Emergence of Mechano-Sensitive Contraction Autoregulation in Cardiomyocytes

The heart has two intrinsic mechanisms to enhance contractile strength that compensate for increased mechanical load to help maintain cardiac output. When vascular resistance increases the ventricular chamber initially expands causing an immediate length-dependent increase of contraction force via the Frank-Starling mechanism. Additionally, the stress-dependent Anrep effect slowly increases contraction force that results in the recovery of the chamber volume towards its initial state. The Anrep effect poses a paradox: how can the cardiomyocyte maintain higher contractility even after the cell length has recovered its initial length? Here we propose a surface mechanosensor model that enables the cardiomyocyte to sense different mechanical stresses at the same mechanical strain. The cell-surface mechanosensor is coupled to a mechano-chemo-transduction feedback mechanism involving three elements: surface mechanosensor strain, intracellular Ca2+ transient, and cell strain. We show that in this simple yet general system, contractility autoregulation naturally emerges, enabling the cardiomyocyte to maintain contraction amplitude despite changes in a range of afterloads. These nontrivial model predictions have been experimentally confirmed. Hence, this model provides a new conceptual framework for understanding the contractility autoregulation in cardiomyocytes, which contributes to the heart’s intrinsic adaptivity to mechanical load changes in health and diseases.

Superficial Peroneal Neuromodulation of Persistent Bladder Underactivity Induced by Prolonged Pudendal Afferent Nerve Stimulation in Cats

The purpose of this study is to determine if superficial peroneal nerve stimulation (SPNS) can reverse persistent bladder underactivity induced by prolonged pudendal nerve stimulation (PNS). In 16 α‐chloralose anesthetized cats, PNS and SPNS were applied by nerve cuff electrodes. Skin surface electrodes were also used for SPNS. Bladder underactivity consisting of a significant increase in bladder capacity to 157.8±10.9% of control and a significant reduction in bladder contraction amplitude to 56.0±5.0% of control was induced by repetitive (4-16 times) application of 30-min PNS. SPNS (1 Hz, 0.2 ms) at 1.5 to 2 times threshold intensity (T) for inducing posterior thigh muscle contractions was applied either continuously (SPNSc) or intermittently (SPNSi) during a cystometrogram (CMG) to determine if the stimulation can reverse the PNS-induced bladder underactivity. SPNSc or SPNSi applied by nerve cuff electrodes during the prolonged PNS inhibition significantly reduced bladder capacity to 124.4±10.7% and 132.4±14.2% of control, respectively, and increased contraction amplitude to 85.3±6.2% and 75.8±4.7%, respectively. Transcutaneous SPNSc and SPNSi also significantly reduced bladder capacity and increased contraction amplitude. Additional PNS applied during the bladder underactivity further increased bladder capacity, while SPNSc applied simultaneously with the PNS reversed the increase in bladder capacity. This study indicates that a non-invasive superficial peroneal neuromodulation therapy might be developed to treat bladder underactivity caused by abnormal pudendal nerve somatic afferent activation that is hypothesized to occur in patients with Fowler's syndrome.

An Experimental Study on Intestine Transmission Function in SD Rats With Slow Transit Constipation After Electro-acupuncture Treatment in BL32 Acupoints

<B>Objective:</B>This study aims to use loperamide by gavage in SD rats to establish the model of STC, and evaluate the degree of similarity between the model and clinical diseases. Furthermore, the effect of electro-acupuncture when stimulating BL32 acupoints in SD rats with slow transit constipation were observed to determine changes in intestinal transmission function. <B>Methods:</B>Thirty SD rats were selected and divided randomly into three groups. Rats in the model group were given 2 mg/kg/d of loperamide tablets by gavage for 15 days. The morphology of the feces of rats was observed, and the dry weight of the feces and the time of first black feces movement with black ink by gavage after molding were measured. After 20 days of electro-acupuncture treatment at the BL32 acupoint, the time of first black feces movement, the ratio of black ink length of the entire length of the intestine, and contraction amplitude and frequency of contraction were measured. <B>Results:</B> The time of black feces movement in the two model groups was significantly prolonged (P<0.05).Furthermore, fecal grains, dry weight and moisture content were significantly reduced (P<0.05). On the 10thand 20thday of treatment, the time of black feces movementin the treatment group significantly decreased (P<0.05). The ratio of black ink length of the entire length of the intestine in the electro-acupuncture group was significantly higher than that in the model group (P<0.05). Moreover, contraction amplitude was significantly higher than in the model control group (P<0.05). <B>Conclusion:</B> Through loperamide gavage, the model of slow transit constipation in SD rats was successfully established in a relatively short period of time. Electro-acupuncture treatment had a rapid onset of action, and its mechanism might have been caused through strengthening the ability of intestinal smooth muscle contraction, and are independent with increased smooth muscle contraction frequency.

Bladder underactivity induced by prolonged pudendal afferent activity in cats

The purpose of this study was to determine the effects of pudendal nerve stimulation (PNS) on reflex bladder activity and develop an animal model of underactive bladder (UAB). In six anesthetized cats, a bladder catheter was inserted via the urethra to infuse saline and measure pressure. A cuff electrode was implanted on the pudendal nerve. After determination of the threshold intensity (T) for PNS to induce an anal twitch, PNS (5 Hz, 0.2 ms, 2 T or 4 T) was applied during cystometrograms (CMGs). PNS (4-6 T) of 30-min duration was then applied repeatedly until bladder underactivity was produced. Following stimulation, control CMGs were performed over 1.5-2 h to determine the duration of bladder underactivity. When applied during CMGs, PNS (2 T and 4 T) significantly ( P < 0.05) increased bladder capacity while PNS at 4 T also significantly ( P < 0.05) reduced bladder contraction amplitude, duration, and area under contraction curve. Repeated application of 30-min PNS for a cumulative period of 3-8 h produced bladder underactivity exhibiting a significantly ( P < 0.05) increased bladder capacity (173 ± 14% of control) and a significantly ( P < 0.05) reduced contraction amplitude (50 ± 7% of control). The bladder underactivity lasted more than 1.5-2 h after termination of the prolonged PNS. These results provide basic science evidence supporting the proposal that abnormal afferent activity from external urethral/anal sphincter could produce central inhibition that underlies nonobstructive urinary retention (NOUR) in Fowler’s syndrome. This cat model of UAB may be useful to investigate the mechanism by which sacral neuromodulation reverses NOUR in Fowler’s syndrome.

Assessment of pupillary light reflex using dynamic pupillometry in laser-treated eyes with retinal vein occlusion

Purpose: This study aims to evaluate the pupillary light reflex measured with dynamic pupillometry in patients who underwent retinal laser photocoagulation due to unilateral retinal vein occlusion (RVO). Methods: A total of 48 patients with unilateral RVO were included in the study. Thirty-four patients had undergone retinal laser photocoagulation while the remaining 14 patients that did not undergo laser treatment were observed for control purposes. Of the laser-treated eyes, 14 eyes (41.2%) had central RVO (CRVO) and 20 eyes (58.8%) had branch RVO (BRVO). Among the 14 patients with RVO without laser treatment, nine eyes (64.3%) had CRVO and five eyes (35.7%) had BRVO. Pupillary light reflexes were assessed with dynamic pupillometry (MonPackOne®; Metrovision, France). The parameters of the eyes with RVO were compared with that of fellow healthy eyes. Results: Mean patient age was 65.8 ± 10.4 years and median time after photocoagulation was 25.5 months. Eyes that received laser photocoagulation had lower pupil contraction amplitude ( p = 0.037), prolonged contraction latency ( p = 0.027), slower contraction velocity ( p = 0.043), and slower dilation velocity ( p < 0.001) compared to healthy fellow eyes. Subgroup analysis revealed that eyes with CRVO had lower contraction amplitude ( p = 0.013) and slower dilation velocity ( p = 0.003), and eyes with BRVO had slower dilation velocity ( p = 0.003). Non-laser-treated eyes with RVO revealed no significant difference in any of the pupillary light reflex parameters compared to fellow eyes. Conclusion: Laser-treated eyes with RVO demonstrated changes in pupillary light reflex parameters including reduced contraction amplitude, prolonged contraction latency, and slower contraction and dilation velocities measured with dynamic pupillometry.

Experimental faecal peritonitis alters response to 5-hydroxytryptamine in mesenteric lymphatic vessels

Aim. To compare the reactions to 5-hydroxytryptamine (5-HT, serotonin) in the mesenteric lymphangions upon endothelial denudation and during experimental faecal peritonitis as compared with the control lymphangions. Materials and Methods. Experiments were performed on the intestinal lymph trunk lymphangions of rats using a pressure myograph system. We examined the changes in contraction frequency and amplitude as well as tonic reactions upon the addition of 5-HT (10-8-10-4 M). Experimental peritonitis was caused by an intraperitoneal injection of feces. Results. Faecal peritonitis reduced contraction frequency and amplitude in mesenteric lymphangions. 5-HT increased contraction amplitude only at low concentration (10-8 M) and did not alter the tonic reactions. Upon endothelial denudation, serotonin inhibited contraction frequency and amplitude in the lymphangions. As 5-HT stimulates motility through 5-НТ2 receptors and α2-adrenoceptors on endothelial cells, faecal peritonitis abates the sensitivity of such receptors to 5-HT. Conclusion. In experimental faecal peritonitis, alterations in lymphatic vessels are reminiscent of those in blood vessels. Endothelial dysfunction disturbs the response of lymphatic vessels to 5-HT.

Contraction fatigability during interleaved neuromuscular electrical stimulation of the ankle dorsiflexors does not depend on contraction amplitude

Interleaved neuromuscular electrical stimulation (iNMES) involves alternating stimulus pulses between the tibialis anterior muscle and common peroneal nerve. The current investigation aimed to characterize the relationship between contraction amplitude, motor unit (MU) “overlap”, and contraction fatigability during iNMES. It was hypothesized that as iNMES generates progressively larger contractions, more MUs would be recruited from both sites (i.e., more MU overlap), resulting in more fatigability for larger than smaller contractions. Fourteen participants completed 3 sessions. Fatigability was assessed as the decline in torque over 180 contractions (0.3 s “on”, 0.7 s “off”) when iNMES was delivered to produce initial contractions of ∼5%, 15%, or 30% of a maximal voluntary contraction. Although MU overlap increased significantly with contraction amplitude, the relative (percent) decline in torque was not different between the contraction amplitudes and torque declined on average by 23%. Contraction fatigability was not significantly correlated with either MU overlap or initial contraction amplitude. In conclusion, iNMES can produce fatigue-resistant contractions across a functionally-meaningful range of contraction amplitudes for rehabilitation. Novelty Interleaved neuromuscular electrical stimulation progressively recruits MUs as contraction amplitude increases. However, the relative amount of fatigability of recruited MUs was not different as contraction amplitude increased. This suggests iNMES can be used effectively to produce fatigue-resistant and functionally meaningful contractions.

Endoscopic Endoclip Papilloplasty Preserves Sphincter of Oddi Function After Endoscopic Sphincterotomy in Porcine Models

Background Endoscopic sphincterotomy (EST) can destroy sphincter of Oddi (SO) function and plays a role in recurrent choledocholithiasis and cholangitis development. The purpose of this study was to assess the feasibility of endoscopic endoclip papilloplasty (EEPP) in restoring SO function after EST. Methods Seven 26-week-old domestic pigs were divided into control and EEPP groups. Necropsy, hematoxylin-eosin staining, anti-α-smooth muscle actin (α-SMA) staining of papilla and sphincter of Oddi manometry (SOM) were conducted in animals at three independent time points. Results EST and EEPP were safely performed in all 7 pigs without serious adverse events. For primary outcome, compared to the controls, EEPP generated smaller dilation with less inflammation. Fibrous repair of the papilla was observed at 24 weeks after EEPP. For secondary outcome, in the control group, SO basal pressure (17.25 ± 18.14 to 5.50 ± 0.71 mmHg), SO contraction amplitude (46.00 ± 19.20 to 34.50 ± 48.79 mmHg), peak (4.50 ± 4.04 to 1.50 ± 2.12) and frequency (3.05 ± 3.29 to 1.41 ± 2.19 /min) reduced after EST. Further reductions to almost 0 were observed 3 weeks later, including common bile duct pressure and SO contraction period. In contrast, in the EEPP group, these manometric data recovered to pre-EST levels, such as CBD pressure (11.5 ± 7.31 vs 11 ± 2.16 mmHg), SO pressure (17.50 ± 17.75 vs 18.20 ± 21.39 mmHg) and SO contraction amplitude (53.67 ± 21.54 vs 60.00 ± 36.08 mmHg). However, no significant differences were observed by Student t-test. Conclusions In this porcine study, EEPP had accelerated and improved papillary healing after EST, and preserved SO function.

Evaluation of Disk Halo Size after Implantation of a Collamer Lens with a Central Hole (ICL V4c)

Purpose. To investigate disk halo size changes produced by a glare source after surgical insertion of an implantable collamer lens with a central hole (ICL V4c) for myopia correction. Methods. In this prospective study, disk halo size and pupillary light response with a vision monitor were measured preoperatively and at 1 week, 1 month, and 3 months postoperatively. Pupillary light response parameters included contraction amplitude, latency, duration, and velocity; dilation latency, duration, and velocity; and initial, maximum, minimum, and average pupil diameters. Results. Forty-two right eyes of 42 patients were enrolled. Postoperative uncorrected distance visual acuity was better than or equal to 20/20 in all eyes. Compared to preoperative values, disk halo size showed no significant difference at 1 week postoperatively (P>0.05) and then decreased significantly at 1 and 3 months postoperatively (both P<0.001). Contraction amplitude and velocity, as well as dilation velocity, decreased significantly at all postoperative time points (all P<0.001). Disk halo size at 3 months postoperatively was significantly correlated with initial (r = 0.446, P=0.003), maximum (r = 0.483, P=0.001), minimum (r = 0.425, P=0.005), and average pupil diameters (r = 0.474, P=0.002). Conclusions. After ICL V4c implantation, disk halo size was reduced in the short term. Patients with smaller pupil sizes during pupillary response to light experienced smaller halos after ICL V4c implantation.