Muscle Sympathetic Nerve Activity Is Related to a Surrogate Marker of Endothelial Function in Healthy Individuals

BACKGROUND: Evidence from animal studies indicates the importance of an interaction between the sympathetic nervous system and the endothelium for cardiovascular regulation. However the interaction between these two systems remains largely unexplored in humans. The aim of this study was to investigate whether directly recorded sympathetic vasoconstrictor outflow is related to a surrogate marker of endothelial function in healthy individuals. METHODS AND RESULTS: In 10 healthy normotensive subjects (3 f/7 m), (age 37+/-11 yrs), (BMI 24+/-3 kg/m(2)) direct recordings of sympathetic action potentials to the muscle vascular bed (MSNA) were performed and endothelial function estimated with the Reactive Hyperaemia- Peripheral Arterial Tonometry (RH-PAT) technique. Blood samples were taken and time spent on leisure-time physical activities was estimated. In all subjects the rate between resting flow and the maximum flow, the Reactive Hyperemic index (RH-PAT index), was within the normal range (1.9-3.3) and MSNA was as expected for age and gender (13-44 burst/minute). RH-PAT index was inversely related to MSNA (r = -0.8, p = 0.005). RH-PAT index and MSNA were reciprocally related to time (h/week) spent on physical activity (p = 0.005 and p = 0.006 respectively) and platelet concentration (PLT) (p = 0.02 and p = 0.004 respectively). CONCLUSIONS: Our results show that sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy normotensive individuals, indicating that sympathetic outflow may be modulated by changes in endothelial function. In this study time spent on physical activity is identified as a predictor of sympathetic nerve activity and endothelial function in a group of healthy individuals. The results are of importance in understanding mechanisms underlying sympathetic activation in conditions associated with endothelial dysfunction and emphasise the importance of a daily exercise routine for maintenance of cardiovascular health

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans

Comparison of diagnosis and treatment of invasive breast cancer between Iceland and Sweden

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadTILGANGUR Rannsóknin var liður í innleiðingu gæðaskráningar brjóstakrabbameina á Íslandi og markmiðið að bera saman greiningu og meðferð ífarandi brjóstakrabbameina á Íslandi og í Svíþjóð. EFNIVIÐUR OG AÐFERÐIR Upplýsingar um alla einstaklinga sem greindust með ífarandi brjóstakrabbamein á Íslandi 2016-2017 fengust frá Krabbameinsskrá. Breytur úr sjúkraskrám voru skráðar í eyðublöð í Heilsugátt að fyrirmynd sænsku gæðaskráningarinnar og voru niðurstöður bornar saman við niðurstöður fyrir ífarandi brjóstakrabbamein af heimasíðu sænsku krabbameinsskrárinnar. Notað var tvíhliða kí-kvaðrat-próf til að bera saman hlutföll. NIÐURSTÖÐUR Á rannsóknartímabilinu greindust 486 ífarandi brjóstakrabbamein á Íslandi og 15.325 í Svíþjóð. Hlutfallslega færri 40-69 ára konur greindust við hópleit á Íslandi (46%) en í Svíþjóð (60%) (p<0,01). Á Íslandi voru haldnir heldur færri samráðsfundir fyrir fyrstu meðferð (92%) og eftir aðgerð (96%) miðað við Svíþjóð árið 2016 (98% og 99%) (p<0,05) en ekki var marktækur munur 2017. Varðeitlataka var gerð í 69% aðgerða á Íslandi en í 94% aðgerða í Svíþjóð (p<0,01). Ef æxlið var ≤30 mm var á Íslandi gerður fleygskurður í 48% tilvika en í 80% tilvika í Svíþjóð (p<0,01). Á Íslandi fengu 87% geislameðferð eftir fleygskurð en 94% í Svíþjóð (p<0,01). Ef eitlameinvörp greindust í brottnámsaðgerð þá fengu 49% geislameðferð eftir aðgerð á Íslandi en 83% í Svíþjóð (p<0,01). ÁLYKTANIR Marktækur munur er á ýmsum þáttum greiningar og meðferðar ífarandi brjóstakrabbameina milli Íslands og Svíþjóðar. Með gæðaskráningu brjóstakrabbameina á Íslandi er hægt að fylgjast með og setja markmið um ákveðna þætti greiningar og meðferðar í því skyni að veita sem flestum einstaklingum bestu meðferð.PURPOSE: As part of the implementation of quality registration in Iceland we used retrospective data to compare diagnosis and treatment of invasive breast cancer between Iceland and Sweden. MATERIALS AND METHODS: Information on all patients diagnosed with invasive breast cancer in Iceland 2016-2017 was obtained from the Icelandic Cancer Registry. Hospital records were used to register variables in an electronic form adapted from the Swedish quality registration, and compared with data from Sweden for the same period. A chi-square test was used to compare ratios. RESULTS: A total of 486 cases of breast cancer were diagnosed in Iceland and 15.325 in Sweden. A lower proportion of 40-69 year old women were diagnosed within the screening programme in Iceland (46%) compared to Sweden (60%) (p<0,01). Multidisciplinary tumor board meetings held before and after surgery were less frequent in Iceland (92% vs. 96%) compared to Sweden (98% vs. 99%) in 2016 (p<0,01) but no difference was seen in 2017. A sentinel node surgery was done in 69% of the cases in Iceland compared to 94% in Sweden (p<0,01). For cancers ≤30mm breast conserving surgery was done in 48% cases in Iceland but 80% in Sweden (p<0,01). In Iceland 87% of the cases had radiation therapy after breast conserving surgery but 94% in Sweden (p<0,01). Among mastectomy patients with lymph node metastases, 49% received radiation therapy in Iceland compared to 83% in Sweden (p<0,01). CONCLUSION: Differences were seen in several areas of diagnosis and treatment of invasive breast cancer between Iceland and Sweden. With quality registration it will be possible to monitor and set goals for the diagnosis and treatment, with the aim of providing the best treatment to as many patients as possible.Krabbameinsfélag Reykjavíku

Differentiated baroreflex modulation of sympathetic nerve activity during deep brain stimulation in humans.

Targeted electric deep brain stimulation in midbrain nuclei in humans alters cardiovascular parameters, presumably by modulating autonomic and baroreflex function. Baroreflex modulation of sympathetic outflow is crucial for cardiovascular regulation and is hypothesized to occur at 2 distinct brain locations. The aim of this study was to evaluate sympathetic outflow in humans with deep brain stimulating electrodes during ON and OFF stimulation of specific midbrain nuclei known to regulate cardiovascular function. Multiunit muscle sympathetic nerve activity was recorded in 17 patients undergoing deep brain stimulation for treatment of chronic neuropathic pain (n=7) and Parkinson disease (n=10). Sympathetic outflow was recorded during ON and OFF stimulation. Arterial blood pressure, heart rate, and respiratory frequency were monitored during the recording session, and spontaneous vasomotor and cardiac baroreflex sensitivity were assessed. Head-up tilt testing was performed separately in the patients with Parkinson disease postoperatively. Stimulation of the dorsal most part of the subthalamic nucleus and ventrolateral periaqueductal gray resulted in improved vasomotor baroreflex sensitivity, decreased burst frequency and blood pressure, unchanged burst amplitude distribution, and a reduced fall in blood pressure after tilt. Stimulation of the dorsolateral periaqueductal gray resulted in a shift in burst amplitude distribution toward larger amplitudes, decreased spontaneous beat-to-beat blood pressure variability, and unchanged burst frequency, baroreflex sensitivity, and blood pressure. Our results indicate that a differentiated regulation of sympathetic outflow occurs in the subthalamic nucleus and periaqueductal gray. These results may have implications in our understanding of abnormal sympathetic discharge in cardiovascular disease and provide an opportunity for therapeutic targeting

Formulation development for first-order release caffeine tablets

Caffeine is an alkaloid that is found in nature in e.g., coffee beans, cocoa beans, tea, guarana herbs, and cola nuts. Today, more than 60 plants containing caffeine have been identified. Caffeine stimulates the central nervous system and has several effects, but the main action is an antagonism effect on the adenosine receptor. The aim of the project was to develop a dosage form that has caffeine as the API, has a first-order release and was supposed to meet certain requirements in a solubility test. First order release is the most common release for most formulations, when the amount of drug released is proportional to the amount left in the pharmaceutical form. Caffeine with excipients has a first-order release that did not reach all the desired limits. Therefore, it was decided to add disintegrants to increase the release of the API in the tablets. Various disintegrants were tested, along with different hardness values and diameters. A total of 24 formulations were made and formulation no. 24 was chosen as the final formulation because it met all the required properties and requirements. Quality tests were performed on the tablets according to the European Pharmacopoeia and the tablets passed with flying colours.Koffín er beiskjuefni (e. alkaloid) sem finnst í náttúrunni í m.a. kaffibaunum, kakóbaunum, tei, guarana-jurtum og kólahnetum. Í dag er búið að auðkenna yfir 60 plöntur sem innihalda koffín. Koffín örvar miðtaugakerfið og hefur nokkrar verkanir, en helsta verkun þess er að það andverkar á adenósín viðtaka sem eru staðsettir í heila og sléttum vöðvum. Markmið verkefnisins var að þróa lyfjaform sem inniheldur koffín sem virka efnið og hefur fyrsta stigs losun og átti að uppfylla ákveðnar kröfur í leysnihraðaprófi. Fyrsta stigs losun er algengasta losun fyrir flest lyfjaform, þar sem losunarhraði lyfsins er í réttu hlutafalli við magn lyfs sem eftir er í lyfjaforminu. Koffín ásamt burðarefnum er með fyrsta stigs losun en náði ekki öllum tilætluðum mörkum svo ákveðið var að bæta sundrunarefnum við til að flýta fyrir losun virka efnisins úr töflunum. Margskonar sundrunarefni voru prófuð, ásamt mismunandi hörkum og þvermáli stimpla. Alls voru 24 formúleringar gerðar og var formúlering númer 24 valin sem lokaformúlering vegna þess að hún uppfyllti allar kröfur um eiginleika og aðrar kröfum sem um var beðið. Framkvæmdar voru gæðaprófanir á töflunum samkvæmt Evrópsku lyfjaskránni og stóðust töflurnar allar þær prófanir með glæsibrag

Brca1 promoter methylation status in 1031 primary breast cancers predicts favorable outcomes following chemotherapy

The authors would like to thank The Icelandic Research Fund (www.rannis.is) (14193–051 and 152077–051) and Gongum saman (www.gongumsaman.is) for funding. Publisher Copyright: © 2020 Oxford University Press. All rights reserved.Background: Breast Cancer 1 gene (BRCA1) is known to be inactivated in breast tumors by promoter methylation. Tumor cells in patients carrying a germline mutation in BRCA1 are sensitive to cytotoxic drugs that cause DNA double strand breaks. However, very little is known on whether patients with BRCA1 promoter methylated tumors are similarly sensitive to cytotoxic drugs. In this study, we address this by making use of extensive follow-up data on patients treated with cyclophosphamide, methotrexate, and fluorouracil in Iceland between 1976 and 2007. Methods: We analyzed BRCA1 promoter methylation by pyrosequencing DNA from tumor samples from 1031 patients with primary breast cancer. Of those, 965 were sporadic cases, 61 were BRCA2, and five were BRCA1 germline mutation carriers. All cases were examined with respect to clinicopathological parameters and breast cancer-specific survival in patients treated with cytotoxic drugs. Information on chemotherapy treatment in noncarriers was available for 26 BRCA1 methylated tumors and 857 unmethylated tumors. Results: BRCA1 was promoter methylated in 29 sporadic tumors or in 3.0% of cases (29 of 965), whereas none of the tumors derived from BRCA germline mutation carriers were promoter methylated. Important to note, patients with BRCA1 promoter methylation receiving chemotherapeutic drug treatment show highly improved breast cancer-specific survival compared with unmethylated controls (hazard ratio 0.10, 95% confidence interval 0.01 to 0.75, two-sided P .02). Conclusions: BRCA1 promoter methylation is predictive of improved disease outcome in patients receiving cyclophosphamide, methotrexate, and fluorouracil drug treatment. Our results support the use of markers indicative of "BRCAness" in sporadic breast cancers to identify patients that are likely to benefit from the use of DNA-damaging agents.Peer reviewe