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The American Heart Association/American Stroke Association released the adult stroke rehabilitation and recovery guidelines in 2016. A working group of stroke rehabilitation experts reviewed these guidelines and identified a subset of recommendations that were deemed suitable for creating performance measures. These 13 performance measures are reported here and contain inclusion and exclusion criteria to allow calculation of rates of compliance in a variety of settings ranging from acute hospital care to postacute care and care in the home and outpatient setting.

Advances in the development of innovative medical devices and telehealth technologies create the potential to improve the quality and efficiency of diabetes care through collecting, aggregating, and interpreting relevant health data in ways that facilitate more informed decisions among all stakeholder groups. Although many medical societies publish guidelines for utilizing these technologies in clinical practice, we believe that the methodologies used for the selection and grading of the evidence should be revised. In this article, we discuss the strengths and limitations of the various types of research commonly used for evidence selection and grading and present recommendations for modifying the process to more effectively address the rapid pace of device and technology innovation and new product development.

In June 2020, the Taskforce of the Guideline Workshop 2019 convened via teleconferencing to initiate a pilot project that demonstrates the various processes and considerations involved in developing high-quality, evidence-based clinical practice guidelines for the medical management of individuals with type 2 diabetes (T2D) and its associated comorbidities, including cardiovascular disease (CVD) and chronic kidney disease (CKD). The goal of the pilot project was to create evidence-based guidelines for use of sodium-glucose transport protein 2 inhibitors (SGLT2-I) when managing very high risk T2D patients, evidenced by the presence of both CVD and CKD. For this purpose the Taskforce represented a guideline panel and made use of synthesized evidence from an ongoing BMJ Rapid Recommendations project on SGLT2-I and GLP-1 receptor agonists. Results from the Taskforce pilot project demonstrated the value, feasibility and utility of using a step-wise approach to identifying and grading evidence and then developing actionable recommendations for utilizing SGLT2-I in this at-risk T2D population. This report describes the various steps involved in the process and explains how it can be utilized to rapidly develop recommendations in a format that is easy to use and can be quickly updated as new evidence becomes available, also within the emerging concept of living guidelines.

Chronic intermittent hypoxia (CIH) is a model of the hypoxemia from sleep apnea that causes a sustained increase in blood pressure. Inhibition of the central renin-angiotensin system or FosB in the median preoptic nucleus (MnPO) prevents the sustained hypertensive response to CIH. We tested the hypothesis that angiotensin type 1a (AT1a) receptors in the MnPO, which are upregulated by CIH, contribute to this hypertension. In preliminary experiments, retrograde tract tracing studies showed AT1a receptor expression in MnPO neurons projecting to the paraventricular nucleus. Adult male rats were exposed to 7 days of intermittent hypoxia (cycling between 21% and 10% O2 every 6 min, 8 h/day during light phase). Seven days of CIH was associated with a FosB-dependent increase in AT1a receptor mRNA without changes in the permeability of the blood-brain barrier in the MnPO. Separate groups of rats were injected in the MnPO with an adeno-associated virus containing short hairpin (sh)RNA against AT1a receptors to test their role in intermittent hypoxia hypertension. Injections of shRNA against AT1a in MnPO blocked the increase in mRNA associated with CIH, prevented the sustained component of the hypertension during normoxia, and reduced circulating advanced oxidation protein products, an indicator of oxidative stress. Rats injected with shRNA against AT1a and exposed to CIH had less FosB staining in MnPO and the rostral ventrolateral medulla after intermittent hypoxia than rats injected with the control vector that were exposed to CIH. Our results indicate AT1a receptors in the MnPO contribute to the sustained blood pressure increase to intermittent hypoxia.

Sustained hypertension is an important consequence of obstructive sleep apnea. An animal model of the hypoxemia associated with sleep apnea, chronic intermittent hypoxia (CIH), produces increased sympathetic nerve activity (SNA) and sustained increases in blood pressure. Many mechanisms have been implicated in the hypertension associated with CIH, including the role of ΔFosB within the median preoptic nucleus (MnPO). Also, the renin-angiotensin system (RAS) has been associated with CIH hypertension. We conducted experiments to determine the possible association of FosB/ΔFosB with a RAS component, angiotensin-converting enzyme 1 (ACE1), within the MnPO following 7 days of CIH. Retrograde tract tracing from the paraventricular nucleus (PVN), a downstream region of the MnPO, was used to establish a potential pathway for FosB/ΔFosB activation of MnPO ACE1 neurons. After CIH, ACE1 cells with FosB/ΔFosB expression increased colocalization with a retrograde tracer that was injected unilaterally within the PVN. Also, Western blot examination showed ACE1 protein expression increasing within the MnPO following CIH. Chromatin immunoprecipitation (ChIP) assays demonstrated an increase in FosB/ΔFosB association with the ACE1 gene within the MnPO following CIH. FosB/ΔFosB may transcriptionally target ACE1 within the MnPO following CIH to affect the downstream PVN region, which may influence SNA and blood pressure.

Neuropeptide Y (NPY) Y1 receptors are implicated in CNS regulation of food intake, but their role in hypoglycemic hyperphagia remains unclear. The present studies utilized a pharmacological approach to investigate the hypothesis that NPY acts via Y1 receptor-dependent mechanisms to regulate feeding and blood glucose profiles during intermediate insulin-induced hypoglycemia. Groups of ovariectomized, estradiol benzoate-treated female rats were injected subcutaneously with one or four doses of neutral protamine Hagedorn insulin (NPH), on as many days, or with diluent alone. Before final treatments on day four, the animals were pretreated by intracerebroventricular ( icv ) delivery of the NPY Y1 receptor antagonist, 1229U91, or the vehicle, artificial cerebrospinal fluid (acsf). Food intake during acute hypoglycemia was significantly diminished between t o and + 2 h in animals pretreated with the Y1 receptor antagonist versus vehicle. Administration of 1229U91 prior to the fourth of four NPH doses suppressed hypoglycemic hyperphagia over a relatively longer interval, e.g. 4 h, after t o relative to the acute insulin group. Blood glucose levels after a single NPH injection were similar in acsf- and antagonist-pretreated rats at + 2, + 4, and + 6 h, but were lower at + 9 h in the latter group. Pretreatment with 1229U91 did not modify glucose profiles between + 2 and + 9 h after multiple dosing with NPH, but prevented recovery from hypoglycemia at + 12 h. The present results show that central NPY Y1 receptor antagonism inhibits hypoglycemic hyperphagia, and that this suppressive effect on feeding was of greater duration during recurring hypoglycemia. The data also show that Y1 receptor blockade decreases glycemic responses to both single and serial NPH dosing, albeit at different post-injection time points. The current studies support the view that NPY Y1 receptors function within central neural pathways that govern feeding and glycemic responses to intermediate-acting insulin, and that Y1 receptor-mediated stimulation of food intake may habituate in a positive manner to repetitive insulin-induced hypoglycemia. Further research is needed to evaluate the impact of chronic insulin-induced hypoglycemia on neuropeptide Y neurotransmission and Y1 receptor expression within regulatory circuitries that control food intake and glucostasis.

Diabetes in Mexican Americans is a major cause of morbidity and mortality. Older Mexican Americans experience higher rates of depression than other groups and are especially susceptible to comorbid...

Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures ( P < 0.05). During the normoxic dark phase in the CIH groups, only the SCM-injected group exhibited a sustained increase in MAP ( P < 0.05). The AT1aR-CIH group showed significant decreases in FosB/ΔFosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/ΔFosB expression in forebrain autonomic nuclei associated with CIH.

Transient receptor potential vanilloid family type 4 (TRPV4) channels are expressed in central neuroendocrine neurons and have been shown to be polymodal in other systems. We previously reported that in the rodent, a model of dilutional hyponatremia associated with hepatic cirrhosis, TRPV4 expression is increased in lipid rafts from the hypothalamus and that this effect may be angiotensin dependent. In this study, we utilized the immortalized neuroendocrine rat hypothalamic 4B cell line to more directly test the effects of angiotensin II (ANG II) on TRPV4 expression and function. Our results demonstrate the expression of corticotropin-releasing factor (CRF) transcripts, for sex-determining region Y (SRY) (male genotype), arginine vasopressin (AVP), TRPV4, and ANG II type 1a and 1b receptor in 4B cells. After a 1-h incubation in ANG II (100 nM), 4B cells showed increased TRPV4 abundance in the plasma membrane fraction, and this effect was prevented by the ANG II type 1 receptor antagonist losartan (1 μM) and by a Src kinase inhibitor PP2 (10 μM). Ratiometric calcium imaging experiments demonstrated that ANG II incubation potentiated TRPV4 agonist (GSK 1016790A, 20 nM)-induced calcium influx (control 18.4 ± 2.8% n = 5 and ANG II 80.5 ± 2.4% n = 5). This ANG II-induced increase in calcium influx was also blocked by 1 μM losartan and 10 μM PP2 (losartan 26.4 ± 3.8% n = 5 and PP2 19.7 ± 3.9% n = 5). Our data suggests that ANG II can increase TRPV4 channel membrane expression in 4B cells through its action on AT1R involving a Src kinase pathway.

Bile duct ligation (BDL) causes congestive liver failure that initiates hemodynamic changes, resulting in dilutional hyponatremia due to increased water intake and vasopressin release. This project tested the hypothesis that angiotensin signaling at the subfornical organ (SFO) augments drinking behavior in BDL rats. A genetically modified adeno-associated virus containing short hairpin RNA (shRNA) for ANG II receptor subtype 1a (AT1aR) gene was microinjected into the SFO of rats to knock down expression. Two weeks later, BDL or sham surgery was performed. Rats were housed in metabolic chambers for measurement of fluid and food intake and urine output. The rats were euthanized 28 days after BDL surgery for analysis. A group of rats was perfused for immunohistochemistry, and a second group was used for laser-capture microdissection for analysis of SFO AT1aR gene expression. BDL rats showed increased water intake that was attenuated in rats that received SFO microinjection of AT1aR shRNA. Among BDL rats treated with scrambled (control) and AT1aR shRNA, we observed an increased number of vasopressin-positive cells in the supraoptic nucleus that colocalized with ΔFosB staining, suggesting increased vasopressin release in both groups. These results indicate that angiotensin signaling through the SFO contributes to increased water intake, but not dilutional hyponatremia, during congestive liver failure.

Sleep apnea is a major risk to public health due to its close association with metabolic diseases. Exposure of rats to our 7 days of CIH protocol during their nocturnal period mimics repetitive bou...

Chronic Intermittent Hypoxia (CIH) is a model for the arterial hypoxemia seen in sleep apnea and is associated with a sustained increase in blood pressure throughout the diurnal cycle. Studies indi...

Transient receptor potential canonical subtype 4 (TRPC4) is expressed in the magnocellular paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. In this study, the regulation of TRPC4 expression was investigated in water deprivation and hepatic cirrhosis. We used laser capture microdissection technique for precise dissection of pure AVP cell population in the PVN and SON followed by quantitative real-time RT-PCR, and immunodetection techniques by Western blot analysis and immunofluorescence. Bile duct ligation elevated TRPC4 transcripts in the SON but not PVN with correlated changes in the protein expression in these regions, as well as increased colocalization with AVP in the SON, with no changes in the PVN. Water deprivation resulted in increased TRPC4 mRNA expression in the PVN, while it decreased channel expression levels in the SON. In both of these regions, protein expression measured from tissue punches were unaltered following water deprivation, with no changes in the number of TRPC4-positive cells. Thus, TRPC4 expression is differentially regulated in physiological and pathophysiological models of vasopressin release.

Chronic intermittent hypoxia (CIH) increases mean arterial pressure (MAP) and FosB/ΔFosB staining in central autonomic nuclei. To test the role of the brain renin-angiotensin system (RAS) in CIH hypertension, rats were implanted with intracerebroventricular (icv) cannulae delivering losartan (1 μg/h) or vehicle (VEH) via miniosmotic pumps and telemetry devices for arterial pressure recording. A third group was given the same dose of losartan subcutaneously (sc). Two groups of losartan-treated rats served as normoxic controls. Rats were exposed to CIH or normoxia for 7 days and then euthanized for immunohistochemistry. Intracerebroventricular losartan attenuated CIH-induced increases in arterial pressure during CIH exposure (0800-1600 during the light phase) on days 1, 6, and 7 and each day during the normoxic dark phase. FosB/ΔFosB staining in the organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO), paraventricular nucleus of the hypothalamus (PVN), the rostral ventrolateral medulla (RVLM), and the nucleus of the solitary tract (NTS) was decreased in icv losartan-treated rats. Subcutaneous losartan also reduced CIH hypertension during the last 2 days of CIH and produced bradycardia prior to the effect on blood pressure. Following sc losartan, FosB/ΔFosB staining was reduced only in the OVLT, MnPO, PVN, and NTS. These data indicate that the central and peripheral RAS contribute to CIH-induced hypertension and transcriptional activation of autonomic nuclei and that the contribution of the central RAS is greater during the normoxic dark phase of CIH hypertension.

Background: Repeated intermediate-acting insulin administration attenuates genomic reactivity of neurons in key autonomic metabolic structures in the male, but not female rat brain – results that support a central neural component of sex-specific response desensitization. The glucokinase (GK) enzyme functions as a glucose sensor in a body-wide system of metabolic monitoring structures, including the brain, and is expressed at high levels in the hypothalamic arcuate nucleus (ARH). Method: Quantitative real-time RT-PCR was used to investigate the hypothesis that habituation of ARH GK gene expression to neutral protamine Hagedorn insulin (NPH) injection differs among sexes. In lieu of evidence for region-based functional heterogeneity in this structure, effects of NPH on in situ GK protein-staining patterns were evaluated at different rostrocaudal levels of the ARH by immunocytochemistry. Results: Basal ARH GK mRNA levels were equivalent in sham-operated (SHAM) and orchidectomized (ORDX) male rats. SHAM males exhibited augmented GK gene profiles in response to acute NPH injection, as well as elevated numbers of GK-immunoreactive (-ir) neurons in the rostral ARH. ORDX abolished this stimulatory transcriptional response, but did not prevent increased GK labeling throughout this structure. Stimulatory effects of precedent insulin administration on baseline GK mRNA were reversed by ORDX. Serial dosing of SHAM males with NPH elicited no change in ARH GK transcription, but decreased GK-ir in the rostral ARH. Acute NPH injection had no impact on GK gene profiles in estradiol benzoate (EB)- or oil-implanted ovariectomized (OVX) female rats, but diminished GK-ir cell counts in the OVX + EB caudal ARH. Precedent NPH treatment did not modify baseline GK mRNA levels in either group of females, but resulted in decreased or elevated GK gene and protein expression during recurring injection in the presence or absence of EB, respectively. Conclusion: These results provide novel evidence for sex-specific patterns of acclimation of GK mRNA and protein expression within the rat ARH to serial NPH injection, and support the need to elucidate the physiological ramifications of these adaptations regarding behavioral and physiological responses to recurring intermediate insulin administration.

The ovarian steroid hormone, estradiol, is one of several peripheral metabolic signal modulators that are integrated at the level of the arcuate nucleus of the hypothalamus (ARH), and is implicated in the control of ARH neuropeptides that maintain energy balance, including neuropeptide Y (NPY) and proopiomelanocortin (POMC). The present studies utilized quantitative real-time RT-PCR techniques to examine the hypothesis that estradiol regulates ARH NPY, POMC, and cocaine- and amphetamine-related transcript (CART) gene expression during acute insulin-induced hypoglycemia (IIH) and that adaptive modifications in transcriptional reactivity during recurring exposure are steroid dependent. ARH tissue was obtained by micropunch dissection from estradiol benzoate- and oil-implanted ovariectomized (OVX) rats that were treated by subcutaneous injection of one or four doses of the intermediate insulin formulation, Humulin NPH, over as many days, or vehicle alone. Our data show that in OVX plus estradiol benzoate and OVX plus oil groups, a single injection of insulin did not modify gene expression profiles, with the exception of acute hypoglycemic reduction of ARH NPY transcripts in the presence of estrogen. Prior exposure to daily hypoglycemia significantly diminished basal NPY and POMC mRNA levels in estradiol benzoate-, but not oil-implanted OVX rats, but elevated baseline CART transcripts in oil-treated animals. Recurring IIH enhanced ARH NPY gene expression relative to baseline, irrespective of the estradiol manipulation, but net tissue levels were greater in the absence of estrogen. In contrast, reexposure to hypoglycemia decreased POMC and CART gene transcription in estradiol benzoate- and oil-implanted OVX animals, respectively, relative to the single-dose groups. These studies show that estrogen modulates the impact of precedent exposure to IIH on basal and/or hypoglycemia-associated patterns of expression of ARH neuropeptide genes of characterized significance for energy homeostasis. The novel evidence for transcriptional acclimation of NPY, POMC, and CART to recurring IIH supports the possibility that adaptation of compensatory behavioral and physiological responses to acute versus chronic exposure to this metabolic stress may reflect neural regulatory mechanisms involving one or more neurotransmitters encoded by these genes.