BackgroundThe World Health Organization increased the number of antenatal care (ANC) visits from ... more BackgroundThe World Health Organization increased the number of antenatal care (ANC) visits from Four (4) to Eight (8) visits or more, to reduce the exponentiated incidences of preventable deaths of newborns, maternal mortality, perinatal, and stillbirths. Unfortunately, previous studies have indicated that pregnant women are noncompliant and nonadherence to the number of antenatal visits recommended by WHO. Therefore, the study measured the level of acceptability of the Eight (8) antenatal care contacts and determined the predictors’ variable that influenced compliance to 8-ANC visit in women attending ANC in the Wakiso district.MethodologyThis was a hospital-based medical records observational-cross-section study design, that used a multi-stage-stratified sampling technique to collect data from eligible women, Antenatal Progressive examination cards, and ANC registers, after obtaining ethical approval. A questionnaire survey and checklist were used to collect the data on the accep...
We demonstrate how nanojunctions between lysosomes and sarcoplasmic reticulum (L-SR junctions) se... more We demonstrate how nanojunctions between lysosomes and sarcoplasmic reticulum (L-SR junctions) serve to couple lysosomal activation to regenerative, ryanodine receptor-mediated cellular calcium (Ca2+) waves. In pulmonary artery smooth muscle cells (PASMCs) nicotinic acid adenine dinucleotide phosphate (NAADP) may trigger increases in cytoplasmic Ca2+ via L-SR junctions, in a manner that requires initial Ca2+ release from lysosomes and subsequent Ca2+-induced Ca2+ release (CICR) via ryanodine receptor (RyR) subtype 3 on the SR membrane proximal to lysosomes. L-SR junction membrane separation has been estimated to be <400 nm and thus beyond the resolution of light microscopy. This study utilizes transmission electron microscopy to provide a thorough ultrastructural characterization of the L-SR junctions in PASMCs. These junctions are prominent features in these cells and we estimate that the membrane separation and extension are about 15 nm and 300 nm, respectively. We also develop...
We recently demonstrated that the role of the AMP-activated protein kinase (AMPK), a ubiquitously... more We recently demonstrated that the role of the AMP-activated protein kinase (AMPK), a ubiquitously expressed enzyme that governs cell-autonomous metabolic homeostasis, has been extended to system-level control of breathing and thus oxygen and energy (ATP) supply to the body. Here we assess the contribution to the hypoxic ventilatory response (HVR) of two upstream kinases that govern the activities of AMPK. Lkb1, which activates AMPK in response to metabolic stress and CaMKK2 which mediates the alternative Ca2+ dependent mechanism of AMPK activation. HVRs remained unaffected in mice with global deletion of the CaMKK2 gene. By contrast, HVRs were markedly attenuated in mice with conditional deletion of LKB1 in catecholaminergic cells, including carotid body type I cells and brainstem respiratory networks. In these mice hypoxia evoked hypoventilation, apnoea and Cheyne-Stokes-like breathing, rather than hyperventilation. Attenuation of HVRs, albeit less severe, was also conferred in mic...
Two-pore segment channel 2 (TPC2) is a ubiquitously expressed, lysosomally targeted ion channel t... more Two-pore segment channel 2 (TPC2) is a ubiquitously expressed, lysosomally targeted ion channel that aids in terminating autophagy and is inhibited upon its association with mechanistic target of rapamycin (mTOR). It is controversial whether TPC2 mediates lysosomal Ca release or selectively conducts Na and whether the binding of nicotinic acid adenine dinucleotide phosphate (NAADP) or phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] is required for the activity of this ion channel. We show that TPC2 is required for intracellular Ca signaling in response to NAADP or to mTOR inhibition by rapamycin. In pulmonary arterial myocytes, rapamycin and NAADP evoked global Ca transients that were blocked by depletion of lysosomal Ca stores. Preincubation of cells with high concentrations of rapamycin resulted in desensitization and blocked NAADP-evoked Ca signals. Moreover, rapamycin and NAADP did not evoke discernable Ca transients in myocytes derived from knockout mice, which showed normal r...
American journal of respiratory and critical care medicine, May 15, 2015
Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, fo... more Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, yet the precise molecular mechanisms remain controversial. Among those genes influenced by natural selection in high-altitude populations is that for the AMP-activated protein kinase (AMPK) α1 catalytic subunit, which governs cell autonomous adaptations during metabolic stress. We investigated whether or not AMPK-α1 and/or AMPK-α2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency. Experiments utilized plethysmography, electrophysiology, functional magnetic resonance imaging and immediate early gene (cfos) expression to assess the hypoxic ventilatory response of mice with conditional deletion of the AMPK-α1 and/or AMPK-α2 genes in catecholaminergic cells, which comprise the hypoxia-responsive respiratory network from carotid body to brainstem. AMPK-α1+α2 deletion virtually a...
Advances in experimental medicine and biology, 2015
Perhaps the defining characteristic of pulmonary arteries is the process of hypoxic pulmonary vas... more Perhaps the defining characteristic of pulmonary arteries is the process of hypoxic pulmonary vasoconstriction (HPV) which, under physiological conditions, supports ventilation-perfusion matching in the lung by diverting blood flow away from oxygen deprived areas of the lung to oxygen rich regions. However, when alveolar hypoxia is more widespread, either at altitude or with disease (e.g., cystic fibrosis), HPV may lead to hypoxic pulmonary hypertension. HPV is driven by the intrinsic response to hypoxia of pulmonary arterial smooth muscle and endothelial cells, which are acutely sensitive to relatively small changes in pO2 and have evolved to monitor oxygen supply and thus address ventilation-perfusion mismatch. There is now a consensus that the inhibition by hypoxia of mitochondrial oxidative phosphorylation represents a key step towards the induction of HPV, but the precise nature of the signalling pathway(s) engaged thereafter remains open to debate. We will consider the role of...
Vital homeostatic mechanisms monitor O2 supply and adjust respiratory and circulatory function to... more Vital homeostatic mechanisms monitor O2 supply and adjust respiratory and circulatory function to meet demand. The pulmonary arteries and carotid bodies are key systems in this respect. Hypoxic pulmonary vasoconstriction (HPV) aids ventilation−perfusion matching in the lung by diverting blood flow from areas with an O2 deficit to those rich in O2, while a fall in arterial pO2 increases sensory
BackgroundThe World Health Organization increased the number of antenatal care (ANC) visits from ... more BackgroundThe World Health Organization increased the number of antenatal care (ANC) visits from Four (4) to Eight (8) visits or more, to reduce the exponentiated incidences of preventable deaths of newborns, maternal mortality, perinatal, and stillbirths. Unfortunately, previous studies have indicated that pregnant women are noncompliant and nonadherence to the number of antenatal visits recommended by WHO. Therefore, the study measured the level of acceptability of the Eight (8) antenatal care contacts and determined the predictors’ variable that influenced compliance to 8-ANC visit in women attending ANC in the Wakiso district.MethodologyThis was a hospital-based medical records observational-cross-section study design, that used a multi-stage-stratified sampling technique to collect data from eligible women, Antenatal Progressive examination cards, and ANC registers, after obtaining ethical approval. A questionnaire survey and checklist were used to collect the data on the accep...
We demonstrate how nanojunctions between lysosomes and sarcoplasmic reticulum (L-SR junctions) se... more We demonstrate how nanojunctions between lysosomes and sarcoplasmic reticulum (L-SR junctions) serve to couple lysosomal activation to regenerative, ryanodine receptor-mediated cellular calcium (Ca2+) waves. In pulmonary artery smooth muscle cells (PASMCs) nicotinic acid adenine dinucleotide phosphate (NAADP) may trigger increases in cytoplasmic Ca2+ via L-SR junctions, in a manner that requires initial Ca2+ release from lysosomes and subsequent Ca2+-induced Ca2+ release (CICR) via ryanodine receptor (RyR) subtype 3 on the SR membrane proximal to lysosomes. L-SR junction membrane separation has been estimated to be <400 nm and thus beyond the resolution of light microscopy. This study utilizes transmission electron microscopy to provide a thorough ultrastructural characterization of the L-SR junctions in PASMCs. These junctions are prominent features in these cells and we estimate that the membrane separation and extension are about 15 nm and 300 nm, respectively. We also develop...
We recently demonstrated that the role of the AMP-activated protein kinase (AMPK), a ubiquitously... more We recently demonstrated that the role of the AMP-activated protein kinase (AMPK), a ubiquitously expressed enzyme that governs cell-autonomous metabolic homeostasis, has been extended to system-level control of breathing and thus oxygen and energy (ATP) supply to the body. Here we assess the contribution to the hypoxic ventilatory response (HVR) of two upstream kinases that govern the activities of AMPK. Lkb1, which activates AMPK in response to metabolic stress and CaMKK2 which mediates the alternative Ca2+ dependent mechanism of AMPK activation. HVRs remained unaffected in mice with global deletion of the CaMKK2 gene. By contrast, HVRs were markedly attenuated in mice with conditional deletion of LKB1 in catecholaminergic cells, including carotid body type I cells and brainstem respiratory networks. In these mice hypoxia evoked hypoventilation, apnoea and Cheyne-Stokes-like breathing, rather than hyperventilation. Attenuation of HVRs, albeit less severe, was also conferred in mic...
Two-pore segment channel 2 (TPC2) is a ubiquitously expressed, lysosomally targeted ion channel t... more Two-pore segment channel 2 (TPC2) is a ubiquitously expressed, lysosomally targeted ion channel that aids in terminating autophagy and is inhibited upon its association with mechanistic target of rapamycin (mTOR). It is controversial whether TPC2 mediates lysosomal Ca release or selectively conducts Na and whether the binding of nicotinic acid adenine dinucleotide phosphate (NAADP) or phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] is required for the activity of this ion channel. We show that TPC2 is required for intracellular Ca signaling in response to NAADP or to mTOR inhibition by rapamycin. In pulmonary arterial myocytes, rapamycin and NAADP evoked global Ca transients that were blocked by depletion of lysosomal Ca stores. Preincubation of cells with high concentrations of rapamycin resulted in desensitization and blocked NAADP-evoked Ca signals. Moreover, rapamycin and NAADP did not evoke discernable Ca transients in myocytes derived from knockout mice, which showed normal r...
American journal of respiratory and critical care medicine, May 15, 2015
Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, fo... more Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, yet the precise molecular mechanisms remain controversial. Among those genes influenced by natural selection in high-altitude populations is that for the AMP-activated protein kinase (AMPK) α1 catalytic subunit, which governs cell autonomous adaptations during metabolic stress. We investigated whether or not AMPK-α1 and/or AMPK-α2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency. Experiments utilized plethysmography, electrophysiology, functional magnetic resonance imaging and immediate early gene (cfos) expression to assess the hypoxic ventilatory response of mice with conditional deletion of the AMPK-α1 and/or AMPK-α2 genes in catecholaminergic cells, which comprise the hypoxia-responsive respiratory network from carotid body to brainstem. AMPK-α1+α2 deletion virtually a...
Advances in experimental medicine and biology, 2015
Perhaps the defining characteristic of pulmonary arteries is the process of hypoxic pulmonary vas... more Perhaps the defining characteristic of pulmonary arteries is the process of hypoxic pulmonary vasoconstriction (HPV) which, under physiological conditions, supports ventilation-perfusion matching in the lung by diverting blood flow away from oxygen deprived areas of the lung to oxygen rich regions. However, when alveolar hypoxia is more widespread, either at altitude or with disease (e.g., cystic fibrosis), HPV may lead to hypoxic pulmonary hypertension. HPV is driven by the intrinsic response to hypoxia of pulmonary arterial smooth muscle and endothelial cells, which are acutely sensitive to relatively small changes in pO2 and have evolved to monitor oxygen supply and thus address ventilation-perfusion mismatch. There is now a consensus that the inhibition by hypoxia of mitochondrial oxidative phosphorylation represents a key step towards the induction of HPV, but the precise nature of the signalling pathway(s) engaged thereafter remains open to debate. We will consider the role of...
Vital homeostatic mechanisms monitor O2 supply and adjust respiratory and circulatory function to... more Vital homeostatic mechanisms monitor O2 supply and adjust respiratory and circulatory function to meet demand. The pulmonary arteries and carotid bodies are key systems in this respect. Hypoxic pulmonary vasoconstriction (HPV) aids ventilation−perfusion matching in the lung by diverting blood flow from areas with an O2 deficit to those rich in O2, while a fall in arterial pO2 increases sensory
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