The role of ADAMT-13 in platelet adhesion in flow: methods for diagnosis of thrombotic thrombocytopenic purpura

Von willebrand factor (VWF) is synthesized and released from endothelial cells and megakaryocytes. VWF multimers that are immobilized on the activated endothelial cells and unfolded by high shear stress, undergo proteolysis by specific VWF-cleaving protease, ADAMTS-13. Severe deficiency of ADAMTS-13 is followed by accumulation of ultralarge VWF multimers and development of thrombotic thrombocytopenic purpura (TTP). Several methods for detection of ADAMTS-13 activity are proposed. However, all these assays are lacking the condition of shear stress, in which rapid cleavage of VWF multimeric strings by the ADAMTS-13 occurs. Impact- R method testing the effect of plasma on normal platelet adhesion under shear stress allows rapid screening of acute TTP and discrimination from other thrombotic microangiopathies.     

Severity score system for progressive myelopathy: development and validation of a new clinical scale

Progressive myelopathies can be secondary to inborn errors of metabolism (IEM) such as mucopolysaccharidosis, mucolipidosis, and adrenomyeloneuropathy. The available scale, Japanese Orthopaedic Association (JOA) score, was validated only for degenerative vertebral diseases. Our objective is to propose and validate a new scale addressing progressive myelopathies and to present validating data for JOA in these diseases. A new scale, Severity Score System for Progressive Myelopathy (SSPROM), was constructed covering motor disability, sphincter dysfunction, spasticity, and sensory losses. Inter-and intra-rater reliabilities were measured. External validation was tested by applying JOA, the Expanded Disability Status Scale (EDSS), the Barthel index, and the Osame Motor Disability Score. Thirty-eight patients, 17 with adrenomyeloneuropathy, 3 with mucopolysaccharidosis I, 3 with mucopolysaccharidosis IV, 2 with mucopolysaccharidosis VI, 2 with mucolipidosis, and 11 with human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy participated in the study. The mean ± SD SSPROM and JOA scores were 74.6 ± 11.4 and 12.4 ± 2.3, respectively. Construct validity for SSPROM (JOA: r = 0.84, P < 0.0001; EDSS: r = −0.83, P < 0.0001; Barthel: r = 0.56, P < 0.002; Osame: r = −0.94, P < 0.0001) and reliability (intra-rater: r = 0.83, P < 0.0001; inter-rater: r = 0.94, P < 0.0001) were demonstrated. The metric properties of JOA were similar to those found in SSPROM. Several clinimetric requirements were met for both SSPROM and JOA scales. Since SSPROM has a wider range, it should be useful for follow-up studies on IEM myelopathies.     

Expression of β-catenin and c-myc during human common bile duct development: a possible role in the morphogenesis of the common bile duct

β-catenin and c-myc play important roles in the development of tissues and organs. However, little is known about their expression patterns during the development of the human common bile duct. Immunohistochemistry was used to detect β-catenin and c-myc expression in common bile duct samples from postmortem tissues of 14 premature infants and 6 spontaneously aborted fetuses. The expression of β-catenin and c-myc was also analyzed by Western blot. The samples were divided into four groups based on the stage of human fetal development: 12, 13-27, 28-37, and >37 weeks. The Image-Pro Plus v. 6.0 image analysis software was used to calculate the mean qualifying score (MQS). At fetal stages 12, 13-27, 28-37, and >37 weeks, MQS of β-catenin were 612.52±262.13, 818.38±311.73, 706.33±157.19, and 350.69±110.19, respectively. There was a significant difference in MQS among the four groups (ANOVA, P=0.0155) and between the scores at >37 and 13-27 weeks (Student-Newman-Keuls, P<0.05). At fetal stages 12, 13-27, 28-37, and >37 weeks, the MQS of c-myc were 1376.64±330.04, 1224.18±171.66, 1270.24±320.75, and 741.04±219.19, respectively. There was a significant difference in MQS among the four groups (ANOVA, P=0.0087) and between the scores at >37 and 12 weeks, >37 and 13-27 weeks, and >37 and 28-37 weeks (all P<0.05, Student-Newman-Keuls). Western blots showed that β-catenin and c-myc expression were significantly higher in fetal than in postnatal control duct tissue (P<0.05). c-myc and β-catenin are involved in the normal development of the human common bile duct.     

Real-world clinical outcomes of treatment with casirivimab-imdevimab among patients with mild-to-moderate coronavirus disease 2019 during the Delta variant pandemic

Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan.Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635).Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021).Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.     

Hemodynamic mechanisms of the attenuated blood pressure response to mental stress after a single bout of maximal dynamic exercise in healthy subjects

To determine the hemodynamic mechanisms responsible for the attenuated blood pressure response to mental stress after exercise, 26 healthy sedentary individuals (age 29 ± 8 years) underwent the Stroop color-word test before and 60 min after a bout of maximal dynamic exercise on a treadmill. A subgroup (N = 11) underwent a time-control experiment without exercise. Blood pressure was continuously and noninvasively recorded by infrared finger photoplethysmography. Stroke volume was derived from pressure signals, and cardiac output and peripheral vascular resistance were calculated. Perceived mental stress scores were comparable between mental stress tests both in the exercise (P = 0.96) and control (P = 0.24) experiments. After exercise, the systolic blood pressure response to mental stress was attenuated (pre: 10 ± 13 vs post: 6 ± 7 mmHg; P < 0.01) along with lower values of systolic blood pressure (pre: 129 ± 3 vs post: 125 ± 3 mmHg; P < 0.05), stroke volume (pre: 89.4 ± 3.5 vs post: 76.8 ± 3.8 mL; P < 0.05), and cardiac output (pre: 7.00 ± 0.30 vs post: 6.51 ± 0.36 L/min; P < 0.05). Except for heart rate, the hemodynamic responses and the mean values during the two mental stress tests in the control experiment were similar (P > 0.05). In conclusion, a single bout of maximal dynamic exercise attenuates the blood pressure response to mental stress in healthy subjects, along with lower stroke volume and cardiac output, denoting an acute modulatory action of exercise on the central hemodynamic response to mental stress.     

Reduction of blood nitric oxide levels is associated with clinical improvement of the chronic pelvic pain related to endometriosis

The objective of this prospective study was to determine the plasma levels of nitric oxide (NO) in women with chronic pelvic pain secondary to endometriosis (n=24) and abdominal myofascial pain syndrome (n=16). NO levels were measured in plasma collected before and 1 month after treatment. Pretreatment NO levels (μM) were lower in healthy volunteers (47.0±12.7) than in women with myofascial pain (64.2±5.0, P=0.01) or endometriosis (99.5±12.9, P<0.0001). After treatment, plasma NO levels were reduced only in the endometriosis group (99.5±12.9 vs 61.6±5.9, P=0.002). A correlation between reduction of pain intensity and reduction of NO level was observed in the endometriosis group [correlation = 0.67 (95%CI = 0.35 to 0.85), P<0.0001]. Reduction of NO levels was associated with an increase of pain threshold in this group [correlation = -0.53 (-0.78 to -0.14), P<0.0001]. NO levels appeared elevated in women with chronic pelvic pain diagnosed as secondary to endometriosis, and were directly associated with reduction in pain intensity and increase in pain threshold after treatment. Further studies are needed to investigate the role of NO in the pathophysiology of pain in women with endometriosis and its eventual association with central sensitization.     

Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD₅₀) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.     

Trace elements in type 2 diabetes mellitus and their association with glycemic control

BackgroundAlterations in serum levels of trace elements reported in type 2 diabetes mellitus (T2DM) have been linked with induction of T2DM and associated complications.ObjectivesTo assess serum levels of copper (Cu), zinc (Zn) and selenium (Se) in T2DM patients with adequate and poor glycemic control.Patients and methodsThis study was performed at King Khalid University Hospital, Riyadh. A total of 100 consenting T2DM patients comprising of 50 patients with glycated hemoglobin (HbA1c) less than 6.5% and 50 patients with HbA1c more than 6.5% along with a group of 50 normal healthy individuals were included in the study. Serum levels of Cu, Zn and Se were measured by inductively coupled plasma-mass spectrometry (ICP-MS) instrument.ResultsAmong T2DM patients with HbA1c <6.5%, mean serum Cu levels (13.4+4.3µmol/L) were not different from the controls (14.5+1.92µmol/L) whereas Zn (9.9+2.7µmol/Lvs15+3.2µmol/L;p<0.0001) and Se levels (1+0.2µmol/Lvs1.62+0.2µmol/L; p<0.0004) were lower than the controls. Among T2DM patients with HbA1c >6.5% mean serum Cu (18.1+4.1µmol/Lvs14.5+1.9µmol/L; p<0.0001), Zn (15+3.2µmol/Lvs13.5+1.9µmol/L; p<0.009) and Se (1.62+0.2µmol/Lvs1.17+0.16µmol/L;p<0.0001) were significantly higher than the controls. HbA1c% negatively correlated with HbA1c >6.5% (r = -0.302; p<0.03).ConclusionCu, Zn and Se homeostasis was altered in T2DM patients and varied with glycemic control.     

Manifestations of type 2 diabetes in corneal endothelial cell density,corneal thickness and intraocular pressure

We sought to evaluate central corneal thickness (CCT), corneal endothelial cell density (ECD) and intraocular pressure (IOP) in patients with type 2 diabetes mellitus (DM) and to associate potential differences with diabetes duration and treatment modality in a prospective, randomized study. We measured ECD, CCT and IOP of 125 patients with type 2 DM (mean age 57.1±11.5 years) and compared them with 90 age-matched controls. Measured parameters were analyzed for association with diabetes duration and glucose control modalities (insulin injection or oral medication) while controlling for age. In the diabetic group, the mean ECD (2511±252 cells/mm²), mean CCT (539.7±33.6 µm) and mean IOP (18.3±2.5 mmHg) varied significantly from those the control group [ECD: 2713±132 cells/mm² (P<0.0001), CCT: 525.0±45.3 µm (P=0.003) and IOP: 16.7±1.8 mmHg (P<0.0001)]. ECD was significantly reduced by about 32 cell/mm² for diabetics with duration of >10 years when compared with those with duration of <10 years (P<0.05). CCT was thicker and IOP was higher for diabetics with duration of >10 years than those with duration of <10 years (P>0.05). None of the measured parameters was significantly associated with diabetes duration and treatment modality (P>0.05). In conclusion, subjects with type 2 DM exhibit significant changes in ECD, IOP and CCT, which, however, are not correlated with disease duration or if the patients receive on insulin injection or oral medications.     

Genetic and environmental influences on blood pressure and physical activity: a study of nuclear families from Muzambinho,Brazil

Blood pressure (BP) and physical activity (PA) levels are inversely associated. Since genetic factors account for the observed variation in each of these traits, it is possible that part of their association may be related to common genetic and/or environmental influences. Thus, this study was designed to estimate the genetic and environmental correlations of BP and PA phenotypes in nuclear families from Muzambinho, Brazil. Families including 236 offspring (6 to 24 years) and their 82 fathers and 122 mothers (24 to 65 years) were evaluated. BP was measured, and total PA (TPA) was assessed by an interview (commuting, occupational, leisure time, and school time PA). Quantitative genetic modeling was used to estimate maximal heritability (h²), and genetic and environmental correlations. Heritability was significant for all phenotypes (systolic BP: h² = 0.37 ± 0.10, P < 0.05; diastolic BP: h² = 0.39 ± 0.09, P < 0.05; TPA: h² = 0.24 ± 0.09, P < 0.05). Significant genetic (r_g) and environmental (r_e) correlations were detected between systolic and diastolic BP (r_g = 0.67 ± 0.12 and r_e = 0.48 ± 0.08, P < 0.05). Genetic correlations between BP and TPA were not significant, while a tendency to an environmental cross-trait correlation was found between diastolic BP and TPA (r_e = -0.18 ± 0.09, P = 0.057). In conclusion, BP and PA are under genetic influences. Systolic and diastolic BP share common genes and environmental influences. Diastolic BP and TPA are probably under similar environmental influences.     

Correlation between Fluorescein Angiographic Findings and Visual Acuity in Beh?et Retinal Vasculitis

Purpose

To identify significant fluorescein angiographic (FA) characteristics associated with visual acuity (VA) in Behçet retinal vasculitis.

Materials and Methods

Retrospective review of 86 eyes of 48 patients (age: 35.6±10.2 years) with Behçet retinal vasculitis were performed. VA and FA findings as well as correlation between them were assessed.

Results

The mean initial VA of eyes with posterior pole-involved vasculitis (63 eyes; 73.3%) was significantly worse than that of those with peripheral vasculitis (23 eye; 26.7%) (logarithm of the minimum angle of resolution VA: 0.554±0.572 vs. 0.078±0.148; p<0.0001). Subgroup analysis revealed a more severe and diffuse pattern of vascular leakage in posterior pole-involved vasculitis compared to peripheral vasculitis (p<0.0001). Retinal vascular leakage (β=0.345; p<0.0001), optic disc hyperfluorescence (β=0.147; p=0.032), and macular leakage (β=0.107; p=0.047) were significantly associated with worse initial VA. During the follow up (mean: 33.3±17.9 months), the change of leakage showed no significant correlation with change of VA in posterior pole-involved vasculitis (τ=0.199, p=0.092).

Conclusion

Posterior pole involvement, the degree of retinal vascular leakage, optic disc hyperfluorescence, and macular leakage are significantly associated with VA in Behçet retinal vasculitis.     

Clinical effects of sevoflurane anesthesia induction with a portable inhalational anesthetic circuit in pediatric patients

Introduction

Pediatric anesthesia induction with sevoflurane usually needs a special vaporizer and gas source, which limits its use to the operating room (OR). Many children feel anxious and cry when entering the OR because of being separated from their parents, which impairs anesthesia safety and their physical and mental health. In this study, we used a portable circuit to perform sevoflurane anesthesia induction outside the OR, assessed its effects and compared them with those of ketamine anesthesia in pediatric patients.

Material and methods

One hundred children had anesthesia induced with either sevoflurane (sevoflurane group) through the portable inhalational anesthetic circuit, or ketamine by intramuscular injection (ketamine group), then were transferred to the OR. Peak inspired concentration (Cp) and steady state concentration (Cs) of sevoflurane were measured. Heart rate (HR) and saturation of peripheral oxygen (SpO₂) were monitored. Time for anesthesia induction, awakening, leaving the OR and duration of the operation were recorded. The patients’ reaction during anesthesia was also analyzed.

Results

The Cp and Cs of sevoflurane were correlated with bodyweight. Compared with the ketamine group, the sevoflurane group showed shorter time for anesthesia induction (28 ±7 s vs. 195 ±34 s, p < 0.0001), awakening (11.2 ±3.6 s vs. 63.5 ±6.7 s, p < 0.0001) and leaving the OR (20.5 ±5.6 s vs. 43.4 ±10.6, p < 0.0001), less noncooperation during anesthesia induction (10% vs. 80%, p < 0.0001), lower HR (130 ±16 beats/min vs. 143 ±19 beats/min, p = 0.0004) and higher SpO₂ (98.9 ±0.9% vs. 96.1 ±2.5%, p < 0.0001) on arrival at the OR.

Conclusions

Pediatric anesthesia induction by sevoflurane with the portable inhalational anesthetic circuit is convenient, safe and effective outside the OR.     

Influence of Exercise on the Metabolic Profile Caused by 28 days of Bed Rest with Energy Deficit and Amino Acid Supplementation in Healthy Men

Objective Muscle loss and metabolic changes occur with disuse [i.e. bed rest (BR)]. We hypothesized that BR would lead to a metabolically unhealthy profile defined by: increased circulating tumor necrosis factor (TNF)-α, decreased circulating insulin-like-growth-factor (IGF)-1, decreased HDL-cholesterol, and decreased muscle density (MD; measured by mid-thigh computerized tomography).Methods We investigated the metabolic profile after 28 days of BR with 8±6% energy deficit in male individuals (30-55 years) randomized to resistance exercise with amino acid supplementation (RT, n=24) or amino acid supplementation alone (EAA, n=7). Upper and lower body exercises were performed in the horizontal position. Blood samples were taken at baseline, after 28 days of BR and 14 days of recovery.Results We found a shift toward a metabolically unfavourable profile after BR [compared to baseline (BLN)] in both groups as shown by decreased HDL-cholesterol levels (EAA: BLN: 39±4 vs. BR: 32±2 mg/dL, RT: BLN: 39±1 vs. BR: 32±1 mg/dL; p<0.001) and Low MD (EAA: BLN: 27±4 vs. BR: 22±3 cm², RT: BLN: 28±2 vs. BR: 23±2 cm²; p<0.001). A healthier metabolic profile was maintained with exercise, including NormalMD (EAA: BLN: 124±6 vs. BR: 110±5 cm², RT: BLN: 132±3 vs. BR: 131±4 cm²; p<0.001, time-by-group); although, exercise did not completely alleviate the unfavourable metabolic changes seen with BR. Interestingly, both groups had increased plasma IGF-1 levels (EAA: BLN:168±22 vs. BR 213±20 ng/mL, RT: BLN:180±10 vs. BR: 219±13 ng/mL; p<0.001) and neither group showed TNFα changes (p>0.05).Conclusions We conclude that RT can be incorporated to potentially offset the metabolic complications of BR.     

Prolidase,Matrix Metalloproteinases 1 and 13 Activity,Oxidative-Antioxidative Status as a Marker of Preterm Premature Rupture of Membranes and Chorioamnionitis in Maternal Vaginal Washing Fluids

Objective: Etiology of premature preterm rupture of membranes (PPROM) is not yet completely known and chorioamnionitis is one of the most important complications of its. We aimed to evaluate whether prolidase, matrix metalloproteinases, oxidative-antioxidative status, and inflammation markers in vaginal washing fluid (VWF) were associated with etiology of PPROM and whether these markers could be used to predict chorioamnionitis in PPROM.Study Design: This prospective case control study enrolled fifty pregnant women with PPROM and 50 healthy pregnant women. The VWF samples were taken at the time of admission in the PPROM group and patients were followed for chorioamnionitis. Prolidase, matrix metalloproteinases, oxidative-antioxidative status, and inflammation markers in VWF were assayed.Results: VWF levels of prolidase, matrix metalloproteinases 1-13 (p< 0.001), oxidative stress parameters, total oxidative stress (TOS) (p < 0.001) and oxidative stress index (OSI) (p = 0.002), and hs-CRP (p = 0.045) were significantly higher in the PPROM group than in the controls. Antioxidative status parameters, levels of paroxanase (PON-1) (p < 0.001) and total antioxidant capacity (TAC) (p < 0.001), were significantly lower in the PPROM group than in the controls. Mean VWF levels of prolidase (p < 0.001), metalloproteinases (p<0.05), and oxidative-antioxidative status parameters (p<0.05) were significantly different in women with versus women without chorioamnionitis in the PPROM group. Prolidase, MMP-13, TOS, TAC, and PON-1 were found as important predictors for chorioamnionitis in the PPROM group by the multivariate logistic regression analysis. When the ROC curve analysis for prolidase, MMP-13, TOS, TAC, and PON-1 were performed, all of them were statistically significant for area under the curve (areas under the curve were 0.94, 0.90, 0.80, 0.25, and 0.19, respectively).Conclusions: This study showed that collagen turnover mediators, especially prolidase, and increased oxidative stress are significantly associated with PPROM. Also, chorioamnionitis can be predicted with prolidase, MMP-13, TOS, TAC, and PON-1 in PPROM patients.     

Changes in the activity of connective tissue matrix enzymes in the metabolic syndrome

Introduction

Early atherosclerotic changes in the endothelium associated with metabolic syndrome are generated with the participation of inflammatory cells, cytokines and enzymes of the extracellular matrix. The study is aimed at a comparison between the activity of inflammatory agents, tumour necrosis factor α (TNF-α) and the enzymes of the connective tissue matrix in the blood of healthy female patients as well as those suffering from the metabolic syndrome.

Material and methods

The examination included 35 women with metabolic syndrome (MS). The control group (C) comprised 35 healthy women. Lipidogram, C-reactive protein level (CRP), fasting glucose level (FGL), matrix metalloproteinase (MMP)-8 and -9 activity, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TNF-α levels in blood were determined.

Results

As compared with the control group, the level of inflammatory factors and the activity of extracellular matrix enzymes in the metabolic syndrome were statistically higher (p < 0.05) and concerned the following parameters: TNF-α (pg/ml): MS 6.59 ±3.18, C 4.78 ±2.91; CRP (mg/dl): MS 2.18 ±2.04, C 1,26 ±1.35; TIMP-1 (ng/ml): MS 265.5 ±2.9, C 205.4 ±72.6; MMP-9 (ng/ml): MS 198.2 ±138.6, C 138.6 ±116.1. Statistically significant correlations were also found between TIMP-1 and the following factors: BMI (R = 0.400, p < 0.001), waist/hip ratio (WHR) (R = 0.278, p < 0.05), waistline (R = 0.417, p < 0.001), FGL (R = 0.290, p < 0.05), HDL cholesterol (R = –0.253, p < 0.05) and triglycerides (R = 0.269, p < 0.05).There were positive correlations of MMP-9 with FGL (R = 0.446, p < 0.001) and waistline (R = 0.260, p < 0.05); MMP-8 with FGL (R = 0.308, p < 0.05); and CRP with BMI (R = 0.370, p < 0.01), WHR (R = 0.325, p < 0.01) and waistline (R = 0.368, p < 0.01).

Conclusions

Metabolic syndrome is connected with higher activity of cytokines (TNF-α), inflammatory markers (CRP) and matrix enzymes (MMP-9, MMP-8, TIMP-1).     

Effectiveness of low‐dose intravenous immunoglobulin therapy in minor primary antibody deficiencies: A 2‐year real‐life experience

Primary antibody deficiencies (PAD) are the most prevalent group of primary immunodeficiencies (PID) in adults and immunoglobulin replacement therapy (IRT) is the mainstay therapy to improve clinical outcomes. IRT is, however, expensive and, in minor PAD, clear recommendations concerning IRT are lacking. We conducted a retrospective real‐life study to assess the effectiveness of low‐dose IRT in minor PAD on 143 patients fulfilling European Society for Immunodeficiencies (ESID) diagnostic criteria for immunoglobulin (Ig)G subclass deficiency (IgGSD) or unclassified antibody deficiency (UAD). All patients were treated with intravenous low‐dose IRT (0.14 ± 0.06 g/kg/month). Immunoglobulin (Ig) classes and IgG subclasses were measured at baseline and after 1 year of IRT. The annual rate of total infections, upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI) and hospitalizations was measured at baseline and after 1 and 2 years of IRT. After 1 year of IRT significant improvement was demonstrated in: (a) serum IgG (787.9 ± 229.3 versus 929.1 ± 206.7 mg/dl; p < 0.0001); (b) serum IgG subclasses (IgG1 = 351.4 ± 109.9 versus 464.3 ± 124.1, p < 0.0001; IgG2 = 259.1 ± 140 versus 330.6 ± 124.9, p < 0.0001; IgG3 = 50.2 ± 26.7 versus 55.6 ± 28.9 mg/dl, p < 0.002); (c) annual rate of total infections (5.75 ± 3.87 versus 2.13 ± 1.74, p < 0.0001), URTI (1.48 ± 3.15 versus 0.69 ± 1.27; p < 0.005), LRTI (3.89 ± 3.52 versus 1.29 ± 1.37; p < 0.0001) and hospitalizations (0.37 ± 0.77 versus 0.15 ± 0.5; p < 0.0002). The improvement persisted after 2 years of IRT. No significant improvement in URTI annual rate was noted in UAD and in patients with bronchiectasis. In conclusion, low‐dose IRT can improve clinical outcomes in UAD and IgGSD patients, providing a potential economical advantage over the standard IRT dose.     

Nighttime Blood Pressure in Normotensive Subjects With Chronic Insomnia: Implications for Cardiovascular Risk

Objective:

To assess as whether insomniacs have higher nighttime blood pressure (BP) and a blunted day-to-night BP reduction, recognized markers of increased risk of cardiovascular morbidity and mortality.

Design:

Prospective case-control study.

Setting:

University hospital-based sleep research laboratory.

Participants:

Thirteen normotensive subjects with chronic primary insomnia (9 women, 42 ± 7 y) and 13 sex- and age-matched good sleepers.

Measurements and results:

Subjects underwent 2-week sleep diary and 3 sleep studies to provide subjective and objective sleep variables, and 24-h beat-to-beat BP recording to provide daytime, night-time and day-to-night BP changes ([nighttime-daytime]/daytime)*100) (BP dipping). Spectral analysis of the electroencephalogram (EEG) was also performed during sleep of night 3 to assess EEG activity in the β frequency (16-32 Hz), a measure of brain cortical activation. Nighttime SBP was higher (111 ± 15 vs 102 ± 12 mm Hg, P < 0.01) and day-to-night SBP dipping was lower (−8% ± 6% vs −15% ± 5%, P < 0.01) in insomniacs than good sleepers. Insomniacs also had higher activity in EEG β frequency (P < 0.05). Higher nighttime SBP and smaller SBP dipping were independently associated with increased EEG β activity (P < 0.05).

Conclusions:

Higher nighttime SBP and blunted day-to-night SBP dipping are present in normotensive subjects with chronic insomnia and are associated with a hyperactivity of the central nervous system during sleep. An altered BP profile in insomniacs could be one mechanism implicated in the link between insomnia and cardiovascular morbidity and mortality documented in epidemiological studies.

Citation:

Lanfranchi PA; Pennestri MH; Fradette L; Dumont M; Morin CM; Montplaisir J. Nighttime blood pressure in normotensive subjects with chronic insomnia: implications for cardiovascular risk. SLEEP 2009;32(6):760-766.     

A Randomized,Double-Blind,Placebo-Controlled,Crossover Study of XP13512/GSK1838262 in the Treatment of Patients With Primary Restless Legs Syndrome

Study Objective:

To evaluate the efficacy and tolerability of XP13512/GSK1838262, an investigational nondopaminergic agent for the treatment of moderate-to-severe primary restless legs syndrome (RLS).

Design:

Randomized, double-blind, placebo-controlled, crossover trial.

Setting:

Nine US clinical sites.

Patients:

Thirty-eight treatment-naïve subjects with RLS (mean ± SD age 50.1 ± 13.2 years).

Interventions:

XP13512 1800 mg/day followed by placebo or placebo followed by XP13512 1800 mg/day for 14 days, with a 7-day washout between treatment periods.

Measurements and Results:

The primary endpoint was mean change from baseline International RLS Study Group rating scale (IRLS) total score on Day 14, analyzed using analysis of variance with sequence, period, and treatment as fixed effects and subjects within sequence as a random effect. XP13512 significantly reduced IRLS total score on Day 14 compared with placebo (mean ± SD: XP13512 −12.1 ± 6.5, placebo −1.9 ± 6.3; P < 0.0001). Polysomnographic data showed that XP13512 significantly improved sleep architecture on Day 14 compared with placebo (mean ± SD change from baseline sleep time [minutes]: stage 1: XP13512 −9.8 ± 23.9, placebo 0.4 ± 23.2; adjusted P < 0.0054, nominal P < 0.0001; stage 3/4 (slow-wave sleep): XP13512 22.8 ± 40.8, placebo 1.4 ± 34.3; adjusted P = 0.0092, nominal P = 0.0002). The most frequently reported adverse events were somnolence (XP13512 30.6%, placebo 2.8%) and dizziness (XP13512 27.8%, placebo 5.6%).

Conclusions:

XP13512 1800 mg/day significantly reduced RLS symptoms, improved sleep, and was generally well tolerated in subjects with moderate-to-severe primary RLS across 14 days of treatment.

Citation:

Kushida CA; Walters AS; Becker P; Thein SG; Perkins AT; Roth T; Canafax D; Barrett RW. A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome. SLEEP 2009;32(2):159-168.     

Correlation between exon 3 polymorphism of growth hormone receptor gene and the responses to rhGH therapy

Objective: To investigate the correlation between the exon 3 polymorphism of growth hormone receptor (GHR) gene and the responses to the recombinant human growth hormone (rhGH) therapy in children with short stature. Methods: Forty-five growth hormone deficiency (GHD) children (male: 30, female: 15, aged 10.39±2.73 yrs) and twenty-five idiopathic short stature (ISS) children (male: 15, female: 10, aged 10.58±2.56 yrs) admitted to our hospital were included. The polymorphism of exon 3 of GHR gene was determined using multiple PCR amplification. Treatment duration for each subject was at least 12 months. On this basis, we evaluated the correlation between treatment efficiency of rhGH therapy and GHR exon 3 polymorphism, GHD, and treatment duration. Results: Significant difference was noted in the growth velocity (GV) of GHD children with a genotype of GHRfl compared with those with a genotype of GHRd3 (9.44±2.35 vs. 11.36±2.49, P < 0.05). Meanwhile, the GV of ISS patients with a genotype of GHRfl were remarkably decreased compared with those with a genotype of GHRd3 (8.74±2.36 vs. 11.18±2.44, P < 0.05). For the children with peak GH response of less than 5 ng/ml, statistical difference was noted in the GV of children with a genotype of GHRfl compared with those with a genotype of GHRd3 (9.55±2.76 vs. 10.84±1.53, P < 0.05). For the patients with peak GH response to clonidine or pyridostigmine bromide of > 5 ng/ml, a satisfactory response to rhGH therapy was noted in children with a genotype of GHRd3 compared with those of GHRfl (P < 0.05). Conclusions: GHRd3 was correlated with the response to rhGH therapy in children with short stature. For the patients with the same genotype, GHD caused no obvious effects on the final height. However, for the patients with peak GH response of > 5 ng/ml, a satisfactory response to rhGH therapy was noted in children with a genotype of GHRd3 compared with those of GHRfl (P < 0.05). A higher treatment efficiency was obtained in those received rhGH at an early age.