MicroRNAs: protective regulators for neuron growth and development.

MicroRNAs (miRNAs) play an important regulatory role in neuronal growth and development. Different miRNAs target different genes to protect neurons in different ways, such as by avoiding apoptosis, preventing degeneration mediated by conditional mediators, preventing neuronal loss, weakening certain neurotoxic mechanisms, avoiding damage to neurons, and reducing inflammatory damage to them. The high expression of miRNAs in the brain has significantly facilitated their development as protective targets for therapy, including neuroprotection and neuronal recovery. miRNA is indispensable to the growth and development of neurons, and in turn, is beneficial for the development of the brain and checking the progression of various diseases of the nervous system. It can thus be used as an important therapeutic target for models of various diseases. This review provides an introduction to the protective effects of miRNA on neurons in case of different diseases or damage models, and then provides reference values and reflections on the relevant treatments for the benefit of future research in the area.

Elbow Dislocation with Irretrievable Rotating-Rope Injury of the Forearm: Case Report and Literature Review.

BACKGROUND: Simultaneous dislocation of the elbow, radioulnar joint and proximal radius fracture with rotary noose injury to the medial ulna tubercle is extremely rare. An emergency surgery was performed to reduce it. The radial head with the backbone was reset after two hammers were fixed, then the radial capitulum safety was fixed with a locking plate. After the ulnar instability was examined, two Kirschner wires were drilled percutaneously to fix the elbow flexion at 100° under closed reduction, and two Kirschner wires were drilled percutaneously to fix the ulnar joint. Good follow-up results were achieved. To the best of our knowledge, this is the first report on this particular type of injury and on this approach to treating this type of injury. CASE PRESENTATION: We report the case of a 36-year-old male, who extended and landed on his left hand to protect his child in right arm before felling, resulting in severe pain and deformity of his left elbow and wrist and loss of movement in these joints. X-ray examination found proximal distal radioulnar joints, a proximal radial fracture and a dislocation bowstring in the ulna nodule. For a timely diagnosis in an emergency open reduction situation, accurate judgment of this injury is highly important. After 12 months of postoperative follow-up, the patient was symptom-free, and radiographs showed fracture healing. CONCLUSION: We performed emergency reduction and internal fixation of the elbow and successfully saved elbow function, no stability decrease and movement restriction. This case also provides a new reference for the treatment of this type of elbow fracture dislocation.

Left heart chamber quantification in obese patients: how does larger body size affect echocardiographic measurements?

BACKGROUND: Accurate normalization of cardiac chamber size in the obese population is a challenge. The aim of this study was to develop and assess the performance of allometric models for scaling left heart chamber sizes, including left atrial anteroposterior dimension (LADAP), left atrial volume (LAV), left ventricular end-diastolic volume (LVEDV), and left ventricular end-diastolic dimension (LVEDD), in an obese population. METHODS: To normalize left heart chamber measurements (Y: LADAP, LAV, LVEDV, and LVEDD) to body size variables (X: height, weight, body mass index, and body surface area), both isometric models (Y = aX) and optimal allometric models (Y = aX(b)) were tested. A logarithmic transformation (LnY = Lna + b × LnX) and ordinary least squares linear regression was performed to estimate the allometric scaling exponents. Pearson's correlation coefficients were obtained for measured and indexed left chamber sizes using both isometric and allometric models against body size variables. Gender-specific allometric models were also derived as sensitivity analyses. RESULTS: A total of 717 healthy obese subjects were included in the analysis. The mean body surface area and body mass index were 2.3 m(2) and 42.2 kg/m(2), respectively. Measured LADAP, LAV, LVEDD, and LVEDV were positively correlated with body size variables. Allometric scaling of LADAP, LAV, LVEDD, and LVEDV showed stronger correlation with measured chamber sizes compared with isometric scaling. The overcorrection caused by isometric scaling significantly improved after allometric models were used. The sensitivity analysis showed no significant differences in scaling exponents between men and women. CONCLUSIONS: Normalizing cardiac chamber measurements with allometric scaling methods is superior to the use of isometric methods in removing the effects of body size and minimizing overcorrection in the obese population. Using an allometric model with height provides the most accurate results.

Depression is an early disease manifestation in lupus-prone MRL/lpr mice.

Many lupus patients develop neuropsychiatric manifestations, including cognitive dysfunction, depression, and anxiety. However, it is not clear if neuropsychiatric lupus is a primary disease manifestation, or is secondary to non-CNS disease. We found that MRL/lpr lupus-prone mice exhibited significant depression-like behavior already at 8 weeks of age, despite normal visual working memory, locomotor coordination and social preference. Moreover, depression was significantly correlated with titers of autoantibodies against DNA, NMDA receptors and cardiolipin. Our results indicate that lupus mice develop depression and CNS dysfunction very early in the course of disease, in the absence of substantial pathology involving other target organs.

Hypoxia-induced vasodilation in the right coronary circulation of conscious dogs: role of adrenergic activation.

The role of adrenergic activation in the right coronary (RC) flow response to hypoxia has not been previously delineated, and limited information from left coronary studies is inconsistent. Seven dogs were instrumented with catheters implanted in the aorta and in the right ventricle to measure aortic pressure and right ventricular (RV) pressure, respectively. A flow transducer was placed around the RC artery to measure RC flow. After recovery from surgery, the dogs were exposed to systemic hypoxia in a Plexiglas chamber ventilated with N(2). Percent O(2) in the chamber was monitored, and blood samples and hemodynamic data were collected as chamber O(2) was progressively reduced to approximately 6%. The chamber was then opened, and the dog breathed room air. Phentolamine, 1 mg/kg, and propranolol, 2 mg/kg, were then administered via the RV catheter to achieve adrenergic blockade, and the hypoxia protocol was repeated. During hypoxia, arterial PO(2) progressively fell from 87+/-3 to 25+/-1 mmHg during untreated control condition and from 90+/-4 to 23+/-1 mmHg during adrenergic blockade. In the unblocked condition, hypoxia caused increases in aortic pressure, heart rate, RV pressure, and RV dP/dt(max). After adrenergic blockade, normoxic aortic pressure was reduced; heart rate and RV dP/dt(max) tended to be lower. Aortic pressure rose during hypoxia, but to lesser values than before blockade. Heart rate and RV dP/dt(max) also increased, but only at more severe hypoxia, and these values were less than before blockade. Normoxic flow and hypoxia-induced increases in RC flow and conductance were not altered by blockade. The relationship between RC conductance and RV triple product, an index of RV O(2) demand, was steeper after blockade. These findings indicate that in the normal, unblocked condition, RC flow during hypoxia is restrained by an adrenergic-mediated increase in RC vasomotor tone.

Mechanisms of oxygen demand/supply balance in the right ventricle.

Few studies have investigated factors responsible for the O2 demand/supply balance in the right ventricle. Resting right coronary blood flow is lower than left coronary blood flow, which is consistent with the lesser work of the right ventricle. Because right and left coronary artery perfusion pressures are identical, right coronary conductance is less than left coronary conductance, but the signal relating this conductance to the lower right ventricular O2 demand has not been defined. At rest, the left ventricle extracts approximately 75% of the O2 delivered by coronary blood flow, whereas right ventricular O2 extraction is only ~50%. As a result, resting right coronary venous PO2 is approximately 30 mm Hg, whereas left coronary venous PO2 is approximately 20 mm Hg. Right coronary conductance does not sufficiently restrict flow to force the right ventricle to extract the same percentage of O2 as the left ventricle. Endogenous nitric oxide impacts the right ventricular O2 demand/supply balance by increasing the right coronary blood flow at rest and during acute pulmonary hypertension, systemic hypoxia, norepinephrine infusion, and coronary hypoperfusion. The substantial right ventricular O2 extraction reserve is used preferentially during exercise-induced increases in right ventricular myocardial O2 consumption. An augmented, sympathetic-mediated vasoconstrictor tone blunts metabolically mediated dilator mechanisms during exercise and forces the right ventricle to mobilize its O2 extraction reserve, but this tone does not limit resting right coronary flow. During exercise, right coronary vasodilation does not occur until right coronary venous PO2 decreases to approximately 20 mm Hg. The mechanism responsible for right coronary vasodilation at low PO2 has not been delineated. In the poorly autoregulating right coronary circulation, reduced coronary pressure unloads the coronary hydraulic skeleton and reduces right ventricular systolic stiffness. Thus, normal right ventricular external work and O2 demand/supply balance can be maintained during moderate coronary hypoperfusion.

Nitric oxide contributes to right coronary vasodilation during systemic hypoxia.

As arterial partial pressure of O(2) (Pa(O(2))) is reduced during systemic hypoxia, right ventricular (RV) work and myocardial O(2) consumption (MVo(2)) increase. Mechanisms responsible for maintaining RV O(2) demand/supply balance during hypoxia have not been delineated. To address this problem, right coronary (RC) blood flow and RV O(2) extraction were measured in nine conscious, instrumented dogs exposed to normobaric hypoxia. Catheters were implanted in the right ventricle for measuring pressure, in the ascending aorta for measuring arterial pressure and for sampling arterial blood, and in an RC vein. A flow transducer was placed around the RC artery. After recovery from surgery, dogs were exposed to hypoxia in a chamber ventilated with N(2), and blood samples and hemodynamic data were collected as chamber O(2) was reduced progressively to approximately 8%. After control measurements were made, the chamber was opened and the dog was allowed to recover. N(omega)-nitro-L-arginine (L-NNA) was then administered (35 mg/kg, via RV catheter) to inhibit nitric oxide (NO) production, and the hypoxia protocol was repeated. RC blood flow increased during hypoxia due to coronary vasodilation, because RC conductance increased from 0.65 +/- 0.05 to 1.32 +/- 0.12 ml x min(-1) x 100 g(-1) x L-NNA blunted the hypoxia-induced increase in RC conductance. RV O(2) extraction remained constant at 64 +/- 4% as Pa(O(2)) was decreased, but after L-NNA, extraction increased to 70 +/- 3% during normoxia and then to 78 +/- 3% during hypoxia. RV MVo(2) increased during hypoxia, but after L-NNA, MVo(2) was lower at any respective Pa(O(2)). The relationship between heart rate times RV systolic pressure (rate-pressure product) and RV MVo(2) was not altered by l-NNA. To account for L-NNA-mediated decreases in RV MVo(2), O(2) demand/supply variables were plotted as functions of MVo(2). Slope of the conductance-MVo(2) relationship was depressed by L-NNA (P = 0.03), whereas the slope of the extraction-MVo(2) relationship increased (P = 0.003). In summary, increases in RV MVo(2) during hypoxia are met normally by increasing RC blood flow. When NO synthesis is blocked, the large RV O(2) extraction reserve is mobilized to maintain RV O(2) demand/supply balance. We conclude that NO contributes to RC vasodilation during systemic hypoxia.

Intermittent hypoxic training protects canine myocardium from infarction.

This investigation examined cardiac protective effects of normobaric intermittent hypoxia training. Six dogs underwent intermittent hypoxic training for 20 consecutive days in a normobaric chamber ventilated intermittently with N2 to reduce fraction of inspired oxygen (FiO2) to 9.5%-10%. Hypoxic periods, initially 5 mins and increasing to 10 mins, were followed by 4-min normoxic periods. This hypoxia-normoxia protocol was repeated, initially 5 times and increasing to 8 times. The dogs showed no discomfort during intermittent hypoxic training. After 20 days of hypoxic training, the resistance of ventricular myocardium to infarction was assessed in an acute experiment. The left anterior descending (LAD) coronary artery was occluded for 60 mins and then reperfused for 5 hrs. At 30 mins of LAD occlusion, radioactive microspheres were injected through a left atrial catheter to assess coronary collateral blood flow into the ischemic region. After 5 hrs reperfusion, the heart was dyed to delineate the area at risk (AAR) of infarction and stained with triphenyl tetrazolium chloride to identify infarcted myocardium. During LAD occlusion and reperfusion, systemic hemodynamics and global left ventricular function were stable. Infarction was not detected in 4 hearts and was 1.6% of AAR in the other 2 hearts. In contrast, 6 dogs sham-trained in a chamber ventilated with compressed air and 5 untrained dogs subjected to the same LAD occlusion/reperfusion protocol had infarcts of 36.8% +/- 5.8% and 35.2% +/- 9.5% of the AAR, respectively. The reduction in infarct size of four of the six hypoxia-trained dogs could not be explained by enhanced collateral blood flow to the AAR. Hypoxia-trained dogs had no ventricular tachycardia or ventricular fibrillation. Three sham-trained dogs had ventricular tachycardia and two had ventricular fibrillation. Three untrained dogs had ventricular fibrillation. In conclusion, intermittent hypoxic training protects canine myocardium from infarction and life-threatening arrhythmias during coronary artery occlusion and reperfusion. The mechanism responsible for this potent cardioprotection merits further study.

Alpha-adrenergic vasoconstrictor tone limits right coronary blood flow in exercising dogs.

In exercising dogs, increased myocardial O2 consumption (MVO2) of the left ventricle is met primarily by hyperemia, whereas increased O2 extraction makes a greater contribution to right ventricular (RV) O2 supply. We hypothesized that alpha-adrenergic vasoconstrictor tone limits right coronary (RC) blood flow during exercise, forcing increased O2 extraction. This tone might also contribute to lesser RC vascular conductance at rest. Accordingly, RV O2 balance was examined at rest and during graded treadmill exercise before and during alpha-adrenergic blockade with phentolamine (1 mg/kg, i.v., n=6). The transmural distribution of RC flow was measured with radiolabeled microspheres in 4 additional dogs. At rest, alpha-adrenergic receptor blockade did not significantly increase RC flow or conductance. During exercise, alpha-adrenergic blockade increased RC flow and conductance responses to increased RV MVO2 by 25% and 60%, respectively. The transmural distribution of RC flow was not altered by exercise or by alpha-adrenergic blockade. Before alpha-adrenergic blockade, hyperemia provided 39%-66% of the additional O2 consumed by the right ventricle during graded exercise; after alpha-adrenergic blockade, hyperemia contributed 74%-85%. After alpha-adrenergic blockade, the slope of the relationship between RC venous PO2 and RV MVO2 became less steep, reflecting less O2 extraction due to enhanced hyperemia. Additional experiments were conducted on 5 anesthetized, open-chest dogs with constant RC perfusion pressure and beta-adrenergic blockade. The RC flow response to intracoronary norepinephrine was shifted to the left compared with that measured in the left coronary circulation, consistent with observations in the conscious exercising dogs. In conclusion, alpha-adrenergic vasoconstrictor tone does not restrict resting RC blood flow, but during exercise, this tone transmurally blunts RC hyperemia and forces the right ventricle to mobilize its O2 extraction reserve. This effect is more pronounced than has been reported for the left ventricle.

Endogenous nitric oxide regulates right coronary blood flow during acute pulmonary hypertension in conscious dogs.

This study investigated the role of nitric oxide (NO) in the control of right coronary (RC) blood flow at rest and during acute pulmonary hypertension. Experiments were performed in seven chronically instrumented, conscious dogs. NO synthesis was inhibited by systemic administration of N(omega)-nitro-L-arginine (LNA, 35 mg/kg). Inflation of a balloon in the main pulmonary artery raised right ventricular (RV) peak systolic pressure from 34 +/- 2 to 47 +/- 3 mmHg before LNA and from 37 +/- 2 to 47 +/- 3 mmHg after LNA, but did not affect mean systemic arterial pressure. RV O(2) consumption (MVO(2)) increased from 4.4 +/- 0.7 to 6.1 +/- 0.7 ml/min/100 g. 82 % of the elevated RV MVO(2) was provided by RC blood flow, which increased from 46 +/- 7 to 61 +/- 8 ml/min/100 g. After LNA, resting RV MVO(2) and RC flow fell. RC venous PO(2) fell, but RV lactate uptake was not altered. During pulmonary hypertension, the increase in RC blood flow was blunted by LNA, so that only 66 % of the elevated RV MVO(2) was supplied by increased RC flow. Analysis of O(2) supply variables as functions of RV MVO(2) further demonstrated a significant role of NO in regulating RC flow at rest and during moderate pulmonary hypertension. Conclusions NO is required for the RC hyperemic response to acute pulmonary hypertension as well as for normal resting RC blood flow. After blockade of NO synthesis, RV O(2) supply at rest and during pulmonary hypertension was sustained by increased RV O(2) extraction.

Coronary blood flow control is impaired at rest and during exercise in conscious diabetic dogs.

This study tested whether diabetes mellitus impairs coronary blood flow control sufficiently to alter the balance between myocardial oxygen delivery and metabolism. Dogs (n = 7) were instrumented with catheters in the aorta and coronary sinus, and with a flow transducer on the circumflex coronary artery. Coronary blood flow, myocardial oxygen consumption (MVO2), heart rate and aortic pressure were measured at rest and during treadmill exercise before and after induction of diabetes with alloxan monohydrate (40 - 60 mg/kg). Arterial plasma glucose concentration increased from 4.6+/-0.2 mM in non-diabetic, control dogs to 20.2+/-2.3 mM one week after alloxan injection. In non-diabetic control dogs, exercise increased MVO2 3.1-fold, coronary blood flow 2.7-fold, and heart rate 2.4-fold. Coronary venous PO2 decreased from 19.4+/-0.6 mmHg at rest to 14.7+/-0.7 mmHg during exercise. Diabetes significantly attenuated exercise coronary hyperemia and reduced coronary venous PO2 at rest (15.6+/-0.5 mmHg) and during exercise (12.6+/-0.8 mmHg). Diabetes also significantly reduced myocardial oxygen delivery at each level of exercise. Acute hyperglycemia alone did not alter exercise-induced coronary vasodilation or reduce coronary venous PO2. These findings demonstrate that experimental diabetes attenuates functional coronary hyperemia and impairs the balance between coronary blood flow and myocardial metabolism. However, this deleterious effect is not related to acute hyperglycemia but to the chronic disease process of diabetes mellitus.