Endogenous Angiotensin II‐induced p44/42 Mitogen‐Activated Protein Kinase Activation Mediates Sodium Appetite but not Thirst or Neurohypophysial Secretion in Male Rats

The renin–angiotensin–aldosterone system makes a critical contribution to body fluid homeostasis, and abnormalities in this endocrine system have been implicated in certain forms of hypertension. The peptide hormone angiotensin II (AngII) regulates hydromineral homeostasis and blood pressure by acting on both peripheral and brain targets. In the brain, AngII binds to the angiotensin type 1 receptor (AT1R) to stimulate thirst, sodium appetite and both arginine vasopressin (AVP) and oxytocin (OT) secretion. The present study used an experimental model of endogenous AngII to examine the role of p44/42 mitogen‐activated protein kinase (MAPK) as a signalling mechanism to mediate these responses. Animals were given a combined treatment of furosemide and a low dose of captopril (furo/cap), comprising a diuretic and an angiotensin‐converting enzyme inhibitor, respectively, to elevate endogenous AngII levels in the brain. Furo/cap induced p44/42 MAPK activation in key brain areas that express AT1R, and this effect was reduced with either a centrally administered AT1R antagonist (irbesartan) or a p44/42 MAPK inhibitor (U0126). Additionally, furo/cap treatment elicited water and sodium intake, and irbesartan markedly reduced both of these behaviours. Central injection of U0126 markedly attenuated furo/cap‐induced sodium intake but not water intake. Furthermore, p44/42 MAPK signalling was not necessary for either furo/cap‐ or exogenous AngII‐induced AVP or OT release. Taken together, these results indicate that p44/42 MAPK is required for AngII‐induced sodium appetite but not thirst or neurohypophysial secretion. This result may allow for the discovery of more specific downstream targets of p44/42 MAPK to curb sodium appetite, known to exacerbate hypertension, at the same time as leaving thirst and neurohypophysial hormone secretion undisturbed.     

Unmet Needs of Women Living with Parkinson's Disease: Gaps and Controversies

Personalized medicine considering sex, gender, and cultural context has become the vanguard of delivery of care. However, women's issues in Parkinson disease (PD), especially from a psychosocial standpoint, have been an overlooked field. The key research areas include women-inclusive drug and device studies and genetic and hormonal considerations. Moreover, women with PD need to be educated and empowered on how to communicate their symptoms and needs, get engaged in research, get organized as a community, and support one another. Women with PD need tools to help track and convey their unique motor and nonmotor symptoms and psychological and social support needs. The management of PD needs to be customized to include the unique stages of women's lives, including menstrual cycles, pregnancy, perimenopause, menopause, and postmenopause. Specific guidelines for the use of hormonal treatments and customized dopamine replacement dosing need to be developed. Women need guidance on culturally sensitive wellness and self-care strategies that are customized for them. Basic core competencies in knowledge for all clinicians treating women with PD need to be established, including how to accurately diagnose, proactively identify, and treat the symptoms of PD in women and to ensure timely referral for specialty care, advanced therapies, and research studies. Caregivers and families need guidance on holistically supporting women with PD. The voices of women living with PD must be amplified to catalyze real change in this neglected field. This paper provides an overview of the current knowledge, gaps, and possible strategies to deal with the unmet needs of women living with PD with a focus on the clinical and psychosocial aspects. © 2022 International Parkinson and Movement Disorder Society     

Radial scars/complex sclerosing lesions and malignancy in a screening programme: incidence and histological features revisited

AIMS: Radial scars (RS) are benign entities, frequently identified on screening mammography, which may be associated with malignancy. Much debate has been generated with regard to the optimum management of RS. We present our experience of RS in the first 5 years of a screening programme. The aim was to evaluate (i) the incidence of atypia and malignancy and (ii) the value of the preoperative core biopsy. We also further characterize the histological features. METHODS AND RESULTS: One hundred and twenty-five histologically confirmed cases of RS were reviewed (111 had preoperative biopsies). Thirty-one (24.8%) patients had a final malignant diagnosis (11 with invasive malignancy) and 28 (22.4%) showed atypia (including lobular carcinoma in situ). In those with core biopsies and a final malignant diagnosis, 12 cases were categorized as B5 (41.3%), three as B4 (10.3%), 12 as B3 (41.3%) and two as B2 (7%). Common histological features included obliterated ducts and chronic inflammation with, less frequently, neural hyperplasia (16.8%) and perineural invasion (3.2%). CONCLUSIONS: The high incidence of atypia and malignancy identified in our study justifies our policy of removing all mammographically detected RS. We emphasize the utility of preoperative core biopsy evaluation in permitting one-stage surgical therapy in those with B5 diagnoses.     

The clinical and pathological differences in prevalent round screen-detected and symptomatic invasive breast cancer

The potential benefits of breast cancer screening include the detection of cancers at a more favourable stage, however, cancers detected during the prevalent round of screening may differ from true screen-detected cancers. These differences are poorly defined. This study prospectively assessed all women between 50 and 64 years of age undergoing curative surgery for breast cancer, both screen-detected and symptomatic, in one screening centre during the prevalent round of the national breast cancer-screening programme. Four hundred and thirty seven patients (364 screen-detected and 73 symptomatic patients) underwent surgery for breast cancer. Symptomatic breast cancers were of a higher grade (p < 0.0001; Chi2) and less likely to be oestrogen receptor positive (49% versus 88%; p < 0.0001; Fisher's exact test); however there was no difference in size of tumour or axillary nodal positivity. This study suggests that tumours detected by screening during the prevalent round of a screening programme are of a more prognostically favourable type than symptomatic breast cancers in the same age group.     

The prevalence of Down syndrome in County Galway

This is a retrospective survey of all cases of Down syndrome recorded between 1981 and 2000 to mothers resident in Co. Galway. The study compares the incidence of Down syndrome in both decades and examines the effects of changing demographics on incidence rates. The overall prevalence rate was 26.8/10,000 live births for the full period. Although there were 5119 fewer births in the 1991-2000 period, the prevalence was 29.8/10,000 compared to 24.1/10,000 in the previous decade. Despite the falling birth rates and fertility rates observed in our study between the two decades we found that the higher prevalence of Down syndrome in the second decade was directly related to the significant increase in the proportion of women in the 30 plus age group. Our study also found the place of the child with Down syndrome in the family changed, with 25.3% being the 5th or more child in the first decade compared with 9.5% in the second decade.     

Translating Mechanism-Based Strategies to Break the Obesity−Cancer Link: A Narrative Review

Prevalence of obesity, an established risk factor for many cancers, has increased dramatically over the past 50 years in the United States and across the globe. Relative to normoweight cancer patients, obese cancer patients often have poorer prognoses, resistance to chemotherapies, and are more likely to develop distant metastases. Recent progress on elucidating the mechanisms underlying the obesity?cancer connection suggests that obesity exerts pleomorphic effects on pathways related to tumor development and progression and, thus, there are multiple opportunities for primary prevention and treatment of obesity-related cancers. Obesity-associated alterations, including systemic metabolism, adipose inflammation, growth factor signaling, and angiogenesis, are emerging as primary drivers of obesity-associated cancer development and progression. These obesity-associated host factors interact with the intrinsic molecular characteristics of cancer cells, facilitating several of the hallmarks of cancer. Each is considered in the context of potential preventive and therapeutic strategies to reduce the burden of obesity-related cancers. In addition, this review focuses on emerging mechanisms behind the obesity?cancer link, as well as relevant dietary interventions, including calorie restriction, intermittent fasting, low-fat diet, and ketogenic diet, that are being implemented in preclinical and clinical trials, with the ultimate goal of reducing incidence and progression of obesity-related cancers.     

The role of organic anion‐transporting polypeptides and formulation in the clearance and distribution of a novel Nav1.7 channel blocker

PF‐06456384 is an extremely potent and selective blocker of the Na_v1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Na_v1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion‐transporting polypeptide mediated hepatic uptake and subsequent biliary excretion. However, the physicochemical properties of the i.v. lead matter were substantially different, moving from acidic, amphiphilic chemical space to zwitterions as well as substantially increasing molecular weight. This report describes the continued relevance of organic anion‐transporting polypeptide driven hepatic uptake in this physicochemical space and highlights an apparent impact of the formulation excipient Solutol on the clearance and distribution of PF‐06456384.