Paradoxical Elevation Research Articles

Adiponectin Paradox More Evident in Non-Obese Than in Obese Patients with Diabetic Microvascular Complications

Adiponectin is generally regarded as a beneficial molecule, protecting against insulin resistance and atherosclerosis, and its serum levels are low in individuals with obesity as well as in those with type 2 diabetes (T2DM). However, several clinical studies have shown associations between high adiponectin values and major health concerns. These conflicting findings are termed the "adiponectin paradox". Similarly, these paradoxical adiponectin elevations were observed in patients with diabetic microvascular complications. This cross-sectional study aimed to identify differences in factors, including adiponectin, related to diabetic vascular complications between non-obese and obese patients. Study patients with T2DM were non-obese (n=197) or obese (n=197), matched by a propensity score model adjusted with age and gender. Independent factors for each of the microvascular complications were determined using multivariate logistic regression analyses. The prevalence of nephropathy was high in obese T2DM patients. In addition to long diabetes duration, elevated adiponectin was a common characteristic of patients with microvascular complications. Logistic regression analyses for microvascular complications revealed adiponectin to be highly related to retinopathy (odds ratio [OR], 1.138; 95%confidence intervals [CI], 1.004-1.289, p<0.001), nephropathy (OR, 1.192; CI, 1.077-1.319, p<0.001) and neuropathy (OR, 1.217; CI, 1.071-1.384, p<0.001), in non-obese patients. In contrast, the association between adiponectin values and complications was modest in obese patients. Adiponectin regulation in response to vascular damage differed between non-obese and obese patients, suggesting that adiponectin regulation is compromised by fat accumulation. Assuming that paradoxical elevation of adiponectin in vascular damage is a compensatory response, we speculate that responsive upregulation might be insufficient in obese patients. These newly-recognized differences in adiponectin values might lead to novel insights into adiponectin regulation and our understanding of the adiponectin paradox.

Acromegaly with empty sella syndrome.

SummaryAcromegaly is a rare, chronic progressive disorder with characteristic clinical features caused by persistent hypersecretion of growth hormone (GH), mostly from a pituitary adenoma (95%). Occasionally, ectopic production of GH or growth hormone-releasing hormone (GHRH) with resultant GH hypersecretion may lead to acromegaly. Sometimes localizing the source of GH hypersecretion may prove difficult. Rarely, acromegaly has been found in patients with an empty sella (ES) secondary to prior pituitary radiation and/or surgery. However, acromegaly in patients with primary empty sella (PES) is exceeding rarely and has only been described in a few cases. We describe a 47-year-old male who presented with overt features of acromegaly (macroglossia, prognathism, increased hand and feet size). Biochemically, both the serum GH (21.6 μg/L) and insulin-like growth factor 1 (635 μg/L) were elevated. In addition, there was a paradoxical elevation of GH following a 75 g oral glucose load. Pituitary MRI demonstrated an ES. In order to exclude an ectopic source of GH hypersecretion, further biochemical tests and imaging were done, which were unremarkable. Notably, increased uptake in the sella turcica on the 68Gallium DOTATATE PET/CT confirmed the ES as the likely source of GH secretion. As no overt lesion was noted, medical treatment (octreotide acetate) was initiated with a good clinical and biochemical response. At his 3 month follow-up, he reported an improvement in symptoms (fatigue and headache), however he still complained of low libido. Due to a persistently low testosterone level at follow-up, a long-acting testosterone was initiated. His GH level normalised, and IGF-1 has significantly reduced.Learning pointsThe commonest cause of acromegaly is due to GH hypersecretion from pituitary adenomas (95%).Acromegaly has rarely been found in patients with ES.It is important to exclude a past history suggestive of pituitary apoplexy.Extra-pituitary source of GH such as ectopic production of GHRH with resultant GH hypersecretion needs to be excluded.In such cases, since there is no resectable mass, medical therapy is the primary treatment option.

Clinical Parameters, Fuel Oxidation, and Glucose Kinetics in Patients With Type 2 Diabetes Treated With Dapagliflozin Plus Saxagliptin.

To examine the mechanisms responsible for improved glycemia with combined sodium-glucose cotransporter 2 inhibitor (SGLT2i) plus dipeptidyl peptidase 4 inhibitor therapy in type 2 diabetes. Fifty-six patients (HbA1c 8.9 ± 0.2% [74 ± 2 mmol/mol]) were randomized to dapagliflozin (DAPA) 10 mg, DAPA/saxagliptin (SAXA) 10/5 mg, or placebo (PCB) for 16 weeks. Basal endogenous glucose production (EGP) (3-3H-glucose), urinary glucose excretion, glucose/lipid oxidation, HbA1c, and substrate/hormone levels were determined before treatment (Pre-Tx) and after treatment (Post-Tx). At week 16, HbA1c decrease was greater (P < 0.05) in DAPA/SAXA (-2.0 ± 0.3%) vs. DAPA (-1.4 ± 0.2%) and greater than PCB (0.2 ± 0.2%). Day 1 of drug administration, EGP (∼2.40 mg/kg/min) decreased by -0.44 ± 0.09 mg/kg/min in PCB (P < 0.05) but only by -0.21 ± 0.02 mg/kg/min in DAPA and DAPA/SAXA (P < 0.05 vs. PCB). At week 16, EGP increased to 2.67 ± 0.09 mg/kg/min (DAPA) and 2.61 ± 0.08 mg/kg/min (DAPA/SAXA), despite reductions in fasting plasma glucose by 47 and 77 mg/dL, respectively, and no changes in PCB. Baseline plasma free fatty acids rose by 40 µmol/L with DAPA but declined by -110 with PCB and -90 µmol/L with DAPA/SAXA (P < 0.05, Pre-Tx vs. Post-Tx). In DAPA, carbohydrate oxidation rates decreased from 1.1 ± 0.1 to 0.7 ± 0.1 mg/kg/min, whereas lipid oxidation rates increased from 0.6 ± 0.1 to 0.8 ± 0.1 mg/kg/min (P < 0.01). In DAPA/SAXA, the shift in carbohydrate (1.1 ± 0.1 to 0.9 ± 0.1 mg/kg/min) and lipid (0.6 ± 0.1 to 0.7 ± 0.1 mg/kg/min) oxidation was attenuated (P < 0.05). The addition of SAXA to DAPA resulted in superior glycemic control compared with DAPA monotherapy partly because of increased glucose utilization and oxidation. Although the decrease in insulin/glucagon ratio was prevented by SAXA, EGP paradoxical elevation persisted, indicating that other factors mediate EGP changes in response to SGLT2i-induced glucosuria.

Paradoxical Elevation of Both Serum B12 and Methylmalonic Acid Levels in Assessing B12 Status in Children With Short-Bowel Syndrome.

Measurement of vitamin B12 (B12) levels is routinely used to monitor B12 sufficiency. However, its accuracy may not be reliable in patients with short-bowel syndrome (SBS). The presence of elevated methylmalonic acid (MMA) levels can also be used as a marker for B12 deficiency. Therefore, our aim was to analyze serum B12 and MMA levels simultaneously in a cohort of children with SBS to evaluate the accuracy of these markers in the assessment of B12 status. Children ages 1-18 with intestinal failure were eligible for enrollment. MMA and B12 levels were checked simultaneously in all patients, with 93 sets of labs obtained over 2 years. Fifty percent of the patients were receiving parenteral nutrition. B12 injections were administered to 14patients who had simultaneously elevated MMA and B12, and a repeat MMA level was measured 4-6 weeks after injection. Data were collected retrospectively. Forty-eight percent of the lab pairs showed evidence of both elevated MMA and high or normal B12, which contradicted the expected inverse relationship of these markers. There was a statistically significant decrease in mean MMA values after treatment with B12 injections (412.7 vs 1037.5, P = 0.001). Paradoxical elevation of MMA with normal or elevated serum B12 is common in children with SBS. Caution should be used when interpreting serum B12 and MMA values in this setting. This may be related to effects of small-bowel bacterial overgrowth, a condition commonly seen in these patients.

TCTAP A-019 Paradoxical Elevation of Cholesterol Efflux Capacity During Acute Coronary Syndrome in Young Heterogenous Asians

HDL cholesterol represents a robust and well-integrated biomarker of cardiovascular risk. The prevalence of low HDL cholesterol is high and likely to increase in coming years in parallel with the epidemic of obesity and type 2 diabetes mellitus. The notion of HDL functionality has circulated in the

Changes in marrow adipose tissue with short-term changes in weight in premenopausal women with anorexia nervosa.

In anorexia nervosa, a psychiatric disease characterized by self-induced starvation and a model of chronic undernutrition, levels of subcutaneous (SAT) and visceral (VAT) adipose tissue are low, whereas marrow adipose tissue (MAT) levels are elevated compared to normal-weight women. The reason for this paradoxical elevation of an adipose tissue depot in starvation is not known. We sought to understand changes in MAT in response to subacute changes in weight and to compare these changes with those of other fat depots and body composition parameters. We conducted a 12-month longitudinal study including 46 premenopausal women (n = 26 with anorexia nervosa and n = 20 normal-weight controls) with a mean (s.e.m.) age of 28.2 ± 0.8 years. We measured MAT, SAT, VAT and bone mineral density (BMD) at baseline and after 12 months. At baseline, SAT (P < 0.0001), VAT (P < 0.02) and BMD of the spine and hip (P ≤ 0.0002) were significantly lower and vertebral and metaphyseal MAT (P ≤ 0.001) significantly higher in anorexia nervosa compared to controls. Weight gain over 12 months was associated with increases not only in SAT and VAT, but also epiphyseal MAT (P < 0.03). Changes in epiphyseal MAT were positively associated with changes in BMD (P < 0.03). In contrast to the steady state, in which MAT levels are higher in anorexia nervosa and MAT and BMD are inversely associated, short-term weight gain is associated with increases in both MAT and BMD. These longitudinal data demonstrate the dynamic nature of this fat depot and provide further evidence of its possible role in mineral metabolism.

Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice.

The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the 16p11.2 deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in 16p11.2 deletion carriers.SIGNIFICANCE STATEMENT The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the 16p11.2 chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the 16p11.2del mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult 16p11.2del mice. These data provide a strong rationale for therapeutic approaches to this disorder.

Paradoxical skin lesions induced by anti-TNF-α agents in SAPHO syndrome.

The objectives of the study were to characterize the clinical picture of paradoxical skin lesions in SAPHO patients treated with anti-TNF-α agents and to explore its pathogenesis. Patients treated with anti-TNF-α therapy were identified from a cohort of 164 SAPHO patients. The clinical data and skin biopsies were collected. The usage, efficacy, and side effects of anti-TNF-α therapy were recorded. Forty-one (25.0%) patients received anti-TNF-α therapy, of which seven (17.1%) developed paradoxical skin lesions after 1 to 14 infusions. Patients with such lesions were older at onset of skin lesions than those without (p = 0.034). Expression of TNF-α in palmoplantar pustulosis increased after anti-TNF-α therapy in the two examined patients with exacerbated skin lesions. Anti-TNF-α therapy induces paradoxical skin lesions in 17.1% SAPHO patients. Late onset of skin manifestations is associated with an increased risk of such lesions. The paradoxical elevation of TNF-α expression in lesions may contribute to this phenomenon.

Paradoxical elevation of serum TRACP5b levels despite increase in lumbar spine bone mineral density during anti-TNFα therapy in patients with inflammatory rheumatic disease: a 2-year prospective assessment of bone mass, bone metabolism, and the trabecular bone score.

To examine the impact of long-term anti-TNFα therapy on bone mass, bone metabolism, and the trabecular bone score (TBS) in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS). In eight patients with RA and 12 with AS, bone mineral densities (BMDs) of the lumbar spine (LS), left and right femoral neck, and total skeleton were measured using dual X-ray absorptiometry at baseline and then at 6, 12, and 24 months after anti TNFα therapy. The TBS was also calculated. At baseline and at 1, 3, 6, 12, 18, and 24 months, bone metabolism was assessed by measurements of pro-collagen-I carboxyterminal propeptide (PICP), osteocalcin, and bone alkaline phosphatase levels in the serum, which are indicative of bone formation and β-isomerized carboxy-terminal telopeptide of type-I collagen (β-CTX-I) and serum isoform 5b of tartrate-resistant acid phosphatase (TRACP5b) levels in the serum, which are indicative of bone resorption. In patients with RA, the LS T-score increased (3.2%, p<0.001) and the TBS progressively decreased (-3.9%, p=0.03). In patients with AS, the LS BMD and T-score increased (4.3% and 6.2%, respectively; p<0.001) with no significant change in the TBS. Serum TRACP5b levels dramatically increased in both groups (227% in patients with RA and 150% in those with AS, p<0.001), while β-CTX-I levels did not change. Serum osteocalcin and PICP levels showed a transitory increase in patients with AS. Long-term anti-TNFα therapy increased LS bone mass and affected bone quality (TBS) with little impact on bone remodeling. Conversely, TRACP5b levels dramatically increased during anti-TNFα therapy but without any detrimental effect on bone mass.

Deficiencia de 3β-hidroxiesteroide deshidrogenasa: una causa rara de hiperplasia adrenal congénita

La hiperplasia adrenal congénita corresponde a un grupo de enfermedades heredadas con defectos enzimáticos que pueden comprometer la biosíntesis del cortisol. La deficiencia de la enzima 3β-hidroxiesteroide deshidrogenasa tipo 2 es una causa rara de este defecto en la que el desarrollo genital masculino se encuentra alterado y presenta una virilización leve en las mujeres afectadas. En humanos se han descrito dos isoenzimas, la tipo I y la tipo II, codificadas por los genes HSD3B1 y HSD3B2, respectivamente, con una distribución tisular específica. Los programas de tamización de la hiperplasia adrenal congénita reportan elevación paradójica de la 17-hidroxiprogesterona secundaria al efecto periférico de la 3β-hidroxiesteroide deshidrogenasa tipo 1, isoenzima de la 3β-hidroxiesteroide deshidrogenasa tipo 2, que tiene una constante de Michaelis menor con el sustrato. A pesar de la baja prevalencia el estudio de este defecto ha tenido importantes avances en cuanto a la información molecular y el diagnóstico hormonal, datos que han sido respaldados por la identificación de la alteración genética y han disminuido la posibilidad del sobrediagnóstico; evento que se estaba presentado frecuentemente con los puntos de cortes establecidos inicialmente para el diagnóstico de la enfermedad, sobre todo en sus formas leves.

Hydrogen Sulfide Suppresses Diabetic Myocardial ER Stress: An Uncanonical Way

Diabetes critically inhibits cardiac endogenous production of hydrogen sulfide (H2S), a cardioprotective gaseous signaling molecule, by suppressing expression of CBS, CSE and 3MST (known H2S producers endogenously) in the mouse models of type 1 diabetes (Akita or C57BL/6‐Ins2Akita/J). Diabetes induced ER stress has been previously identified as an initiator of cardiomyocyte apoptosis and cardiomyopathy. However, the mechanisms of ER stress induction are not clearly illustrated. Furthermore, H2S has been implicated as an inducer or suppressor of ER stress in a tissue type specific manner and molecular mechanisms of H2S mediated ER stress regulation are not entirely known. Here, we show that chronic H2S supplementation resulted in enhanced cardiac function concurrent with suppression of ER stress with significant reversal of elevated CHOP levels in the diabetic hearts. Interestingly, there were no significant changes in the sXBP1 levels in the diabetic hearts with or without H2S treatment suggesting differential regulation of different arms (PERK, ATF6 and IRE1) of ER stress pathway. Importantly, the ER stress suppression is accompanied by suppression of GRP78 (AKA Bip) mRNA levels with a dramatic and paradoxical elevation in its protein levels. Differential translational regulation and/or protein degradation are implicated in regulation of GRP78 protein levels which further highlighted that H2S supplementation not only suppresses ER stress, but also raises the threshold for ER stress induction through elevation of GRP78 protein levels. Remarkably, the H2S mediated diabetic ER suppression was also accompanied with reversal of elevated TLR4 receptors, a well‐known inducer of ER stress upon stimulation. TLR4 mutant diabetic mice (Akita background) are currently studied to unravel relative contribution of TLR4 dependent and independent mechanisms for H2S mediated reversal of ER stress during diabetic cardiomyopathy. In conclusion, H2S mediated raise in threshold for ER stress induction involve GRP78 protein preservation and TLR4 level suppression in the diabetic hearts.Support or Funding InformationNIH grants : HL108621, HL074185 and DK104653.

Paradoxical Elevation of High Density Lipoprotein Cholesterol in Association with Lacunar-Type Cerebral Infarction.

BackgroundThe aim of this study was to evaluate the association between high-density lipoprotein cholesterol (HDLC) levels and the risk of lacunar infarction (LI) in a retrospective cohort study in China.Material/MethodsWe recruited 229 patients with obsolete brain infarctions single side (SOBI), 218 with obsolete brain infarctions bilateral sides (BOBI), 193 with both acute stroke and obsolete lacunar infarctions single side (AI&SOBI), 113 with both acute stroke and obsolete lacunar infarctions bilateral sides (AI&BOBI), and 203 without any infarctions (Control).Results1) The plasma levels of HDLC in group BOBI, AI&SOBI, and AI&BOBI were higher than in the control group, and lower in group SOBI than in the control group (p<0.01). 2) The plasma levels of HDLC in group AI&SOBI were significantly higher than in group SOBI (p<0.01). 3) The plasma levels of HLDL were similar between group AI&SOBI and AI&BOBI. 4) There were significant relationships between HDLC and acute lacunar stroke, even after adjusting for these factors such as age, sex, triglyceride, total cholesterol, low-density lipoprotein cholesterol, and history of diabetes (p=0.001). 4) Compared with the controls, the calculation of odds ratios indicated relative risk estimates of higher HDLC for acute lacunar stroke with obsolete lacunar infarction.ConclusionsElevated HDLC may be an independent predictor of recurrent stroke with obsolete lacunar infarctions single side in Chinese people, justifying clinical trials for secondary prevention of stroke by generally increasing HLDL level. According to the difference between single and bilateral side multiple silent lacunar infarcts, it is inferred that HDLC may increase the risk of atherothrombotic infarction but reduce the risk of cardioembolic infarction in the general Chinese population.

Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis

Inorganic nitrate and nitrite from endogenous and dietary sources have emerged as alternative substrates for nitric oxide (NO) formation in addition to the classic L-arginine NO synthase (NOS)-dependent pathway. Here, we investigated a potential cross-talk between these two pathways in the regulation of vascular function. Long-term dietary supplementation with sodium nitrate (0.1 and 1 mmol kg(-1) day(-1)) in rats caused a reversible dose-dependent reduction in phosphorylated endothelial NOS (eNOS) (Ser1177) in aorta and a concomitant increase in phosphorylation at Thr495. Moreover, eNOS-dependent vascular responses were attenuated in vessels harvested from nitrate-treated mice or when nitrite was acutely added to control vessels. The citrulline-to-arginine ratio in plasma, as a measure of eNOS activity, was reduced in nitrate-treated rodents. Telemetry measurements revealed that a low dietary nitrate dose reduced blood pressure, whereas a higher dose was associated with a paradoxical elevation. Finally, plasma cyclic guanosine monophosphate increased in mice that were treated with a low dietary nitrate dose and decreased with a higher dose. These results demonstrate the existence of a cross-talk between the nitrate-nitrite-NO pathway and the NOS-dependent pathway in control of vascular NO homeostasis.

Abstract 18679: Abnormal Stress Induced Changes in Arterial Stiffness in Middle Aged Men and Women With Impaired Fasting Glucose at Risk of Their First Episode of Symptomatic Heart Failure

Background: Abnormal arterial stiffness is associated with future heart failure (HF). We hypothesized that abnormal stress associated increase in arterial stiffness may be present in middle aged and elderly individuals with diabetes (DM) or the pre-diabetic state of impaired fasting glucose (IFG) that are at risk for their first episode of symptomatic HF. Methods: We analyzed dobutamine magnetic resonance stress imaging (DMRI) results from 373 consecutively recruited community dwelling individuals aged 55-85 years at risk for but yet to develop symptomatic HF, that had resting LVEF &gt;45% and were without inducible ischemia. According to previously published techniques, personnel blinded to participant identifiers measured arterial stiffness (brachial pulse pressure/left ventricular stroke volume indexed to body surface area (PP/SVI) and the aortic elastance index or EaI (brachial end-systolic pressure/SVI) at rest and peak stress (80% of maximum predicted heart rate response for age). Participants were classified as normal fasting glucose (NFG), IFG or DM according to the ADA criteria. Results: Participants averaged 69 ± 8 years, were 79% white, 92% hypertensive and 66% women. After accounting for hypertension, gender, coronary artery disease, smoking, medications, dyslipidemia and visceral fat, we observed an abnormal paradoxical elevation in PP/SVI and EaI in those with IFG or DM aged 55 to 69 years; whereas in those ≥ 70 years, this abnormal increase was seen in all individuals regardless of their glucose state (Figure 1). Conclusion: Middle aged individuals with DM or the prediabetic state of IFG exhibit abnormal increases in arterial stiffness during dobutamine stress that is similar to elderly individuals’ ≥ 70 years at risk of their first episode of symptomatic heart failure. These data may help to explain why middle aged men and women with DM or IFG are predisposed to stress induced increase in episodic HF.

Rapamycin has paradoxical effects on S6 phosphorylation in rats with and without seizures

Accumulating data have demonstrated that seizures induced by kainate (KA) or pilocarpine activate the mammalian target of rapamycin (mTOR) pathway and that mTOR inhibitor rapamycin can inhibit mTOR activation, which subsequently has potential antiepileptic effects. However, a preliminary study showed a paradoxical exacerbation of increased mTOR pathway activity reflected by S6 phosphorylation when rapamycin was administrated within a short period before KA injection. In the present study, we examined this paradoxical effect of rapamycin in more detail, both in normal rats and KA-injected animals. Normal rats or KA-treated rats pretreated with rapamycin at different time intervals were sacrificed at various time points (1, 3, 6, 10, 15, and 24 h) after rapamycin administration or seizure onset for western blotting analysis. Phosphorylation of mTOR signaling target of Akt, mTOR, Rictor, Raptor, S6K, and S6 were analyzed. Seizure activity was monitored behaviorally and graded according to a modified Racine scale (n = 6 for each time point). Neuronal cell death was detected by Fluoro-Jade B staining. In normal rats, we found that rapamycin showed the expected dose-dependent inhibition of S6 phosphorylation 3-24 h after injection, whereas a paradoxical elevation of S6 phosphorylation was observed 1 h after rapamycin. Similarly, pretreatment with rapamycin over 10 h before KA inhibited the KA seizure-induced mTOR activation. In contrast, rapamycin administered 1-6 h before KA caused a paradoxical increase in the KA seizure-induced mTOR activation. Rats pretreated with rapamycin 1 h prior to KA exhibited an increase in severity and duration of seizures and more neuronal cell death as compared to vehicle-treated groups. In contrast, rapamycin pretreated 10 h prior to KA had no effect on the seizures and decreased neuronal cell death. The paradoxical effect of rapamycin on S6 phosphorylation was correlated with upstream mTOR signaling and was reversed by pretreatment of perifosine, an Akt inhibitor. These data indicate the complexity of S6 regulation and its effect on epilepsy. Paradoxical effects of rapamycin need to be considered in clinical applications, such as for potential treatment for epilepsy and other neurologic disorders.

Phenytoin toxicity associated with hypoalbuminaemia and the paradoxical elevation of serum concentration

Phenytoin toxicity associated with hypoalbuminaemia and the paradoxical elevation of serum concentration

A woman with severe lupus nephritis and difficult to control diabetes mellitus

A woman with severe lupus nephritis and difficult to control diabetes mellitus

Paradoxical ATP Elevation in Ischemic Penumbra Revealed by Quantitative Imaging Mass Spectrometry

Local responses of energy metabolism during brain ischemia are too heterogeneous to decipher redox distribution between anoxic core and adjacent salvageable regions such as penumbra. Imaging mass spectrometry combined by capillary electrophoresis/mass spectrometry providing quantitative metabolomics revealed spatio-temporal changes in adenylates and NADH in a mouse middle-cerebral artery occlusion model. Unlike the core where ATP decreased, the penumbra displayed paradoxical elevation of ATP despite the constrained blood supply. It is noteworthy that the NADH elevation in the ischemic region is clearly demarcated by the ATP-depleting core. Results suggest that metabolism in ischemic penumbra does not respond passively to compromised circulation, but actively compensates energy charges.

Plasmin-induced procoagulant effects in the blood coagulation: a crucial role of coagulation factors V and VIII

Plasminogen activators provide effective treatment for patients with acute myocardial infarction. However, paradoxical elevation of thrombin activity associated with failure of clot lysis and recurrent thrombosis has been reported. Generation of thrombin in these circumstances appears to be owing to plasmin (Plm)-induced activation of factor (F) XII. Plm catalyzes proteolysis of several coagulant factors, but the roles of these factors on Plm-mediated procoagulant activity remain to be determined. Recently developed global coagulation assays were used in this investigation. Rotational thromboelastometry using whole blood, clot waveform analysis and thrombin generation tests using plasma, showed that Plm (> or =125 nmol/l) shortened the clotting times in similar dose-dependent manners. In particular, the thrombin generation test, which was unaffected by products of fibrinolysis, revealed the enhanced coagulation with an approximately two-fold increase of peak level of thrombin generation. Studies using alpha2-antiplasmin-deficient plasma revealed that much lower dose of Plm (> or =16 nmol/l) actually contributed to enhancing thrombin generation. The shortening of clotting time could be observed even in the presence of corn trypsin inhibitor, supporting that Plm exerted the procoagulant activity independently of FXII. In addition, using specific coagulation-deficient plasmas, the clot waveform analysis showed that Plm did not shorten the clotting time in only FV-deficient or FVIII-deficient plasma in prothrombin time-based or activated partial thromboplastin time-based assay, respectively. Our results indicated that Plm did possess procoagulant activity in the blood coagulation, and this effect was likely attributed by multicoagulation factors, dependent on FV and/or FVIII.

Losing Control: Positive and Negative Feedback in the Renin Angiotensin System

The renin angiotensin system (RAS) is a key homeostatic regulator that relies on feedback regulation to achieve and sustain the delicate balance required for healthy physiological function. A number of negative feedback loops exist within the RAS that counterbalance the effects of conventional RAS blockade. Indeed, instead of reducing levels of Ang II and aldosterone, exaggerated feedback responses lead to a paradoxical elevation in many patients treated with RAS blockers. This ‘escape’ has been used to explain a number of clinically-relevant phenomena including progressive left ventricular hypertrophy, deteriorating cardiac and renal function in the face of full-dose RAS blockade. Escape has been thought to be mediated by reactive increases in renin activity and Ang I, which is then converted to Ang II, via non- ACE pathways (or by ACE when inhibitors are cleared). The reduced expression and activity of the angiotensinase Angiotensin Converting Enzyme 2 (ACE2) following RAS blockade may have a role. Bystander activation of the uninhibited AT2 receptor during long-term angiotensin receptor blockade (ARB) can also increase aldosterone synthesis. Feed forward or positive feedback loops also exist within the RAS, which exaggerate the effects of signaling and contribute to progressive hypertension and vascular damage. For example, Ang II acts to increase the expression of angiotensinogen in the kidney and the liver. The strong association between adverse outcomes and activation of feedback pathways provide a strong rationale for specifically targeting feedback as part of any vasculo-protective strategy.