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.

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.

Structural and antigenic polymorphism of the 35- to 48-kilodalton merozoite surface antigen (MSA-2) of the malaria parasite Plasmodium falciparum.

Merozoite surface antigen MSA-2 of the human parasite Plasmodium falciparum is being considered for the development of a malaria vaccine. The antigen is polymorphic, and specific monoclonal antibodies differentiate five serological variants of MSA-2 among 25 parasite isolates. The variants are grouped into two major serogroups, A and B. Genes encoding two different variants from serogroup A have been sequenced, and their DNA together with deduced amino acid sequences were compared with sequences encoded by other alleles. The comparison shows that the serological classification reflects differences in DNA sequences and deduced primary structure of MSA-2 variants and serogroups. Thus, the overall homologies of DNA and amino acid sequences are over 95% among variants in the same serogroup. In contrast, similarities between the group A variants and a group B variant are only 70 and 64% for DNA and amino acid sequences, respectively. We propose that the MSA-2 protein is encoded by two highly divergent groups of alleles, with limited additional polymorphism displayed within each group.

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.

Cryospectrophotometric determination of tumor intravascular oxyhemoglobin saturations: dependence on vascular geometry and tumor growth.

To delineate the complex relationships between overall tumor oxygenation and vascular configuration, intravascular oxyhemoglobin (HbO2) saturation distributions were measured with cryospectrophotometric techniques. Four factors related to vascular morphometry and tumor growth were evaluated: a) vessel diameter, b) distance of vessel from the tumor surface, c) tumor volume, and d) vascular density. To measure intertumor heterogeneity, two murine sarcomas (RIF-1 and KHT) and two human ovarian carcinoma xenografts (OWI and MLS) were utilized. In contrast to skeletal muscle, a preponderance of very low HbO2 saturations was observed for both large and small tumors of all lines. Saturations up to about 90% were also generally present, however, even in very large tumors. Variations in vascular configuration were predominantly tumor-line dependent rather than due to inherent characteristics of the host vasculature, and widely disparate HbO2 distributions were found for alternate lines implanted in identical host mice. Although peripheral saturations remained fairly constant with tumor growth, HbO2 values were markedly lower for vessels nearer the tumor center and further decreased with increasing tumor volume. HbO2 saturations did not change substantially with increasing vascular density (except for KHT tumors), although density did decrease with increasing distance from tumor surface. Combined effects of vessel diameter, tumor volume, and vessel location on HbO2 saturations were complex and varied markedly with both tumor line and vessel class. For specific classes, HbO2 distributions correlated closely with radiobiological hypoxic fractions, i.e., for tumor lines in which hypoxic fraction increased substantially with tumor volume, corresponding HbO2 values decreased, while for lines in which hypoxic fraction remained constant, HbO2 values also were unchanged. Although these trends may also be a function of differing oxygen consumption rates between tumor lines, functional alterations in the rapidly expanding tumor vasculature undoubtedly play a primary role in explaining spatial oxygenation heterogeneities.

31P nuclear magnetic resonance spectroscopy studies of tumor energy metabolism and its relationship to intracapillary oxyhemoglobin saturation status and tumor hypoxia.

Relationships between tumor bioenergetic status on the one hand and intracapillary oxyhemoglobin (HbO2) saturation status and fraction of radiobiologically hypoxic cells on the other were studied using two murine sarcoma lines (KHT, RIF-1) and two human ovarian carcinoma xenograft lines (MLS, OWI). Tumor energy metabolism was studied in vivo by 31P nuclear magnetic resonance (NMR) spectroscopy and the resonance area ratio (PCr + NTP beta)/Pi was used as parameter for bioenergetic status. Intracapillary HbO2 saturation status reflects the oxygen supply conditions in tumors and was measured in vitro using a cryospectrophotometric method. The KHT, RIF-1, and MLS lines showed decreasing bioenergetic status, i.e., decreasing PCr and NTP beta resonances and an increasing Pi resonance, with increasing tumor volume, whereas the OWI line showed no changes in these resonances during tumor growth. The volume-dependence of the HbO2 saturation status differed similarly among the tumor lines; HbO2 saturation status decreased with increasing tumor volume for the KHT, RIF-1, and MLS lines and was independent of tumor volume for the OWI line. Moreover, linear correlations were found between bioenergetic status and HbO2 saturation status for individual tumors of the KHT, RIF-1, and MLS lines. These observations together indicated a direct relationship between 31P-NMR spectral parameters and tumor oxygen supply conditions. However, this relationship was not identical for the different tumor lines, suggesting that it was influenced by intrinsic properties of the tumor cells such as rate of respiration and ability to survive under hypoxia. Similarly, there was no correlation between bioenergetic status and fraction of radiobiologically hypoxic cells across the four tumor lines. This indicates that 31P-NMR spectroscopy data have to be supplemented with other data, e.g., rate of oxygen consumption, cell survival time under hypoxic stress, and/or fraction of metabolically active, nonclonogenic hypoxic cells, to be useful in quantitative determination of tumor hypoxia and hence prediction of tumor radioresistance caused by hypoxia.

Interleukin 2 expression by tumor cells alters both the immune response and the tumor microenvironment.

Microenvironmental conditions within solid tumors can have marked effects on the growth of the tumors and their response to therapies. The disorganized growth of tumors and their attendant vascular systems tends to result in areas of the tumors that are deficient in oxygen (hypoxic). Cells within these hypoxic areas are more resistant to conventional therapies such as radiation and chemotherapy. Here, we examine the hypoxic state of EMT6 mouse mammary tumors and the location of host cells within the different areas of the tumors to determine whether such microenvironmental conditions might also affect their ability to be recognized by the immune system. Hypoxia within tumors was quantified by flow cytometry and visualized by immunohistochemistry using a monoclonal antibody (ELK3-51) against cellular adducts of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetam ide (EF5), a nitroimidazole compound that binds selectively to hypoxic cells. Thy-1+ cells, quantified using a monoclonal antibody, were found only in the well-oxygenated areas. The location of these Thy-1+ cells was also examined in EMT6 tumors that had been transfected with the gene for interleukin-2 (IL-2) because these tumors contain greatly increased numbers of host cells. Surprisingly, we found that IL-2-transfected tumors had significantly decreased hypoxia compared to parental tumors. Furthermore, using the fluorescent dye Hoechst 33342, an in vivo marker of perfused vessels, combined with immunochemical staining of PECAM-1 (CD31) as a marker of tumor vasculature, we found increased vascularization in the IL-2-transfected tumors. Thus, expression of IL-2 at the site of tumor growth may enhance tumor immunity not only by inducing the generation of tumor-reactive CTLs but also by allowing increased infiltration of activated T cells into the tumors.

Assessment of tumor energy and oxygenation status by bioluminescence, nuclear magnetic resonance spectroscopy, and cryospectrophotometry.

The energy and oxygenation status of tumors from two murine sarcoma lines (KHT, RIF-1) and two human ovarian carcinoma xenograft lines (MLS, OWI) were assessed using three independent techniques. Tumor energy metabolism was investigated in vivo by 31P nuclear magnetic resonance spectroscopy. After nuclear magnetic resonance measurements, tumors were frozen in liquid nitrogen to determine the tissue ATP concentration by imaging bioluminescence and to register the intracapillary oxyhemoglobin (HbO2) saturation using the cryospectrophotometric method. There was a positive correlation between the nucleoside triphosphate beta/total resonance ratio or a negative correlation between the Pi/total resonance ratio and the model ATP concentration obtained by bioluminescence, respectively. This was true for small tumors with no extended necrosis irrespective of tumor type. Moreover, a positive correlation was obtained between the HbO2 saturations and the ATP concentration measured with bioluminescence. The results demonstrate the potential of combined studies using noninvasive, integrating methods and high-resolution imaging techniques for characterizing the metabolic milieu in tumors.

Intratumoral administration of endostatin plasmid inhibits vascular growth and perfusion in MCa-4 murine mammary carcinomas.

Endostatin, a fragment of the COOH-terminal domain of mouse collagen XVIII is a recently demonstrated endogenous inhibitor of tumor angiogenesis and endothelial cell growth. Antiangiogenic therapy with endostatin in animals requires multiple and prolonged administration of the protein. Gene therapy could provide an alternative approach to continuous local delivery of this antiangiogenic factor in vivo. Established MCa-4 murine mammary carcinomas, grown in immunodeficient mice, were treated with intratumoral injection of endostatin plasmid at 7-day intervals. At the time of sacrifice, 14 days after the first injection, endostatin-treated tumor weights were 51% of controls (P < 0.01). Tumor growth inhibition was accompanied by a marked reduction in total vascular density. Specifically, computerized image analysis showed a 18-21% increase in the median distances between tumor cells and both the nearest anatomical (CD31-stained) vessel [48.1 +/- 3.8 versus 38.3 +/- 1.6 microm (P < 0.05)] and the nearest tumor-specific (CD105-stained) vessel [48.5 +/- 1.5 versus 39.8 +/- 1.5 microm (P < 0.01)]. An increased apoptotic index of tumor cells in endostatin-treated tumors [3.2 +/- 0.5% versus 1.9 +/- 0.3% (P < 0.05)] was observed in conjunction with a significant decrease in tumor perfused vessels (DiOC7 staining), and an increase in tumor cell hypoxia (EF5 staining). Hypoxia resulting from endostatin therapy most likely caused a compensatory increase of in situ vascular endothelial growth factor (VEGF) and VEGF receptor mRNA expression. Increased immunoreactivity of endostatin staining in endostatin-treated tumors was also associated with an increased thrombospondin-1 staining [1.12 +/- 0.16 versus 2.44 +/- 0.35]. Our data suggest that intratumoral delivery of the endostatin gene efficiently suppresses murine mammary carcinoma growth and support the potential utility of the endostatin gene for cancer therapy.

Hemodynamic, ventilatory, and biochemical responses of panic patients and normal controls with sodium lactate infusion and spontaneous panic attacks.

Hemodynamic, ventilatory, and biochemical variables were measured in ten healthy adults and ten panic patients during infusion of 0.5 mol/L of sodium lactate. Physical activity, fitness level, and ambulatory electrocardiograms were also recorded. Lactate infusion doubled cardiac output, increased blood lactate levels by sixfold, and produced hypernatremia, hypocalcemia, and decreased serum bicarbonate levels in both groups but raised arterial pressure only in the patients. The patients hyperventilated before and during the infusion. Physiological responses and somatic complaints with the infusion differed little between the groups, but emotional complaints were six times more frequent among the panic patients. Eight patients but no control subjects interpreted their symptoms as a panic attack. Heart rate increased with only 14 of 31 recorded spontaneous outpatient panic attacks. Sodium lactate infusions appear to produce panic by mimicking the physiology of spontaneous panic. Treatment with cardioactive agents is not indicated in the absence of cardiopulmonary or autonomic nervous system abnormalities.

Familial transmission of substance use disorders.

BACKGROUND: There is increasing evidence that substance use disorders are familial and that genetic factors explain a substantial degree of their familial aggregation. To perform a controlled family study of probands with several different predominant drugs of abuse, including opioids, cocaine, cannabis, and/or alcohol. METHODS: The subjects for the present study included 231 probands with dependence on opioids, cocaine, cannabis, and/or alcohol and 61 control probands, and their 1267 adult first-degree relatives. Diagnostic estimates were based on semistructured diagnostic interviews and/or structured family history interviews regarding each proband, spouse, and adult first-degree relative. The interview data were reviewed blindly and independently by clinicians with extensive experience in the evaluation and treatment of substance use disorders. RESULTS: There was an 8-fold increased risk of drug disorders among the relatives of probands with drug disorders across a wide range of specific substances, including opioids, cocaine, cannabis, and alcohol, which is largely independent from the familial aggregation of both alcoholism and antisocial personality disorder. There was also evidence of specificity of familial aggregation of the predominant drug of abuse. CONCLUSIONS: Elevation in risk of this magnitude places a family history of drug disorder as one of the most potent risk factors for the development of drug disorders. These results suggest that there may be risk factors that are specific to particular classes of drugs as well as risk factors that underlie substance disorders in general.

Learned helplessness and urinary MHPG levels in unipolar depression.

OBJECTIVE: Studies of the learned helplessness paradigm in laboratory animals show increased central noradrenergic activity following exposure to uncontrollable stressors. In clinical studies, depressed patients as a group report higher perceptions of helplessness and powerlessness. The authors examined the relationship between perceptions of powerlessness and noradrenergic activity in depressed patients. METHOD: Twenty drug-free patients (12 women and 8 men) meeting DSM-III criteria for major depressive disorder were given the Kobasa Hardiness Questionnaire, which contains subscales measuring feelings of powerlessness, security, and alientation. Concurrently, 24-hour urine samples were collected for measurement of urinary MHPG. RESULTS: Significant correlations were found between MHPG levels and total hardiness scores as well as between MHPG levels and total powerlessness scores but not between MHPG levels and total security or total alientation scores. CONCLUSIONS: These results suggest that depressed patients with high urinary output of MHPG are more likely to show the cognitive features of learned helplessness.

A biopsychosocial approach to treating patients with affective disorders.

The authors describe the development of an affective disorders consultation service that implemented a biopsychosocial model of subspecialty consultation within a university-affiliated community mental health center. They retrospectively analyzed the first 2 years of consultations, assessing the process of consultation and examining patterns of consultee inquiries and consultation recommendations. Consultants recommended combined psychopharmacologic and psychodynamic therapies for most patients and found psychodynamic psychotherapy strikingly overlooked by consultees, all of whom were psychiatrists or other mental health professionals. This evaluation documents the psychiatric consultees' deemphasis of the biopsychosocial perspective in clinical practice.

Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study.

OBJECTIVE: Although genetic factors have been implicated in the etiology of bipolar disorder, no specific gene has been conclusively identified. Given the link between abnormalities in serotonergic neurotransmission and bipolar disorder, a candidate gene association approach was applied to study the involvement of the monoamine oxidase A (MAOA) gene, which codes for a catabolic enzyme of serotonin, in the susceptibility to bipolar disorder. METHOD: In France and Switzerland, 272 patients with bipolar disorder and 122 healthy subjects were typed for three polymorphic markers of the MAOA gene: the MAOA-CA repeat, the MAOA restriction fragment length polymorphism (RFLP), and a repeat directly adjacent to the variable number of tandem repeats (VNTR) locus. RESULTS: A significant difference in the distribution of the alleles for the MAOA-CA repeat was observed between the female bipolar patients and comparison group. CONCLUSIONS: The results obtained in the French and Swiss population confirm findings from two studies conducted in the United Kingdom.

Association between migraine and stroke in a large-scale epidemiological study of the United States.

OBJECTIVE: To examine the association between stroke and migraine in an epidemiological study. DATA SOURCES AND DESIGN: The National Health and Nutrition Examination Survey baseline and first follow-up data were used to investigate cross-sectional and longitudinal associations between headache/migraine and stroke. SETTING: Study participants from a national probability sample of the civilian noninstitutionalized population of the United States. MAIN OUTCOME MEASURE: Self-reported physician diagnosis of stroke. RESULTS: After controlling for established risk factors for stroke (hypertension, diabetes, heart disease, and gender), both migraine and severe nonspecific headache were associated with a significantly increased risk for stroke reported at follow-up. The risk for stroke associated with migraine decreased as the age at stroke increased. CONCLUSIONS: Our results strengthen previous evidence regarding a nonrandom association of both headache and migraine with stroke, particularly among young women. To our knowledge, this is the first systematic examination in a large-scale prospective epidemiological study of men and women with sufficient statistical power to test the association between migraine and stroke in women. Severe headache and migraine should be considered as risk factors for the development of stroke, particularly in the absence of other well-established stroke risk factors. Further investigation is required to identify the putative mechanisms underlying comorbidity of migraine and stroke.

Effects of ionizing radiation on the adhesive interaction of human tumor and endothelial cells in vitro.

A centrifugation assay was used to determine the effects of ionizing radiation on the adhesive interaction of A549 human lung adenocarcinoma tumor cells and human umbilical vein endothelial cells (HUVEC). The tumor cells were fluorescently labeled and divided into control (sham-irradiated) and irradiated groups. The irradiated groups were exposed to irradiation levels ranging from 5 to 20 Gy using a 137Cs source. A specified number of these A549 tumor cells were then delivered into each well of 96-well cell culture plates containing confluent monolayers of human umbilical cord vein endothelial cells (HUVEC), and were given time to adhere to the endothelial cells. The wells were then sealed and were exposed to an acceleration field varying from 1 to 42 g (0-500 rpm) for 10 min. Finally, the wells were drained, and the number of tumor cells adhering to the endothelial monolayer were counted using a fluorescent microscope system. Our results indicate that the irradiation of A549 tumor cells significantly increased their adhesive interaction with endothelial cells (number of adhering irradiated cells/number of adhering control cells = 1.0, 1.3, 1.9, 2.2 for 0, 5, 10, 20 Gy respectively). In contrast, when endothelial cells were irradiated, rather than tumor cells, adhesive interaction decreased with an increase in the radiation dose (irradiated/control = 1.0, 0.9, 0. 8, 0.5 for 0, 5, 10, 20 Gy respectively). Simultaneous irradiation of both the tumor cells and the endothelial cells did not alter their adhesive interaction significantly. These findings may have important implications for the metastatic ability of irradiated tumor cells.