Search

Sheran Li,1,2 Jacqueline K Phillips1 1Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia; 2Department of Emergency Medicine, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Sheran Li, Department of Emergency Medicine, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 West Yanjiang Road, Yuexiu District, Guangzhou, Guangdong Province, 510120, People’s Republic of China, Tel +86 20 81332723, Fax +86 20 8133 2650, Email lishr36@mail.sysu.edu.cnAbstract: Renal denervation (RDN) as a therapeutic intervention in patients with hypertension has been intensively studied for over a decade, yet a critical question remains unanswered: what kind of patients are the ideal target population for RDN to achieve its maximum clinical benefit? We herein provide a review of current literature to answer questions related to patient selection to identify populations that will benefit most from RDN, drawing first from human studies but also important clues derived from preclinical animal models. Different aspects that may influence the selection of patients such as the cause of hypertension, the severity of hypertension, concurrent pharmaceutical treatment, renal function, and renal artery anatomy are discussed. Based on current evidence, patients who have severe primary hypertension, regardless of medication or degree of renal dysfunction, who have an accessible accessory renal artery, can achieve a desirable response if a thorough ablation is achieved. In preclinical models, as in humans, RDN shows variable impact, with evidence indicating it does not work in specific conditions such as reduced renal mass, salt-sensitive hypertension, and autosomal recessive polycystic kidney disease. The thresholds, however, for indicators are such that it is still not possible to reliably predict which patients could benefit from the technique. Confirmation of predictive factors and identification of biomarkers are needed before RDN can be integrated in clinical practice on clear and reliable grounds.Keywords: renal denervation, hypertension, accessory renal artery, renal function, preclinical hypertensive models

The purpose of this qualitative study was to examine the challenges that recent graduates of nurse anesthesia programs coped with during their anesthesia curriculum from their perspective. The initial research questions for this study were: From the graduates' perspective, what were the Stressors that they encountered during their nurse anesthesia program? And how did they successfully negotiate those Stressors in order to graduate from their program? This phenomenon was studied using grounded theory methodology. The data were collected by individual, semistructured, in-depth interviews with 12 recent nurse anesthesia program graduates, from 5 different nurse anesthesia programs, who have been out of school for less than 2 years. This exploration into student nurse anesthetist stress and coping articulates 3 phases of development as these students progressed through their program. The phases are transitioning in (first 9 months of program), finding their way (9 to 18 months into program), and transitioning out (18 to 28 months into program). Coping mechanisms employed by the participants were problem focused, emotion focused, and a combination of the 2. Recommendations for action and future research are discussed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Studies have suggested that the incidence of preeclampsia may be partially dependent on the month or season of delivery. We sought to evaluate whether preeclampsia occurs seasonally in our population and whether the timing of conception or delivery is more strongly associated with risk. METHODS: Between January 1995 and August 2003, we identified 142 primiparous women with singleton pregnancies who met the American College of Obstetricians and Gynecologists' definition for preeclampsia and compared them with 7,762 primiparous control deliveries. We analyzed rates of preeclampsia by individual month and 3-month seasonal blocks based on conception and delivery. Data were analyzed with the chi2 test, and logistic regression and odds ratios were calculated where appropriate. RESULTS: Preeclampsia occurred in 1.8% of singleton primiparous gestations (142/7,904). Cases were younger than controls (26.5 +/- 5.6 versus 28.0 +/- 0 6.0 years, P < .003), of similar race (97% white versus 96% white, P = .69), and equally likely to have a female child (45% versus 48%, P = .41). We found no significant association of month (logistic regression P = .20) of delivery with the risk of preeclampsia. There was a significant association of month (P = .003) of conception with risk of preeclampsia. Conception during the summer months had the highest risk (incidence 2.3%; odds ratio 1.7; 95% confidence limits 1.06, 2.75) compared with spring (incidence 1.4%). Fall (1.7%) and winter (1.6%) conceptions were associated with intermediate rates of preeclampsia. CONCLUSION: We identified a seasonal variation in preeclampsia that appears to be more strongly related to timing of conception than to the timing of delivery. The highest incidence of preeclampsia was associated with conception in the summer months. LEVEL OF EVIDENCE: II-2. [ABSTRACT FROM AUTHOR]

The stakes are high for your patient--an aneurysm plus the factors that led to its development can be life-threatening. Find our how you can minimize his risks. [ABSTRACT FROM AUTHOR]

BACKGROUND: Loss of sensory function in scar after burn is common, although the basis for this loss is not clear. Additionally, little is known about the effects of different treatment modalities on sensory function and neuroanatomical outcomes in burn patients. Here, we investigated the effects of the use of the INTEGRA((R)) dermal scaffold on neuroanatomy and sensory function in acute burn patients. HYPOTHESIS AND OBJECTIVES: We hypothesized that the use of artificial dermal templates would inhibit or reduce reinnervation after excision, since regrowth of nerves requires complex molecular interactions. Therefore the primary objective of this study was to identify whether there is regrowth of nerve fibres in the INTEGRA((R)) dermal scaffold. The secondary objective was to identify whether the INTEGRA((R)) dermal scaffold reduced nerve regrowth or limited sensory function outcomes in acute burn patients. METHODS: Five patients treated with INTEGRA((R)), cultured epithelial autograft spray (prepared using ReCell((R)) (CEA)) and split skin graft (SSG) were assessed for sensory function in scar and uninjured contralateral control skin. Neuroanatomy of scar and control sites was assessed using immunohistochemistry for PGP9.5, CGRP and substance P neuronal markers. Nerve density and sensory function was also assessed in a comparative group (n=8) treated with CEA and SSG only. RESULTS: Neuroanatomy was not significantly different in the INTEGRA((R)) patients when compared to the CEA/SSG group only. The patients treated with INTEGRA((R)) had worse sensory function than those with CEA/SSG only. CONCLUSIONS: Peripheral nerves do reinnervate the INTEGRA((R)) dermal scaffold. There is no statistically significant reduction in reinnervation observed when compared to a control group. It is possible that the use of artificial dermal constructs, while permissive for nerve regrowth, limit functionality when compared to nerves that regrow through dermal tissue. Further research to understand the causes of this, and into enhancing reinnervation in dermal scaffolds may improve sensory outcome in the most severely burned patients. [ABSTRACT FROM AUTHOR]

In the rat, the activity of laryngeal adductor muscles, the crural diaphragm, and sympathetic vasomotor neurons is entrained to the post-inspiratory (post-I) phase of the respiratory cycle, a mechanism thought to enhance cardiorespiratory efficiency. The identity of the central neurons responsible for transmitting respiratory activity to these outputs remains unresolved. Here we explore the contribution of the Kölliker-Fuse/Parabrachial nuclei (KF-PBN) in the generation of post-I activity in vagal and sympathetic outputs under steady-state conditions and during acute hypoxemia, a condition that potently recruits post-I activity. In artificially ventilated, vagotomised and urethane-anesthetised rats, bilateral KF-PBN inhibition by microinjection of the GABA A receptor agonist isoguvacine evoked stereotypical responses on respiratory pattern, characterised by a reduction in phrenic nerve burst amplitude, a modest lengthening of inspiratory time, and an increase in breath-to-breath variability, while post-I vagal nerve activity was abolished and post-I sympathetic nerve activity diminished. During acute hypoxemia, KF-PBN inhibition attenuated tachypnoeic responses and completely abolished post-I vagal activity while preserving respiratory-sympathetic coupling. Furthermore, KF-PBN inhibition disrupted the decline in respiratory frequency that normally follows resumption of oxygenation. These findings suggest that the KF-PBN is a critical hub for the distribution of post-I activities to vagal and sympathetic outputs and is an important contributor to the dynamic adjustments to respiratory patterns that occur in response to acute hypoxia. While KF-PBN appears essential for post-I vagal activity, it only partially contributes to post-I sympathetic nerve activity, suggesting the contribution of multiple neural pathways to respiratory-sympathetic coupling.

Spontaneous or atraumatic splenic rupture (ASR) is a rare but life-threatening condition that requires swift recognition and intervention. We report the case of a 66-year-old female with a history of hypothyroidism, appendiceal goblet cell adenocarcinoma, and new-onset atrial fibrillation (Afib) requiring anticoagulation. She initially presented with right upper quadrant abdominal pain. She had previously undergone an appendectomy followed by a right hemicolectomy to achieve clear surgical margins after the appendiceal carcinoma diagnosis. In the post-anesthesia care unit, she developed Afib and was started on therapeutic anticoagulation. Cardiac catheterization later revealed three-vessel coronary artery disease, prompting a transition from heparin to apixaban. Three days later, the patient suddenly experienced left shoulder pain and was found to be diaphoretic and hypotensive. Three days post-catheterization, the patient developed sudden left shoulder pain, along with diaphoresis and hypotension. An initial concern for post-catheterization myocardial infarction was ruled out. A subsequent CT of the abdomen and pelvis revealed a large splenic hematoma with rupture and hemoperitoneum, necessitating emergent open splenectomy. Post-operatively, the patient required intensive care monitoring and transfusion support before being discharged to a long-term acute care facility. ASR is typically associated with identifiable pathological conditions; however, this case highlights the complexity of multifactorial etiologies. It emphasizes the need to consider ASR in patients presenting with sudden left shoulder pain and hemodynamic instability, particularly when anticoagulation therapy or recent abdominal surgery are factors. This case underscores the importance of a high index of suspicion and timely intervention to prevent fatal outcomes. Further research is warranted to explore the relationship between anticoagulation therapy and ASR., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Bowers et al.)

Background: Integrative medicine (IM) is the healing-oriented practice of medicine that emphasizes the relationship between practitioner and patient. It considers the whole person, their environment, lifestyle, and social and cultural factors. It is evidence based and makes use of all appropriate therapies, conventional and complimentary. Objective: To evaluate the impact of IM services on health outcomes and care costs of chronic pain management patients compared with standard care. Methods: This article uses University of New Mexico hospital billing data from 10/2016 to 09/2019 to identify patients with nervous system or musculoskeletal pain. A total of 1,304 patients were matched using propensity scores into IM services (treatment: 652) and standard care (control: 652) cohorts for difference-in-differences analysis. The patients were matched based on age, sex, race, zip code, insurance type, ICD-10s, prescriptions, health care events, and medical claim costs. Results: Patients who used IM services had better health outcomes and lower costs at 3-month, 6-month, and 12-month follow-up. At the 12-month follow-up, the IM group showed a 19% decrease in utilization of inpatient care, a 37% decrease in Emergency Department utilization, and an 11.3% reduction in claim costs compared with the control group. Conclusion: Patients who utilize IM services as part of chronic pain management have overall lower health care costs and better health outcomes. Unfortunately, in the health system studied, less than 3% of patients utilize these services. Promotion of and education about IM services should be aimed at both patients and their providers.

Rosai-Dorfman disease (RDD) is a rare disease characterized by histiocytic proliferation which typically presents as massive, painless, cervical lymphadenopathy in children or young adults. GI involvement is exceedingly rare with only 20 documented cases to date. Of those 20 cases, only 3 cases have involved the rectum. Here, we present 2 cases of rectal RDD with attention paid to the diagnostic and technical challenges presented by this disease. When presenting as a perirectal mass, RDD can be mistaken for other lesions to include malignancy, leading to surgical removal. We present a video of a robotic low-anterior resection with intracorporeal anastomosis in order to remove a pelvic mass involving the rectum, initially considered to be a stromal tumor. In addition, we describe a copy number variation in AKT and 3 point mutations detected by next generation sequencing, which had not been previously reported in association with this disease.

Autosomal recessive polycystic kidney disease (ARPKD) is an early onset genetic disorder characterized by numerous renal cysts resulting in end stage renal disease. Our study aimed to determine if metabolic reprogramming and tryptophan (Trp) metabolism via the kynurenine pathway (KP) is a critical dysregulated pathway in PKD. Using the Lewis polycystic kidney (LPK) rat model of PKD and Lewis controls, we profiled temporal trends for KP metabolites in plasma, urine, and kidney tissues from 6- and 12-week-old mixed sex animals using liquid and gas chromatography, minimum n  = 5 per cohort. A greater kynurenine (KYN) concentration was observed in LPK kidney and plasma of 12-week rats compared to age matched Lewis controls ( P  ⩽ .05). LPK kidneys also showed an age effect ( P  ⩽ .05) with KYN being greater in 12-week versus 6-week LPK. The metabolites xanthurenic acid (XA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA) were significantly greater in the plasma of 12-week LPK rats compared to age matched Lewis controls ( P  ⩽ .05). Plasma XA and 3-HK also showed an age effect ( P  ⩽ .05) being greater in 12-week versus 6-week LPK. We further describe a decrease in Trp levels in LPK plasma and kidney (strain effect P  ⩽ .05). There were no differences in KP metabolites in urine between cohorts. Using the ratio of product and substrates in the KP, a significant age-strain effect ( P  ⩽ .05) was observed in the activity of the KYN/Trp ratio (tryptophan-2,3-dioxygenase [TDO] or indoleamine-2,3-dioxygenase [IDO] activity), kynurenine 3-monooxygenase (KMO), KAT A (kynurenine aminotransferase A), KAT B, total KAT, total KYNU (kynureninase), KYNU A, KYNU B, and total KYNU within LPK kidneys, supporting an activated KP. Confirmation of the activation of these enzymes will require verification through orthogonal techniques. In conclusion, we have demonstrated an up-regulation of the KP in alignment with progression of renal impairment in the LPK rat model, suggesting that KP activation may be a critical contributor to the pathobiology of PKD., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Infections caused by Chlamydia trachomatis and Neisseria gonorrhoeae are increasing in the United States. Because most infections are asymptomatic, screening is key to preventing complications such as pelvic inflammatory disease and infertility and decreasing community and vertical neonatal transmission. All sexually active people with a cervix who are younger than 25 years and older people with a cervix who have risk factors should be screened annually for chlamydial and gonococcal infections. Sexually active men who have sex with men should be screened at least annually. Physicians should obtain a sexual history free from assumptions about sex partners or practices. Acceptable specimen types for testing include vaginal, endocervical, rectal, pharyngeal, and urethral swabs, and first-stream urine samples. Uncomplicated gonococcal infection should be treated with a single 500-mg dose of intramuscular ceftriaxone in people weighing less than 331 lb (150 kg). Preferred chlamydia treatment is a seven-day course of doxycycline, 100 mg taken by mouth twice per day. All nonpregnant people should be tested for reinfection approximately three months after treatment or at the first visit in the 12 months after treatment. Pregnant patients diagnosed with chlamydia or gonorrhea should have a test of cure four weeks after treatment.

Aims: Hypertension is a prevalent yet poorly understood feature of polycystic kidney disease. Previously, we demonstrated that increased glutamatergic neurotransmission within the hypothalamic paraventricular nucleus produces hypertension in the Lewis Polycystic Kidney (LPK) rat model of polycystic kidney disease. Here, we tested the hypothesis that augmented glutamatergic drive to the paraventricular nucleus in Lewis polycystic kidney rats originates from the forebrain lamina terminalis, a sensory structure that relays blood-borne information throughout the brain., Methods and Results: Anatomical experiments revealed that 38% of paraventricular nucleus-projecting neurons in the subfornical organ of the lamina terminalis expressed Fos/Fra, an activation marker, in LPK rats while <1% of neurons were Fos/Fra+ in Lewis control rats (P = 0.01, n = 8). In anaesthetized rats, subfornical organ neuronal inhibition using isoguvacine produced a greater reduction in systolic blood pressure in LPK vs. Lewis rats (-21±4 vs. -7±2 mmHg, P < 0.01; n = 10), which could be prevented by prior blockade of paraventricular nucleus ionotropic glutamate receptors using kynurenic acid. Blockade of ionotropic glutamate receptors in the paraventricular nucleus produced an exaggerated depressor response in LPK relative to Lewis rats (-23±4 vs. -2±3 mmHg, P < 0.001; n = 13), which was corrected by prior inhibition of the subfornical organ with muscimol but unaffected by chronic systemic angiotensin II type I receptor antagonism or lowering of plasma hyperosmolality through high-water intake (P > 0.05); treatments that both nevertheless lowered blood pressure in LPK rats (P < 0.0001)., Conclusion: Our data reveal multiple independent mechanisms contribute to hypertension in polycystic kidney disease, and identify high plasma osmolality, angiotensin II type I receptor activation and, importantly, a hyperactive subfornical organ to paraventricular nucleus glutamatergic pathway as potential therapeutic targets., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Introduction: Angiotensin (Ang) II signalling in the hypothalamic paraventricular nucleus (PVN) via Ang type-1a receptors (AT1R) regulates vasopressin release and sympathetic nerve activity - two effectors of blood pressure regulation. We determined the cellular expression and function of AT1R in the PVN of a rodent model of polycystic kidney disease (PKD), the Lewis polycystic kidney (LPK) rat, to evaluate its contribution to blood pressure regulation and augmented vasopressin release in PKD., Methods: PVN AT1R gene expression was quantified with fluorescent in situ hybridization in LPK and control rats. PVN AT1R function was assessed with pharmacology under urethane anaesthesia in LPK and control rats instrumented to record arterial pressure and sympathetic nerve activity., Results: AT1R gene expression was upregulated in the PVN, particularly in corticotrophin-releasing hormone neurons, of LPK versus control rats. PVN microinjection of Ang II produced larger increases in systolic blood pressure in LPK versus control rats (36 ± 5 vs. 17 ± 2 mm Hg; p < 0.01). Unexpectedly, Ang II produced regionally heterogeneous sympathoinhibition (renal: -33%; splanchnic: -12%; lumbar: no change) in LPK and no change in controls. PVN pre-treatment with losartan, a competitive AT1R antagonist, blocked the Ang II-mediated renal sympathoinhibition and attenuated the pressor response observed in LPK rats. The Ang II pressor effect was also blocked by systemic OPC-21268, a competitive V1A receptor antagonist, but unaffected by hexamethonium, a sympathetic ganglionic blocker., Discussion/conclusion: Collectively, our data suggest that upregulated AT1R expression in PVN sensitizes neuroendocrine release of vasopressin in the LPK, identifying a central mechanism for the elevated vasopressin levels present in PKD., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

The exponential rise in our understanding of the aetiology and pathophysiology of genetic cystic kidney diseases can be attributed to the identification of cystogenic genes over the last three decades. The foundation of this was laid by positional cloning strategies which gradually shifted towards next-generation sequencing (NGS) based screenings. This shift has enabled the discovery of novel cystogenic genes at an accelerated pace unlike ever before and, most notably, the past decade has seen the largest increase in identification of the genes which cause nephronophthisis (NPHP). NPHP is a monogenic autosomal recessive cystic kidney disease caused by mutations in a diverse clade of over 26 identified genes and is the most common genetic cause of renal failure in children. NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations. This review provides a timely update on our knowledge of this disease, including epidemiology, pathophysiology, anatomical and molecular features. We delve into the diversity of the NPHP causing genes and discuss known molecular mechanisms and biochemical pathways that may have possible points of intersection with polycystic kidney disease (the most studied renal cystic pathology). We delineate the pathologies arising from extra-renal complications and co-morbidities and their impact on quality of life. Finally, we discuss the current diagnostic and therapeutic modalities available for disease management, outlining possible avenues of research to improve the prognosis for NPHP patients.

A fundamental aspect of classification systems in Paralympic sport is having valid and reliable measures of impairment. However, minimal consensus exists for assessing impaired strength, coordination and range of motion. This review aimed to systematically identify measures of upper body strength, coordination and range of motion impairments that meet the requirements for use in evidence-based classification systems in wheelchair sports. Three electronic databases were searched from 2003 until 31 August 2019 for studies that assessed upper body function of participants and used a measurement tool that assessed strength, coordination or range of motion. The body of evidence for each identified measure was appraised using the Grading of Recommendations Assessment, Development and Evaluation framework. Twenty-three studies were included: ten measured strength and coordination, and six measured range of motion. There was "moderate" confidence in using isometric strength for assessing strength impairment. Tapping tasks for the assessment of coordination impairment received a "low" confidence rating. All other identified measures of coordination and range of motion impairment received a "very low" confidence rating. Several potential measures were identified for assessing upper body strength, coordination and range of motion impairments. Further research is warranted to investigate their use for classification in Paralympic wheelchair sports.

Chronic kidney disease (CKD) is a significant health challenge associated with high cardiovascular mortality risk. Historically, cardiovascular mortality risk has been found to higher in men than women in the general population. However, recent research has highlighted that this risk may be similar or even higher in women than men in the CKD population. To address the inconclusive and inconsistent evidence regarding this relationship between sex and cardiovascular mortality within CKD patients, a systematic review and meta-analysis of articles published between January 2004 and October 2020 using PubMed/Medline, EMBASE, Scopus and Cochrane databases was performed. Forty-eight studies were included that reported cardiovascular mortality among adult men relative to women with 95% confidence intervals (CI) or provided sufficient data to calculate risk estimates (RE). Random effects meta-analysis of reported and calculated estimates revealed that male sex was associated with elevated cardiovascular mortality in CKD patients (RE 1.13, CI 1.03-1.25). Subsequent subgroup analyses indicated higher risk in men in studies based in the USA and in men receiving haemodialysis or with non-dialysis-dependent CKD. Though men showed overall higher cardiovascular mortality risk than women, the increased risk was marginal, and appropriate risk awareness is necessary for both sexes with CKD. Further research is needed to understand the impact of treatment modality and geographical distribution on sex differences in cardiovascular mortality in CKD., Competing Interests: The authors have declared that no competing interests exist.

We examined the effect of total and afferent renal denervation (RDN) on hypertension and the renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic kidney disease (PKD). Lewis Polycystic Kidney (LPK) and control rats received total, afferent or sham RDN by periaxonal application of phenol, capsaicin or normal saline, respectively, and were monitored for 4-weeks. Afferent RDN did not affect systolic blood pressure (SBP) determined by radiotelemetry in either strain (n = 19) while total RDN significantly reduced SBP in Lewis rats 4-weeks post-denervation (total vs. sham, 122 ± 1 vs. 130 ± 2 mmHg, P = 0.002, n = 25). Plasma and kidney renin content determined by radioimmunoassay were significantly lower in LPK vs. Lewis (plasma: 278.2 ± 6.7 vs. 376.5 ± 11.9 ng Ang I/ml/h; kidney: 260.1 ± 6.3 vs. 753.2 ± 37.9 ng Ang I/mg/h, P < 0.001, n = 26). These parameters were not affected by RDN. Intrarenal mRNA expression levels of renin, angiotensinogen, angiotensin-converting enzyme (ACE)2, and angiotensin II receptor type 1a were significantly lower, whereas ACE1 expression was significantly higher in the LPK vs. Lewis (all P < 0.05, n = 26). This pattern of intrarenal RAS expression was not changed by RDN. In conclusion, RDN does not affect hypertension or the RAS in the LPK model and indicates RDN might not be a suitable antihypertensive strategy for individuals with juvenile-onset PKD., (© 2021. The Author(s).)

Carotid body feedback and hypoxia may serve to enhance respiratory-sympathetic nerve coupling (respSNA) and act as a driver of increased blood pressure. Using the Lewis polycystic kidney (LPK) rat model of chronic kidney disease, we examined respSNA in adult female rodents with CKD and their response to acute hypoxia or hypercapnia compared to Lewis control animals. Under urethane anesthesia, phrenic nerve activity, splanchnic sympathetic nerve activity (sSNA), and renal sympathetic nerve activity (rSNA) were recorded under baseline conditions and during mild hypoxic or hypercapnic challenges. At baseline, tonic SNA and blood pressure were greater in female LPK rats versus Lewis rats (all P < 0.05) and respSNA was at least two-fold larger [area under the curve (AUC), sSNA: 7.8 ± 1.1 vs. 3.4 ± 0.7 μV s, rSNA: 11.5 ± 3 vs. 4.8 ± 0.7 μV s, LPK vs. Lewis, both P < 0.05]. Mild hypoxia produced a larger pressure response in LPK [Δ mean arterial pressure (MAP) 30 ± 6 vs. 12 ± 6 mmHg] and augmented respSNA (ΔAUC, sSNA: 8.9 ± 3.4 vs. 2 ± 0.7 μV s, rSNA: 6.1 ± 1.2 vs. 3.1 ± 0.7 μV s, LPK vs. Lewis, all P ≤ 0.05). In contrast, central chemoreceptor stimulation produced comparable changes in blood pressure and respSNA (ΔMAP 13 ± 3 vs. 9 ± 5 mmHg; respSNA ΔAUC, sSNA: 2.5 ± 1 vs. 1.3 ± 0.7 μV s, rSNA: 4.2 ± 0.9 vs. 3.5 ± 1.4 μV s, LPK vs. Lewis, all P > 0.05). These results demonstrate that female rats with CKD exhibit heightened respSNA coupling at baseline that is further augmented by mild hypoxia, and not by hypercapnia. This mechanism may be a contributing driver of hypertension in this animal model of CKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Saha, Sun, Hildreth, Burke and Phillips.)

Three-dimensional (3D), submillimeter-scale constructs of neural cells, known as cortical spheroids, are of rapidly growing importance in biological research because these systems reproduce complex features of the brain in vitro. Despite their great potential for studies of neurodevelopment and neurological disease modeling, 3D living objects cannot be studied easily using conventional approaches to neuromodulation, sensing, and manipulation. Here, we introduce classes of microfabricated 3D frameworks as compliant, multifunctional neural interfaces to spheroids and to assembloids. Electrical, optical, chemical, and thermal interfaces to cortical spheroids demonstrate some of the capabilities. Complex architectures and high-resolution features highlight the design versatility. Detailed studies of the spreading of coordinated bursting events across the surface of an isolated cortical spheroid and of the cascade of processes associated with formation and regrowth of bridging tissues across a pair of such spheroids represent two of the many opportunities in basic neuroscience research enabled by these platforms., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

This study investigated dietary supplementation as a prophylactic for neuroinflammation following traumatic brain injury (TBI) in a preclinical model. Adult male Sprague-Dawley rats received 30 days of supplementation with either water or two dietary supplements. The first consisted of high-dose omega-3 fatty acid (O3FA) (supplement A) along with vitamin D3 and vitamin E. The second had the same ingredients at different doses with an addition of cannabidiol (supplement B). Rats were subjected to an impact TBI and then euthanized 7 days post-injury and neuroinflammation quantified by histological detection of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, and CD68, a marker of microglial activity. There was a trend toward increased GFAP staining in injured, unsupplemented animals as compared to sham, unsupplemented animals, consistent with increased activation of astrocytes in response to trauma which was reversed by supplement A but not by supplement B. The pattern of CD68 staining across groups was similar to that of GFAP staining. There was a trend toward an increase in the injured unsupplemented group, relative to sham which was reversed by supplement A but not by supplement B. CD68 staining in injured animals was concentrated in the perivascular domain. The consistency between trends across different measures of neuroinflammation showing benefits of high-dose O3FA supplementation following TBI suggests that the observed effects are real. These findings are preliminary, but they justify further study to determine the functional benefits associated with improvements in histological outcomes and understand associated dose-response curves., Competing Interests: Conflict of interest: Dr. Bailes is a consultant for Trident Brands Inc., a nutritional supplement company, and is a consultant for and receives royalties from Mizuho, Inc. The remaining authors state no conflict of interest., (© 2021 Elise K. Black et al., published by De Gruyter.)

After peripheral nerve injury, regeneration or collateral sprouting of noradrenergic nerve fibres in the papillary dermis of the injured limb may contribute to sympathetically-maintained pain. The aim of this study was to determine whether noradrenergic nerve fibre regeneration after partial sciatic nerve ligation (PSL) in Wistar rats was accompanied by parallel shifts in expression of the noradrenaline transporter (NAT). Four or 28 days after PSL surgery, immunohistochemistry was used to examine NAT expression in plantar hind paw skin in relation to pan-neuronal markers (class III beta-tubulin and protein gene product 9.5), peptidergic afferents containing calcitonin gene-related peptide (CGRP), nonpeptidergic afferents labelled by isolectin B 4 (IB 4 ), and tyrosine hydroxylase (TH), a marker for cutaneous noradrenergic nerve fibres. Most dermal nerve fibre populations decreased shortly after PSL. However, four weeks after PSL, an increase in staining intensity of CGRP and novel expression of TH were observed in the papillary dermis on the injured side. In contrast, neural expression of NAT was reduced in this region. Loss of NAT might have implications for sympathetically-maintained pain, as failure to rapidly clear noradrenaline could exacerbate aberrant sympathetic-sensory signalling between closely apposed noradrenergic and peptidergic nerve fibres., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Hypertension is a common comorbidity associated with chronic kidney disease (CKD). Treatment in these patients often involves L-type Ca2+ channel (LTCC) blockers. The effect of chronic LTCC-blockade treatment on resistance vasculature was investigated in a genetic hypertensive rat model of CKD, the Lewis Polycystic Kidney (LPK) rat., Methods: Mixed-sex LPK and Lewis control rats (total n = 38) were allocated to treated (amlodipine 20 mg/kg/day p.o. from 4 to 18 weeks) and vehicle groups. Following systolic blood pressure and renal function assessment, animals were euthanized and mesenteric vasculature was collected for functional and structural assessment using pressure myography and histology., Results: Amlodipine treatment reduced LPK rat blood pressure (untreated vs. treated: 185 ± 5 vs. 165 ± 9 mm Hg; P = 0.019), reduced plasma creatinine (untreated vs. treated: 197 ± 17 vs. 140 ± 16 µmol/l; P = 0.002), and improved some vascular structural parameters (internal and external diameters and wall-lumen ratios); however wall thickness was still increased in LPK relative to Lewis despite treatment (Lewis vs. LPK: 31 ± 2 vs. 41 ± 2 µm, P = 0.047). Treatment improved LPK rats' endothelium dysfunction, and nitric oxide-dependent and endothelium-derived hyperpolarization vasorelaxation components, and downregulated prostanoid contributions. LTCC blockade had no effect on biomechanical properties of compliance and intrinsic stiffness, nor artery wall composition., Conclusions: Our results indicate that blockade of LTCCs with amlodipine is effective in improving, to a certain extent, detrimental structural and functional vascular features of resistance arteries in CKD., (© American Journal of Hypertension, Ltd 2020. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The noradrenaline transporter (NAT) transfers noradrenaline released into the synaptic cleft back into the presynaptic terminal, thus terminating neurotransmission. Although the distribution of NAT within the central nervous system has been well-characterized, less is known about its distribution elsewhere in the peripheral nervous system and in organs such as the skin. To address this in the present study, NAT expression was investigated using immunohistochemistry in the hind paw skin and more proximally in the sciatic nerve, dorsal root ganglia and spinal cord of five male Wistar rats. It was hypothesised that NAT would be expressed exclusively on nerve fibres labelled by dopamine beta hydroxylase (DβH), an enzyme involved in the conversion of dopamine to noradrenaline. NAT co-localised with DβH in neurons in the spinal cord, dorsal root ganglia and sciatic nerve. Unexpectedly, however, NAT-like immunoreactivity was not observed in DβH immuno-reactive fibres that innervated dermal blood vessels, suggesting that a mechanism other than presynaptic re-uptake of noradrenaline through NAT regulates transmission at neurovascular junctions in the skin. Furthermore, a novel association between NAT-like immunoreactivity and the myelin marker myelin basic protein (MBP) was identified in peripheral nerves. Specifically, NAT and MBP appeared to congregate around primary afferent nerve fibres labelled by neurofilament 200, a marker of neurons with medium- and large-diameter axons. NAT-like immunoreactivity was also detected in cultured Schwann cells immunohistochemically and at the mRNA level. Together, these findings imply a hitherto unrecognised role of Schwann cells in clearance of noradrenaline in the peripheral nervous system., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Breathing results from sequential recruitment of muscles in the expiratory, inspiratory, and postinspiratory (post-I) phases of the respiratory cycle. Here we investigate whether neurons in the medullary intermediate reticular nucleus (IRt) are components of a central pattern generator (CPG) that generates post-I activity in laryngeal adductors and vasomotor sympathetic nerves and interacts with other members of the central respiratory network to terminate inspiration. We first identified the region of the (male) rat IRt that contains the highest density of lightly cholinergic neurons, many of which are glutamatergic, which aligns well with the putative postinspiratory complex in the mouse (Anderson et al., 2016). Acute bilateral inhibition of this region reduced the amplitudes of post-I vagal and sympathetic nerve activities. However, although associated with reduced expiratory duration and increased respiratory frequency, IRt inhibition did not affect inspiratory duration or abolish the recruitment of post-I activity during acute hypoxemia as predicted. Rather than representing an independent CPG for post-I activity, we hypothesized that IRt neurons may instead function as a relay that distributes post-I activity generated elsewhere, and wondered whether they could be a site of integration for para-respiratory CPGs that drive the same outputs. Consistent with this idea, IRt inhibition blocked rhythmic motor and autonomic components of fictive swallow but not swallow-related apnea. Our data support a role for IRt neurons in the transmission of post-I and swallowing activity to motor and sympathetic outputs, but suggest that other mechanisms also contribute to the generation of post-I activity. SIGNIFICANCE STATEMENT Interactions between multiple coupled oscillators underlie a three-part respiratory cycle composed from inspiratory, postinspiratory (post-I), and late-expiratory phases. Central post-I activity terminates inspiration and activates laryngeal motoneurons. We investigate whether neurons in the intermediate reticular nucleus (IRt) form the central pattern generator (CPG) responsible for post-I activity. We confirm that IRt activity contributes to post-I motor and autonomic outputs, and find that IRt neurons are necessary for activation of the same outputs during swallow, but that they are not required for termination of inspiration or recruitment of post-I activity during hypoxemia. We conclude that this population may not represent a distinct CPG, but instead may function as a premotor relay that integrates activity generated by diverse respiratory and nonrespiratory CPGs., (Copyright © 2019 the authors.)

Polycystic kidney disease (PKD) encompasses a spectrum of inherited disorders that lead to end-stage renal disease (ESRD). There is no cure for PKD and current treatment options are limited to renal replacement therapy and transplantation. A better understanding of the pathobiology of PKD is needed for the development of new, less invasive treatments. The Lewis Polycystic Kidney (LPK) rat phenotype has been characterized and classified as a model of nephronophthisis (NPHP9, caused by mutation of the Nek8 gene) for which polycystic kidneys are one of the main pathologic features. The aim of this study was to use a GC-MS-based untargeted metabolomics approach to determine key biochemical changes in kidney and liver tissue of the LPK rat. Tissues from 16-week old LPK (n = 10) and Lewis age- and sex-matched control animals (n = 11) were used. Principal component analysis (PCA) distinguished signal corrected metabolite profiles from Lewis and LPK rats for kidney (PC-1 77%) and liver (PC-1 46%) tissue. There were marked differences in the metabolite profiles of the kidney tissues with 122 deconvoluted features significantly different between the LPK and Lewis strains. The metabolite profiles were less marked between strains for liver samples with 30 features significantly different. Five biochemical pathways showed three or more significantly altered metabolites: transcription/translation, arginine and proline metabolism, alpha-linolenic and linoleic acid metabolism, the citric acid cycle, and the urea cycle. The results of this study validate and complement the current literature and are consistent with the understood pathobiology of PKD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Respiratory modulation of sympathetic nerve activity (respSNA) was studied in a hypertensive rodent model of chronic kidney disease (CKD) using Lewis Polycystic Kidney (LPK) rats and Lewis controls. In adult animals under in vivo anaesthetised conditions (n = 8-10/strain), respiratory modulation of splanchnic and renal nerve activity was compared under control conditions, and during peripheral (hypoxia), and central, chemoreceptor (hypercapnia) challenge. RespSNA was increased in the LPK vs. Lewis (area under curve (AUC) splanchnic and renal: 8.7 ± 1.1 vs. 3.5 ± 0.5 and 10.6 ± 1.1 vs. 7.1 ± 0.2 μV.s, respectively, P < 0.05). Hypoxia and hypercapnia increased respSNA in both strains but the magnitude of the response was greater in LPK, particularly in response to hypoxia. In juvenile animals studied using a working heart brainstem preparation (n = 7-10/strain), increased respSNA was evident in the LPK (thoracic SNA, AUC: 0.86 ± 0.1 vs. 0.42 ± 0.1 μV.s, P < 0.05), and activation of peripheral chemoreceptors (NaCN) again drove a larger increase in respSNA in the LPK with no difference in the response to hypercapnia. Amplified respSNA occurs in CKD and may contribute to the development of hypertension., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Maternal insufficiency during fetal development can have long-lasting effects on the offspring, most notably on nephron endowment. In polycystic kidney disease (PKD), variability in severity of disease is observed and maternal environment may be a modifying factor. In this study, we first established that in a rodent model of PKD, the Lewis polycystic kidney (LPK) rat's nephron numbers are 25% lower compared with wildtype animals. We then investigated the effects of prenatal and postnatal maternal environment on phenotype and nephron number. LPK pups born from and raised by homozygous LPK dams (control) were compared with LPK pups cross-fostered onto heterozygous LPK dams to improve postnatal environment; with LPK pups born from and raised by heterozygous LPK dams to improve both prenatal and postnatal environment and with LPK pups born from and raised by Wistar Kyoto-LPK heterozygous dams to improve both prenatal and postnatal environment on a different genetic background. Improvement in both prenatal and postnatal environment improved postnatal growth, renal function and reduced blood pressure, most notably in animals with different genetic background. Animals with improved postnatal environment only showed improved growth and blood pressure, but to a lesser extent. All intervention groups showed increased nephron number compared with control LPK. In summary, prenatal and postnatal environment had significant effect in delaying progression and reducing severity of PKD, including nephron endowment.

Background: Excessive gestational weight gain, particularly among overweight and obese women, is associated with adverse perinatal outcomes. Current interventions to limit gestational weight gain have achieved only modest success., Objective: We sought to improve adherence to gestational weight gain guidelines with a dual intervention of financial incentives and antenatal behavioral weight management., Study Design: This was a prospective randomized controlled trial at a single academic medical center in which women were assigned randomly to the intervention group or standard care. The primary outcome was adherence to gestational weight gain guidelines. Secondary outcomes included total gestational weight gain, mode of delivery, birthweight, neonatal intensive care unit admission, and development of gestational diabetes mellitus and hypertensive disorders of pregnancy., Results: A total of 136 women were assigned randomly, with data available for analysis of 124 women. Gestational weight gain within the Institutes of Medicine guidelines was similar (30% vs 29%) in the intervention and standard care groups, respectively. There were no statistically significant differences in total gestational weight gain or perinatal outcomes. There was a nonstatistically significant decrease in macrosomia in the intervention compared with standard care condition., Conclusion: A combined financial incentive and behavioral weight management intervention did not improve adherence to gestational weight gain guidelines. Modifications to the intervention may achieve improved results., (Copyright © 2019. Published by Elsevier Inc.)

Background: Unbiased screening studies have repeatedly identified actin-related proteins as one of the families of proteins most influenced by neurotrauma. Nevertheless, the status quo model of cytoskeletal reorganization after neurotrauma excludes actin and incorporates only changes in microtubules and intermediate filaments. Actin is excluded in part because it is difficult to image with conventional techniques. However, recent innovations in fluorescent microscopy provide an opportunity to image the actin cytoskeleton at super-resolution resolution in living cells. This study applied these innovations to an in vitro model of neurotrauma., New Method: New methods are introduced for traumatizing neurons before imaging them with high speed structured illumination microscopy or lattice light sheet microscopy. Also, methods for analyzing structured illumination microscopy images to quantify post-traumatic neurite dystrophy are presented., Results: Human induced pluripotent stem cell-derived neurons exhibited actin organization typical of immature neurons. Neurite dystrophy increased after trauma but was not influenced by jasplakinolide treatment. The F-actin content of dystrophies varied greatly from one dystrophy to another., Comparison With Existing Methods: In contrast to fixation dependent methods, these methods capture the evolution of the actin cytoskeleton over time in a living cell. In contrast to prior methods based on counting dystrophies, this quantification scheme parameterizes the severity of a given dystrophy as it evolves from a local swelling to an almost-perfect spheroid that threatens to transect the neurite., Conclusions: These methods can be used to investigate genetic factors and therapeutic interventions that modulate the course of neurite dystrophy after trauma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Hypertension and baroreflex dysfunction confer poorer outcomes in patients with polycystic kidney disease (PKD)., Method: We examined whether hypothalamic paraventricular nucleus (PVN) activation or circulating vasopressin contribute to hypertension and baroreflex dysfunction in the Lewis polycystic kidney (LPK) rat., Results: Bilateral PVN inhibition with muscimol reduced SBP further in urethane-anaesthetized adult LPK rats than in control Lewis rats (-43 ± 4 vs. -18 ± 3 mmHg; P < 0.0001, n = 14), but was not associated with a greater reduction in sympathetic nerve activity (SNA) or improvement in HR or SNA baroreflex function. Blockade of ionotropic glutamatergic input to the PVN with kynurenic acid also reduced SBP (P < 0.001), but not SNA, further in both adult and juvenile LPK rats. No differences in AMPA or NMDA receptor mRNA expression were noted. Systemic V1A receptor antagonism using OPC-21268 reduced SBP in adult LPK rats only (P < 0.001) and had no effect on the depressor response to PVN inhibition (P = 0.39). Combined peripheral V1A receptor antagonism and PVN inhibition, however, normalized SBP in adult LPK rats (122 ± 11 vs. 115 ± 6 mmHg; LPK vs. Lewis, P > 0.05, n = 10)., Conclusion: Our data show that in the LPK rat model of PKD, hypertension is contributed to by increased PVN neuronal activity and, through an independent mechanism, systemic V1A receptor activation. Treatments that reduce PVN neuronal activity and/or inhibit peripheral V1A receptors may provide novel treatment strategies to ameliorate hypertension in individuals with PKD and limit overall disease progression.

Excessive gestational weight gain (GWG) in pregnancy may be driven in part by greater motivation to eat, and studying the relative reinforcing value of food versus non-food commodities may provide insight into factors important for excessive GWG. This study was a cross-sectional examination of the relationship between women meeting the Institute of Medicine (IOM) guidelines for GWG and the relative reinforcing value of food vs. non-food commodities during pregnancy. Two-hundred and thirty-three pregnant women (1st trimester, n = 44; 2nd trimester, n = 105; 3rd trimester, n = 84), aged 18-40, were recruited via a crowdsourcing platform and completed an online survey. Relative food reinforcement (RRV food ), relative non-food activity reinforcement (RRV active ) and relative non-food cognitively enriching activity reinforcement (RRV cognitive ) were measured by a questionnaire at the point of contact. Self-reports of gestational age and weight gain during pregnancy were collected. The relationship between food and non-food reinforcement was assessed based on IOM classifications for weight gain during pregnancy. After adjustment for women's education level and parity, higher RRV food (p = 0.036) and lower RRV cognitive (p = 0.040) responses were associated with greater GWG. Food reinforcing ratio (FRR) analysis was then conducted to systematically examine the effect of non-food behaviors on GWG when food reinforcement was accounted for. Women who gained below the IOM weight gain guidelines had significantly higher FRR cognitive than those gaining above (p = 0.013), indicating cognitively enriching activities may better compete with food among pregnant women. Interventions that help to increase the reinforcing value of cognitively enriching activities may be a new avenue to regulate eating to minimize GWG., (Copyright © 2018. Published by Elsevier Ltd.)

Integrative Medicine is a model of health care that combines both conventional and unconventional therapies that serve the whole person and focus on prevention and whole health. Women are the highest utilizers of health care and Integrative Medicine for a variety of reasons. Integrative Medicine represents a more "female energy" in the field of medicine, which is needed even more today as health care moves toward value-based care and out of high-cost and high-harm care. Integrative Medicine can be incorporated into medical practice and into health workers' lives for wellness., (Published by Elsevier Inc.)

Research conducted through clinical trials is essential for evaluating new treatment modalities, establishing new standards of cancer care, and ultimately improving and prolonging the lives of patients with cancer. However, participation in trials has been low, and this is attributable to various factors including patient financial barriers. Such financial barriers include the rising cost of cancer care; a lack of transparency in coverage policy; and the perception of ethical, compliance, or institutional impediments to patient financial support. ASCO convened a roundtable discussion with a variety of stakeholders to define the scope of the problem, as well as to identify clinical practice and policy solutions applicable at the institutional and system-wide levels. This statement summarizes key discussions from the ASCO Roundtable, as well as findings from the literature, and provides ASCO's recommendations for overcoming financial barriers that may otherwise prevent participation in clinical trials. These recommendations broadly address the following key areas: (1) improving the policy environment for coverage of clinical trials; (2) facilitating transparency among providers, patients, and payers for trial-related out-of-pocket costs; (3) refuting the specter of inducement to enable targeted financial support for patients; and (4) improving the available data on costs of cancer clinical trials.

Introduction: Understanding patterns of single and multiple tobacco product use among reproductive-aged women is critical given the potential for adverse health effects on mother and infant should a woman become pregnant., Methods: Patterns of tobacco use over a 2-year period were examined among all women (18-44 years) who completed wave 1 (W1) and wave 2 (W2) of the US Population Assessment of Tobacco and Health (PATH, 2013-2014, 2014-2015) Study. We examined the most common patterns of single and multiple tobacco product use in W1, and longitudinal trajectories of women engaged in each of these patterns of use from W1 to W2, among women not pregnant in either wave (n = 7480), not pregnant in W1 and pregnant in W2 (n = 332), and pregnant in W1 and not pregnant in W2 (n = 325)., Results: The most prevalent patterns of tobacco use in W1 among all three subgroups were using cigarettes alone followed by using cigarettes plus e-cigarettes. In all three subgroups, women using multiple products in W1 were more likely to adopt new use patterns in W2 relative to single-product users, with the new patterns generally involving dropping rather than adding products. The majority of multiple product use included cigarettes, and transitions to single product use typically involved dropping the noncigarette product. The most common trajectory among tobacco users transitioning to or from pregnancy was to use cigarettes alone in W2., Discussion: This study contributes new knowledge characterizing tobacco use patterns across time and reproductive events among reproductive-aged women.

Neuromuscular-blocking agents are commonly used in laboratory animal research settings. Due to actions of cholinergic receptors at locations other than the motor end-plate, these agents have a strong propensity to modulate autonomic outflow and may therefore not be desirable in studies examining autonomic function. This study aimed to compare the effect of two non-depolarizing neuromuscular-blocking agents, pancuronium and cisatracurium, on blood pressure, heart rate and non-invasive indices of autonomic function (heart rate variability, systolic blood pressure variability and baroreflex sensitivity) under two different types of anaesthesia in Lewis rats. Pancuronium produced a profound vagolytic response characterized by tachycardia, reduction in heart rate variability and baroreflex sensitivity under urethane anaesthesia, and with minimal effect under isoflurane anaesthesia. Conversely, cisatracurium produced no evidence of vagolytic action under either urethane or isoflurane anaesthesia. Therefore, for studies interested in examining autonomic function, particularly baroreflex or vagal function, neuromuscular blockade would be best achieved using cisatracurium.

Maternal obesity and smoking are associated with adverse perinatal outcomes. These prevalent conditions contribute to health disparities. In this study, we examine whether maternal BMI moderates the impact of smoking cessation on short-term perinatal outcomes. This is a secondary analysis of assessments conducted from several prospective clinical trials examining the efficacy of incentives to promote smoking cessation during pregnancy. Participants were randomly assigned to receive financial incentives contingent upon smoking abstinence or a control condition. Pregnancy outcomes were abstracted from the medical record. ANCOVA and multiple logistic regression were used for statistical analysis. Among 388 women, there was a significant interaction between maternal pre-pregnancy BMI and smoking status on gestational age at delivery (p = .03) and admission to the NICU (p = .04). Among underweight/normal weight gravidas, smoking resulted in earlier deliveries and a greater likelihood of NICU admission than in those who abstained. Among overweight/obese gravidas, there was no effect of smoking on gestational age at delivery and infants of smokers were less likely to be admitted to the NICU. Maternal obesity and smoking have significant individual effects on perinatal outcome. Maternal overweight/obesity appears to moderate the effect of smoking on gestational age at delivery and on NICU admissions.

Background: The renin-angiotensin system, in particular Angiotensin II (AngII), plays a significant role in the pathogenesis of hypertension in chronic kidney disease (CKD). Effects of chronic AT1 receptor antagonism were investigated in a genetic hypertensive rat model of CKD, the Lewis polycystic kidney (LPK) rat., Methods: Mixed-sex LPK and Lewis control rats (total n = 31) were split between treated (valsartan 60 mg/kg/day p.o. from 4 to 18 weeks) and vehicle groups. Animals were assessed for systolic blood pressure and urine biochemistry, and after euthanasia, blood collected for urea and creatinine analysis, confirming the hypertensive and renal phenotype. Mesenteric resistance vasculature was assessed using pressure myography and histology., Results: Valsartan treatment improved vascular structure in LPK rats, increasing internal and external diameter values and reducing wall thickness (untreated vs. treated LPK: 53.19 ± 3.29 vs. 33.93 ± 2.17 μm) and wall-lumen ratios (untreated vs. treated LPK: 0.52 ± 0.09 vs. 0.16 ± 0.01, all P < 0.0001). Endothelium dysfunction, as measured by maximal response to acetylcholine (Rmax), was normalized with treatment (untreated vs. treated LPK: 69.56 ± 4.34 vs. 103.05 ± 4.13, P < 0.05), increasing the relative contributions of nitric oxide and endothelium-derived hyperpolarization to vasorelaxation while downregulating the prostanoid contribution. Biomechanical properties also improved with treatment, as indicated by an increase in compliance, decrease in intrinsic stiffness and alterations in the artery wall composition, which included decreases in collagen density and collagen/elastin ratio., Conclusions: Our results highlight the importance of AngII as a driver of resistance vessel structural, functional, and biomechanical dysfunction and provide insight as to how AT1 receptor blockade exerts therapeutic efficacy in CKD.

Traumatic brain injury (TBI) is a major clinical challenge with high morbidity and mortality. Despite decades of pre-clinical research, no proven therapies for TBI have been developed. This paper presents a novel method for pre-clinical neurotrauma research intended to complement existing pre-clinical models. It introduces human pathophysiology through the use of human induced pluripotent stem cell-derived neurons (hiPSCNs). It achieves loading pulse duration similar to the loading durations of clinical closed head impact injury. It employs a 96-well format that facilitates high throughput experiments and makes efficient use of expensive cells and culture reagents. Silicone membranes are first treated to remove neurotoxic uncured polymer and then bonded to commercial 96-well plate bodies to create stretchable 96-well plates. A custom-built device is used to indent some or all of the well bottoms from beneath, inducing equibiaxial mechanical strain that mechanically injures cells in culture in the wells. The relationship between indentation depth and mechanical strain is determined empirically using high speed videography of well bottoms during indentation. Cells, including hiPSCNs, can be cultured on these silicone membranes using modified versions of conventional cell culture protocols. Fluorescent microscopic images of cell cultures are acquired and analyzed after injury in a semi-automated fashion to quantify the level of injury in each well. The model presented is optimized for hiPSCNs but could in theory be applied to other cell types.

Polycystic kidney disease (PKD) is a group of monogenetic conditions characterised by the progressive accumulation of multiple renal cysts and hypertension. One of the earliest features of PKD is a reduction in urinary concentrating capacity that impairs extracellular fluid conservation. Urinary concentrating impairment predisposes PKD patients to periods of hypohydration when fluid loss is not adequately compensated by fluid intake. The hypohydrated state provides a blood hyperosmotic stimulus for vasopressin release to minimise further water loss. However, over-activation of renal V2 receptors contributes to cyst expansion. Although suppressing vasopressin release with high water intake has been shown to impair disease progression in rodent models, whether this approach is efficacious in patients remains uncertain. The neural osmoregulatory pathway that controls vasopressin secretion also exerts a stimulatory action on vasomotor sympathetic activity and blood pressure during dehydration. Recurrent dehydration leads to a worsening of hypertension in rodents and cross-sectional data suggests that reduced urinary concentrating ability may contribute to hypertension development in the clinical PKD population. Experimental studies are required to evaluate this hypothesis and to determine the underlying mechanism., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Unhealthy behaviors and lifestyle choices are contributing to the obesity epidemic and associated morbidities. Among reproductive aged women, obesity adversely affects perinatal outcomes and longer term maternal and child health. Interventions utilizing strategies of behavior change have the potential to improve outcomes, especially during pregnancy. Antenatal interventions to improve adherence to gestational weight gain guidelines are one such example. Although behaviorally-based intervention trials have been associated with modest decreases in gestational weight gain, the effect on short term perinatal outcomes has thus far been minimal. This commentary aims to discuss possible reasons behind the failure to improve perinatal outcomes as well as to encourage future areas of study., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Renal denervation is a novel device based therapy promoted to reduce high blood pressure. We examined the impact of renal denervation on systolic blood pressure, renal function, and arterial stiffness in the Lewis Polycystic Kidney disease (LPK) rodent model of kidney disease. Animals were subjected to bilateral renal denervation or sham surgeries at age 6 and 12 weeks. Systolic blood pressure was monitored by tail-cuff plethysmography and renal function by urinalysis and creatinine clearance. At age 16 weeks, beat-to-beat aortic pulse wave velocity as a functional indicator of arterial stiffness was determined. Renal denervation produced an overall reduction in blood pressure in the LPK [(denervated 164±4 vs. sham-operated 180±6 mmHg, n = 6 per group, P=0.003)] and delayed, but did not prevent, the decline in renal function. Aortic pulse wave velocity was markedly elevated in the LPK compared with Lewis and was not altered by renal denervation in the LPK however a reduction was seen in the control Lewis animals. These results support the hypothesis that renal nerves contribute to secondary hypertension in conditions such as kidney disease.