Prevention of fibrinolytic shut-down after major surgery by intramuscular stanozolol

The effects of a single pre-operative intramuscular injection of the anabolic steroid stanozolol (Stromba, 50 mg) on fibrinolysis and blood viscosity were evaluated in 14 patients at high risk of post-operative deep venous thrombosis. A control group of 13 high risk patients was also studied. The mean level of plasma plasminogen activator activity decreased significantly (p<0.05) on the first post-operative day in the control group. In contrast, the fibrinolytic activator activity showed a non-significant rise on the first post-operative day in the stanozolol treated group. The difference in plasminogen activator levels on the first post-operative day between treated and control groups was significant (p<0.05). Plasma plasminogen levels on the first post-operative day increased from pre-operative levels in the treated group (p<0.01), but not in the control group. The prevention of fibrinolytic shut-down and stimulation of plasminogen levels by a single pre-operative injection suggests that trials of intramuscular stanozolol in the prevention of post-operative deep venous thrombosis are indicated.     

Different effects of insulin and 2-deoxy-D-glucose administration on tyrosine hydroxylase gene expression in the locus coeruleus and the adrenal medulla in rats

The major brain norepinephrinergic nucleus, locus coeruleus, is an important integrating element of extero- and interoceptive stimuli in organisms facing different physiological challenges. We investigated the effects of single and repeated (seven times) exposure to immobilization stress (120 min daily), insulin (5 IU/kg, i.p. daily) or 2-deoxy-d-glucose (500 mg/kg, i.p. daily) administration on tyrosine hydroxylase (TH) mRNA levels, the rate-limiting enzyme in catecholamine biosynthesis, by in situ hybridization in locus coeruleus and by Northern blot analysis in the adrenal medulla of rats. Both the single and repeated immobilization caused a significant increase in TH mRNA levels in the locus coeruleus (1.5–2-fold; p < 0.05) and in the adrenal medulla (about 4-fold; p < 0.05) when compared with unstressed controls. Hypoglycemia induced by a single or repeated insulin administration led to about fourfold (p < 0.01) elevation in adrenal medullary TH mRNA levels, whereas TH mRNA in locus coeruleus remained unchanged when compared with saline-treated controls. In contrast to the effect of insulin-induced hypoglycemia, cellular glucoprivation caused by a single or repeated 2-deoxy-d-glucose administration significantly elevated TH mRNA levels in both the adrenal medulla (fourfold; p < 0.01) and the locus coeruleus (twofold; p < 0.01). Our data suggest that in contrast to immobilization or cellular glucoprivation caused by 2-deoxy-d-glucose administration, insulin-induced hypoglycemia is not a specific or quantitatively sufficient stimulus for induction of TH gene expression in the locus coeruleus, although all these stressors strongly activate the process in the adrenal medulla.     

Relationship between the flow pattern and vasomotor reactivity in the ophthalmic artery,siphon and vessels within the circle of Willis in the unilateral internal carotid artery occlusion

Abstract

The aim was to study a relationship between the flow pattern in the ophthalmic artery (OA), the siphon and vessels within the circle of Willis. 27 patients, 22 males and 5 females; mean age 63 ± 15 years (SD) with unilateral occlusion of the internal carotid artery (ICA) were examined by 3-dimensional Transcranial Doppler scanner Flow signals from the OA, the siphon and intracranial vessels were registered before and after i.v. injection of 1 g acetazolamide. Pathological flow pattern was found in 18 patients in the OA on the occluded side consisting of 12 retrograde and 6 isoelectric flow directions. After acetazolamide injection retrograde systolic velocities (SV) increased significantly (p < 0.01), but anterograde velocities remained unchanged as did 3 isoelectric flow patterns, 2 turned to retrograde and one to anterograde flow direction. In the siphon lower resting anterograde mean velocities (MV) were found on both sides (p < 0.05) compared to normal subjects. Six patients had the same retrograde flow as in the OA. After acetazolamide MV in the siphon increased (p <0.01) only on the nonoccluded side. Baseline retrograde ophthalmic SVand MV in the siphon correlated (p < 0.01 and p < 0.05 respectively) with MV in the middle cerebral artery (MCA) according to linear regression analysis (x - 0.78 and 0.59 respectively). All patients, having impaired vasomotor reactivity (VMR) <11% in the anterior cerebral artery (ACA) on the occluded side, had pathological flow pattern in the OA. Patients with greatest difference (A) between MV in the ACA on the nonoccluded and occluded side had a tendency to anterograde flow (r = 0.56, p < 0.05). Pulsative index (PI) in the ACA on the occluded side was lowest in the category with retrograde flow in the OA (0.67± 0.14) and differed (p < 0.05) from normals and from the category with isoelectric and anterograde flow. Correlation of retrograde flow direction in the OA and baseline MV in the MCA and low PI in the ACA on the occluded side indicates a supplying ophthalmic collateral to the anterior brain circulation. Impaired VMR in the ACA on the occluded side in connection with pathological flow pattern in the OA may reflect an exhaustion of the ACA as a supplying vessel. [Neurol Res 1996; 18: 521-527]     

Measurement of thrombin generation intra-operatively and its association with bleeding tendency after cardiac surgery

Introduction

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are susceptible to haemostatic disturbances. Monitoring the haemostatic capacity by conventional clotting tests is challenging.

Materials and Methods

Thrombin generation (TG) by Calibrated Automated Thrombography, clotting tests and tissue factor pathway inhibitor (TFPI) measurements were performed to describe the relationship between haemostatic changes and alterations in these tests. Blood samples were collected before, during and after CPB. Furthermore, it was investigated whether TG measured intraoperatively, is associated with increased risk of bleeding postoperatively.

Results

TG diminished significantly (p < 0.01) after heparinization in the presence and absence of platelets (37% and 50%) compared to baseline. After the start of CPB, TG elevated and persisted till the end of surgery but remained lower than preoperatively. Activated clotting time increased after heparinization and after the start of bypass compared to baseline (400% and 500%). Anti-FXa activity reduced on the start of CPB compared to the level after heparinization, to almost the baseline value following protamine reversal of heparin. The plasma levels of total and free TFPI elevated 9 and 14 fold during bypass and remained after protamine administration higher than preoperatively. Plasma D-dimer levels reduced (p < 0.01) when bypass started. However, a marked elevation was observed in the following time points. TG in platelet-rich plasma measured after heparinization and after the start of CPB associated (p < 0.05) with postoperative blood loss.

Conclusions

TG can be determined during CPB despite the high heparinization level, it reflects the haemostatic capacity better than clotting-based assays and might better predict bleeding when performed intraoperatively.     

Increased feeding and neuropeptide Y (NPY) but not NPY mRNA levels in the hypothalamus of the rat following central administration of the serotonin synthesis inhibitorp-chlorophenylalanine

Neurons containing serotonin (5-HT), a potent anorexic agent, come into contact with neuropeptide Y-ergic neurons, that project from the arcuate nucleus (ARC) to the paraventricular nucleus (PVN). NPY powerfully stimulates feeding and induces obesity when injected repeatedly into the PVN. We hypothesize that 5-HT tonically inhibits the ARC-PVN neurons and that balance between the two systems determines feeding and energy homeostasis. This study aimed to determine whether central injection of the 5-HT synthesis inhibitor p-chlorophenylalanine (pCPA), which increases feeding, increased hypothalamic NPY and NPY mRNA levels. pCPA (10 mg/kg in 3 μl) was administered into the third ventricle either as a single injection (n = 8) or daily for 7 days (n = 8). Control rats received a similar injection of saline. pCPA significantly increased food intake compared with controls after both single and repeated injections (P < 0.05). NPY levels were measured by radioimmunoassay in microdissected hypothalamic extracts. NPY levels in the acutely treated group were significantly increased in the paraventricular nucleus (PVN; by 41%,P = 0.01), anterior hypothalamic area (AHA; by 34%,P < 0.01) and lateral hypothalamic area (LHA; by 41%,P < 0.02). In the 7-day-treated group, NPY levels were also increased in the same areas, i.e. PVN (by 24%,P < 0.01), AHA (by 30%,P < 0.01) and LHA (by 38%,P = 0.01). There were no significant changes in the ARC or any other region or in hypothalamic NPY mRNA levels. pCPA administration increased NPY levels in several regions notably the PVN. This is a major site of NPY release, where NPY injection induces feeding. We suggest that the hyperphagia induced by pCPA is mediated by increased NPY levels and secretion in the PVN. This is further evidence for interactions between NPY and 5-HT in the control of energy homeostasis.     

Gut epithelial barrier markers in patients with obstructive sleep apnea

BackgroundObstructive sleep apnea (OSA) is now being recognized as an additional contributing factor to the pathogenesis of obesity-related comorbidities. At the same time, there is now increasing evidence to suggest that intestinal wall permeability plays a role in the development of metabolic syndrome. In the present study, circulating zonulin and fatty acid binding protein (I-FABP) were measured in association with metabolic, hepatic, and inflammatory parameters.ResultsCompared with controls, plasma I-FABP levels were significantly higher in patients with OSA (571 pg/mL [IQR 290–950] vs 396 pg/mL [IQR 234–559], p = 0.04). Zonulin levels were similar between groups. Significant relationships were observed between zonulin levels and waist circumference (p < 0.05), glucose (p < 0.05), and insulin (p < 0.05). In addition, in the OSA group, zonulin levels correlated negatively with the mean nocturnal oxygenation saturation (p < 0.05) and positively with total cholesterol (p < 0.05), alanine aminotransferase (ALT) (p < 0.005), aminotransferase (AST) (p < 0.01), gamma glutamyltransferase (GGT) (p < 0.005), and high-sensitivity C-reactive protein (hs-CRP) (p < 0.05). Multivariate analysis showed that associations between zonulin and ALT, AST, and hs-CRP were attenuated, but not eliminated, after adjustment for other variables.ConclusionsThe results of this study suggest that OSA is a risk factor for intestinal damage, regardless of metabolic profile, and that intestinal permeability might be a possible contributor to nonalcoholic fatty liver disease in patients with OSA.     

Simultaneous monitoring of endothelin-1 and vasopressin plasma levels in migraine

Vasopressin levels in plasma rise during migraine attacks. Vasopressin also induces endothelin-1 synthesis in endothelial cells, suggesting a role as a mediator of elevated plasma endothelin-1 in migraine. To explore a possible relationship between endothelin-1 and vasopressin in migraine, plasma concentrations of both peptides were monitored simultaneously throughout an attack and during two migraine-free intervals (control) in 20 patients. Endothelin-1 was elevated 6 h after the onset of an attack (3.3 +/- 0.3 pg/ml vs 2.7 +/- 0.2 pg/ml during migraine-free intervals; p = 0.12) whereas vasopressin was increased over control levels (2.8 +/- 0.3 pg/ml) by 3 h (3.6 +/- 0.4 pg/ml; p < 0.05) and remained elevated at 6 h (3.9 +/- 0.5 pg/ml; p < 0.01). These data suggest that vasopressin may act as a peripheral mediator of increased plasma endothelin-1 in migraine.     

Nonenzymatic antioxidants of blood in multiple sclerosis

Free radical action has been suggested as a causal factor in multiple sclerosis. We investigated the plasma level of lipid peroxides expressed in terms of malone dialdehyde and changes in blood nonenzymatic antioxidants (glutathione, α-tocopherol, retinol, plasma sulfhydryl groups, and uric acid) in multiple sclerosis patients with exacerbation or in remission, including a group treated with β-interferon. The malone dialdehyde level was increased by 38% (n.s.) during exacerbations. The blood concentration of oxidized glutathione was likewise elevated (P < 0.05), while the ratio of plasma α-tocopherol to cholesterol plus triglyceride was decreased (P < 0.001). These changes suggest increased free radical production and consumption of the scavenger molecules during the active phase of the disease. Blood reduced glutathione level was increased (P < 0.01) during exacerbation and remission as well. The rise in this thiol is likely to be a compensatory mechanism defending the cells from further oxidant injuries. β-Interferon increased plasma α-tocopherol levels (P < 0.001) but not the lipid corrected α-tocopherol value. Other parameters were not influenced by the drug. Received: 7 April 1998 Received in revised form: 20 October 1998 Accepted: 3 December 1998     

Brain region-dependent increases in β-amyloid and apolipoprotein E levels in hypercholesterolemic rabbits

Summary. Recent studies indicate a possible link between serum cholesterol level, β-amyloid (Aβ) peptide concentrations, and the incidence of Alzheimer's disease (AD). In the present report, the effects of dietary cholesterol on Aβ and apolipoprotein E (APOE) levels in several brain regions were examined using diet-induced hypercholesterolemic rabbits as the animal model. Increased dietary cholesterol levels increased Aβ concentrations in temporal cortex (p = 0.02). A similar trend was observed in the frontal cortex (p = 0.06), yet not in the cerebellum. Interestingly, the regional levels of Aβ in the hypercholesterolemic rabbit paralleled the amyloid pathology observed in AD brain. Elevated APOE levels were also noticed in temporal (p < 0.01) and frontal (p < 0.01) cortices, but not in cerebellum, in the rabbit fed with cholesterol-abundant diet. These results suggest that high serum cholesterol levels could induce the elevation of brain APOE, which may play a role in aggravating the Aβ accumulation. Received June 20, 2002; accepted December 16, 2002 Published online February 19, 2003 Acknowledgements This work is supported in part by grants from National Science Council in Taiwan (NSC90-2320-B-006-072 and NSC90-2320-B006-052). Authors' address: Dr. Y.-M. Kuo, Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, 1 Ta Hsueh Road, Tainan 70101, Taiwan, R.O.C., e-mail: kuoym@mail.ncku.edu.tw     

Urokinase-type plasminogen activator regulates neurodegeneration and neurogenesis but not vascular changes in the mouse hippocampus after status epilepticus

Expression of urokinase-type plasminogen activator (uPA) is increased after brain injury, suggesting that, like in cancer tissue, uPA plays roles in brain remodeling. Here we injured brain with intrahippocampal kainic acid (KA) injection in adult Wt and uPA?/? mice. At 20 days post-injury, uPA?/? mice had more severe loss of contralateral pyramidal (p < 0.05) and hilar neurons (p < 0.05) than Wt mice. The number of doublecortin (DCX)-positive newly born neurons was also reduced in uPA?/? mice as compared to Wt (p < 0.01). No difference was observed in granule cell dispersion or distribution of DCX-positive neurons in the dentate gyrus. uPA deficiency did not affect the total length of hippocampal blood vessels or vessel density. No differences were observed in the severity of status epilepticus or consequent epilepsy between the genotypes. These data indicate that uPA deficiency can unfavorably modulate both delayed neurodegeneration and neurogenesis but has little effect on post-injury neuronal migration and vascular density. Our results favor the idea that elevated uPA during the post-injury phase is neuroprotective.     

Increased level of von Willebrand factor is significantly and independently associated with diabetes in postinfarction patients. THROMBO Investigators

Diabetes is an established risk factor for reinfarction and cardiac death in postinfarction patients. Since the underlying mechanism of diabetes-related risk is not fully understood we aimed to evaluate the association between lipids, thrombogenic factors and diabetes in postinfarction patients. The study population consisted of 1,045 postinfarction patients (846 non-diabetic, 125 non-insulin- and 74 insulin-requiring diabetics) with the following blood tests performed 2 months after an index myocardial infarction: lipoprotein (a), apolipoprotein-B, apolipoprotein-A, cholesterol, HDL cholesterol, triglycerides, insulin, von Willebrand factor (vWF), fibrinogen, factor VII, D-dimer, and plasminogen activator inhibitor (PAI-1). After adjustment for relevant clinical covariates, non-insulin-requiring diabetes was significantly (p < 0.05) associated with elevated levels of (odd ratios per 1 log unit increase in parenthesis) vWF (1.74) and PAI-1 (1.42) whereas insulin requiring diabetes was associated with even more elevated levels of vWF (4.68), but not with increased levels of PAI-1. No significant differences in lipid levels were observed among three groups. In conclusion, increased level of von Willebrand factor is significantly and independently associated with diabetes in postinfarction patients, suggesting that endothelial damage is the primary mechanisms contributing to an increased occurrence of vascular and cardiac events in diabetic postinfarction patients.     

Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis

Background The role of oxidative stress in patients with multiple sclerosis (MS) is poorly understood. Objective To investigate oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of MS. Methods Diene conjugate (DC) levels (a measure of lipid peroxidation), total antioxidative activity (AOA) and total antiradical activity (ARA) were measured in serum and peripheral blood leukocytes from 30 patients with benign relapsing remitting MS (BMS), 27 with secondary progressive MS (SPMS), 29 with primary progressive MS (PPMS), and 30 healthy controls. All MS patients were in a clinically stable phase. Results Serum DC levels were elevated in patients with BMS (p <0.05), SPMS (p <0.01) and PPMS (p <0.001). Serum total AOA and ARA were not different between MS patients and controls. Compared to controls, leukocyte DC levels were not different in each MS subgroup, but total ARA was elevated. There was a strong correlation, both in controls and MS patients, between leukocyte DC levels and leukocyte total ARA (p <0.0001) and leukocyte total AOA (p <0.0001). Conclusion Oxidative stress occurs in progressive as well as benign MS. The finding that cells withstand oxidative stress, due to upregulated cellular antioxidant defence mechanisms, suggests that reactive oxygen species (ROS) formation in MS is not necessarily deleterious. This work was supported by Multiple Sclerosis Internationaal (MSI),Amsterdam, The Netherlands.     

Taurine improves neuron injuries and cognitive impairment in a mouse Parkinson’s disease model through inhibition of microglial activation

Clinical and experimental findings support the view that activation of hippocampus microglia through NADPH oxidase contributes to cognitive impairment in Parkinson's disease (PD). Taurine, an antioxidant, displays an exclusive physical property on brain function, such as learning and memory. To date, the role of taurine in improving cognitive impairment in PD is not fully uncovered. Hence, we evaluated the protective effect of taurine on cognitive ability and explored the related mechanism in the model built by paraquat and maneb (P + M)-induced PD mice. Then the ability of learning and memory was observed by Morris water maze, neuron loss was evaluated by immunohistochemistry in hippocampus, the level of postsynaptic density 95 (PSD95) and microglia activation was assessed by immunostaining, the molecules (gp91^phox, p47^phox, mac1, p-Src/Src and p-Erk/Erk) were examined by western blot. The results showed that taurine could alleviate the impairments in learning and memory induced by P + M injection in mice (decreased escape latency on day 4, P < 0.01; decreased swimming distance on day 4, P < 0.05; increased percent time in target quadrant, P < 0.05), corresponding with activation of microglia (decreased IBa-1 density, P < 0.001; decreased the protein expression of p47^phox, P < 0.05; decreased protein expression of gp91^phox, P < 0.01; decreased p-Src/Src, P < 0.01; decreased p-Erk/Erk, P < 0.01; decreased mac 1, P < 0.01), decreased neuron loss (increased number of NeurN⁺ neuron, P < 0.001; increased protein expression of NeruN, P < 0.01; decreased protein expression of caspase 3, P < 0.01) and increased PSD95 level in hippocampus (P < 0.01). The results indicated that mac1 and Src-Erk signaling was involved in increased NADPH oxidase expression in hippocampus microglia of P + M mice, and taurine could improve injuries in learning and memory through mac1 reduction. The new findings in mac1 triggering hippocampal microglia NADPH oxidase through Src/Erk pathway of the present study might provide a therapy target for PD.     

Apolipoprotein A5 gene promoter region T-1131C polymorphism associates with elevated circulating triglyceride levels and confers susceptibility for development of ischemic stroke

The possible pathogenic role of triglycerides (TG) in the development of ischemic stroke is still under extensive investigation. Recently, apolipoprotein (apo)A5 gene promoter region T-1131C polymorphism has been shown to associate with elevated serum TG levels. In the current work, a total of 302 subjects were classified as being large vessel-associated, small vessel-associated, or belonging to a mixed group of ischemic stroke-affected patients. The level of TG was increased in all groups (p<0.01). The apoA5-1131C allele frequency was approximately twofold in all groups of stroke patients compared with the controls (5 vs 10–12%; p<0.05); and the apoA5-1131C allele itself was also found to associate with increased TG levels in all groups. In a multivariate logistic regression analysis model adjusted for differences in age, gender, serum cholesterol, hypertension, pressence of diabetes mellitus, smoking and drinking habits, and ischemic heart disease, a significantly increased risk of developing stroke disease was found in patients carrying the apoA5-1131C allele (p<0.05; odds ratio OR=2.1 [1.3–4.7]); this association was also proven for all subtypes of the stroke. The results presented here suggest that the apoA5-1131C allele is an independent risk factor for the development of stroke. Being that apoA5 gene is under the control of the peroxisome proliferator-activated receptor α, theoretically, the current observations also can have long-term therapeutic consequences.     

Increase of low serum concentrations of high-density lipoprotein (HDL) cholesterol in TIA-patients treated with phenytoin

Serum high density lipoprotein (HDL) cholesterol and other lipoproteins were measured in 27 TIA-patients with a mean age of 49 +/- 10 years before and during phenytoin therapy. The pretreatment concentrations of HDL-cholesterol (mmol/l, mean +/- SD) were lower (p less than 0.001) in male (1.03 +/- 0.25) and in female patients (1.15 +/- 0.44) than in healthy male (1.28 +/- 0.34) and female controls (1.52 +/- 0.31) respectively. After one month's phenytoin therapy HDL cholesterol concentrations reached normal levels (men 1.33 +/- 0.38, women 1.61 +/- 0.27) and after 9 months of therapy even surpassed them (men 1.47 +/- 0.27, p less than 0.05; women 1.91 +/- 0.33, p less than 0.01). Percent increase of HDL cholesterol after 9 months of therapy was 42 +/- 25 in men and 68 +/- 46 in women. There was a positive correlation (r = 0.43, p less than 0.05) between serum phenytoin level and increase of HDL cholesterol. HDL/LDL cholesterol ratio increased (p less than 0.01) also during 9 months of therapy (men from 0.26 +/- 0.05 to 0.36 +/- 0.10, women from 0.26 +/- 0.07 to 0.43 +/- 0.13) and showed a positive correlation (r = 0.91, p less than 0.001) with increase of serum HDL cholesterol. The HDL cholesterol levels achieved have been maintained with a mean serum phenytoin level of 5.6 +/- 3.6 mg/l. Phenytoin induced increase in serum HDL levels should not yet be equated with protection against atherosclerosis.     

A study of hemostasis in ischemic cerebrovascular disease: IV. A five year follow-up of some blood coagulation parameters also including fibrinopeptide A,factor XII and prekallikrein

Twentyseven young adults (mean age 46) with ischemic cerebrovascular disease (ICD) were reinvestigated about 5 years after discharge and compared to 67 healthy controls. Factor VIII related antigen was again found significantly (p < 0.005 and p < 0.001) increased in male as well as female patients and a significant (r = 0.66, p < 0.001) correlation was found with earlier data. Factor VIII biological activity was again found increased, significantly (p < 0.001) in males. In contrast to earlier results antithrombin antigen and activity were significantly (p < 0.001) decreased in males. This finding and decreased levels of factor XII in female patients (p < 0.001) and of prekallikrein in male patients (p < 0.01) could reflect disturbed regulatory functions or possibly constitutional differences. As in most subjects no increase of fibrinopeptide A was found, there was no sign of continuous activation of the whole coagulation sequence. Since hemostatic abnormalities were unrelated to acute phase reacting proteins they were obviously of a different nature than unspecific response to tissue damage and acute stress. High levels of factor VIII and low levels of antithrombin imply that the coagulation system could be more easily activated when other factors coincide, e.g. intimal lesions in carotide arteries.     

Depression of tissue plasminogen activator (t-PA) activity and rise of t-PA inhibition and acute phase reactants in blood of patients with acute myocardial infarction (AMI)

We determined during the acute stage of myocardial infarction selected fibrinolysis variables (tissue-type plasminogen activator, intrinsic plasminogen activators, tissue-type plasminogen activator inhibition, C1-inactivator) and related the observed changes to changes in two acute phase reactants (C-reactive protein, fibrinogen). Acute myocardial injury induce significant increases in blood of tissue-type plasminogen activator inhibition (day one, p less than 0.05), C-reactive protein (day three, p less than 0.01), fibrinogen (day six, p less than 0.01), and C1-inactivator (day eight, p less than 0.01). Tissue-type plasminogen activator activity measured as C1-inactivator resistant fibrinolytic activity showed a minimum day two after the acute attack (p less than 0.01), whereas plasminogen activator activities arising from the intrinsic system of fibrinolysis remained constant. The observed changes did not parallel the occurrence of deep vein thrombosis indicated by a positive Tc-plasmin test (41% of the patients).     

Different effects of insulin and 2-deoxy- -glucose administration on tyrosine hydroxylase gene expression in the locus coeruleus and the adrenal medulla in rats

The major brain norepinephrinergic nucleus, locus coeruleus, is an important integrating element of extero- and interoceptive stimuli in organisms facing different physiological challenges. We investigated the effects of single and repeated (seven times) exposure to immobilization stress (120 min daily), insulin (5 IU/kg, i.p. daily) or 2-deoxy- -glucose (500 mg/kg, i.p. daily) administration on tyrosine hydroxylase (TH) mRNA levels, the rate-limiting enzyme in catecholamine biosynthesis, by in situ hybridization in locus coeruleus and by Northern blot analysis in the adrenal medulla of rats. Both the single and repeated immobilization caused a significant increase in TH mRNA levels in the locus coeruleus (1.5–2-fold; p < 0.05) and in the adrenal medulla (about 4-fold; p < 0.05) when compared with unstressed controls. Hypoglycemia induced by a single or repeated insulin administration led to about fourfold (p < 0.01) elevation in adrenal medullary TH mRNA levels, whereas TH mRNA in locus coeruleus remained unchanged when compared with saline-treated controls. In contrast to the effect of insulin-induced hypoglycemia, cellular glucoprivation caused by a single or repeated 2-deoxy- -glucose administration significantly elevated TH mRNA levels in both the adrenal medulla (fourfold; p < 0.01) and the locus coeruleus (twofold; p < 0.01). Our data suggest that in contrast to immobilization or cellular glucoprivation caused by 2-deoxy- -glucose administration, insulin-induced hypoglycemia is not a specific or quantitatively sufficient stimulus for induction of TH gene expression in the locus coeruleus, although all these stressors strongly activate the process in the adrenal medulla.     

Genetically Determined Low-Density Lipoprotein Cholesterol and Risk of Subarachnoid Hemorrhage

We evaluated whether genetically elevated low-density lipoprotein cholesterol (LDL-C) levels are associated with lower risk of intracranial aneurysms and subarachnoid hemorrhage (IA/SAH). We conducted a 2-sample Mendelian randomization (MR) study. Our primary analysis used the inverse-variance weighted method. In secondary analyses, we implemented the MR-PRESSO method, restricted our analysis to LDL-C–specific instruments, and performed multivariate MR. A 1-mmol/l increase in genetically instrumented LDL-C levels was associated with a 17% lower risk of IA/SAH (odds ratio = 0.83, 95% confidence interval = 0.73–0.94, p = 0.004). Results remained consistent in secondary and multivariate analyses (all p < 0.05). Our results provide evidence for an inverse causal relationship between LDL-C levels and risk of IA/SAH. ANN NEUROL 2022;91:145–149