Circulating Tumour Necrosis Factor is highly correlated with brainstem serotonin transporter availability in humans

Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [123I] -beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8 weeks was associated with a significant reduction in 5-HTT availability (Z= 2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression

Exercise training reduces the acute physiological severity of post-menopausal hot flushes.

A hot-flush is characterised by feelings of intense heat, profuse elevations in cutaneous vasodilation and sweating, and reduced brain blood flow. Exercise training reduces self-reported hot-flush severity, but underpinning physiological data are lacking. We hypothesised that exercise training attenuates the changes in cutaneous vasodilation, sweat rate and cerebral blood flow during a hot flush. In a preference trial, 18 symptomatic post-menopausal women underwent a passive heat stress to induce hot-flushes at baseline and follow-up. Fourteen participants opted for a 16-week moderate intensity supervised exercise intervention, while 7 participants opted for control. Sweat rate, cutaneous vasodilation, blood pressure, heart rate and middle cerebral artery velocity (MCAv) were measured during the hot-flushes. Data were binned into eight equal segments, each representing 12.5% of hot flush duration. Weekly self-reported frequency and severity of hot flushes were also recorded at baseline and follow-up. Following training, mean hot-flush sweat rate decreased by 0.04 mg·cm2 ·min-1 at the chest (95% CI: 0.02-0.06, P = 0.01) and by 0.03 mg·cm2 ·min-1 (0.02-0.05, P = 0.03) at the forearm, compared with negligible changes in control. Training also mediated reductions in cutaneous vasodilation by 9% (6-12) at the chest and by 7% (4-9) at forearm (P≤0.05). Training attenuated hot flush MCAv by 3.4 cm/s (0.7-5.1, P = 0.04) compared with negligible changes in control. Exercise training reduced the self-reported severity of hot-flush by 109 arbitrary units (80-121, P<0.001). These data indicate that exercise training leads to parallel reductions in hot-flush severity and within-flush changes in cutaneous vasodilation, sweating and cerebral blood flo

Elinzanetant: a phase III therapy for postmenopausal patients with vasomotor symptoms

IntroductionMenopausal vasomotor symptoms (VMS) are experienced by most women and are often debilitating and can last for years. While hormone replacement therapy is effective, it carries risks that have impacted its wider use, and it can be contraindicated. There is a large unmet need for a safe, effective non-hormonal therapy.Areas coveredThe importance of the neurokinin (NK) system in the hypothalamic regulation of the vasomotor center has become clear. NK antagonists, previously developed for other indications, have therefore been investigated for the treatment of VMS. Elinzanetant is a potent antagonist at both NK1 (endogenous ligand Substance P) and NK3 (neurokinin B) receptors, whereas other related drugs in development are selective NK3 antagonists. Elinzanetant has been investigated in 2 Phase II trials for menopausal VMS, demonstrating rapid onset and dose-dependant efficacy for the relief of VMS and improvement in quality of life for up to 12 weeks. Phase III trials are underway in women both with physiological menopause and after treatment for breast cancer.Expert opinionElinzanetant is a very promising non-hormonal approach to a highly prevalent symptom constellation, with rapid onset and high efficacy. Wider indications are being explored in current Phase III trials

Management of induced menopause in gynaecological cancers and their challenges

Purpose of Review: The consequence of treatment for gynaecological cancers can cause sudden onset of intense menopausal symptoms, such as vasomotor symptoms, sexual dysfunction and emotional instability. Hormone replacement therapy (HRT) is often effective and can overcome these unpleasant and severe symptoms. However, data regarding its safety remains controversial. The big question therefore is whether HRT in gynaecological cancer survivors is possible. This is due to the fear of disease relapse. So, the purpose of this study was to review the evidence regarding cancer recurrence or death following use of HRT in survivors of gynaecological cancers. Recent Findings: For endometroid endometrial cancer, most of the retrospective studies concluded that there was no increase in recurrence rate of endometrial cancers in HRT versus non-HRT users. HRT should be particularly avoided in epithelial ovarian tumours particularly serous cancers and serous borderline tumours due to expression of oestrogen receptors. Given the lack of evidence on the impact of HRT on recurrence and disease-free survival in survivors of cervical cancers, it would seem perfectly reasonable to prescribe HRT, particularly if they are premenopausal. Many clinical guidelines would consider the use of HRT to be contraindicated in breast cancer survivors based on limited RCT evidence. Summary: Current scientific data, comprising mainly of retrospective studies, suggest that recurrence rates and survival are comparable between HRT users and non-users. Women should know the paucity of safety data regarding the use of HRT. Wherever possible, non-hormonal alternatives to HRT should be considered in all women. If non-hormonal alternatives fail to achieve adequate control of symptoms, then it is possible to consider the HRT after careful counselling of the patient as well as involvement of the oncology team in the decision-making process. However, more robust randomised controlled trials are needed to get convincing data regarding the safety of HRT in gynaecological cancer survivors

Production model under the integrated approach of lean manufacturing and SLP to increase efficiency in a company of the metal mechanic sector

Metal mechanics plays a relevant role in the entire productive structure of the economy since it is an indispensable supplier of capital goods such as equipment, infrastructure, spare parts, and machines. However, the lack of efficient production processes, the high rate of defective products, and unnecessary routes in factories and production workshops are some of the frequent problems that companies in this area have that directly affect their productivity. Consequently, extreme routes and the profiling area have been identified as the main bottlenecks in the production process, impacting production efficiency. Therefore, the main objective of this case study is to demonstrate how the implementation of Lean tools has managed to increase the efficiency of the process for the production of thermoacoustic panels, reducing unnecessary routes and defective products. The proposed model comprises Lean tools such as the standardization of work and the 5S methodology, and the SLP was also applied to carry out the redistribution of activities. A simulation was carried out in the Arena software to validate the improvement proposal's results. The results obtained from the simulation were an increase of 19.24% in the overall efficiency of the process, a decrease of 42.4% in hours lost due to defective products, and a 26.7% reduction in downtimeEl objetivo principal en este caso de estudio es demostrar cómo la implementación de herramientas de Lean Manufacturing han logrado aumentar la eficiencia general del proceso, principal problema encontrado en la investigación, para la elaboración de paneles termoacústicos, logrando disminuir las causas raíces: recorridos innecesarios y los productos defectuosos. El modelo propuesto se encuentra compuesto por herramientas de Lean Manufacturing como la estandarización del trabajo y la metodología 5S; además, se aplicó la herramienta SLP para poder realizar la redistribución de las actividades lo que permite organizar y optimizar la disposición de elementos en un espacio limitado. La metodología 5S permite tener un ambiente de trabajo organizado, ordenado, limpio, estandarizado y sostenible en el tiempo. El trabajo estandarizado permite establecer procedimientos y métodos de trabajo específicos para realizar una actividad de la misma manera siempre que se realice. Este enfoque combinado ha contribuido a mejorar la organización general de la planta, facilitando el flujo de trabajo y minimizando los recorridos innecesarios. Para poder validar los resultados de la propuesta de mejora se hizo uso de la simulación realizada en el software Arena. Los resultados obtenidos de la simulación fueron el aumento en 19.24% en la eficiencia general del proceso, la disminución de horas perdidas por productos defectuosos en 42.4% y la disminución por tiempos muertos en 26.7%

Investigating the aetiology of hot flushing in postmenopausal women and hypogonadal men

Hot flushes are the most commonly reported symptom in postmenopausal women, occurring in approximately 73% of women and causing significant morbidity in 25%, affecting social life and even the ability to work. With improved healthcare and increased life expectancy (death rates decreased by 19% in the last 10 years), women spend a considerable proportion of their lives (30 years on average) in the menopause. At present 36% of the women in the UK are over 50 years of age. If left untreated, hot flushes resolve within one year, or less, in the majority of postmenopausal women. A third will report symptoms that last up to 5 years after natural menopause, and in 20% hot flushes persist for up to 15 years. This equates to as many as 1.5 million women in the UK. Despite this the mechanism of flushing is still poorly understood. A hot flush resembles a heat dissipation response, in that both are characterised by sweating and peripheral vasodilation. It follows that the underlying mechanism may involve some dysfunction in thermoregulation, which in humans is controlled by the medial preoptic area of the hypothalamus (MPOA), and effectors include cutaneous vessels for vasodilation and vasoconstriction. Therefore a dysfunction in thermoregulation may lie within the control centre (MPOA), its messengers (adrenergic neurones controlling vasoconstriction and cholinergic neurones controlling vasodilation) or the effectors (cutaneous vessels). Studies by Freedman et al, using an ultrasensitive temperature probe, suggest that hot flushes are triggered by small elevations in core body temperature (Tc) acting within a narrowed thermoneutral zone, mainly due to a lowering of the sweating threshold, in symptomatic postmenopausal women. However, the trigger remains unknown. Oestrogen is likely involved as these changes occur at times of relative oestrogen withdrawal; however, there is little correlation between hot flushes and circulating oestrogen levels. This suggests that other mechanisms are involved. Noradrenaline is thought to be the primary neurotransmitter responsible for lowering the thermoregulatory set point and triggering hot flushes. Animal studies have shown that intrahypothalamic injection of noradrenaline acts to narrow the thermoregulatory zone and hot flushes can be provoked in symptomatic postmenopausal women with the α2-adrenergic antagonist yohimbine, and ameliorated with clonidine, an α-adrenergic agonist. Furthermore, clonidine has been shown to widen the thermoregulatory zone in humans. Serotonin or 5-hydroxytriptamine (5-HT) is involved in many bodily functions including mood, anxiety, sleep, sexual behaviour and eating, and is thought to play a key role in thermoregulation. Oestrogen withdrawal is associated with decreased blood serotonin levels, which is returned to normal with oestrogen therapy. Furthermore, selective serotonin reuptake inhibitors (SSRI), designed to increase the available serotonin at the serotonergic synapse, have been shown in placebo-controlled trials to be effective in reducing the number and severity of hot flushes. It has also been shown that flushing women have a diminished vasoconstrictor response to cold and that they have increased blood flow to the forearm and hand during a flushing episode. Alterations in skin blood flow during a flushing attack have also been demonstrated in castrate men, and, as with women, improvements in symptoms are seen with hormone replacement. The aim of this thesis was to better understand the mechanism of flushing in postmenopausal women and hypogonadal men by assessing the role of cutaneous vessels. I measured cutaneous microvascular perfusion, using LASER Doppler imaging with iontophoresis, in postmenopausal women who flush and compared it with postmenopausal women with no flushing, and found that perfusion responses to vasoactive agents were increased in women with flushing. Paradoxically, these women with apparently ‘better’ endothelial function had evidence of serum cardiovascular risk factors. In a double-blind longitudinal cross over study, the role of the alpha-adrenergic system in the pathophysiology of flushing was investigated, by treating women with clonidine and placebo. There was an increase in perfusion responses with both clonidine and placebo. Clonidine was not shown to be superior to placebo in reducing the number and severity of flushes. The role of serotonin, both peripherally and centrally was studied by treating postmenopausal women, who experienced severe flushing, with venlafaxine (a serotonin and noradrenaline reuptake inhibitor that acts as a selective serotonin reuptake inhibitor at low doses). Flushing symptoms, as assessed by hot flush diaries and Greene climacteric scale (GCS) scores, were reduced, as were skin blood flow perfusion responses. Central serotonin transporters (SERT) were assessed in vivo using SPECT (single photon computed tomography) imaging and a radioligand, [123I] -beta-carbomethoxy-3-β-(4 iodophenyl)tropane ([123I] beta-CIT), with a high affinity for serotonin transporters. [123I] beta-CIT binding was significantly reduced, and this was associated with a significant reduction in BDI scores; in a group of non-depressed women. Adiposity is associated, both, with an increased risk of postmenopausal flushing and impaired endothelial function, but in this study, there were no differences demonstrated between obese and lean participants at baseline, despite significant differences in serum markers of endothelial dysfunction. Oestrogen receptors are also present on endothelial cells and as the most commonly used, and most effective, treatment for vasomotor symptoms, cutaneous microvascular perfusion was assessed following 8 weeks of HRT, and demonstrated an increase in both endothelium dependent and independent vasodilation. Hot flushes are also common in men on luteinising hormone releasing hormone (LHRH) agonists for prostate cancer therapy. Perfusion responses in these men were assessed prior to commencement of therapy (baseline), and after 8 and then 24 weeks of therapy. No differences were detected at baseline, between those who developed flushing as a result of treatment, and those who did not. At 8 weeks, those with flushing demonstrated increased skin blood flow compared to those without flushing. At 24 weeks, 2 gentlemen with flushing had kept diaries and these demonstrated an improvement in flushing, but no alteration in perfusion responses. ACh- and SNP-stimulated vasodilation was, however, reduced when compared to healthy controls. In this thesis, the data appear to support a role of skin blood flow in the mechanism of hot flushing in both postmenopausal women and hypogonadal men, which may be controlled or altered via neurotransmitters at a local level. The placebo response was significant, but alterations in skin blood flow do not appear to have mediated the adiposity effect

Nuclear moments in density functional theory: an analysis of magnetic dipole and electric quadrupole moments within nuclear DFT of one-particle and one-hole neighbours of doubly magic nuclei

The density functional theory (DFT) code, HFODD, was used to calculate magnetic dipole $\mu$ and electric quadrupole $Q$ moments, with emphasis on the former, of the odd neighbours of eight doubly magic nuclei (16O, 40Ca, 48Ca, 56Ni, 78Ni, 100Sn, 132Sn and 208Pb). In our approach, we made use of pure Hartree-Fock using the Skyrme and Gogny functionals while aligning the angular momenta along the axial-symmetry axis and breaking time-reversal symmetry, which allowed for a full analysis of the spin polarization effects due to the unpaired nucleon. In order to restore the broken symmetries, the projection-after-variation (PAV) method was used which provides us with the spectroscopic moments. Our results were achieved by adjusting one coupling constant in the time-odd mean-field sector of the nuclear functional, namely the time-odd spin-spin isovector Landau parameter g0'. The results were compared with experimental data, where available, to determine the validity of our work. From the analysis, we have concluded that our approach is promising and stands as a solid base for further work into the area and allowing the opportunity to refine the work through additional approaches e.g. deformed-configuration interaction. We note that as a consequence of our work, we determined that the use of effective charges and effective g-factors are not needed to describe the nuclear moments

Global analysis of electromagnetic moments in odd near doubly magic nuclei

We use the nuclear DFT approach to determine nuclear electric quadrupole and magnetic dipole moments in all one-particle and one-hole neighbors of eight doubly magic nuclei. We align angular momenta along the intrinsic axial-symmetry axis with broken time-reversal symmetry, which allows us to explore fully the self-consistent charge, spin, and current polarizations. Spectroscopic moments are determined for symmetry-restored wave functions and compared with available experimental data. We find that the obtained polarizations do not call for using quadrupole- or dipole-moment operators with effective charges or effective g-factors.Comment: 15 LaTeX pages, 9 figure

Diseño aerodinámico de un aerodeslizador ligero con capacidad para dos pasajeros

Los aerodeslizadores son vehículos capaces de suspenderse al lanzar un chorro de aire contra una superficie que se encuentra debajo del mismo. Este caudal de aire genera un colchón de aire capaz de suspender el vehículo, lo cual le permite transitar sobre superficies lo suficientemente regulares sin entrar en contacto con las mismas Actualmente en el Perú, el uso y desarrollo de este tipo de vehículos es casi nulo. Creemos que su uso será beneficioso por la gran variedad de superficies con las que contamos, superficies que pueden ser tranquilamente transitadas por estos vehículos. En este trabajo se plantea el diseño aerodinámico de un vehículo de estas características con capacidad para dos pasajeros, de manera que se pueda demostrar la factibilidad de su uso en nuestro país. Cabe recalcar que el presente estudio consiste solamente en el diseño de los sistemas de suspensión y propulsión, ya que otros componentes tales como la falda flexible, el sistema de dirección y el casco han quedado fuera del mismo. Esto debido a la extensión del mismo, además que desde un principio se planteo solo el diseño de los componentes antes mencionados. En primer lugar se estudia el concepto de los aerodeslizadores, sus usos y sus principales antecedentes históricos. Posterior a esto se describen los componentes que lo conforman y se selecciona los componentes principales que llevara nuestro vehículo. Una vez definida la geometría y los componentes que compondrán nuestro vehículo se procede a presentar la teoría aerodinámica que rige el diseño de esta clase de vehículos, de manera que se pueda comprender la física que rige su funcionamiento. Finalmente se realizaran los cálculos aerodinámicos que permiten realizar la selección y diseño de los componentes principales, para terminar con el diseño general de los sistemas de suspensión y propulsión, el cual incluye las estructuras que soportaran los componentes y sus respectivas transmisiones.Tesi