Increase in migraine diagnoses and guideline-concordant treatment in veterans, 2004-2012.

Background and aim Health administrators, policy makers, and educators have attempted to increase guideline adherence of migraine medications while reducing inappropriate use of opioid- and barbiturate-containing medications. We evaluated the burden of migraine and proportion of guideline-concordant care in a large, national health care system over time. Methods We conducted a time-series study using data from the Veterans Health Administration (VHA) electronic health record. Veterans with migraines were identified by ICD-9 code (346.X). Prescriptions and comorbid conditions were evaluated before and after migraine diagnosis. Chi-square tests and logistic regression were performed. Results A total of 57,064 veterans were diagnosed with migraine headache (5.3%), with women significantly more likely diagnosed (11.6% vs. 4.4%, p < 0.0001). The number of veterans diagnosed with migraine has significantly increased over the years. By 2012, triptans were prescribed to 43% of people with migraine, with no difference by gender. However, triptan prescriptions increased from 2004 to 2012 in men, but not women, veterans. Preventive medicines showed a significant increase with the year of migraine diagnosis, after controlling for age, sex, race, and for comorbidities treated with medications used for migraine prevention. Conclusions The burden of migraines is increasing within the VHA, with a corresponding increase in the delivery of guideline-concordant acute and prophylactic migraine-specific medication.

Latent profile analysis of pelvic floor muscle pain in patients with chronic pelvic pain.

AIM: Chronic pelvic pain (CPP) is a syndrome of related diagnoses including pain originating from the muscles of the pelvic floor. The objective of this study was to evaluate which muscles are important to examine, in what manner pelvic floor muscle pain contributes to patients' pain experience, or what thresholds should be applied to identify significant pelvic floor muscle pain by comparing exam findings with outcome measures METHODS: A total of 428 patients meeting the definition for CPP were evaluated using a standardized physical examination of the abdominal wall, pelvic floor, and vestibule along with the 12 domain Patient Reported Outcome Measures Information System (PROMIS). These scores were evaluated for unidimensionality followed by latent profile analysis. The areas under the receiver operator characteristic curves were used to identify the best pain threshold for each muscle. RESULTS: The eight pelvic floor muscle sites all loaded onto a single factor, separate from other areas examined. Two latent classes were found within all the variables. Patients in the severe pelvic floor pain class had significantly worse pain related PROMIS scores. Optimal thresholds for identifying significant pelvic floor pain ranged between 3 and 5. CONCLUSION: Pain in the pelvic floor muscles is distinguishable from pain in the abdominal wall and vulva. Any of the lateral muscle sites evaluated can be used to identify patients with significant pelvic floor pain. Two latent classes of CPP patients were identified: those with limited and those with severe pain, as identified by moderate to severe pelvic floor tenderness.

Phenotyping chronic pelvic pain based on latent class modeling of physical examination.

Introduction. Defining clinical phenotypes based on physical examination is required for clarifying heterogeneous disorders such as chronic pelvic pain (CPP). The objective of this study was to determine the number of classes within 4 examinable regions and then establish threshold and optimal exam criteria for the classes discovered. Methods. A total of 476 patients meeting the criteria for CPP were examined using pain pressure threshold (PPT) algometry and standardized numeric scale (NRS) pain ratings at 30 distinct sites over 4 pelvic regions. Exploratory factor analysis, latent profile analysis, and ROC curves were then used to identify classes, optimal examination points, and threshold scores. Results. Latent profile analysis produced two classes for each region: high and low pain groups. The optimal examination sites (and high pain minimum thresholds) were for the abdominal wall region: the pair at the midabdomen (PPT threshold depression of > 2); vulvar vestibule region: 10:00 position (NRS > 2); pelvic floor region: puborectalis (combined NRS > 6); vaginal apex region: uterosacral ligaments (combined NRS > 8). Conclusion. Physical examination scores of patients with CPP are best categorized into two classes: high pain and low pain. Standardization of the physical examination in CPP provides both researchers and general gynecologists with a validated technique.

Chronic pelvic pain syndrome-related diagnoses in an outpatient office setting.

BACKGROUND: Chronic pelvic pain (CPP) is a syndrome composed of one or more pain diagnoses arising from pelvic organs. Although the prevalence of many individual diagnoses has been determined in a variety of settings, the concurrent assessment of overlapping pain syndromes in an outpatient gynecology clinic, which would be most pertinent to practitioners, has not been reported. METHODS: Patients waiting to be seen in an outpatient general gynecology clinic completed a survey composed of validated instruments for different pain diagnoses. Cyclic and constant CPP, irritable bowel syndrome (IBS), interstitial cystitis (IC), and vulvodynia (VVD) were assessed. RESULTS: In the 498 completed surveys, 24% of patients met at least one criterion for CPP, and of these, 23% also met criteria for a second diagnosis. Of all patients, 15% reported symptoms consistent with IBS, 6% with IC, and 5% with VVD. Cyclic CPP was found in 20%, and of these patients, 30% had at least one other CPP-related diagnosis. DISCUSSION: Although limited by its design as a survey, this study demonstrates that CPP frequently (between 30 and 43%) occurs with other pain syndromes. Clinicians should be prepared to evaluate nongynecologic causes of pelvic pain.

Analysis of meiosis and cell cycle genes of the facultatively asexual pea aphid, Acyrthosiphon pisum (Hemiptera: Aphididae).

Phenotypic plasticity in response to environmental change is a common phenomenon, yet is poorly understood at the genetic and molecular level. Aphids exhibit a reproductive plasticity whereby seasonal changes result in asexual or sexual reproduction. To investigate the genetic basis of this reproductive plasticity, we assessed the meiosis and cell cycle gene repertoire in the genome of the pea aphid, Acyrthosiphon pisum. Aphids possess meiotic recombination genes and G1-to-S phase transition regulatory genes in gene copy numbers similar to other metazoans. However, mitotic and meiotic regulatory genes have duplicated, and several paralogues exhibit differential expression between reproductive morphs. Together, this suggests that cell cycle plasticity may be important in the evolution and mechanism of aphid reproductive plasticity.

Reproductive performance of asexual clones of the peach-potato aphid, ( Myzus persicae, Homoptera: Aphididae), colonising Scotland in relation to host plant and field ecology.

The population of peach-potato aphid, Myzus persicae (Sulzer), in Scotland comprises large numbers of a few superclones with much smaller numbers of other clones, and the reason for their differential success has yet to be elucidated. In the current study, the reproduction of lineages derived from these clones was measured by counting the numbers of offspring produced by a one-day-old nymph after 15 days. This was measured on four plant species, including local agricultural hosts and at two different temperatures (14 and 18 degrees C). There were significant differences in clonal lineage reproduction on different hosts and at different temperatures and amongst clonal lineages on the same hosts at the same temperature. Lineages of local insecticide sensitive clones did not have the best reproductive potential; instead, a recently introduced clonal lineage carrying MACE insecticide resistance was the best reproducer. The clonal lineage with the lowest reproductive potential also carried insecticide resistance, but this was kdr. A lineage from a local insecticide-sensitive clone was the least affected by reduced temperature. There was evidence of host plant specialisation in some of the clonal lineages.

Robotic radical hysterectomy.

Robotic radical hysterectomy is increasingly being utilized in the treatment of cervical cancer and initial studies are promising. Compared to open radical hysterectomy, robotic radical hysterectomy is expected to result in decreased pain, infection, length of stay, and adhesions and quicker return to activity. Prospective randomized controlled trials are needed to compare robotic, laparoscopic and open radical hysterectomy for the treatment of cervical cancer.

Clonal turnover of MACE-carrying peach-potato aphids (Myzus persicae (Sulzer), Homoptera: Aphididae) colonizing Scotland.

Peach-potato aphids, Myzus persicae (Sulzer), collected in Scotland in the years 1995 and 2002-2004 were characterized using four microsatellite loci and three insecticide resistance mechanisms. From 868 samples, 14 multilocus genotypes were defined (designated clones A-N). Five of these (denoted A, B, H, M and N) carried modified acetylcholinesterase (MACE) resistance, the most recent resistance mechanism to have evolved in M. persicae. The current paper shows that the continued presence of MACE aphids is due to turnover, as clones A and B were replaced in field samples by clones H, M and N in later seasons. Thus, insecticide-resistant populations in Scotland can be attributed to multiple waves of rapid clone colonisations and not to the continued presence of stable resistant clones or mutation or sexual recombination in local populations. The MACE clones carried varying levels of the other insecticide resistance mechanisms, kdr and esterase. The presence of these mechanisms could alter the clones success in the field depending on insecticide spraying (positive selection) and resistance fitness costs (negative selection).

Effect of zinc replacement on lipids and lipoproteins in type 2-diabetic patients.

Abnormal zinc and lipid plasma levels occur more frequently in metabolically uncontrolled diabetic patients. These lipid alterations are key factors in the emergence of microvascular complications, which lead to death in those patients. Yet, zinc sulfate supplementation may be a therapeutical resource to recover some functioning and improve life span. This article reports the assessment of lipid profile from type 2-diabetes mellitus patients treated with hypoglycemic therapy drugs, who additionally presented zinc levels lower than average in Mexican reference. The patients received a 100 mg zinc sulfate treatment in a crossover double-blind design of clinically controlled study with starch as placebo. The diabetic patients had changes in their lipid profile after a 12-week zinc treatment as compared with placebo treatment. The 100 mg zinc sulfate treatment was well tolerated, significantly reduced total cholesterol and triglyceride concentrations, and increased those corresponding to zinc as well as HDL cholesterol in the bloodstream. Thus, using this treatment the cardiovascular involvement is expected to decrease in the type 2-diabetes mellitus patients, especially those with myocardial infarction and stroke, which are the main death causes in Mexico.

Microsatellite marker analysis of peach-potato aphids (Myzus persicae, Homoptera: Aphididae) from Scottish suction traps.

The peach-potato aphid Myzus persicae (Sulzer) is an important vector of plant viruses. A network of suction traps collects aerial samples of this aphid in order to monitor and help predict its spatial distribution and likely impact on virus transmission in crops. A suction trap catch is thought to be a good representation of the total aphid pool. Sensitive molecular markers have been developed that determine the genetic composition of the M. persicae population. In Scotland, UK, these were applied to field collections revealing a limited number of clones. Molecular markers are less successful when applied to specimens that have been preserved in an ethanol-based trap fluid designed to preserve morphology. An assessment of different DNA extraction and PCR techniques is presented and the most efficient are used to analyse M. persicae specimens caught in the Dundee suction trap in 2001, a year when exceptionally high numbers were caught. The results reveal that the majority of the M. persicae caught belonged to two highly insecticide resistant clones. In addition, it was possible to compare the relative frequencies of genotypes caught in the trap with those collected at insecticide treated and untreated field sites in the vicinity. These results indicate that, in addition to suction trap data, the ability to sample field sites provides valuable early warning data which have implications for pest control and virus management strategies.

The attack of the clones: tracking the movement of insecticide-resistant peach-potato aphids Myzus persicae (Hemiptera: Aphididae).

Myzus persicae (Sulzer) collected in Scotland were characterized for four microsatellite loci, intergenic spacer fingerprints and the resistance mechanisms modified acetylcholinesterase (MACE), overproduced carboxylesterase and knockdown resistance (kdr). Microsatellite polymorphisms were used to define a limited number of clones that were either fully susceptible to insecticides or possessed characteristic combinations of resistance mechanisms. Within these clones, intergenic spacer fingerprints could either be very consistent or variable, with the latter indicating ongoing evolution within lineages, most likely derived from the same zygote. Two clones (termed A and B) possessed all three resistance mechanisms and predominated at sites treated with insecticides. Their appearance on seed potatoes and oilseed rape in Scotland in 2001 coincided with extensive insecticide use and severe control failures. Clones C, I and J, with no or fewer resistance mechanisms, were found in samples from 1995 and were dominant at untreated sites in 2001. A comparison of Scottish collections with those from other UK and non-UK sites provides insight into the likely origins, distribution and dynamics of M. persicae clones in a region where asexual (anholocyclic) reproduction predominates, but is vulnerable to migration by novel genotypes from areas of Europe where sexual (holocyclic) reproduction occurs.

Super-infections of Wolbachia in byturid beetles and evidence for genetic transfer between A and B super-groups of Wolbachia.

Wolbachia are maternally inherited bacteria responsible for altering host reproduction. The two main groups found in insects, A and B, are based on molecular characterization using ribosomal, ftsZ, wsp (Wolbachia surface protein) or groE genes. We have used the wsp and ftsZ genes to study Wolbachia in byturid beetles. Byturus affinis contained a single copy of the ftsZ gene which grouped with A ftsZ sequences and a single copy of the wsp gene which grouped with B wsp sequences. This suggests that genetic exchange between A and B groups has occurred in the Wolbachia of this beetle. FtsZ and wsp sequences that were identical or nearly identical to those of B. affinis were found in B. tomentosus, suggesting that it also contains the same recombinant Wolbachia genotype. Most other byturids had more than one wsp sequence with at least one from the A and B groups, suggesting multiple copies of bacterial genes or multiple infections. B. ochraceus and B. unicolor both had four distinct wsp gene sequences. All the byturids had a closely related A wsp sequence and most a closely related B wsp sequence. Therefore, there appears to be an association between specific A and B wsp types.

Tumor Detection in vivo with Optical Spectroscopy.

Ultrasound induced blood stasis has been observed for a long time, but to date most experimental observations have been in vitro. In this paper we discuss a possible diagnostic use for this previously undesirable effect of ultrasound - tumor detection in vivo. We demonstrate that, using optical spectroscopy, effects of ultrasound can be used to differentiate tumor from non-tumor in murine tissue. Finally, we propose a novel diagnostic algorithm that quantitatively differentiates tumor from non-tumor with maximum specificity 0.83, maximum sensitivity 0.79, and area under ROC curve 0.90.

In vivo Optical Spectroscopy of Acoustically Induced Blood Stasis.

Ultrasound-induced blood stasis has been observed for more than thirty years. Most of the literature has been focused on the health risks associated with this phenomenon and methods employed to prevent stasis from occurring during ultrasound imaging. To date, experimental observations have been either in vitro or invasive. The current work demonstrates ultrasound- induced blood stasis in murine tumor and nontumor tissue, observed through noninvasive measurements of optical spectroscopy, and discusses possible diagnostic uses for this previously undesirable effect of ultrasound.

Overexpression of VEGF121, but not VEGF165 or FGF-1, improves oxygenation in MCF-7 breast tumours.

Vascular endothelial growth factor (VEGF) is an intensively studied molecule that has significant potential, both in stimulating angiogenesis and as a target for antiangiogenic approaches. We utilised MCF-7 breast cancer cells transfected with either of two of the major VEGF isoforms, VEGF(121) or VEGF(165), or fibroblast growth factor-1 (FGF-1) to distinguish the effects of these factors on tumour growth, vascular function, and oxygen delivery. While each transfectant demonstrated substantially increased tumorigenicity and growth rate compared to vector controls, only VEGF(121) produced a combination of significantly reduced total and perfused vessel spacing, as well as a corresponding reduction in overall tumour hypoxia. Such pathophysiological effects are of potential importance, since antiangiogenic agents designed to block VEGF isoforms could in turn result in the development of therapeutically unfavourable environments. If antiangiogenic agents are also combined with conventional therapies such as irradiation or chemotherapy, microregional deficiencies in oxygenation could play a key role in ultimate therapeutic success.

Mechanism of IL-12 mediated alterations in tumour blood vessel morphology: analysis using whole-tissue mounts.

New blood vessel formation within tumours is a critical feature for tumour growth. A major limitation in understanding this complex process has been the inability to visualise and analyse vessel formation. Here, we report on the development of a whole-tissue mount technique that allows visualisation of vessel structure. Mice expressing green fluorescent protein (GFP) made it possible to easily see GFP(+) vessels within non-GFP-expressing B16 melanoma tumours. The small fragments of tumour used in this technique were also effectively stained with fluorescent probe-conjugated antibodies, allowing characterisation of the vessels based on surface marker phenotype. The vessels within tumour tissue were much more irregular and tortuous compared to those within surrounding normal muscle. B16 tumours stably transfected with the genes for IL-12 were used to assess the effects of this cytokine on tumour growth and vessel formation. The IL-12-expressing tumours grew more slowly and had much smaller blood vessels than the large, webbed vessels characteristic of the parental tumours, effects that were dependent on interferon gamma (IFN-gamma). Vessels in the parental tumours were found to express VEGFR-3, the receptor for VEGF-C and VEGF-D. Expression of this receptor by the endothelial cells of the blood vessels was lost in the cytokine expressing tumours, thus suggesting a mechanism for the antiangiogenic effects of IL-12. The combination of the whole mount technique and the GFP transgenic mice provides a powerful method for visualising tumour vasculature and characterising the effects of agents such as cytokines.

Zonal image analysis of tumour vascular perfusion, hypoxia, and necrosis.

A number of laboratories are utilising both hypoxia and perfusion markers to spatially quantify tumour oxygenation and vascular distributions, and scientists are increasingly turning to automated image analysis methods to quantify such interrelationships. In these studies, the presence of regions of necrosis in the immunohistochemical sections remains a potentially significant source of error. In the present work, frozen MCa-4 mammary tumour sections were used to obtain a series of corresponding image montages. Total vessels were identified using CD31 staining, perfused vessels by DiOC(7) staining, hypoxia by EF5/Cy3 uptake, and necrosis by haematoxylin and eosin staining. Our goal was to utilise image analysis techniques to spatially quantitate hypoxic marker binding as a function of distance from the nearest blood vessel. Several refinements to previous imaging methods are described: (1) hypoxia marker images are quantified in terms of their intensity levels, thus providing an analysis of the gradients in hypoxia with increasing distances from blood vessels, (2) zonal imaging masks are derived, which permit spatial sampling of images at precisely defined distances from blood vessels, as well as the omission of necrotic artifacts, (3) thresholding techniques are applied to omit holes in the tissue sections, and (4) distance mapping is utilised to define vascular spacing.

Characterization of the effects of antiangiogenic agents on tumor pathophysiology.

A variety of strategies have been proposed to control tumor growth and metastasis by inhibiting tumor angiogenesis. To optimally combine such antiangiogenic approaches with conventional therapy, improved methods are needed to characterize the underlying pathophysiologic changes. The objective of the current work was to demonstrate the utility of a combination of recently developed immunohistochemical and image analysis techniques in quantitating changes in tumor vasculature and hypoxia. Murine MCa-35 mammary carcinomas were frozen after administration of two COX-2 inhibitors: meloxicam and celecoxib (Celebrex). Total blood vessels were visualized using anti-CD31 staining, perfused vessels by intravenous injection of DiOC7, and tumor hypoxia by EF5 uptake. Although both agents produced similar reductions in tumor volume compared with untreated tumors, varied effects on tumor vasculature and hypoxia were noted. Meloxicam reduced total vessel numbers significantly, whereas celecoxib had no effect. Both drugs substantially increased perfused vessel densities. Although mean hypoxic marker uptake was unchanged from matched controls, intratumor EF5 heterogeneities were significantly different between drugs. The results suggest that COX-2 inhibitors can have varying effects on tumor pathophysiology. Successful use of these drugs to enhance radiation response will likely require optimization of drug choice, dose schedule, and direct physiologic monitoring.

Keratinocyte growth factors radioprotect bowel and bone marrow but not KHT sarcoma.

Various members of the fibroblast growth factor (FGF) family of proteins have been shown to protect against acute and late radiation damage of normal tissues. Protection of the small bowel, for example, occurs via both increased proliferation and reduced apoptosis. Other beneficial effects of FGFs include promotion of bone growth, pneumonitis prevention, and apoptosis suppression of endothelium in vivo and in vitro after irradiation. This protection against radiation requires only low and infrequent doses of FGFs. Two newly identified members of the FGF family, FGF7 and FGF10, have effects similar to many of the other FGF family proteins, but with more specificity for normal epithelial structures. For this reason, they have also been named keratinocyte growth factors one and two (KGF1 and KGF2, respectively). We therefore examined the potential utility of KGFs for radioprotection of the bone marrow and small bowel and examined safety issues concerning their adverse effects on KHT sarcoma. The results suggest that KGFs could be safely used to prevent radiation toxicity of the abdomen or pelvis and may in fact improve tumor response to radiation.

PFA, a novel mollusk agglutinin, is structurally related to the ribosome-inactivating protein superfamily.

The structural organization of PFA, a novel beta-galactose-specific agglutinin from the snail Pomacea flagellata, was partially characterized. Using mass spectrometry, the molecular weight of this glycoprotein was determined as 32,444 Da (7.4% carbohydrate). The agglutinin was found to form very large aggregates in solution, which were dissociated to monodisperse native-like dimers upon addition of polyethyleneglycol. The identity of the first 38 and the last 11 residues of the polypeptide chain was determined. It was found that PFA and the N-glycosidase subunit of ricin, a heterodimeric cytotoxin isolated from castor bean seeds, are homologous to each other in the N-terminal region. Furthermore, the far-UV circular dichroism spectra of these proteins were found to be nearly superimposable, evidencing that they share common general features in their secondary and tertiary structures. On the basis of these similarities, it can be concluded that PFA is structurally related to the ribosome-inactivating protein superfamily.