Rationale Sympathetic nervous system control of inflammation plays a central role in hypertension. The gut receives significant sympathetic innervation, is densely populated with a diverse microbial ecosystem, and contains immune cells that greatly impact overall inflammatory homeostasis. Despite this uniqueness, little is known about the involvement of the gut in hypertension. Objective Test the hypothesis that increased sympathetic drive to the gut is associated with increased gut wall permeability, increased inflammatory status, and microbial dysbiosis and that these gut pathological changes are linked to hypertension. Methods and Results Gut epithelial integrity and wall pathology were examined in spontaneously hypertensive rat (SHR) and chronic Angiotensin II infusion rat models. The increase in blood pressure in SHR was associated with gut pathology that included increased intestinal permeability and decreased tight junction proteins. These changes in gut pathology in hypertension were associated with alterations in microbial communities relevant in blood pressure control. We also observed enhanced gut-neuronal communication in hypertension originating from paraventricular nucleus of the hypothalamus and presenting as increased sympathetic drive to the gut. Finally, angiotensin converting enzyme inhibition (captopril) normalized blood pressure and was associated with reversal of gut pathology. Conclusions A dysfunctional sympathetic-gut communication is associated with gut pathology, dysbiosis, and inflammation, and plays a key role in hypertension. Thus, targeting of gut microbiota by innovative probiotics, antibiotics, and fecal transplant, in combination with current pharmacotherapy, may be a novel strategy for hypertension treatment.

Human C-tactile (CT) afferents respond vigorously to gentle skin stroking and have gained attention for their importance in social touch. Pharmacogenetic activation of the mouse CT equivalent has positively reinforcing, anxiolytic effects, suggesting a role in grooming and affiliative behavior. We recorded from single CT axons in human participants, using the technique of microneurography, and stimulated a unit's receptive field using a novel, computer-controlled moving probe, which stroked the skin of the forearm over five velocities (0.3, 1, 3, 10, and 30 cm s Ϫ1 ) at three temperatures (cool, 18°C; neutral, 32°C; warm, 42°C). We show that CTs are unique among mechanoreceptive afferents: they discharged preferentially to slowly moving stimuli at a neutral (typical skin) temperature, rather than at the cooler or warmer stimulus temperatures. In contrast, myelinated hair mechanoreceptive afferents proportionally increased their firing frequency with stroking velocity and showed no temperature modulation. Furthermore, the CT firing frequency correlated with hedonic ratings to the same mechano-thermal stimulus only at the neutral stimulus temperature, where the stimuli were felt as pleasant at higher firing rates. We conclude that CT afferents are tuned to respond to tactile stimuli with the specific characteristics of a gentle caress delivered at typical skin temperature. This provides a peripheral mechanism for signaling pleasant skin-to-skin contact in humans, which promotes interpersonal touch and affiliative behavior.

8 for the iStent inject Study Group* Purpose: Evaluate the safety and effectiveness of an ab interno implanted (iStent inject) Trabecular Micro-Bypass System (Glaukos Corporation, San Clemente, CA) in combination with cataract surgery in subjects with mild to moderate primary open-angle glaucoma (POAG). Design: Prospective, randomized, single-masked, concurrently controlled, multicenter clinical trial. Participants: Eyes with mild to moderate POAG and preoperative intraocular pressure (IOP) 24 mmHg on 1 to 3 medications, unmedicated diurnal IOP (DIOP) 21 to 36 mmHg, and cataract requiring surgery. Methods: After uncomplicated cataract surgery, eyes were randomized 3:1 intraoperatively to ab interno implantation of iStent inject (Model G2-M-IS; treatment group, n ¼ 387) or no stent implantation (control group, n ¼ 118). Subjects were followed through 2 years postoperatively. Annual washout of ocular hypotensive medication was performed. Main Outcome Measures: Effectiveness end points were !20% reduction from baseline in month 24 unmedicated DIOP and change in unmedicated month 24 DIOP from baseline. Safety measures included best spectacle-corrected visual acuity (BSCVA), slit-lamp and fundus examinations, gonioscopy, pachymetry, specular microscopy, visual fields, complications, and adverse events. Results: The groups were well balanced preoperatively, including medicated IOP (17.5 mmHg in both groups) and unmedicated DIOP (24.8AE3.3 mmHg vs. 24.5AE3.1 mmHg in the treatment and control groups, respectively, P ¼ 0.33). At 24 months, 75.8% of treatment eyes versus 61.9% of control eyes experienced !20% reduction from baseline in unmedicated DIOP (P ¼ 0.005), and mean reduction in unmedicated DIOP from baseline was greater in treatment eyes (7.0AE4.0 mmHg) than in control eyes (5.4AE3.7 mmHg; P < 0.001). Of the responders, 84% of treatment eyes and 67% of control eyes were not receiving ocular hypotensive medication at 23 months. Furthermore, 63.2% of treatment eyes versus 50.0% of control eyes had month 24 medication-free DIOP 18 mmHg (difference 13.2%; 95% confidence interval, 2.9e23.4). The overall safety profile of the treatment group was favorable and similar to that in the control group throughout the 2-year follow-up. Conclusions: Clinically and statistically greater reductions in IOP without medication were achieved after iStent inject implantation with cataract surgery versus cataract surgery alone, with excellent safety through 2 years.

We used a "current signature" method to subclassify acutely dissociated dorsal root ganglion (DRG) cells into nine subgroups. Cells subclassified by current signature had uniform properties. The type 1 cell had moderate capsaicin sensitivity (25.9 pA/pF), powerful, slowly desensitizing (tau = 2,300 ms), ATP-activated current (13.3 pA/pF), and small nondesensitizing responses to acidic solutions (5.6 pA/pF). Type 1 cells expressed calcitonin gene-related peptide immunoreactivity (CGRP-IR), manifested a wide action potential (7.3 ms), long duration afterhyperpolarization (57.0 ms), and were IB4 positive. The type 2 cell exhibited large capsaicin activated currents (134.9 pA/pF) but weak nondesensitizing responses to protons (15.3 pA/pF). Currents activated by ATP and alphabeta-m-ATP (51.7 and 44.6 pA/pF, respectively) had fast desensitization kinetics (tau = 214 ms) that were distinct from all other cell types. Type 2 cells were IB4 positive but did not contain either substance P (SP) or CGRP-IR. Similar to capsaicin-sensitive nociceptors in vivo, the afterhyperpolarization of the type 2 cell was prolonged (54.7 ms). The type 3 cell expressed, amiloride-sensitive, rapidly desensitizing (tau = 683 ms) proton-activated currents (127.0 pA/pF), and was insensitive to ATP or capsaicin. The type 3 cell was IB4 negative and contained neither CGRP nor SP-IR. The afterhyperpolarization (17.5 ms) suggested nonnociceptive function. The type 4 cell had powerful ATP-activated currents (17.4 pA/pF) with slow desensitization kinetics (tau = 2, 813 ms). The afterhyperpolarization was prolonged (46.5 ms), suggesting that this cell type might belong to a capsaicin-insensitive nociceptor population. The type 4 cell did not contain peptides. The type 7 cell manifested amiloride-sensitive, proton-activated currents (45.8 pA/pF) with very fast desensitization kinetics (tau = 255 ms) and was further distinct from the type 3 cell by virtue of a nondesensitizing amiloride-insensitive component (6.0 pA/pF). Capsaicin and ATP sensitivity were relatively weak (4.3 and 2.9 pA/pF, respectively). Type 7 cells were IB4 positive and contained both SP and CGRP-IR. They exhibited an exceptionally long afterhyperpolarization (110 ms) that was suggestive of a silent (mechanically insensitive) nociceptor. We concluded that presorting of DRG cells by current signatures separated them into internally homogenous subpopulations that were distinct from other subclassified cell types.

Rationale Microglial activation in autonomic brain regions is a hallmark of neuroinflammation in neurogenic hypertension (HTN). Despite evidence that an impaired sympathetic nerve activity supplying the bone marrow (BM) increases inflammatory cells and decreases angiogenic cells, little is known about the reciprocal impact of BM-derived inflammatory cells on neuroinflammation in HTN. Objective Test the hypothesis that pro-inflammatory BM cells from hypertensive animals contribute to neuroinflammation and HTN via a brain-BM interaction. Methods and Results Following BM ablation in spontaneously hypertensive rats (SHR), and reconstitution with normotensive Wistar-Kyoto (WKY) rat BM, the resultant chimeric SHR displayed significant reduction in mean arterial pressure (MAP) associated with attenuation of both central and peripheral inflammation. In contrast, an elevated MAP along with increased central and peripheral inflammation was observed in chimeric WKY rats reconstituted with SHR BM. Oral treatment with minocycline, an inhibitor of microglial activation, attenuated HTN in both the SHR and chronic angiotensin II (Ang II)-infused rats. This was accompanied by decreased sympathetic drive and inflammation. Furthermore, in chronic Ang II-infused rats, minocycline prevented extravasation of BM-derived cells to the hypothalamic paraventricular nucleus (PVN), presumably via a mechanism of decreased C-C chemokine ligand 2 levels in the cerebrospinal fluid. Conclusions The BM contributes to HTN by increasing peripheral inflammatory cells and their extravasation into the brain. Minocycline is an effective therapy to modify neurogenic components of HTN. These observations support the hypothesis that BM-derived cells are involved in neuroinflammation, and targeting them may be an innovative strategy for neurogenic resistant HTN therapy.

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Study Design: Secure, web-based survey. Objectives: Obtain information from the spinal cord injured (SCI) population regarding sexual dysfunctions, with the aim of developing new basic science and clinical research and eventual therapies targeting these issues. Setting: Worldwide web. Methods: Individuals 18 years or older living with SCI. Participants obtained a pass-code to enter a secure website and answered survey questions. A total of 286 subjects completed the survey. Results: The majority of participants stated that their SCI altered their sexual sense of self and that improving their sexual function would improve their quality of life (QoL). The primary reason for pursuing sexual activity was for intimacy need, not fertility. Bladder and bowel concerns during sexual activity were not strong enough to deter the majority of the population from engaging in sexual activity. However, in the subset of individuals concerned about bladder and/or bowel incontinence during sexual activity, this was a highly significant issue. In addition, the occurrence of autonomic dysreflexia (AD) during typical bladder or bowel care was a significant variable predicting the occurrence and distress of AD during sexual activity. Conclusion: Sexual function and its resultant impact on QoL is a major issue to an overwhelming majority of people living with SCI. This certainly constitutes the need for expanding research in multiple aspects to develop future therapeutic interventions for sexual health and SCI.

Study design: Secure, web-based survey. Objectives: Elicit specific information about sexual function from men with spinal cord injuries (SCI). Setting: World-wide web. Methods: Individuals 18 years or older living with SCI obtained a pass-code to enter a secure website and then answered survey questions. Results: The presence of genital sensation was positively correlated with the ability to feel a build up of sexual tension in the body during sexual stimulation and in the feeling that mental arousal translates to the genitals as physical sensation. There was an inverse relationship between developing new areas of arousal above the level of lesion and not having sensation or movement below the lesion. A positive relationship existed between the occurrence of spasticity during sexual activity and erectile ability. Roughly 60% of the subjects had tried some type of erection enhancing method. Only 48% had successfully achieved ejaculation postinjury and the most commonly used methods were hand stimulation, sexual intercourse, and vibrostimulation. The most commonly cited reasons for trying to ejaculate were for pleasure and for sexual intimacy. Less than half reported having experienced orgasm postinjury and this was influenced by the length of time postinjury and sacral sparing. Conclusion: SCI not only impairs male erectile function and ejaculatory ability, but also alters sexual arousal in a manner suggestive of neuroplasticity. More research needs to be pursued in a manner encompassing all aspects of sexual function.