Dementia predicted one-year mortality for patients with first hip fracture: a population-based study.

Aims: We aimed to determine the effect of dementia and Parkinson's disease on one, three and 12-month mortality following surgery for fracture of the hip in elderly patients from an Asian population. Patients and Methods: Using a random sample of patients taken from the Taiwan National Health Insurance Research Database, this retrospective cohort study analyzed the data on 6626 elderly patients who sustained a fracture of the hip between 1997 and 2012 who had ICD-9 codes within the general range of hip fracture (820.xx). We used Cox regression to estimate the risk of death associated with dementia, Parkinson's disease or both, adjusting for demographic, clinical, treatment, and provider factors. Results: Among 6626 hip fracture patients, 10.20% had dementia alone, 5.60% had Parkinson's disease alone, and 2.67% had both. Corresponding one-year mortality rates were 15.53%, 11.59%, and 15.82%, compared with 9.22% for those without neurological illness. Adjusted hazard ratio for one-year mortality was 1.45 (95% confidence intervals (CI) 1.17 to 1.79) for those with dementia, and 1.57 (95% CI 1.07 to 2.30) with both dementia and Parkinson's disease versus patients with neither. There was no significant association with death for Parkinson's disease alone. Age, male gender and comorbidities were also associated with a higher risk of mortality. Conclusion: Dementia, with or without Parkinson's disease, is an independent predictor of mortality following surgery for fractures of the hip. Age, male gender and comorbidities also increase the risk of death. Parkinson's disease alone has no significant effect. Cite this article: Bone Joint J 2018;100-B:1220-6.

A novel RING finger protein, Znf179, modulates cell cycle exit and neuronal differentiation of P19 embryonal carcinoma cells.

Znf179 is a member of the RING finger protein family. During embryogenesis, Znf179 is expressed in a restricted manner in the brain, suggesting a potential role in nervous system development. In this report, we show that the expression of Znf179 is upregulated during P19 cell neuronal differentiation. Inhibition of Znf179 expression by RNA interference significantly attenuated neuronal differentiation of P19 cells and a primary culture of cerebellar granule cells. Using a microarray approach and subsequent functional annotation analysis, we identified differentially expressed genes in Znf179-knockdown cells and found that several genes are involved in development, cellular growth, and cell cycle control. Flow cytometric analyses revealed that the population of G0/G1 cells decreased in Znf179-knockdown cells. In agreement with the flow cytometric data, the number of BrdU-incorporated cells significantly increased in Znf179-knockdown cells. Moreover, in Znf179-knockdown cells, p35, a neuronal-specific Cdk5 activator that is known to activate Cdk5 and may affect the cell cycle, and p27, a cell cycle inhibitor, also decreased. Collectively, these results show that induction of the Znf179 gene may be associated with p35 expression and p27 protein accumulation, which lead to cell cycle arrest in the G0/G1 phase, and is critical for neuronal differentiation of P19 cells.

Effects of MDL 28,133A, a 5-HT2 receptor antagonist, on platelet aggregation and coronary thrombosis in dogs.

We wished to characterize MDL 28,133A (1-(4-fluorophenyl)-2-[4-[(4-methanesulfonamidophenyl)carbonyl]-1- piperidinyl-ethanone HCl), a potent 5-HT2 receptor antagonist, on platelet aggregation and platelet thrombosis and determined its effect on thrombolysis with streptokinase (SK) in dogs with coronary thrombosis. MDL 28,133A and ritanserin, 0.3-1 microM, competitively inhibited 5-HT-induced platelet aggregation in dog platelet-rich plasma (PRP) in vitro. The pA2 values and slopes were 6.29 +/- 0.09, -0.96 +/- 0.14, and 6.58 +/- 0.09, =1.64 +/- 0.34 for MDL 28,133A and ritanserin, respectively, suggesting that both agents are similar in potency to 5-HT2 receptor antagonists. MDL 28,133A (0.01 mg/kg, p.o.) produced inhibition of arachidonic acid-induced platelet aggregation in whole blood from conscious dogs ex vivo for > or = 2 h, indicating oral bioavailability. The magnitude and duration of the effect of MDL 28,133A on platelet aggregation in whole blood was similar to that of ketanserin (2.5 mg/kg, p.o.). MDL 28,133A (0.001-0.03 mg/kg, i.v.) completely abolished cyclic flow reductions (CFRs) in stenosed and partially deendothelialized left anterior descending coronary arteries of anesthetized dogs for at least 120 min without affecting systemic blood pressure (BP) and heart rate, thus indicating that MDL 28,133A is a potent antithrombotic agent. Ketanserin (0.5 mg/kg, i.v.) also abolished CFRs, but produced a significant decrease in systemic BP as well. MDL 28,133A (0.001 mg/kg, i.v.) shortened time to reperfusion (15 +/- 1 vs. 36 +/- 8 min), prolonged time to reocclusion (112 +/- 6 vs. 85 +/- 6 min), and increased total volume reflow (20 +/- 2 vs. 10 +/- 2%) in dogs with coronary artery thrombosis undergoing thrombolysis with SK (1,000 U/min, i.a.). Reocclusion rate was not affected by MDL 28,133A (4 of 5 vs. 4 of 6). Treatment with heparin (150 U/kg, i.v. every hour for 2 h) alone or in combination with MDL 28,133A did not improve time to reperfusion but enhanced total volume reflow and prevented reocclusion. MDL 28,133A is a potent 5-HT2 receptor antagonist that inhibits platelet thrombosis and facilitates thrombolysis in vivo. The impeding effect of MDL 28,133A in coronary thrombosis and the lack of hemodynamic effects suggests that MDL 28,133A may be of benefit in treatment of hyperthrombotic conditions without having hemodynamic side effects.

A comparative study of evaluating renal scars by 99mTc-DMSA planar and SPECT renal scans, intravenous urography, and ultrasonography.

The purpose of this prospective study is to compare 3 types of 99mTc-DMSA renal scan [(a) planar, (b) x-ray type film static SPECT presentation (SPECT-1) and (c) dynamic three-view display of SPECT slices (SPECT-2)], intravenous urography, and ultrasonography in the diagnosis of renal scars. All these studies were performed in 130 pediatric patients, with urinary tract infection (42 patients), vesicoureteral reflux (37), and unilateral or bilateral small kidney(s) (51). The number of renal scars detected was highest with the 99mTc-DMSA renal SPECT-1 scan and next came the 99mTc-DMSA renal SPECT-2 studies. There is a significant difference (p < 0.05) between the ability of planar and SPECT-1 to recognize renal defects. However, SPECT-2 may provide the best stereotactic localization and image quality of all the methods.

Pharmacology of enoximone.

Enoximone is a new cardiotonic agent, active by both intravenous and oral routes of administration, that is being studied clinically for the treatment of patients with congestive heart failure. The animal pharmacology pertinent to the clinical development of enoximone is reviewed. Direct positive inotropic, positive chronotropic and vasodilator properties have been demonstrated for enoximone in several in vivo and in vitro preparations. However, positive inotropism and vasodilation are the principal effects of this agent with the inotropic effect being the most prominent. In anesthetized dogs, the cardiovascular effects produced by enoximone (0.1 to 1 mg/kg) were not accompanied by significant alterations in myocardial oxygen consumption. Cardiac function was improved by enoximone in anesthetized dogs given myocardial depressant amounts of propranolol. Studies in vivo and in vitro have indicated that the actions of enoximone are direct and not mediated by stimulation of adrenergic receptors, histaminic receptors, cholinergic receptors, Ca++-adenosine triphosphatase, Mg++-adenosine triphosphatase, adenyl cyclase or inhibition of Na+, K+-adenosine triphosphatase. However, enoximone reversed the depressant effects of verapamil in the dog heart-lung preparation; this suggests that its action resulted in the activation of slow calcium channels. Enoximone was found to be potent and highly selective inhibitor of a high affinity cyclic adenosine monophosphate-phosphodiesterase type IV-phosphodiesterase from dog heart, whereas standard inhibitors (e.g., 3-isobutyl-1-methylxanthine and papaverine) inhibit all 3 cardiac phosphodiesterases. Further, enoximone produced an increase in cyclic adenosine monophosphate, but not cyclic guanosine monophosphate, in the isolated, blood perfused dog papillary muscle during the peak inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of enoximone and isobutylmethylxanthine on contractile tension and cyclic nucleotide levels in isolated blood-perfused dog papillary muscle.

The effects of enoximone (MDL 17,043) and 3-isobutyl-1-methylxanthine (IBMX) on developed tension, blood flow, and cyclic nucleotide levels were investigated in the isolated blood-perfused dog papillary muscle preparation. Intraarterial infusion of each agent, over 15 s, in doses ranging from 0.001 to 3 mg, produced a dose-dependent positive inotropic effect accompanied by increases in rate of contraction, rate of relaxation, and blood flow. The dose-response relationships for enoximone were always less steep than those for IBMX. Enoximone did not enhance automaticity at any dose, whereas the higher doses of IBMX (0.3, 1, and 3 mg) enhanced automaticity and produced arrhythmic preparations. Both agents produced increases in cyclic AMP during the peak positive inotropic effect (45 s); however, only IBMX produced an increase in cyclic GMP. The increase in cyclic AMP produced by enoximone lagged behind tension development by at least 15 s, whereas the increases in cyclic nucleotides produced by IBMX occurred concurrently with the development of the positive inotropic effect. The evaluation in cyclic AMP produced by enoximone is consistent with the reported property of this agent to inhibit specifically and selectively the particulate high-affinity cyclic AMP phosphodiesterase from dog heart, and supports a cyclic AMP-dependent mechanism of positive inotropism for enoximone.

Cardiovascular properties of a new cardiotonic agent, MDL 19205.

The cardiovascular properties of a new cardiotonic agent, MDL 19205, were investigated in anesthetized and conscious dogs and in a dog heart-lung preparation. MDL 19205 (0.1-1 mg/kg), administered to anesthetized dogs by intravenous injection, produced a dose-related increase in cardiac contractile force lasting up to 1 h. It also produced a relatively minor increase in heart rate and a brief decrease in blood pressure. These effects did not involve beta-adrenergic receptor stimulation, as they were observed in dogs after a myocardial-depressant dose of propranolol. Given orally to conscious dogs, MDL 19205 (1 and 3 mg/kg) produced a dose-related increase in dP/dt without producing a significant alteration in heart rate or blood pressure. When administered to anesthetized dogs by constant intravenous infusion, MDL 19205 (0.1 mg/kg/min) produced a marked and sustained increase in cardiac contractile force and decreases in blood pressure and left atrial pressure, but did not produce a significant change in cardiac output or stroke volume, indicating an enhancement of cardiac pump function. Intravenous MDL 19205 reversed the hemodynamic characteristics of heart failure produced by propranolol in anesthetized dogs. In addition, it reversed the depressant effect of pentobarbital on cardiac function in a dog heart-lung preparation. These studies show that MDL 19205 is a potent, direct-acting cardiotonic agent in animals.

Vasodilation by medroxalol mediated by beta 2-adrenergic receptor stimulation.

A contribution by active vasodilation to the hypotensive effect of medroxalol was investigated in anesthetized dogs and reserpinized pithed rats. In anesthetized dogs, intravenous doses of medroxalol, which decreased blood pressure and heart rate, also produced a dose-related vasodilation in the isolated perfused gracilis muscle in situ. This vasodilator effect of medroxalol was completely blocked by propranolol; the hypotensive effect of medroxalol was inhibited 50% by propranolol but not at all by practolol. In reserpinized pithed rats with angiotensin-supported blood pressure, intravenous doses of medroxalol also produced propranolol-sensitive decreases in diastolic blood pressure and did not alter heart rate. Labetalol produced similar effects but was significantly less potent. Comparatively, equivalent amounts of isoproterenol and pindolol decreased diastolic blood pressure but increased heart rate. In the isolated guinea pig trachea, medroxalol produced a propranolol-sensitive relaxation at concentrations that antagonized the relaxant effects of salbutamol. Identical concentrations of medroxalol did not increase rate of isolated guinea pig atria. It is concluded that a substantial portion of the hypotensive effect of medroxalol is due to a beta 2-adrenergic-receptor-mediated vasodilation.

Cardiovascular properties of a new cardiotonic agent: MDL 17,043 (1.3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one).

The cardiovascular properties of a new noncatechol, nonglycoside cardiotonic agent, MDL 17,043, were investigated in anesthetized and conscious dogs and the dog heart-lung preparation. MDL 17,043 (0.1-1 mg/kg), administered to anesthetized dogs by intravenous injection, produced dose-related increases in cardiac contractile force lasting more than 1 h. It also produced relatively minor and shorter-lasting increases in heart rate, and brief decreases in blood pressure. These effects were not blocked by propranolol. Of these effects, the increase in cardiac contractile force was, by far, the most prominent. the cardiac effects were also observed in the dog heart-lung preparation. When administered to anesthetized dogs by constant intravenous infusion, MDL 17,043 (09.03 and 0.1 mg/kg/min) produced a marked and sustained increase in cardiac contractile force and a sustained decrease in blood pressure without altering heart rate, suggesting a wide separation between the inotropic instrumented dogs, MDL 17,043 (3-30 mg/kg) produced a sustained increase in dP/dt without altering heart rate or blood pressure. It reversed the depressant effect of pentobarbital on the ventricular function curve in the dog heart-lung. When the hemodynamic characteristics of compensated heart failure were produced by propranolol in anesthetized dogs, MDL 17,043 reversed these effects. These studies suggest that MDL 17,043 may have a beneficial effect in the treatment of heart failure.

Direct vasodilatation by labetalol in anaesthetized dogs.

1 The effects of several doses of labetalol (0.03 to 1 mg/kg) given intravenously and into the vertebral artery were examined in anaesthetized dogs. Labetalol produced to immediate (5 min) change in blood pressure or heart rate when given by either route, with one exception. Heart rate increased after the first dose (0.03 mg/kg i.v.) of labetalol. By contrast, clonidine (1 micrograms/kg) elicited an immediate and prolonged fall in blood pressure and heart rate when given into the vertebral artery, but not intravenously. 2 In the isolated perfused gracilis muscle of the dog, following alpha- and beta-adrenoceptor blockade, intra-arterial injections of labetalol (0.3 to 10 mg) or diazoxide (0.3 to 1 mg) produced decreases in perfusion pressure that were dose-related in both magnitude and duration. The doses of labetalol and diazoxide required to produce a half-maximal vasodilatation were 1.5 mg and 0.7 mg respectively. 3 In adrenalectomized, vagotomized spinal dogs, both labetalol (0.1 to 1 mg/kg i.v.) and hydralazine (1 mg/kg i.v.) elicited a fall in blood pressure without changing heart rate or cardiac output. 4. These results suggest that the hypotension produced by systemically administered labetalol does not involve an action in the brain. It may involve instead a direct vasodilatation of resistance blood vessels, since labetalol in sufficient amounts, directly dilates resistance vessels and lowers blood pressure in dogs devoid of adrenergic tone. Direct vasodilatation may be a component of the hypotensive action of labetalol.

Comparison of vascular effects of gastrointestinal hormones on various organs.

Vascular effects of raising local arterial concentration of pentagastrin (2-1,500ng/ml), secretin (0.2-150mU/ml), and cholecystokinin (0.2-150mU/ml) in the duodenum, jejunum, heart, kidney, forelimb, spleen, and the skin and muscle of the forelimb were studied in 54 anesthetized dogs. Secretin produced similar vasodilation in all organs. The minimal increment in local blood secretin concentration for vasodilation ("concentration requirement") was between 7 and 32 mU/ml. Pentagastrin produced vasodilation only in the duodenum and jejunum and the concentration requirement was between 25 and 50 ng/ml. Cholecystokinin did not affect vascular resistance of the forelimb, skin, or muscle. In the heart, kidney, and spleen, cholecystokinin produced vasodilation but the concentration requirement was above 21-33 mU/ml. In contrast, vasodilation in the duodenum and jejunum appeared when cholecystokinin concentration was increased by only 2.5 mU/ml. Furthermore, almost all its vasodilating effect occurred below an increment of 10 mU/ml. Comparison of our data with the reported cardiovascular adjustments and blood concentration of gastrointestinal hormones following a meal suggests that cholecystokinin may contribute to postprandial intestinal hyperemia.

Localization of mesenteric hyperemia during digestion in dogs.

For localization of the site of post-prandial mesenteric hyperemia, low-fat, low-protein food was placed in either the stomach, duodenum, or jejunum while blood flow was measured in the celiac artery, superior mesenteric artery (SMA), or jejunal vein of anesthetized dogs. Distribution of flow in the jejunal wall was also measured. After intragastric placement of food, celiac arterial flow increased within 5 min and remained elevated for 30-60 min; SMA flow increased within 30 min and stayed up for at least 3 h. Intra-duodenal infusion of digested food increased SMA flow but did not alter celiac flow or flow to an isolated jejunal segment. Placement of digested food into one jejunal segment increased flow to that segment did not affect flow was localized to the mucosal layer. These studies indicate that during digestion, blood flow increases in the mucosa of the intestine when exposed to chyme and is not changed in other areas of the gastrointestinal tract. Postprandial mesenteric hyperemia induced by low-fat, low-protein food is a local phenomenon.