Among numerous challenges encountered at the beginning of extrauterine life, the most celebrated is the first breath that initiates a life-sustaining motor activity 1 . The neural systems that regulate breathing are fragile early in development, and how they adjust to support breathing at the time of birth is not well understood. Here, we identify a neuropeptide system that becomes activated immediately upon birth and supports breathing. Mice lacking pituitary adenylate cyclase-activating peptide (PACAP) selectively in retrotrapezoid nucleus (RTN) neurons displayed increased apneas and blunted CO 2 -stimulated breathing; re-expression of PACAP in RTN neurons corrected these breathing deficits. Deletion of the PACAP receptor, PAC1, from the pre-Bötzinger Complex (preBötC), an RTN target region responsible for respiratory rhythm generation, phenocopied breathing deficits observed with RTN deletion of PACAP, and suppressed PACAP-evoked respiratory stimulation in the preBötC. Notably, a striking postnatal burst of PACAP expression occurred in RTN neurons precisely at the time of birth, coinciding with exposure to the external environment. Neonatal mice with deletion of PACAP in RTN neurons displayed increased apneas that were further exacerbated by changes in ambient temperature. Our findings demonstrate that well-timed PACAP expression by RTN neurons provides an important supplementary respiratory drive immediately after birth, and reveal key molecular components of a peptidergic neural circuit that supports breathing at a particularly vulnerable period in life.
Signal transduction cascades initiated by G‐protein‐coupled receptors (GPCRs) integrate a number of components including seven‐pass transmembrane receptors (7TM), heterotrimeric G‐proteins, downstream protein kinases and responsive transcription factors. This signalling pathway has evolved to facilitate a number of cellular responses related to metabolism, cell proliferation, neurotransmission, DNA repair and many other critical processes. Gene duplication and subfunctionalisation events have contributed to the emergence of several core components of the GPCR signalling pathway over the course of eukaryotic evolutionary history. Four key components of this pathway include GPCRs, receptor‐associated heterotrimeric G‐proteins, downstream kinase targets, such as protein kinase A (PKA) and transcription factors such as cAMP response element binding protein (CREB). Key Concepts G‐protein‐coupled receptors (GPCRs) are seven‐pass transmembrane proteins, which have diversified into five main families over evolutionary time. Heterotrimeric G‐proteins transduce nuanced responses via different combinations of α, β and γ‐subunits, which have evolved from numerous well‐defined duplication events. Protein kinase A (PKA) is a downstream hub whose catalytic and regulatory subunits have diversified in eukaryotic lineages. The cAMP response element‐binding protein (CREB) function is highly conserved in eukaryotes while the auxiliary components of its pathway have changed.
Objectives: The objectives of the study were to compare the efficacy of injection atracurium 0.5 mg/kg intravenous (IV) versus injection cisatracurium 0.2 mg/kg IV for intubation in patients undergoing endoscopic retrograde cholangiopancreatography procedure (ERCP). Methods: Hundred adult patients of both sexes in the age group of 18–60 years belonging to the American Society of Anesthesiologists I/II category posted for ERCP procedures under general anesthesia were randomly allocated into two groups of 50 each. Group A received injection atracurium besylate 0.5 mg/kg intravenously and Group B received injection cisatracurium besylate 0.2 mg/kg intravenously. Parameters observed were time to the maximum blockade, intubating condition, time required for intubation, duration of action, hemodynamic parameters during intubation, and after 1, 2, 3, 5, and 15 min and any adverse effects. Results: Demographic profile was comparable between the groups. Intubating condition as per Cooper et al. score was excellent in 36 patients in cisatracurium group as compared to 19 patients in atracurium group. The overall intubating condition was found to be better in Group B (p=0.00001). Time to the maximum blockade was significantly high with atracurium as compared to cisatracurium. The mean of intubation time was less with cisatracurium (135±11.1) than that of atracurium (144±9.48) in seconds, which was statistically significant. Duration of neuromuscular blockade was found to be prolonged in Group B as compared to Group A (p=0.000). Hemodynamic parameters during intubation and after 1, 2, 3, 5, and 15 min were comparable between the groups. No adverse effect was seen in both groups. Conclusion: Cisatracurium 0.2 mg/kg provides excellent intubating conditions with rapid onset of action, longer duration of action, and no significant hemodynamic changes as compared with atracurium 0.5 mg/kg for ERCP procedures without any adverse effects.
The brainstem systems that regulate breathing are established prenatally but they remain immature and vulnerable to failure at the time of birth; this reflects, in part, underdevelopment of the respiratory chemosensory systems that typically monitor blood gases (O2, CO2) to regulate breathing. In the mouse retrotrapezoid nucleus (RTN), Phox2b‐expressing respiratory chemoreceptor neurons are a nexus for integration of multiple respiratory‐related inputs, homeostatically regulating blood gases by providing CO2‐modulated drive to brainstem respiratory rhythm generator and pre‐motor circuits. In this work, we demonstrate that postnatal expression of a neuropeptide in chemosensitive RTN neurons is precisely tuned to influence breathing at the time of birth. First, by using single cell qRT‐PCR and multiplex in situ hybridization, we define a striking postnatal burst of pituitary adenylate cyclase‐activating peptide (PACAP) expression in RTN neurons that is activated in neonates within minutes of exposure to the external environment. Further, by using whole body plethysmography, we show that mouse pups (P2‐P12) lacking PACAP in Phox2b neurons (Phox2b::Cre;PACAPfl/fl) have severely blunted CO2‐stimulated ventilation (reduced by >50%) and a striking ~3‐fold greater incidence of apneic episodes. PACAP expression in RTN neurons persists into adulthood, albeit at apparently lower levels. PACAP deletion/depletion in adult RTN neurons (in Phox2b::Cre;PACAPfl/fl mice or by shRNA‐mediated knockdown) also depresses CO2‐regulated breathing (by ~30–40%) and increases apneas (~3‐fold), while viral‐mediated re‐expression of PACAP in RTN neurons corrects these deficits. After PACAP knockdown in RTN, CO2‐dependent Fos expression was retained in RTN neurons but decreased in cells of the preBötzinger complex (preBötC), which contains respiratory rhythm‐generating neurons targeted by the RTN. Consistent with the preBötC as a site of action for RTN‐derived PACAP, we show that: 1) the PACAP receptor, PAC1, is expressed in preBötC; 2) PACAP injection directly into the preBötC stimulated central respiratory output, both in vitro and in vivo; and 3) shRNA‐mediated depletion of PAC1 in the preBötC phenocopied breathing deficits observed with RTN deletion of PACAP. Notably, PACAP variants are associated with sudden infant death syndrome (SIDS), and with a SIDS‐like phenotype in PACAP‐null mice. Collectively, these data demonstrate that well‐timed PACAP expression by RTN neurons protects the developmentally immature respiratory control system from hypoventilation and potentially dangerous apneas at birth, and identifies key molecular components of a circuit that supports breathing at this particularly vulnerable period in life. Support or Funding Information R01 HL108609; R01 HL074011
Background: Chronic kidney disease (CKD) is a progressive loss in renal function which involves in deterioration in mineral homeostasis with disruption of normal serum and tissue concentration of phosphorus and calcium. Also changes in circulating levels of hormonesparathyroid hormone (PTH), calcitriol (1,25(OH)2 D), and fibroblast growth factor-23 (FGF-23). Here our aim is to study the prevalence of markers associated with MBD in CKD stage 3-5 patients. Patients with CKD stage 3-5 were included in this observational study with all necessary parameter. X-RAY abdomen and echocardiography was done to look for evidence of vascular and valvular calcification respectively. Statistical analysis was done using SPSS software. A total of 170 patients (128 males, 42 females) (M:F = 3:1) were included in this study with a mean age of 50.54 years. Among CKD stages 3 to 5, the prevalence of hypocalcemia was 22.2%, 33.3% & 48.9%, hyperphosphatemia was 11.1%, 25.5% & 63%, hyperparathyroidism was 48.1%, 67.3% & 89.1%, high total alkaline phosphatase was 0%, 5.9% & 45.7% , low 25-OH-vit D was 59.2%, 70.6% & 79.4% respectively. Low 25 (OH) D levels, hyperparathyroidism, and hyperphosphatemia were the noticeable markers of CKD-MBD in our patients. Mineral bone disorder are common in CKD patients which start in early CKD stages & worsen with disease progression that causes morbidity and decreased quality of life.
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