Somlyo, Andrew P., and Avril V. Somlyo. Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase. Physiol Rev 83: 1325-1358, 2003; 10.1152...

https://www.physiology.org/doi/pdf/10.1152/physrev.00023.2003

Ca2+ Sensitivity of Smooth Muscle and Nonmuscle Myosin II: Modulated by G Proteins, Kinases, and Myosin Phosphatase

Contraction of smooth muscle is regulated by the cytosolic Ca2+ level ([Ca2+]i)b, and the sensitivity to Ca2+ of the contractile elements in response to changes in the environment surrounding the cell. The first sequence of events in regulation includes the binding of endogenous substances, such as

/pdf/calcium-movements-distribution-and-functions-in-smooth-3zozpe9uj6.pdf

Calcium Movements, Distribution, and Functions in Smooth Muscle

cGMP is a second messenger that produces its effects by interacting with intracellular receptor proteins. In smooth muscle cells, one of the major receptors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG). PKG has been shown to catalyze the phosphorylation of a number of physiologically relevant proteins whose function it is to regulate the contractile activity of the smooth muscle cell. These include proteins that regulate free intracellular calcium levels, the cytoskeleton, and the phosphorylation state of the regulatory light chain of smooth muscle myosin. Other studies have shown that vascular smooth muscle cells (VSMCs) that are cultured in vitro may cease to express PKG and will, coincidentally, acquire a noncontractile, synthetic phenotype. The restoration of PKG expression to the synthetic phenotype VSMC results in the cells acquiring a more contractile phenotype. These more recent studies suggest that PKG controls VSMC gene expression that, in turn, regulates phenotypic modulation of the cells. Therefore, the regulation of PKG gene expression appears to be linked to phenotypic modulation of VSMC. Because several vascular disorders are related to the accumulation of synthetic, fibroproliferative VSMC in the vessel wall, it is likely that changes in the activity of the nitric oxide/cGMP/PKG pathway is involved the development of these diseases.

https://www.physiology.org/doi/pdf/10.1152/jappl.2001.91.3.1421

Invited review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression.

Background
Ventilator-associated pneumonia (VAP) is defined as pneumonia developing in people who have received mechanical ventilation for at least 48 hours. VAP is a potentially serious complication in these patients who are already critically ill. Oral hygiene care (OHC), using either a mouthrinse, gel, toothbrush, or combination, together with aspiration of secretions, may reduce the risk of VAP in these patients.

Objectives
To assess the effects of oral hygiene care on incidence of ventilator-associated pneumonia in critically ill patients receiving mechanical ventilation in hospital intensive care units (ICUs).

Search methods
We searched the following electronic databases: Cochrane Oral Health’s Trials Register (to 17 December 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 11), MEDLINE Ovid (1946 to 17 December 2015), Embase Ovid (1980 to 17 December 2015), LILACS BIREME Virtual Health Library (1982 to 17 December 2015), CINAHL EBSCO (1937 to 17 December 2016), Chinese Biomedical Literature Database (1978 to 14 January 2013), China National Knowledge Infrastructure (1994 to 14 January 2013), Wan Fang Database (January 1984 to 14 January 2013) and VIP Database (January 2012 to 4 May 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials to 17 December 2015. We placed no restrictions on the language or date of publication when searching the electronic databases.

Selection criteria
We included randomised controlled trials (RCTs) evaluating the effects of OHC (mouthrinse, swab, toothbrush or combination) in critically ill patients receiving mechanical ventilation for at least 48 hours.

Data collection and analysis
At least two review authors independently assessed search results, extracted data and assessed risk of bias in included studies. We contacted study authors for additional information. We pooled data from trials with similar interventions and outcomes. We reported risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, using random-effects models unless there were fewer than four studies.

Main results
We included 38 RCTs (6016 participants). There were four main comparisons: chlorhexidine (CHX) mouthrinse or gel versus placebo/usual care; toothbrushing versus no toothbrushing; powered versus manual toothbrushing; and comparisons of oral care solutions. We assessed the overall risk of bias as low in five trials (13%), high in 26 trials (68%), and unclear in seven trials (18%). We did not consider the risk of bias to be serious when assessing the quality of evidence (GRADE) for VAP incidence, but we downgraded other outcomes for risk of bias.

High quality evidence from 18 RCTs (2451 participants, 86% adults) shows that CHX mouthrinse or gel, as part of OHC, reduces the risk of VAP compared to placebo or usual care from 24% to about 18% (RR 0.75, 95% confidence intervals (CI) 0.62 to 0.91, P = 0.004, I2 = 35%). This is equivalent to a number needed to treat for an additional beneficial outcome (NNTB) of 17 (95% CI 9 to 50), which indicates that for every 17 ventilated patients in intensive care receiving OHC including chlorhexidine, one outcome of VAP would be prevented. There is no evidence of a difference between CHX and placebo/usual care for the outcomes of mortality (RR 1.09, 95% CI 0.96 to 1.23, P = 0.20, I2 = 0%, 14 RCTs, 2014 participants, moderate quality evidence), duration of mechanical ventilation (MD -0.09 days, 95% CI -1.73 to 1.55 days, P = 0.91, I2 = 36%, five RCTs, 800 participants, low quality evidence), or duration of intensive care unit (ICU) stay (MD 0.21 days, 95% CI -1.48 to 1.89 days, P = 0.81, I2 = 9%, six RCTs, 833 participants, moderate quality evidence). There is insufficient evidence to determine the effect of CHX on duration of systemic antibiotics, oral health indices, caregivers' preferences or cost. Only two studies reported any adverse effects, and these were mild with similar frequency in CHX and control groups.

We are uncertain as to the effects of toothbrushing (± antiseptics) on the outcomes of VAP (RR 0.69, 95% CI 0.44 to 1.09, P = 0.11, I2 = 64%, five RCTs, 889 participants, very low quality evidence) and mortality (RR 0.87, 95% CI 0.70 to 1.09, P = 0.24, I2 = 0%, five RCTs, 889 participants, low quality evidence) compared to OHC without toothbrushing (± antiseptics). There is insufficient evidence to determine whether toothbrushing affects duration of mechanical ventilation, duration of ICU stay, use of systemic antibiotics, oral health indices, adverse effects, caregivers' preferences or cost.

Only one trial (78 participants) compared use of a powered toothbrush with a manual toothbrush, providing insufficient evidence to determine the effect on any of the outcomes of this review.

Fifteen trials compared various other oral care solutions. There is very weak evidence that povidone iodine mouthrinse is more effective than saline/placebo (RR 0.69, 95% CI 0.50 to 0.95, P = 0.02, I2 = 74%, three studies, 356 participants, high risk of bias), and that saline rinse is more effective than saline swab (RR 0.47, 95% CI 0.37 to 0.62, P < 0.001, I2 = 84%, four studies, 488 participants, high risk of bias) in reducing VAP. Due to variation in comparisons and outcomes among trials, there is insufficient evidence concerning the effects of other oral care solutions.

Authors' conclusions
OHC including chlorhexidine mouthwash or gel reduces the risk of developing ventilator-associated pneumonia in critically ill patients from 24% to about 18%. However, there is no evidence of a difference in the outcomes of mortality, duration of mechanical ventilation or duration of ICU stay. There is no evidence that OHC including both antiseptics and toothbrushing is different from OHC with antiseptics alone, and some weak evidence to suggest that povidone iodine mouthrinse is more effective than saline/placebo, and saline rinse is more effective than saline swab in reducing VAP. There is insufficient evidence to determine whether powered toothbrushing or other oral care solutions are effective in reducing VAP. There is also insufficient evidence to determine whether any of the interventions evaluated in the studies are associated with adverse effects.

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Oral hygiene care for critically ill patients to prevent ventilator‐associated pneumonia

Cyclic nucleotide analogs as biochemical tools and prospective drugs.

cGMP-kinase mediates cGMP- and cAMP-induced Ca2+ desensitization of skinned rat artery

Objective: The purpose of this study was to evaluate the effects of functional training on outbreak frequency of pneumonia for the elderly dysphagia patients who were being tube fed.



Methods:  Subjects were divided into two groups; one group (n = 10) received oral care (i.e. non-training group) and the other group (n = 11) received functional training of dysphagia in addition to oral care (i.e. training group). The dental health team treated subjects once a week for 3 years (1999–2001). The frequency of pneumonia outbreaks and changes in activities of daily living scale (ADL) were evaluated for each year.



Result:  It was recognised that the frequency of pneumonia in the training group decreased year by year (p < 0.05). Cognitive items in ADL improved in two subjects of the training group. No statistical differences were recognised in the non-training group.



Conclusion:  It was suggested that once-a-week functional training of dysphagia with professional oral care might be effective in preventing pneumonia for elderly people who were being tube fed.

/pdf/effects-of-functional-training-of-dysphagia-to-prevent-4mgnwyhopt.pdf

Effects of functional training of dysphagia to prevent pneumonia for patients on tube feeding.

Objective The purpose of the present study is to clarify the frequency of provision of effective professional oral care by dental health workers in order to improve the oral hygiene state of elderly persons requiring long-term care. Methods In 105 patients requiring long-term nursing care, 55 subjects with positive oral Candida albicans were divided into five groups according to the frequency of oral care intervention at intervals of 1, 2, 3, 4 and 6 weeks. The effects of professional oral care on the improvement of the oral hygiene state were investigated taking the frequency and duration of care into consideration. Results The results showed that oral hygienic condition could be improved by performing professional oral care at intervals of 1 week for 12 consecutive weeks, and the improved condition could be maintained when professional oral care was continued at intervals of 1 week thereafter. Conclusion It is necessary to continue professional oral care at intervals of 1 week for 12 consecutive weeks and at intervals of 2 weeks for more than 20 weeks. The oral hygiene state could be improved by professional intervention at intervals of three or four weeks in long-term oral care, but this was limited to subjects whose Functional Independence Measure (FIM) scores were higher than 3.

A study on the effects of short-, medium- and long-term professional oral care in elderly persons requiring long-term nursing care at a chronic or maintenance stage of illness.

A 240-kDa protein isolated from porcine aortic smooth muscle as a substrate for cGMP-dependent protein kinase (cGMP kinase) whose phosphorylation was in a close association with stimulation of partially purified plasma membrane Ca2+-pump ATPase by the kinase was later shown to represent splicing variants of type 1 inositol 1,4,5-trisphosphate (IP3) receptor. To further clarify the role played by this protein in the stimulation of Ca2+-pump ATPase, it was attempted in the present study to specifically remove the protein by immunoprecipitation with an antibody specific to type 1 IP3 receptor. Contrary to expectation, stimulation of the ATPase by cGMP kinase was still observed after removal of the IP3 receptor. Furthermore, cGMP kinase stimulated a highly purified preparation of Ca2+-pump ATPase deprived of IP3 receptor when the concentrations of the ATPase were low enough (10–20 nM) to make it retain a monomeric form, while it did not produce stimulation when the concentration of the enzyme was increased to 40 nM at which the enzyme is known to take an oligomeric, fully activated form insensitive to activation by calmodulin. Heat-inactivated cGMP kinase and cGMP kinase without cGMP failed to stimulate the highly purified Ca2+-pump ATPase. In addition, type Iα but not type Iβ cGMP kinase was found to stimulate the ATPase. The stimulation of Ca2+-pump ATPase by cGMP kinase occurs without any detectable phosphorylation of the ATPase. In conclusion, cGMP kinase can stimulate the plasma membrane Ca2+-pump ATPase when it is in a monomeric form without phosphorylating the Ca2+-pump ATPase and that of the two cGMP kinase isozymes found in the vascular smooth muscle, only type Iα cGMP kinase participates in the stimulation. (Mol Cell Biochem 190: 157–167, 1999)

Stimulation of plasma membrane Ca2+-pump ATPase of vascular smooth muscle by cGMP- dependent protein kinase: Functional reconstitution with purified proteins

Akira Toyosato

Papers

cGMP-kinase mediates cGMP- and cAMP-induced Ca2+ desensitization of skinned rat artery

Effects of functional training of dysphagia to prevent pneumonia for patients on tube feeding.

A study on the effects of short-, medium- and long-term professional oral care in elderly persons requiring long-term nursing care at a chronic or maintenance stage of illness.

Stimulation of plasma membrane Ca2+-pump ATPase of vascular smooth muscle by cGMP- dependent protein kinase: Functional reconstitution with purified proteins

A Relation Between the Piezoelectric Pulse Transducer Waveforms and Food Bolus Passage during Pharyngeal Phase of Swallow