Changes in masticatory muscle activity in children with cerebral palsy

The objective of the study was to determine whether children with cerebral palsy (CP) have abnormal bilateral masseter and temporal muscle activation during mastication. The muscular activity of 32 children aged between 7 and 13 years was assessed during the task of non-habitual mastication by means of surface electromyograms. During non-habitual mastication, the amplitude of all assessed muscles in the inactive period and the amplitude of the Right Masseter and Left Temporal muscles in the active period of children with CP was greater (p < 0.05) in relation to the group of children with Typical Development (TD). Considering each muscle individually, only the duration of the active period of Right Masseter and Right Temporal muscles in children with CP was lower (p < 0.05) than in the TD children. Considering the four analyzed muscles, the duration of time of general active period, when at least one muscle should be activated, was higher in children with CP (p < 0.05) than in children with TD showing greater time variation in inactivation (p < 0.05). The higher muscle activity during the phases of the masticatory cycle, with longer duration of the active period and with greater variability between the muscles to inhibit this activity show greater difficulty in coordinating the muscles of mastication in children with CP compared to children with TD.     

Evaluation of plantar flexion contracture contribution during the gait of children with Duchenne muscular dystrophy

Because of extensor weakness, children with Duchenne muscular dystrophy (DMD) maintain internal flexion moments at the joints of the lower extremities when they walk. We believe that at the ankle, the plantar flexion moments caused by contractures may contribute significantly to the production of the net ankle flexion moment during the gait in these children. The goal of the present study is to quantify ankle plantar flexion passive moments that may be associated with the presence of flexion contractures and to estimate their contribution to the net moment during the gait of children with DMD. Kinematic and kinetic parameters were collected during gait of eleven subjects with DMD. Ankle plantar flexion passive moments were also measured experimentally during the same session. Fourteen control children participated in the study in order to have normal reference values. The presence of ankle plantar flexion contractures in children with DMD was reflected by a rigidity coefficient obtained at a common moment of ?7 Nm that was higher for these children (0.75 Nm/° vs. 0.48 Nm/°; p < 0.05). The relative passive moment contribution to the net plantar flexion moments was higher for the children with DMD at the end of the lengthening phase of the plantar flexors (25% vs. 18%; p < 0.05). We believe that the passive moments can compensate for the presence of progressive muscle weakness in the children with DMD and help these children with gait.     

Angiotensin-(1–7) abolishes AGE-induced cellular hypertrophy and myofibroblast transformation via inhibition of ERK1/2

Angiotensin-(1–7) (Ang-(1–7))/AT₇-Mas receptor axis is an alternative pathway within the renin–angiotensin system (RAS) that generally opposes the actions of Ang II/AT₁ receptor pathway. Advanced glycated end product (AGEs) including glucose- and methylglyoxal-modified albumin (MGA) may contribute to the development and progression of diabetic nephropathy in part through activation of the Ang II/AT₁ receptor system; however, the influence of AGE on the Ang-(1–7) arm of the RAS within the kidney is unclear. The present study assessed the impact of AGE on the Ang-(1–7) axis in NRK-52E renal epithelial cells. MGA exposure for 48 h significantly reduced the intracellular levels of Ang-(1–7) approximately 50%; however, Ang I or Ang II expression was not altered. The reduced cellular content of Ang-(1–7) was associated with increased metabolism of the peptide to the inactive metabolite Ang-(1–4) [MGA: 175 ± 9 vs. Control: 115 ± 11 fmol/min/mg protein, p < 0.05, n = 3] but no change in the processing of Ang I to Ang-(1–7). Treatment with Ang-(1–7) reversed MGA-induced cellular hypertrophy and myofibroblast transition evidenced by reduced immunostaining and protein expression of α-smooth muscle actin (α-SMA) [0.4 ± 0.1 vs. 1.0 ± 0.1, respectively, n = 3, p < 0.05]. Ang-(1–7) abolished AGE-induced activation of the MAP kinase ERK1/2 to a similar extent as the TGF-β receptor kinase inhibitor SB58059; however, Ang-(1–7) did not attenuate the MGA-stimulated release of TGF-β. The AT₇-Mas receptor antagonist D-Ala⁷-Ang-(1–7) abolished the inhibitory actions of Ang-(1–7). In contrast, AT₁ receptor antagonist losartan did not attenuate the MGA-induced effects. We conclude that Ang-(1–7) may provide an additional therapeutic approach to the conventional RAS blockade regimen to attenuate AGE-dependent renal injury.     

In vivo moment generation and architecture of the human plantar flexors after different shortening–stretch cycles velocities

The purpose of this study was to examine the moment generation of the human plantar flexors and the architecture of the gastrocnemius medialis muscle during and after shortening–stretch cycles in vivo. Fourteen male subjects (30 ± 7 years, 177 ± 7 cm, 80 ± 9 kg) performed a series of electro-stimulated shortening–stretch plantar flexion contractions. The shortening–stretch cycles were performed at three constant angular velocities (25°/s, 50°/s, 100°/s), two amplitudes (15° and 25° ankle angle changes) and at two different stimulation frequencies (30 Hz and 85 Hz). The resultant ankle joint moments were calculated through inverse dynamics. Pennation angle and fascicle length of the m. gastrocnemius medialis at rest and during contractions were measured using ultrasonography. The corresponding ankle moments, kinematics and changes in muscle architecture were analysed at seven time intervals. A three-way analysis of variance (amplitude × velocity × stimulation frequency) and post-hoc test with Bonferroni correction were used to check the amplitude, velocity and stimulation level related effects on moment enhancement (α = 0.05). The results show an ankle joint moment enhancement after shortening–stretch cycles influenced by muscle architectural changes. We found 2–3% isometric ankle joint moment enhancement at steady state, 1.5–2.0 s after the shortening–stretch cycle. However, the observed alteration in muscle architecture after the imposed perturbation, could lead to an underestimation (1–3%) of joint moment enhancement due to the force–length relationship of the triceps surae. Furthermore, the enhancement observed was independent of the shortening–stretch amplitude, velocity and stimulation frequency.     

Walking speed effects on the lower limb electromyographic variability of healthy children aged 7–16 years

The evaluation of surface electromyography (sEMG) is commonly performed in children with cerebral palsy (CP) and reliable interpretation necessitates knowledge of the variability in age-matched, typically developing (TD) children. Variance ratio was calculated for inter-trial sEMG linear envelope (LE) and the Instantaneous Mean Frequency (IMNF) variability in the lower limb muscle in TD children, in three different age groups during slow, comfortable speed, and fast walking. Significantly greater variability was found in the 7–9 group compared to the 13–16 years. Variability during both slow and fast walking was significantly greater compared to comfortable speed walking and was profound in the 7–9 year age group. Variability of the IMNF was significantly greater than LE in the Tibialis-Anterior, Biceps-Femoris (BF), Vastus-Lateralis (VL), and Rectus-Femoris (RF). Clinical implications are that children under 10 years are more variable than older children when walking either slower or faster than self-selected walking speed. This suggests that muscle activation patterns in gait mature at a later stage of childhood than do kinematic gait patterns. Greater precaution, therefore, is needed when comparing sEMG patterns of less than 10 years of age patient and TD children.     

Crouch severity is a poor predictor of elevated oxygen consumption in cerebral palsy

Children with cerebral palsy (CP) expend more energy to walk compared to typically-developing peers. One of the most prevalent gait patterns among children with CP, crouch gait, is often singled out as especially exhausting. The dynamics of crouch gait increase external flexion moments and the demand on extensor muscles. This elevated demand is thought to dramatically increase energy expenditure. However, the impact of crouch severity on energy expenditure has not been investigated among children with CP. We evaluated oxygen consumption and gait kinematics for 573 children with bilateral CP. The average net nondimensional oxygen consumption during gait of the children with CP (0.18 ± 0.06) was 2.9 times that of speed-matched typically-developing peers. Crouch severity was only modestly related to oxygen consumption, with measures of knee flexion angle during gait explaining only 5–20% of the variability in oxygen consumption. While knee moment and muscle activity were moderately to strongly correlated with crouch severity (r² = 0.13–0.73), these variables were only weakly correlated with oxygen consumption (r² = 0.02–0.04). Thus, although the dynamics of crouch gait increased muscle demand, these effects did not directly result in elevated energy expenditure. In clinical gait analysis, assumptions about an individual’s energy expenditure should not be based upon kinematics or kinetics alone. Identifying patient-specific factors that contribute to increased energy expenditure may provide new pathways to improve gait for children with CP.     

Mechanical properties of the patellar tendon in adults and children

It is not currently known how the mechanical properties of human tendons change with maturation in the two sexes. To address this, the stiffness and Young's modulus of the patellar tendon were measured in men, women, boys and girls (each group, n=10). Patellar tendon force (F_pt) was calculated from the measured joint moment during a ramped voluntary isometric knee extension contraction, the antagonist knee extensor muscle co-activation quantified from its electromyographical activity, and the patellar tendon moment arm measured from magnetic resonance images. Tendon elongation was imaged using the sagittal-plane ultrasound scans throughout the contraction. Tendon cross-sectional area was measured at rest from ultrasound scans in the transverse plane. Maximal F_pt and tendon elongation were (mean±SE) 5453±307 N and 5±0.5 mm for men, 3877±307 N and 4.9±0.6 mm for women, 2017±170 N and 6.2±0.5 mm for boys and 2169±182 N and 5.9±0.7 mm for girls. In all groups, tendon stiffness and Young's modulus were examined at the level that corresponded to the maximal 30% of the weakest participant's F_pt and stress, respectively; these were 925–1321 N and 11.5–16.5 MPa, respectively. Stiffness was 94% greater in men than boys and 84% greater in women than girls (p<0.01), with no differences between men and women, or boys and girls (men 1076±87 N/mm; women 1030±139 N/mm; boys 555±71 N/mm and girls 561.5±57.4 N/mm). Young's modulus was 99% greater in men than boys (p<0.01), and 66% greater in women than girls (p<0.05). There were no differences in modulus between men and women, or boys and girls (men 597±49 MPa; women 549±70 MPa; boys 255±42 MPa and girls 302±33 MPa). These findings indicate that the mechanical stiffness of tendon increases with maturation due to an increased Young's modulus and, in females due to a greater increase in tendon cross-sectional area than tendon length.     

Electromyographic analysis of rectus femoris activity during seated to standing position and walking in water and on dry land in healthy children and children with cerebral palsy

Purpose: To analyze rectus femoris activity during seated to standing position and walking in water and on dry land comparing a group of children with the spastic diparesis type of cerebral palsy (CP) and a group of children without neurological disorders. Methods: This study included a group of nine children with CP and a control group of 11 children. The study compared the electromyographic activity of the rectus femoris during seated to standing position and walking, in water and on land. Results: A greater activation of the rectus femoris was observed in the group of children with CP compared with the control group when moving from a seated position to a standing position in water (p = 0.0039) and while walking on land (p = 0.0014) or in the pool (p = 0.007). Conclusion: This study demonstrated the activation of the rectus femoris while walking or standing up from a seated position in water was greater in the group of children with CP. Further studies should be performed to better understand the extent of muscular activation during body immersion in individuals with neurological disorders.     

Test–retest reliability of the soleus H-reflex is affected by joint positions and muscle force levels

The purpose of this study was to determine the test–retest reliability of the soleus (SOL) H-reflex during rest and isometric contractions at 10%, 30%, and 50% of the maximal voluntary force (MVC) at the ankle joint angles of neutral (0°), plantarflexion (20°), and dorsiflexion (?20°) respectively, in a sitting position. Ten healthy participants, with mean age of 24.9 ± 5.0 (SD) years, height 168.3 ± 8.8 cm, weight 62.7 ± 12.3 kg, were tested for the SOL H-reflex (H_max) on two separate occasions within 7 days. The intraclass correlation coefficient (ICC) for the test–retest of the SOL H-reflex during rest was found to be high at ankle joint angle of neutral (ICC = 0.92) and plantarflexion (0.96), and moderate at dorsiflexion (0.75). Inconsistent ICC values (range from 0.62 to 0.97) were found during the submaximal voluntary contractions at the three ankle joint positions. High ICCs were also found in H_max/M_max ratio at neutral (0.86), plantarflexion (0.96), and dorsiflexion (0.84) positions. It was concluded that the test–retest reliability of the SOL H-reflex was affected by the intensity of voluntary contraction and ankle joint position. The H-reflex demonstrated a higher reliability at the neutral and plantarflexion positions than that at the dorsiflexion position during rest, and a higher reliability at 10% MVC than that at 30% and 50% MVC.     

Isolation and properties of β-xylosidase from Aspergillus niger GS1 using corn pericarp upon solid state fermentation

There is growing interest in developing high-yield and low-cost production of xylanolytic enzymes for industrial applications using agroindustrial byproducts. A native strain of Aspergillus niger GS1 was used to produce β-xylosidase (EC 3.2.1.37) on solid state fermentation using corn pericarp (CP) with innovative alkaline electrolyzed water (AEW) pretreatment at room temperature. β-xylosidase was purified by ammonium sulfate fractionation followed by anion exchange and hydrophobic interaction chromatographies. β-Xylosidase showed a molecular weight of 111 kDa, isoelectric point of 5.35 and specific activity of 386.7 U (mg protein)^?1, using p-nitrophenyl-β-d-xylopyranoside as substrate, at pH 5 and 60 °C, and optimal activity at pH 4.5. Optimal temperature was 65 °C, showing full activity after 1 h at 60 °C. Activity was reduced by 1 mM β-mercaptoethanol (55.6 ± 0.1%), and enhanced by 1 mM SDS (11.0 ± 0.03%). K_m and V_max were 6.1 ± 0.9 mM and 1364 ± 105 U (mg protein)^?1, respectively, whereas k_cat was 5.1 s^?1. A predominant α-helix (41%) was determined from circular dichroism on β-xylosidase, while thermal transition profiles produced a T_m of 54.1 ± 5.8 °C, enthalpy change for unfolding of 67.4 ± 6.7 kJ/mol, and onset temperature of 37 °C. Pre-treatment of CP using AEW is an ecologically friendly alternative to chemical and heat treatments for the production of relatively high levels of β-xylosidase.     

Efficiency of energy use for maintenance and gain by growing crossbred Boer and Spanish Goats consuming diets differing in forage level

Eight Boer (75%) × Spanish (BS) and eight Spanish (S) wether goats (155 ± 8 days of age and 19.2 ± 2.3 kg BW, initial) were used in a replicated crossover design experiment with a 2 × 2 factorial arrangement of treatments to determine the effects of genotype and diet quality on heat production with ad libitum, near maintenance and fasting levels of feed intake. Diets were 65% concentrate (CON 15% CP, DM basis) and coarsely ground alfalfa hay (FOR 23% CP). There were no significant interactions between genotype and diet. ME intake was similar between genotypes and greater (P < 0.05) for CON versus FOR both when intake was ad libitum (7.60 versus 5.43 MJ/day) and near maintenance (4.31 versus 4.09 MJ/day). DE concentration was greater (P < 0.05) for CON than for FOR with ad libitum (74.4 versus 55.5%) and restricted intake (77.0 versus 59.6%). Energy expenditure (EE), determined by respiration calorimetry, at all levels of intake was similar between genotypes. EE was greater (P < 0.05) for CON than for FOR at each of the three levels of intake, ad libitum (573 and 521 kJ/kg BW^0.75 while fasting), near maintenance (426 and 400 kJ/kg BW^0.75) and fasting (280 and 255 kJ/kg BW^0.75). Efficiencies of ME utilization for maintenance (k_m) and gain (k_g) and the ME requirement for maintenance (ME_m) were similar between genotypes. k_m was similar between diets (0.705 and 0.690 for CON and FOR, respectively), although k_g was greater (P < 0.05) for CON than for FOR (0.603 versus 0.387). ME_m was numerically greater (P < 0.17) for CON than for FOR (407 versus 379 kJ/kg BW^0.75), which may have involved higher ME intake with CON. In conclusion, under the conditions of this experiment energy requirements and efficiency of utilization were not different between growing Boer crossbred and Spanish goats regardless of diet quality.     

Postural reactions following forward platform perturbation in young,middle-age,and old adults

The aim of the study was to examine how individuals of different ages react to forward balance perturbations. Thirty-six volunteers, divided into four groups [young (YA), middle-age (MA₄₀ and MA₅₀), and old (OA) adults], stood on a platform that was either kept stationary, moved backward, or moved forward. EMG onset, EMG time-to-peak, iEMG, and agonist–antagonist co-activation, as well as cumulative angular excursion, maximum center of mass (CM) backward displacement, and CM time-to-reversal were assessed after forward translations. Postural synergies were assessed using principal component analysis (PCA). The results showed that OA activated their muscles later than YA [TA = 25 ms, RF = 17 ms] and OA and MA₅₀ reached the peak of activation later than YA [MA₅₀:TA = 23 ms, RF = 32 ms, OA:TA = 28 ms, RF = 21 ms]. Moreover, OA kept a higher level of activation longer than all younger groups. No differences among groups were observed in co-activation, kinematic, and PCA variables. We conclude that changes in temporal EMG patterns can be seen in the fifth decade. However, such changes have no effect on the CM horizontal displacement and CM time-to-reversal after perturbation, which cannot be justified by the use of different postural synergies, suggesting that temporal aspects of muscle activation could play a minor role in controlling excessive CM displacements after perturbations.     

Low-grade inflammation markers in children and adolescents: Influence of anthropometric characteristics and CRP and IL6 polymorphisms

Overweight and obesity are associated with chronic and subclinical inflammation due to an imbalance of inflammatory mediators. However, the association with gene polymorphism has been rarely studied in children. The aim of this study was to determine if serum concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) are related to the IL6 rs1800795, IL6 rs2069845 and CRP rs1205 polymorphisms (SNPs) according to body mass index (BMI) in a sample of children and adolescents. A cross-sectional study in 470 students between 7 and 17 years of age of anthropometric characteristics, high sensitivity-CRP (Hs-CRP) and IL-6 levels and three SNPs genotyped. The prevalence ratio of hs-CRP > 3 mg/L in obese individuals was 4.15 (CI 2.43–7.06; p = 0.01), and it was 1.91 (CI 1.03–3.55; p = 0.03) in overweight individuals and 1.74 (CI 1.05–2.88 p = 0.03) in females. Individuals with waist circumference (WC) and body fat percentage (BF%) alterations showed elevated levels of hs-CRP (p = 4.3 × 10⁻⁵ and p = 5.3 × 10⁻⁶). The combination of any two anthropometric measurement increases CRP levels, especially combinations with obesity body mass index (BMI): BMI + WC and BMI + BF%. Among the overweight/obesity group, T allele carriers of CRP rs1205 showed lower levels of hs-CRP (0.5, IQR = 0.3–1.8 mg/L) than CC homozygotes (1.5, IQR = 0.4–3.4 mg/L, p = 0.018). Additionally, considering subjects with two or three anthropometric alterations for CRP rs1205: rs1205 T allele carriers had lower levels of hs-CRP (0.7, IQR = 0.3–2.7 mg/L) than CC homozygotes (1.2, IQR = 0.5–3.5 mg/L, p = 0.02). In conclusion, carriers of the rs1205/T allele with higher BMIs had lower levels of hs-CRP. Schoolchildren who were overweight/obese had higher levels of CRP and IL-6, whereas individuals with WC and BF% alterations had higher levels of CRP.     

Application of chemical precipitation and membrane bioreactor hybrid process for piggery wastewater treatment

This study was conducted to investigate the chemical precipitation (CP) and membrane bioreactor (MBR) hybrid process for the treatment of piggery wastewater. Average removal efficiencies for BOD, COD and turbidity in CP process were 64.3%, 77.3% and 96.4%, respectively. CP process had a moderate effect on NH₃–N removal (40.4%) which improved up to 98.2% mainly due to nitrification and filtration processes in MBR. The average removal efficiencies of BOD, COD and turbidity in MBR were 99.5%, 99.4% and 99.8%, respectively. Monod equation was used to explain the microbial activities in terms of specific growth rate. The specific growth rate of bacteria in aeration tank (N-batch) and anoxic tank (D-batch) were 0.013 and 0.005 d^?1 with a biomass yield of 0.78 and 0.43 mg MLSS produced/mg COD utilized, respectively. Microorganisms from the N-batch and D-batch showed a low-level of nitrifying and moderate-level of denitrifying capabilities which were 1.08 mg NH₃–N/(g MLVSS.h) and 2.82 mg NO₃–N/(g MLVSS.h), respectively. Carbohydrates were the main component in extracellular polymeric substance (EPS) compounds that could be attached to the membrane surface easily and led to membrane biofouling. The increase of MLSS, EPS and sludge viscosity concentration, decrease of sludge floc size and incomplete chemical cleaning procedure resulted in the increase of membrane resistance. Total membrane resistance increased from 3.19 × 10¹² m^?1 to 5.43 × 10¹⁴ m^?1.     

Angiotensin III stimulates high stretch-induced ANP secretion via angiotensin type 2 receptor

Angiotensin III (Ang III) is metabolized from Ang II by aminopeptidase (AP) A and in turn, Ang III is metabolized to Ang IV by APN. Ang III is known to have a similar effect to Ang II on aldosterone secretion, but the effect of Ang III on atrial natriuretic peptide (ANP) secretion from cardiac atria is not known. The aim of the present study is to define the effect of Ang III on ANP secretion and its receptor subtype using isolated perfused beating atria. The volume load was achieved by elevating the height of outflow catheter connected with isolated atria from 5 cmH₂O to 7.5 cmH₂O. Atrial stretch by volume load increased atrial contractility and ANP secretion. Ang III stimulated stretch-induced ANP secretion in a dose-dependent manner without change in atrial contractility. The stimulated effect of Ang III (1 μM) on stretch-induced ANP secretion was blocked by the pretreatment of Ang II type 2 (AT₂) receptor antagonist but not by AT₁ or Mas receptor antagonist. Pretreatment with inhibitor of phosphoinositide 3-kinase (PI3K), Akt, nitric oxide synthase, soluble guanylyl cyclase, or protein kinase G (PKG) attenuated Ang III-stimulated ANP secretion. When Ang III (40 nM) or Ang II (4 nM) was infused for 10 min into anesthetized rats, mean arterial pressure was increased about 10%. However, Ang III increased plasma ANP level by 35.81 ± 10.19% but Ang II decreased plasma ANP level by 30.41 ± 7.27%. Therefore, we suggest that Ang III, opposite to Ang II, stimulated stretch-induced ANP secretion through AT₂ receptor/PI3K/Akt/nitric oxide/PKG pathway.     

Diurnal exchanges of CO2 and CH4 across the water–atmosphere interface in a water chestnut meadow (Trapa natans L.)

CH₄ and CO₂ fluxes across the water–atmosphere interface were measured over a 24 h day–night cycle in a shallow oxbow lake colonized by the water chestnut (Trapa natans L.) (Lanca di Po, Northern Italy). Only exchanges mediated by macrophytes were measured, whilst gas ebullition was not considered in this study. Measurements were performed from 29 to 30 July 2005 with short incubations, when T. natans stands covered the whole basin surface with a mean dry biomass of 504 ± 91 g m⁻². Overall, the oxbow lake resulted net heterotrophic with plant and microbial respiration largely exceeding carbon fixation by photosynthesis. The water chestnut stand was a net sink of CO₂ during the day-light period (−60.5 ± 8.5 mmol m⁻² d⁻¹) but it was a net source at night (207.6 ± 6.1 mmol m⁻² d⁻¹), when the greatest CO₂ efflux rate was measured across the water surface (28.2 ± 2.4 mmol m⁻² h⁻¹). The highest CH₄ effluxes (6.6 ± 1.8 mmol m⁻² h⁻¹) were determined in the T. natans stand during day-time, whilst CH₄ emissions across the plant-free water surface were greatest at night (6.8 ± 2.1 mmol m⁻² h⁻¹). Therefore, we assumed that the water chestnut enhanced methane delivery to the atmosphere. On a daily basis, the oxbow lake was a net source to the atmosphere of both CO₂ (147.1 ± 10.8 mmol m⁻² d⁻¹) and CH₄ (116.3 ± 8.0 mmol m⁻² d⁻¹).     

Novel multipotent phenylthiazole–tacrine hybrids for the inhibition of cholinesterase activity, β-amyloid aggregation and Ca2+ overload

In this study, a series of multipotent phenylthiazole–tacrine hybrids (7a–7e, 8, and 9a–9m) were synthesized and biologically evaluated. Screening results showed that phenylthiazole–tacrine hybrids were potent cholinesterase inhibitors with pIC₅₀ (?log IC₅₀) value ranging from 5.78 ± 0.05 to 7.14 ± 0.01 for acetylcholinesterase (AChE), and from 5.75 ± 0.03 to 10.35 ± 0.15 for butyrylcholinesterase (BuChE). The second series of phenylthiazole–tacrine hybrids (9a–9m) could efficiently prevent Aβ_1–42 self-aggregation. The structure–activity relationship revealed that their inhibitory potency relied on the type of middle linker and substitutions at 4′-position of 4-phenyl-2-aminothiazole. In addition, 7a and 7c also displayed the Ca²⁺ overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer’s disease.     

Discovery of novel indazole derivatives as dual angiotensin II antagonists and partial PPARγ agonists

Identification of indazole derivatives acting as dual angiotensin II type 1 (AT₁) receptor antagonists and partial peroxisome proliferator-activated receptor-γ (PPARγ) agonists is described.Starting from Telmisartan, we previously described that indole derivatives were very potent partial PPARγ agonists with loss of AT₁ receptor antagonist activity.Design, synthesis and evaluation of new central scaffolds led us to the discovery of pyrrazolopyridine then indazole derivatives provided novel series possessing the desired dual activity.Among the new compounds, 38 was identified as a potent AT₁ receptor antagonist (IC₅₀ = 0.006 μM) and partial PPARγ agonist (EC₅₀ = 0.25 μM, 40% max) with good oral bioavailability in rat.The dual pharmacology of compound 38 was demonstrated in two preclinical models of hypertension (SHR) and insulin resistance (Zucker fa/fa rat).     

Hormone Substitution after Gastric Bypass Surgery in Patients with Hypopituitarism Secondary to Craniopharyngioma

Objective: Craniopharyngiomas (CPs) are benign brain tumors presenting frequently in childhood and are treated by surgery with or without radiotherapy. About 50% of cured patients suffer from eating disorders and obesity due to hypothalamic damage, as well as hypopituitarism, necessitating subsequent hormone substitution therapy. Gastric bypass surgery has been reported to be an efficient treatment strategy for morbid hypothalamic obesity. However, so far it is unknown whether oral hormone substitution is affected by impaired intestinal drug absorption, potentially leading to severe hypopituitarism or pituitary crisis.Methods: Four morbidly obese CP patients with panhypopituitarism treated by gastric bypass surgery were included in this retrospective analysis. Dosages of hormone substitution therapy, blood concentrations of hormones, potential complications of impaired drug absorption, and anthropometric characteristics were investigated pre- and postoperatively after 6 to 14 months and 13 to 65 months.Results: In all CP patients (3 female/1 male; baseline body mass index, 49 ± 7 kg/m²), gastric bypass resulted in distinct weight loss (-35 ± 27 kg). In follow-up examinations, mean daily dosage of thyroid hormone (levothyroxine_baseline 156 ± 44 μg/day versus levothyroxine_follow-up 150 ± 30 μg/day), hydrocortisone (hydrocortisone_baseline 29 ± 12 mg/day versus hydrocortisone_follow-up 26 ± 2 mg/day), growth-hormone (somatotropin_baseline 0.9 ± 0.5 mg/day versus somatotropin_follow-up 1.0 ± 0.4 mg/day), and desmopressin (desmopressin_baseline 222 ± 96 μg/day versus desmopressin_follow-up 222 ± 96 μg/day) substitution was unchanged. No patient developed adrenal insufficiency. Oral thyroid/hydrocortisone absorption testing performed in 1 patient indicated sufficient gastrointestinal drug absorption after bariatric surgery.Conclusion: Our preliminary results suggest that oral hormone substitution therapy is not impaired following gastric bypass operation in CP patients with morbid obesity, indicating that it might be a safe and effective treatment strategy.Abbreviations:BMI = body mass indexCP = craniopharyngiomafT4 = free thyroxineGH = growth hormoneIGF-1 = insulin-like growth factor 1