surrounding maize site IV (which is genomically encoded as a T in tobacco) does not confer editing of this site, suggesting that trans-acting factors necessary for recognition of site IV are not present in tobacco. The maize sequences surrounding site I were found to compete with the endogenous rpoB for a depletable trans factor and to reduce editing of endogenous site I. The presence of exogenous maize site I was also found to decrease editing of endogenous tobacco site II, indicating that there is a shared aspect of editing for some closely spaced editing sites.

A single alteration 20 nt 5' to an editing target inhibits chloroplast RNA editing in vivo.

Transcripts of typical dicot plant plastid genes undergo C-->U RNA editing at approximately 30 locations, but there is no consensus sequence surrounding the C targets of editing. The cis-acting elements required for editing of the C located at tobacco rpoB editing site II were investigated by introducing translatable chimeric minigenes containing sequence -20 to +6 surrounding the C target of editing. When the -20 to +6 sequence specified by the homologous region present in the black pine chloroplast genome was incorporated, virtually no editing of the transcripts occurred in transgenic tobacco plastids. Nucleotides that differ between the black pine and tobacco sequence were tested for their role in C-->U editing by designing chimeric genes containing one or more of these divergent nucleotides. Surprisingly, the divergent nucleotide that had the strongest negative effect on editing of the minigene transcript was located -20 nt 5' to the C target of editing. Expression of transgene transcripts carrying the 27 nt sequence did not affect the editing extent of the endogenous rpoB transcripts, even though the chimeric transcripts were much more abundant than those of the endogenous gene. In plants carrying a 93 nt rpoB editing site sequence, transgene transcripts accumulated to a level three times greater than transgene transcripts in the plants carrying the 27 nt rpoB editing sites and resulted in editing of the endogenous transcripts from 100 to 50%. Both a lower affinity of the 27 nt site for a trans-acting factor and lower abundance of the transcript could explain why expression of minigene transcripts containing the 27 nt sequence did not affect endogenous editing.

Undiagnosed migraine headaches. A comparison of symptom-based and reported physician diagnosis.

BACKGROUND: Although migraine headaches are a common cause of temporary disability, many people with migraine have not been diagnosed. In a sample of the US population, we sought to determine the proportion of migraineurs diagnosed by a physician and to identify the headache characteristics and sociodemographic profiles associated with undiagnosed migraine. METHODS: A mail questionnaire survey was sent to 15,000 US households, selected from a panel to be representative of the US population. Of a total study base population of 23,611, excluding 3043 subjects less than 12 years of age and respondents with unreported gender, we analyzed data for 20,468 subjects aged 12 to 80 years. Migraine diagnoses were assigned on the basis of reported symptoms by means of operational diagnostic criteria. Physician diagnosis of migraine was ascertained on the basis of self-report. RESULTS: Forty-one percent of female and 29% of male migraineurs reported having been diagnosed by a physician. Diagnosis was more likely in females, in people with high income levels, and in individuals who reported migraine associated with aura, vomiting, or disability. Of the undiagnosed subjects, 80% experienced at least some headache-related disability. CONCLUSIONS: Results of this survey indicate that the majority of people with migraine in the United States do not report having been diagnosed by a physician. Given the high proportion of undiagnosed subjects with headache-related disability, efforts to improve the diagnosis and treatment of migraine are recommended.

Generation of targets for alloreactive CTL using purified H-2Kk in liposomes and polyethylene glycol.

The ability of a purified major histocompatibility antigen to serve as the target cell antigen for alloreactive CTL (H-2d anti-H-2k) was examined. Tumor cells syngeneic with responding CTL were used as targets following modification with purified alloantigen (H-2Kk). A short incubation of tumor cells with H-2Kk liposomes followed by the addition of polyethylene glycol (PEG) yielded modified tumor cells that were recognized and lysed by CTL. The macrophage-like cell line P388D1 was readily recognized following liposome and PEG modification; apparently because these cells can withstand PEG mediated insertion of H-2Kk and lipid into their membrane. The generation of targets by PEG mediated modification was most efficient using liposomes prepared with an H-2Kk:lipid ratio of about 1:500. H-2Kk containing liposomes prepared with negatively charged phospholipids readily attached to P388D1 cells, however these cells were not targets for CTL unless PEG was added. The specificity of CTL recognition and lysis of liposome modified cells was shown by the reactivity of CTL primed against alloantigens other than H-2Kk and by antibody (anti-H-2Kk) blocking of recognition and lysis. These results demonstrate that purified H-2Kk can serve as the alloantigen for CTL lysis and suggest that the H-2 must be oriented in the target cell lipid bilayer to serve as the alloantigen for CTL mediated target cell lysis.

Quantitation of cutaneous Langerhans cells of sarcoidosis patients.

Langerhans cells play a role in cell-mediated immune reactions which are often depressed in sarcoidosis. We examined the epidermis of 17 anergic patients with sarcoidosis (Kveim-reactive and/or biopsy-proved) for the number of Langerhans cells in noninvolved skin and in any cutaneous sarcoidal lesions. Skin biopsies of 10 healthy volunteers served as controls. In comparison to controls, the epidermis overlying noninvolved (p less than 0.05), sarcoidal (p less than 0.0005), and Kveim-reactive (p less than 0.005) skin contained significantly fewer detectable Ia and T6 antigen-bearing Langerhans cells. The reductions within noninvolved skin were most pronounced in patients with multisystem disease. Lower epidermal Langerhans cell densities, in comparison to controls, were detected in both prednisone-treated and untreated patients. Epidermis overlying sarcoidal skin of untreated patients contained significantly fewer Ia and T6 antigen-bearing Langerhans cells (p less than 0.05, p less than 0.0025, respectively) than epidermis from noninvolved skin. Whether reduced numbers of cutaneous Langerhans cells are due to either a local and/or systemic effect of sarcoidosis, or reflect the anergic state of these patients is unknown.

Edited transcripts compete with unedited mRNAs for trans-acting editing factors in higher plant chloroplasts.

Chloroplast RNA transcripts of vascular plants undergo C to U editing at approximately 30 sites, but there is no consensus sequence that identifies a C to be edited. Both sequences closely surrounding an edited C and unidentified site-specific trans-acting factors have been shown to be important for editing. The ability of an already edited transgenic sequence to bind and thus titrate a trans-acting editing factor was evaluated for two editing sites, ndhF and rpoB site 2. The U-containing rpoB transcripts did not affect editing of the endogenous rpoB transcripts, likely because the comparable C-containing transcripts containing 27 nucleotides surrounding the edited C were only 20% edited, indicating a low affinity of a trans-factor for this length of edited sequence. Surprisingly, U-containing ndhF transgene transcripts reduced endogenous ndhF transcript editing to the same degree as a C-containing transgene transcript. This indicates that the C target of editing is not a critical recognition feature for the site-specific trans-acting factor.

Leu-M1 antigen expression in advanced (tumor) stage mycosis fungoides.

The authors describe two patients with clinically and histopathologically documented advanced (tumor) stage mycosis fungoides. In each case the large, pleomorphic neoplastic cells lacked the monoclonal antibody-defined cell surface antigens commonly associated with immature and mature T-cells, i.e., T11, Leu-1, T3, T4, T6, T8, and T10, but expressed various T-cell-associated activation antigens, such as HLA-DR, Tac, and T21. Leu-M1, a monocyte-associated antigen, was not expressed by the small, cerebriform neoplastic cells in the plaque stage lesions of either patient. However, Leu-M1 was expressed by most of the large, pleomorphic neoplastic cells present in the nodular lesions of both patients. The pattern of Leu-M1 antigen expression was identical to that previously reported in the Reed-Sternberg cells of Hodgkin's disease. Identification of these two patients suggests using caution in the interpretation of the results of immunophenotypic analysis of cutaneous lymphoid neoplasms and that Leu-M1 should not be used as a diagnostic indicator of Hodgkin's disease or a histiocytic-derived neoplasm. These studies also suggest that Leu-M1 may be preferentially expressed on a subpopulation of activated, rapidly proliferating, and/or dedifferentiated neoplastic T-cells that proliferate in the advanced (tumor) stages of mycosis fungoides.

Chemical properties, distribution, and physiology of plant and algal carbonic anhydrases.

Plant carbonic anhydrases (CAs) have a range of molecular weights (MW). Among flowering plants, dicotyledons with C3 photosynthesis have two isoenzymes of 140-250K each with 6 subunits, while monocotyledons have two isoenzymes of 42-45K. Plant and animal CAs have a similar amino acid content, subunit size and zinc content, suggesting they are homologous proteins, although the higher plant CAs have no esterase activity and are not strongly inhibited by sulfonamides. Algal CAs vary widely in MW and some are highly sensitive to sulfonamides like the animal enzymes. The two plant isoenzymes, from the chloroplast and cytosol, can be separated by gradient polyacrylamide gel electrophoresis and subsequently visualized by enzymic H+ ion production. In plants, CAs probably facilitate diffusion of CO2 to the site of photosynthetic fixation; they may also have a role in pH regulation, in the use of bicarbonate by aquatic plants and in concentrating inorganic carbon within the chloroplast.

Mal de Meleda treated with 13-cis retinoic acid.

Identical twins with mal de Meleda, a rare genodermatosis, displayed the characteristic "glove and sock" hyperkeratosis, hyperhidrosis, and malodor. Their parents, who are first cousins, are unaffected and originated from Calabria, Italy, which is not far from Meleda (Mljet). The disorder is probably transmitted as an autosomal recessive trait. Previous therapy with grenz rays, topical preparations of adrenocorticosteroids, lactic acid, retinoic acid, and bland emollients had been unsuccessful. One of the twins was treated with 13-cis retinoic acid taken by mouth for 16 weeks with dramatic improvement. The major adverse effect was cheilitis, which did not force discontinuation of the treatment.

Inorganic carbon assimilation in the Isoetids, Isoetes lacustris L. and Lobelia dortmanna L.

The inorganic carbon fixation patterns of Isoetes lacustris and Lobelia dortmanna from an oligotrophic Scottish loch have been examined by following titratable acidity changes in plant sap and light/dark 14CO2 incorporation by roots and shoots. The diurnal pattern of titratable acidity changes in I. lacustris suggests crassulacean acid metabolism (CAM) while the lack of any change in titratable acidity in L. dortmanna suggests C3 metabolism. Of the carbon fixed by L. dortmanna, 99.9% was taken up through the roots and fixation occurred primarily during the day. In Isoetes, CO2 was taken up by both roots and shoots and during both day and night. Regardless of the site of CO2 uptake, fixation occurred only in the shoots of both plants. Analysis of carbon isotope ratios of plant organic material was used to further investigate the photosynthetic mechanisms of these Isoetids. Considering the absence of a nighttime peak in titratable acidity in L. dortmanna, the Δ13C (Δ=δ13C plant-δ13C source) value of the shoots of L. dortmanna (-14.2‰) is indicative of C3 photosynthesis limited by the rate of CO2 diffusion. The less negative Δ of I. lacustris (-6.0‰) is consistent with both dark acidification of CAM and CO2 limited C3 photosynthesis. This is in contrast to the terrestrial Isoetes durieui which is shown to have a Δ value which is similar to a terrestrial C3 plant. The carbon fixation patterns of these Isoetids suggest that the CO2 concentration in the loch may be growth limiting, and that root uptake and/or dark acidification are means of optimising CO2 supply. However, in view of the relatively high levels of CO2 in sediment and bulk water, it is suggested that low levels of nutrients may also limit growth in these plants.

Micromechanical devices for intravascular drug delivery.

Microfabrication technology, more commonly applied to the manufacture of integrated circuits, can be used to build devices useful for mechanical delivery of drugs and genes. Microprobes fabricated using silicon micromachining have been used to deliver DNA into cells as an alternative to bombardment and microinjection. This idea can be extended to intravascular stents with integrated microprobes capable of piercing compressed plaque and delivering anti-restenosis therapies into coronary arteries. Preliminary experiments using filleted rabbit arteries have demonstrated transection of the internal elastic lamina. New nonplanar microfabrication technologies are necessary for creating practical devices with cylindrical symmetry; a promising possibility is to use microfabricated structures of anodic metal oxides.

Reliability and validity of the Direct Observation Form of the Child Behavior Checklist.

This article reports reliability and validity data for the Direct Observation Form (DOF) of the Child Behavior Checklist. Observational data were collected on two samples of boys aged 6-11 in classroom settings. Interobserver agreement was high: r = .92 for behavior problem score and r = .83 for on-task score. Generalizability, as measured by the one-way intraclass correlation, was .86 and .71 for behavior problem score and on-task score, respectively. In terms of validity, DOF scores correlated significantly and in the expected directions with teacher-reported problem behavior, school performance, and adaptive functioning. In addition, boys who had been referred by their teachers due to problem behavior obtained significantly higher behavior problem scores and significantly lower on-task scores than a matched sample of normal boys observed in the same classrooms.

Electrically evoked knee flexion torque increases with increased pelvifemoral angles.

This study was designed to determine the extent to which knee flexion torques would differ when submaximal hamstring muscle contractions were evoked by constant levels of electrical stimulation and when the pelvifemoral angle was increased. Nineteen healthy subjects (ten women and nine men) underwent electrical stimulation of the hamstring muscles while randomly positioned either supine, sitting upright, or sitting leaning forward. The pelvifemoral angle for each position was measured from lateral photographs: the knee flexion torque was calculated from the knee flexion force, and lever arms measured directly at a constant knee angle. A repeated measures ANOVA demonstrated significant differences for pelvifemoral angles (F = 485·00, P < 0·001) and knee flexion torques (F = 21·97, P < 0·001) among the positions. The mean torques in the upright and leaning forward positions were 2·2 and 3·7 times greater, respectively, than mean torques in the supine position. The increase between the supine and leaning forward positions exceeded the increase previously reported in the literature for subjects performing maximal voluntary knee flexion efforts.

A usage-safety study of two new, dry skin formulations in patients with atopic dermatitis.

A usage-safety study involving two new dry skin formulations was conducted using a group of subjects with a history of atopic dermatitis. The results indicate that these formulations are safe in persons with inactive to mildly active dermatitis and are effective in alleviating the signs of dry skin, particularly on the legs. However, one individual with very active dermatitis developed an irritant reaction to one test formulation, possibly related to the fragrance contained therein.

Stent-based gene therapy.

Delivery of gene therapy to inhibit intimal hyperplasia has been proposed to prevent postangioplasty restenosis. We sought to apply gene therapy by using a stent-based technique. There are several hurdles that must be overcome before gene-stent therapy can be applied successfully in clinical trials. These include increasing the efficiency of gene delivery through atherosclerotic plaque; increasing intramural retention times; preventing the inflammatory reaction that stents coated with biodegradable polymers can elicit; overcoming the risk of systemic gene delivery; and accessing the adventitia via percutaneous approach. We evaluated a gene-stent delivery mechanism based on microporous metal microneedles developed with nanotechnology in an attempt to overcome some of these problems. A novel approach to the transfection of genes by microfabricated technology was evaluated in smooth muscle cells in culture. We demonstrated that microneedles can deliver gene therapy to smooth muscle cells in culture and can produce controlled penetration of the IEL and intima. We conclude that taller microneedles need to be developed to reach the media in diseased human arteries and that this technology has the potential to be incorporated in a stent to deliver gene therapy in atherosclerotic plaque.