VSMCs in resistance arteries and arterioles express a diverse array of KV channels with members of the KV1, KV2 and KV7 families being particularly important. Members of the KV channel family: (i) ...are highly expressed in VSMCs; (ii) are active at the resting membrane potential of VSMCs in vivo (−45 to −30 mV); (iii) contribute to the negative feedback regulation of VSMC membrane potential and myogenic tone; (iv) are activated by cAMP‐related vasodilators, hydrogen sulfide and hydrogen peroxide; (v) are inhibited by increases in intracellular Ca2+ and vasoconstrictors that signal through Gq‐coupled receptors; (vi) are involved in the proliferative phenotype of VSMCs; and (vii) are modulated by diseases such as hypertension, obesity, the metabolic syndrome and diabetes. Thus, KV channels participate in every aspect of the regulation of VSMC function in both health and disease.
VSMCs in resistance arteries and arterioles express a diverse array of K
channels with members of the K
1, K
2 and K
7 families being particularly important. Members of the K
channel family: (i) are ...highly expressed in VSMCs; (ii) are active at the resting membrane potential of VSMCs in vivo (-45 to -30 mV); (iii) contribute to the negative feedback regulation of VSMC membrane potential and myogenic tone; (iv) are activated by cAMP-related vasodilators, hydrogen sulfide and hydrogen peroxide; (v) are inhibited by increases in intracellular Ca
and vasoconstrictors that signal through G
-coupled receptors; (vi) are involved in the proliferative phenotype of VSMCs; and (vii) are modulated by diseases such as hypertension, obesity, the metabolic syndrome and diabetes. Thus, K
channels participate in every aspect of the regulation of VSMC function in both health and disease.
Endothelial cells in resistance arteries, arterioles, and capillaries express a diverse array of ion channels that contribute to Cell-Cell communication in the microcirculation. Endothelial cells are ...tightly electrically coupled to their neighboring endothelial cells by gap junctions allowing ion channel-induced changes in membrane potential to be conducted for considerable distances along the endothelial cell tube that lines arterioles and forms capillaries. In addition, endothelial cells may be electrically coupled to overlying smooth muscle cells in arterioles and to pericytes in capillaries
heterocellular gap junctions allowing electrical signals generated by endothelial cell ion channels to be transmitted to overlying mural cells to affect smooth muscle or pericyte contractile activity. Arteriolar endothelial cells express inositol 1,4,5 trisphosphate receptors (IP
Rs) and transient receptor vanilloid family member 4 (TRPV4) channels that contribute to agonist-induced endothelial Ca
signals. These Ca
signals then activate intermediate and small conductance Ca
-activated K
(IK
and SK
) channels causing vasodilator-induced endothelial hyperpolarization. This hyperpolarization can be conducted along the endothelium
homocellular gap junctions and transmitted to overlying smooth muscle cells through heterocellular gap junctions to control the activity of voltage-gated Ca
channels and smooth muscle or pericyte contraction. The IK
- and SK
-induced hyperpolarization may be amplified by activation of inward rectifier K
(K
) channels. Endothelial cell IP
R- and TRPV4-mediated Ca
signals also control the production of endothelial cell vasodilator autacoids, such as NO, PGI
, and epoxides of arachidonic acid contributing to control of overlying vascular smooth muscle contractile activity. Cerebral capillary endothelial cells lack IK
and SK
but express K
channels, IP
R, TRPV4, and other Ca
permeable channels allowing capillary-to-arteriole signaling
hyperpolarization and Ca
. This allows parenchymal cell signals to be detected in capillaries and signaled to upstream arterioles to control blood flow to capillaries by active parenchymal cells. Thus, endothelial cell ion channels importantly participate in several forms of Cell-Cell communication in the microcirculation that contribute to microcirculatory function and homeostasis.
Summary Background Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose ...fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. Methods We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00080912. Findings Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 56% of 358 assessable patients who received 8 Gy vs 229 66% of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 23% of 357 vs 108 31% of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio OR 1·54, 95% CI 0·85–2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73–17·15; p=0·094). Interpretation In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist. Funding Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris.
Resistance arteries and downstream arterioles in the peripheral microcirculation contribute substantially to peripheral vascular resistance, control of blood pressure, the distribution of blood flow ...to and within tissues, capillary pressure, and microvascular fluid exchange. A hall-mark feature of these vessels is myogenic tone. This pressure-induced, steady-state level of vascular smooth muscle activity maintains arteriolar and resistance artery internal diameter at 50–80% of their maximum passive diameter providing these vessels with the ability to dilate, reducing vascular resistance, and increasing blood flow, or constrict to produce the opposite effect. Despite the central importance of resistance artery and arteriolar myogenic tone in cardiovascular physiology and pathophysiology, our understanding of signaling pathways underlying this key microvascular property remains incomplete. This brief review will present our current understanding of the multiple mechanisms that appear to underlie myogenic tone, including the roles played by G-protein-coupled receptors, a variety of ion channels, and several kinases that have been linked to pressure-induced, steady-state activity of vascular smooth muscle cells (VSMCs) in the wall of resistance arteries and arterioles. Emphasis will be placed on the portions of the signaling pathways underlying myogenic tone for which there is lack of consensus in the literature and areas where our understanding is clearly incomplete.
To present a clear and comprehensive summary of the published data on unicompartmental knee replacement (UKA) or total knee replacement (TKA), comparing domains of outcome that have been shown to be ...important to patients and clinicians to allow informed decision making.
Systematic review using data from randomised controlled trials, nationwide databases or joint registries, and large cohort studies.
Medline, Embase, Cochrane Controlled Register of Trials (CENTRAL), and Clinical Trials.gov, searched between 1 January 1997 and 31 December 2018.
Studies published in the past 20 years, comparing outcomes of primary UKA with TKA in adult patients. Studies were excluded if they involved fewer than 50 participants, or if translation into English was not available.
60 eligible studies were separated into three methodological groups: seven publications from six randomised controlled trials, 17 national joint registries and national database studies, and 36 cohort studies. Results for each domain of outcome varied depending on the level of data, and findings were not always significant. Analysis of the three groups of studies showed significantly shorter hospital stays after UKA than after TKA (-1.20 days (95% confidence interval -1.67 to -0.73), -1.43 (-1.53 to -1.33), and -1.73 (-2.30 to -1.16), respectively). There was no significant difference in pain, based on patient reported outcome measures (PROMs), but significantly better functional PROM scores for UKA than for TKA in both non-trial groups (mean difference -0.58 (-0.88 to -0.27) and -0.32 (-0.48 to -0.15), respectively). Regarding major complications, trials and cohort studies had non-significant results, but mortality after TKA was significantly higher in registry and large database studies (risk ratio 0.27 (0.16 to 0.45)), as were venous thromboembolic events (0.39 (0.27 to 0.57)) and major cardiac events (0.22 (0.06 to 0.86)). Early reoperation for any reason was higher after TKA than after UKA, but revision rates at five years remained higher for UKA in all three study groups (risk ratio 5.95 (1.29 to 27.59), 2.50 (1.77 to 3.54), and 3.13 (1.89 to 5.17), respectively).
TKA and UKA are both viable options for the treatment of isolated unicompartmental osteoarthritis. By directly comparing the two treatments, this study demonstrates better results for UKA in several outcome domains. However, the risk of revision surgery was lower for TKA. This information should be available to patients as part of the shared decision making process in choosing treatment options.
PROSPERO number CRD42018089972.
Arterioles in the peripheral microcirculation regulate blood flow to and within tissues and organs, control capillary blood pressure and microvascular fluid exchange, govern peripheral vascular ...resistance, and contribute to the regulation of blood pressure. These important microvessels display pressure-dependent myogenic tone, the steady state level of contractile activity of vascular smooth muscle cells (VSMCs) that sets resting arteriolar internal diameter such that arterioles can both dilate and constrict to meet the blood flow and pressure needs of the tissues and organs that they perfuse. This perspective will focus on the Ca
2+
-dependent ion channels in the plasma and endoplasmic reticulum membranes of arteriolar VSMCs and endothelial cells (ECs) that regulate arteriolar tone. In VSMCs, Ca
2+
-dependent negative feedback regulation of myogenic tone is mediated by Ca
2+
-activated K
+
(BK
Ca
) channels and also Ca
2+
-dependent inactivation of voltage-gated Ca
2+
channels (VGCC). Transient receptor potential subfamily M, member 4 channels (TRPM4); Ca
2+
-activated Cl
−
channels (CaCCs; TMEM16A/ANO1), Ca
2+
-dependent inhibition of voltage-gated K
+
(K
V
) and ATP-sensitive K
+
(K
ATP
) channels; and Ca
2+
-induced-Ca
2+
release through inositol 1,4,5-trisphosphate receptors (IP
3
Rs) participate in Ca
2+
-dependent positive-feedback regulation of myogenic tone. Calcium release from VSMC ryanodine receptors (RyRs) provide negative-feedback through Ca
2+
-spark-mediated control of BK
Ca
channel activity, or positive-feedback regulation in cooperation with IP
3
Rs or CaCCs. In some arterioles, VSMC RyRs are silent. In ECs, transient receptor potential vanilloid subfamily, member 4 (TRPV4) channels produce Ca
2+
sparklets that activate IP
3
Rs and intermediate and small conductance Ca
2+
activated K
+
(IK
Ca
and sK
Ca
) channels causing membrane hyperpolarization that is conducted to overlying VSMCs producing endothelium-dependent hyperpolarization and vasodilation. Endothelial IP
3
Rs produce Ca
2+
pulsars, Ca
2+
wavelets, Ca
2+
waves and increased global Ca
2+
levels activating EC sK
Ca
and IK
Ca
channels and causing Ca
2+
-dependent production of endothelial vasodilator autacoids such as NO, prostaglandin I
2
and epoxides of arachidonic acid that mediate negative-feedback regulation of myogenic tone. Thus, Ca
2+
-dependent ion channels importantly contribute to many aspects of the regulation of myogenic tone in arterioles in the microcirculation.
We examined school days missed for routine dental care versus dental pain or infection to determine the relationship between children's oral health status and school attendance and performance.
We ...used 2008 data from the North Carolina Child Health Assessment and Monitoring Program. The study sample, weighted to reflect the state's population, included 2183 schoolchildren. Variables assessed included school absences and performance, oral health status, parental education, health insurance coverage, race, and gender.
Children with poor oral health status were nearly 3 times more likely (odds ratio = 3.89; 95% confidence interval = 1.96, 7.75) than were their counterparts to miss school as a result of dental pain. Absences caused by pain were associated with poorer school performance (P < .05), but absences for routine care were not. Mediation analyses revealed that oral health status was associated with performance independent of absence for pain.
Children with poorer oral health status were more likely to experience dental pain, miss school, and perform poorly in school. These findings suggest that improving children's oral health status may be a vehicle to enhancing their educational experience.
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