Neuroanatomic Correlates of Female Sexual Dysfunction in Multiple Sclerosis

OBJECTIVE: This study intended to determine associations between alterations of female sexual arousal as well as vaginal lubrication and the site of cerebral multiple sclerosis (MS) lesions. METHODS: In 44 women with MS (mean age: 36.5 ± 9.9 years), we assessed their medical history and evaluated sexual function using the Female Sexual Function Index scores for arousal and vaginal lubrication. We determined potential confounding factors of sexual dysfunction: age; disease duration; physical disability; depression; bladder or urinary dysfunction; and total volume of cerebral lesions. Arousal and lubrication scores were correlated with one another and with potential confounding factors. Cerebral MS lesions were recorded on imaging scans. A voxel-based lesion symptom mapping (VLSM) analysis adjusted for confounding variables was performed correlating cerebral sites of MS lesions with arousal and lubrication scores. RESULTS: Decreased arousal scores correlated with decreased lubrication scores; decreased lubrication scores were associated with bladder or urinary symptoms. Arousal and lubrication scores were not associated with any other variables. Multivariate VLSM analysis, including arousal and lubrication scores as covariables of interest, showed right occipital lesions associated with impaired arousal and left insular lesions associated with decreased lubrication. Impaired lubrication remained associated with left insular lesions after adjustment for bladder or urinary dysfunction. INTERPRETATION: Our data indicate that impaired female sexual arousal is associated with MS lesions in the occipital region, integrating visual information and modulating attention toward visual input. Impaired lubrication correlated with lesions in the left insular region, contributing to mapping and generating visceral arousal states

Management strategies for gastrointestinal, erectile, bladder, and sudomotor dysfunction in patients with diabetes

There are substantial advances in understanding disordered gastrointestinal autonomic dysfunction in diabetes. It occurs frequently. The underlying pathogenesis is complex involving defects in multiple interacting cell types of the myenteric plexus as well. These defects may be irreversible or reversible. Gastrointestinal symptoms represent a major and generally underestimated source of morbidity for escalating health care costs in diabetes. Acute changes in glycaemia are both determinants and consequences of altered gastrointestinal motility. 35–90% of diabetic men have moderate‐to‐severe erectile dysfunction (ED). ED shares common risk factors with CVD. Diagnosis is based on medical/sexual history, including validated questionnaires. Physical examination and laboratory testing must be tailored to patient's complaints and risk factors. Treatment is based on PDE5‐inhibitors (PDE5‐I). Other explorations may be useful in patients who do not respond to PDE5‐I. Patients at high cardiovascular risk should be stabilized by their cardiologists before sexual activity is considered or ED treatment is recommended. Estimates on bladder dysfunction prevalence are 43–87% of type 1 and 25% of type 2 diabetic patients, respectively. Common symptoms include dysuria, frequency, urgency, nocturia and incomplete bladder emptying. Diagnosis should use validated questionnaire for lower urinary tract symptoms. The type of bladder dysfunction is readily characterized with complete urodynamic testing. Sudomotor dysfunction is a cause of dry skin and is associated with foot ulcerations. Sudomotor function can be assessed by thermoregulatory sweat testing, quantitative sudomotor axon reflex test, sympathetic skin response, quantitative direct/indirect axon reflex testing and the indicator plaster. Copyright © 2011 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87058/1/1223_ftp.pd

Polymeric drift control adjuvants for agricultural spraying

The movement of a pesticide or herbicide to an off-target site during agricultural spraying can cause injury to wildlife, plants and contamination of surface water. This phenomenon is known as spray drift and can be controlled by spraying during favorable environmental conditions, and by using low drift nozzles and drift control adjuvants (DCAs). Polymeric DCAs are the most common type of DCA and function by increasing the droplet size produced during spraying. There are, however, two main drawbacks of polymeric DCAs; they are prone to mechanical degradation during spraying which reduces their performance and they can produce oversized drops which reduces the efficacy of the spray. In this trend article, existing DCA technology is reviewed including the mechanism through which they function. This then provides a platform for the discussion of novel polymeric architectures which have currently not been applied in DCA formulations

Fabry disease in children and the effects of enzyme replacement treatment

Fabry disease is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficiency in the activity of the lysosomal enzyme, α-galactosidase A. In affected patients, the enzyme substrate, globotriaosylceramide (Gb3), accumulates in cells of various tissues and organs. Lysosomal accumulation of Gb3 begins in utero, and signs and symptoms of Fabry disease emerge in childhood and adolescence. The earliest presenting symptoms are typically neuropathic pain and gastrointestinal problems, which can have a substantial impact on health-related quality of life. Life-threatening major organ involvement is rare in young patients, but signs of kidney dysfunction (e.g., proteinuria), left ventricular hypertrophy, and stroke have been reported in children. There are two enzyme preparations for therapy: agalsidase alfa and beta. In two clinical trials of enzyme replacement therapy (ERT) with agalsidase alfa, including 37 children, boys demonstrated reductions in plasma Gb3 levels, and both boys and girls reported reductions in neuropathic pain and in the use of neuropathic pain medications. Heart rate variability, which is reduced in boys with Fabry disease, was statistically significantly improved with 6 months of agalsidase alfa treatment. In a single clinical study of agalsidase beta in children (n =16), skin Gb3 deposits and plasma Gb3 levels were reduced in boys. Differences exist in the administration and the safety profile of these two enzyme formulations. Follow-up of these cohorts and additional studies will be necessary to fully evaluate long-term efficacy of ERT in children with Fabry disease

Generation of Large-Scale Vorticity in a Homogeneous Turbulence with a Mean Velocity Shear

An effect of a mean velocity shear on a turbulence and on the effective force which is determined by the gradient of Reynolds stresses is studied. Generation of a mean vorticity in a homogeneous incompressible turbulent flow with an imposed mean velocity shear due to an excitation of a large-scale instability is found. The instability is caused by a combined effect of the large-scale shear motions (''skew-induced" deflection of equilibrium mean vorticity) and ''Reynolds stress-induced" generation of perturbations of mean vorticity. Spatial characteristics, such as the minimum size of the growing perturbations and the size of perturbations with the maximum growth rate, are determined. This instability and the dynamics of the mean vorticity are associated with the Prandtl's turbulent secondary flows. This instability is similar to the mean-field magnetic dynamo instability. Astrophysical applications of the obtained results are discussed.Comment: 8 pages, 3 figures, REVTEX4, submitted to Phys. Rev.

In vitro and in vivo interplay between NAD(P)H: quinone oxidoreductase 1 and flavonoids

Flavonoids are naturally occurring, health-promoting, bioactive compounds, omnipresent in the human diet. The protective effect of these phytochemicals is accomplished for an important part by modulating the activity of enzyme systems responsible for deactivation of chemical carcinogens, such as NAD(P)H: quinone oxidoreductase 1 (NQO1). Several flavonoids act as NQO1 inducers by increasing the NQO1 gene expression level through the electrophile-responsive element (EpRE). On the other hand certain flavonoids are efficient inhibitors of the NQO1 enzyme activity in vitro. The objective of this thesis is to elucidate the complex interplay between flavonoids and NQO1. First, inhibition of NQO1 by flavonoids, pointing at a mechanism contradicting the proven beneficial properties of these natural compounds was studied. Kinetic and molecular dynamics studies were conducted and a method to monitor NQO1 activity in living cells was developed. These studies revealed that although flavonoids possess the potential to inhibit NQO1 activity, inhibition of NQO1 is not likely to happen in cellular systems due to intracellular physiological conditions. Furthermore, the mechanism by which flavonoids are able to induce the EpRE- mediated expression of NQO1 was studied. Reporter gene assays elucidated that upstream XRE-mediated gene expression is not nessessary to induce EpRE-mediated gene expression and quantum-mechanical calculations revealed that flavonoids with a higher intrinsic potential to generate oxidative stress and redox cycling, are the most potent inducers of NQO1. Radioactive binding studies showed Keap1 modification by the flavonoid quercetin, resulting in switching on of EpRE-mediated gene transcription activation. In addition, in vivo metabolites of quercetin were studied on their ability to induce EpRE-mediated gene expression. The results show, that, although quercetin-derived glucuronides are the major metabolites present in the systemic circulation, the deglucuronidated parent compound and its methylated derivatives are the active compounds responsible for the beneficial EpRE-mediated gene expression effects. Overall, the studies presented in this thesis provide insight in the complex interplay between NQO1 and flavonoids on the protein as well as on the gene expression level

Pro-Oxidant Activity of Flavonoids Induces EpRE-Mediated Gene Expression.

Flavonoids are important bioactive dietary compounds. They induce electrophile-responsive element (EpRE)-mediated expression of enzymes, such as NAD(P)H-quinone oxidoreductase (NQO1) and glutathione S-transferases (GSTs), which are major defense enzymes against electrophilic toxicants and oxidative stress. The induction of EpRE-mediated gene transcription involves the release of the transcription factor Nrf2 from a complex with Keap1, either by a direct interaction of the inducer with Keap1 or by protein kinase C (PKC)-mediated phosphorylation of Nrf2. The inhibition of PKC in Hepa1c1c7 cells, stably transfected with human NQO1-EpRE-controlled luciferase revealed that PKC is not involved in flavonoid-induced EpRE-mediated gene transcription. However, the ability of flavonoids to activate an EpRE-mediated response correlates with their redox properties characterized by quantum mechanical calculations. Flavonoids with a higher intrinsic potential to generate oxidative stress and redox cycling are the most potent inducers of EpRE-mediated gene expression. Modulation of the intracellular glutathione (GSH) level showed that the EpRE-activation by flavonoids increased with decreasing GSH and vice versa, supporting an oxidative mechanism. In conclusion, the pro-oxidant activity of flavonoids can contribute to their health-promoting activity by inducing important detoxifying enzymes, pointing to a beneficial effect of a supposed toxic chemical reactio

Central Autonomic Dysfunction Delays Recovery of Fingolimod Induced Heart Rate Slowing

Background In multiple sclerosis (MS) patients, Fingolimod may induce prolonged heart-rate slowing which might be caused by MS-related central autonomic lesions. Objectives To evaluate whether MS-patients with prolonged heart-rate slowing (> six hours) upon Fingolimod show cardiovascular-autonomic dysfunction before Fingolimod-initiation. Methods Before Fingolimod-initiation, we recorded electrocardiographic RR-intervals (RRIs) and blood-pressure (BP) at rest, upon standing-up, during metronomic deep-breathing, Valsalva-maneuver, and “sustained-handgrip-exercise” in 21 patients with relapsing-remitting MS, and 20 healthy persons. We calculated sympathetic and parasympathetic cardiovascular parameters, including low- (LF) and high-frequency (HF) powers of RRI- and BP-oscillations, RRI-RMSSDs, RRI- and BP-changes during handgrip-exercise, parasympathetic heart-rate-slowing in relation to BP-overshoot after Valsalva-strain-release. We compared values of healthy persons and patients with and without prolonged heart-rate slowing after Fingolimod-initiation (ANOVA; significance: p<0.05). Results Upon Fingolimod-initiation, 7/21 patients had prolonged HR-slowing. Before Fingolimod, these patients had higher resting BP and higher BP increase during handgrip-exercise than had the other participants (p<0.05). They did not reduce parasympathetic HR-parameters upon standing-up. After Valsalva-strain-release, their parasympathetic HR-slowing in response to BP-overshoot was four times higher than in the other participants (p<0.05). Conclusions The autonomic cardiovascular dysfunction in MS-patients with delayed HR-re-acceleration upon Fingolimod-initiation suggests that MS-related central autonomic lesions compromise HR-re-acceleration upon Fingolimo