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.

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.

Prevalence and characteristics of allodynia in headache sufferers: a population study.

OBJECTIVE: The authors estimated the prevalence and severity of cutaneous allodynia (CA) in individuals with primary headaches from the general population. METHODS: We mailed questionnaires to a random sample of 24,000 headache sufferers previously identified from the population. The questionnaire included the validated Allodynia Symptom Checklist (ASC) as well as measures of headache features, disability, and comorbidities. We modeled allodynia as an outcome using headache diagnosis, frequency and severity of headaches, and disability as predictor variables in logistic regression. Covariates included demographic variables, comorbidities, use of preventive medication, and use of opioids. RESULTS: Complete surveys were returned by 16,573 individuals. The prevalence of CA of any severity (ASC score >or=3) varied with headache type. Prevalence was significantly higher in transformed migraine (TM, 68.3%) than in episodic migraine (63.2%, p < 0.01) and significantly elevated in both of these groups compared with probable migraine (42.6%), other chronic daily headaches (36.8%), and severe episodic tension-type headache (36.7%). The prevalence of severe CA (ASC score >or=9) was also highest in TM (28.5%) followed by migraine (20.4%), probable migraine (12.3%), other chronic daily headaches (6.2%), and severe episodic tension-type headache (5.1%). In the migraine and TM groups, prevalence of CA was higher in women and increased with disability score. Among migraineurs, CA increased with headache frequency and body mass index. In all groups, ASC scores were higher in individuals with major depression. CONCLUSIONS: Cutaneous allodynia (CA) is more common and more severe in transformed migraine and migraine than in other primary headaches. Among migraineurs, CA is associated with female sex, headache frequency, increased body mass index, disability, and depression.

Migraine in adolescents: association with socioeconomic status and family history.

OBJECTIVE: The influence of socioeconomic status on the prevalence of migraine is unknown in adolescents. Accordingly, we investigated the prevalence of migraine in a large sample of adolescents by sociodemographic features. METHODS: A validated headache questionnaire was mailed to 120,000 households representative of the US population. All individuals in the household were interviewed (probands and their parents). We calculated sex-specific prevalence estimates of migraine in adolescents derived by age, race, urban vs rural residence, household income, region of the country, and parental status of migraine, using log-linear models. RESULTS: A total of 32,015 adolescents were identified. Surveys were returned by 18,714 of them (58.4% response rate). The 1-year prevalence of migraine was 6.3% (5.0% in boys and 7.7% in girls). The prevalence was higher in girls than in boys older than 12 and in whites than African Americans. In families with an annual income lower than $22,500, the adjusted prevalence of migraine in adolescents without a parental history of migraine was 4.4%; in families earning $90,000 or more, it was 2.9% (OR = 0.49, 95% CI 0.38 to 0.63). In adolescents with a parental history of migraine, the prevalence in the lower vs the higher income group was 8.6% vs 8.4% (OR = 0.97, 0.81 to 1.15). CONCLUSIONS: In adolescents with family history of migraine, household income does not have a significant effect, probably because of the higher biologic predisposition. In those without a strong predisposition, household income is associated with prevalence. This suggests social causation rather than social selection, highlighting the need for exploration of environmental risk factors related to low income and migraine and the search for specific comorbidities and stressors in this group.

Probable migraine in the United States: results of the American Migraine Prevalence and Prevention (AMPP) study.

Probable migraine (PM) is a prevalent migraine subtype fulfilling all but one criterion for migraine with or without aura. The aims of this study were: (i) to describe the epidemiology, medical recognition and patterns of treatment for PM in the USA; (ii) to compare the patterns of preventive PM treatment in the population with expert panel guidelines for preventive treatment. A validated self-administered headache questionnaire was mailed to a random sample of 120,000 US households. Subjects were classified as PM according to the second edition of the International Classification of Headache Disorders (ICHD-2). The questionnaire also assessed patterns of migraine treatment. Guidelines for preventive medication use were developed by a panel of headache experts, who used headache frequency and impairment to assess the need for preventive therapy and the gap between current and ideal use. Our sample consisted of 162 576 individuals aged > or = 12 years. The 1-year period prevalence of PM was 4.5% (3.9% in men and 5.1% in women). In women and men, prevalence was higher in middle life, between the ages of 30 and 59 years. The prevalence of PM was significantly higher in African-Americans than in Whites (female 7.4% vs. 4.8%; male 4.8% vs. 3.7%) and inversely related to household income. During their headaches, most (48.2%) had at least some impairment, while 22.1% were severely disabled. The vast majority (97%) of PM sufferers used acute treatments, although 71% usually treated with over-the-counter medication. Most PM sufferers (52.8%) never used a migraine-preventive treatment and only 7.9% were currently using preventive medication. According to the expert panel guidelines, prevention should be offered (16.9%) or considered (11.5%) for 28.4% of the PM sufferers in the survey. We conclude that PM is a frequent, undertreated, sometimes disabling disorder. It has an epidemiological profile similar to migraine. In contrast to migraine, which is less prevalent in African-Americans than in Whites, PM is more prevalent in African-Americans than in Whites. In the USA, many with PM do not receive adequate treatment.

Migraine prevalence, disease burden, and the need for preventive therapy.

OBJECTIVES: 1) To reassess the prevalence of migraine in the United States; 2) to assess patterns of migraine treatment in the population; and 3) to contrast current patterns of preventive treatment use with recommendations for use from an expert headache panel. METHODS: A validated self-administered headache questionnaire was mailed to 120,000 US households, representative of the US population. Migraineurs were identified according to the criteria of the second edition of the International Classification of Headache Disorders. Guidelines for preventive medication use were developed by a panel of headache experts. Criteria for consider or offer prevention were based on headache frequency and impairment. RESULTS: We assessed 162,576 individuals aged 12 years or older. The 1-year period prevalence for migraine was 11.7% (17.1% in women and 5.6% in men). Prevalence peaked in middle life and was lower in adolescents and those older than age 60 years. Of all migraineurs, 31.3% had an attack frequency of three or more per month, and 53.7% reported severe impairment or the need for bed rest. In total, 25.7% met criteria for "offer prevention," and in an additional 13.1%, prevention should be considered. Just 13.0% reported current use of daily preventive migraine medication. CONCLUSIONS: Compared with previous studies, the epidemiologic profile of migraine has remained stable in the United States during the past 15 years. More than one in four migraineurs are candidates for preventive therapy, and a substantial proportion of those who might benefit from prevention do not receive it.

Plant growth-promoting bacteria facilitate the growth of the common reed Phragmites australisin the presence of copper or polycyclic aromatic hydrocarbons.

To test whether plant growth-promoting bacteria might be useful in facilitating the growth of Phragmites australis, the common reed, in the presence of metals and organic compounds, P. australis seeds were treated with plant growth-promoting bacteria. The bacterium Pseudomonas asplenii AC was genetically transformed to express a bacterial gene encoding the enzyme 1-aminocyclopropane-1-carboxylate deaminase, and both the native and transformed bacteria were tested in conjunction with P. australis. Inoculation of seeds, which were subsequently grown in the presence of copper or creosote, with transformed P. asplenii AC significantly increased seed germination. Moreover, the addition of either native or transformed P. asplenii AC to P. australis seeds enabled the plants (shoots and roots) to attain a greater size than noninoculated plants after growth in soil in the presence of either copper or creosote.

Growth of canola (Brassica napus) in the presence of plant growth-promoting bacteria and either copper or polycyclic aromatic hydrocarbons.

Growth of canola (Brassica napus) seeds treated with plant growth-promoting bacteria in copper-contaminated and polycyclic aromatic hydrocarbon (PAH)-contaminated soils was monitored. Pseudomonas asplenii AC, isolated from PAH-contaminated soil, was transformed to express a bacterial gene encoding 1-aminocyclopropane-1-carboxylate (ACC) deaminase, and both native and transformed bacteria were tested for growth promotion. Inoculation of seeds, grown in the presence of copper or creosote, with either native or transformed P. asplenii AC significantly increased root and shoot biomass. Native and transformed P. asplenii AC and transformed P. asplenii AC encapsulated in alginate were equally effective at promoting plant growth in copper-contaminated soils. In creosote-contaminated soils the native bacterium was the least effective, and the transformed encapsulated bacterium was the most effective in growth promotion.

High-level expression of a synthetic red-shifted GFP coding region incorporated into transgenic chloroplasts.

We describe here a synthetic red-shifted variant of GFP that can be introduced into tobacco plastid genomes and is highly expressed in regenerated plants that appear normal and fertile. The variant contains the S65G and S72A mutations which shift the absorption maximum from the 395 nm of wild-type GFP closer to 488 nm, a wavelength emitted by a laser commonly used in confocal microscopy. In addition to enhanced fluorescence, the removal of significant absorption below 450 nm will potentially facilitate double-labelling experiments. The variant GFP encoded by the synthetic gene can be expressed at a high level, forming approximately 5% of total leaf protein.

Single-follicular-unit hair transplantation to correct cleft lip moustache alopecia.

OBJECTIVE: To present the case of an 18-year-old boy with a cleft lip scar and an obligatory need for facial hair who underwent single-follicular-unit graft hair transplantation that resulted in significant moustache hair restoration in a single procedure. SETTING: The surgery was performed in an outpatient private practice setting using oral sedation and local anesthesia. RESULTS: Advances in instrumentation technology and an increased understanding of the anatomical clustering of hair follicles into so-called "follicular units" containing one to six hairs per unit has resulted in a rapid expansion of hair restoration surgery into new areas including female-pattern alopecia, scarring alopecias, and cosmetic surgery scars. These new techniques can be employed to create natural-looking hair lines in front of artificial hair replacement systems; to improve unnatural looking, old "large-plug" hair transplants; and to correct discontinuity of eyebrows and hairlines in patients with congenital facial clefts. Increased awareness is needed to incorporate follicular-unit graft hair transplant surgery into the family of corrective surgery subspecialties.

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.

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.

Patients' perceptions of asthma control and impact on attitudes and self-management.

The objective of this work was to describe the incidence of chronic breathing problems, particularly asthma-related breathing problems, in a cross-section of the United States population and to assess the perceived impact of these problems on daily living. An initial screening survey was used in a nationwide panel of 30,000 households; an in-depth follow-up questionnaire was sent to a random sample of respondents who reported a breathing problem. A sample (n = 2,685) of respondents who reported persistent cough, shortness of breath, or wheezing within the previous 2 years were sent a newly developed questionnaire. A subsample (n = 723) of respondents reported a primary diagnosis of asthma and of these, 59.4% were female and 90.2% were white. Their mean age was 37.4 years. Respondents (n = 723) characterized their level of perceived asthma control as completely controlled, well controlled, somewhat controlled, or poorly/not controlled. At least 31% of those with a perception of some control and 59% of those with a perception of poor/no control reported their breathing problems had increased in the last year. Those who perceived their asthma-related breathing problems as poorly controlled reported significantly greater symptom frequency, activity restriction, fears and concerns about their breathing difficulties, less helpful coping strategies, and less confidence in their doctor's ability to care for them. Responses to many of the questions indicated that the worst levels of disease control were associated with poorer quality of life and a more negative perception of the disease and its effects on daily living. A significant portion of the U.S. population appears to suffer from chronic breathing problems; this requires confirmation and further exploration to reduce the potential mortality and morbidity due to asthma in the United States.

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.

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.

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.

Transgenic cattle resulting from biopsied embryos: expression of c-ski in a transgenic calf.

Producing transgenic cattle by microinjection of DNA into pronuclei has been inefficient and costly, in large part because of the cost of maintaining numerous nontransgenic pregnancies to term. We designed a system for early identification of transgenic embryos in which biopsies of embryos were assayed by polymerase chain reaction for presence of the transgene before embryo transfer. A total of 2555 embryos were microinjected with one of two DNA constructs. Of the 533 embryos biopsied, 112 were judged to be potentially transgenic and were transferred nonsurgically to recipients, resulting in production of 29 putative transgenic fetuses. One fetus and one calf (7% of offspring) were subsequently shown to be definitively transgenic. The calf was transgenic for a chicken c-ski cDNA, and several months after birth developed dramatic muscular hypertrophy followed by muscle degeneration. This phenotype was associated with expression of high levels of mRNA from the transgene.

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.