Influence of sympathetic and AT1‐receptor blockade on angiotensin II and adrenergic agonist‐induced renal vasoconstrictions in spontaneously hypertensive rats

Aim: This study investigated the influence of angiotensin II (Ang II) receptor and adrenergic blockade on the renal vasoconstrictions caused by Ang II and adrenergic agonists in spontaneously hypertensive rats (SHR). Methods: Forty‐eight SHR were subjected to 7 days of losartan (10 mg kg^?1 day^?1 p.o.), carvedilol (5 mg kg^?1 day^?1 p.o.) or losartan + carvedilol (10 mg kg^?1 day^?1 + 5 mg kg^?1 day^?1 p.o.). On day 8, the rats were anaesthetized and renal vasoconstrictor experiments performed. One group of rats underwent acute unilateral renal denervation. Results: There were significant (P < 0.05) reductions in the renal vasoconstrictor responses to noradrenaline, phenylephrine, methoxamine and Ang II after losartan and carvedilol treatments compared with that in untreated rats (all P < 0.05). However, in renally denervated SHR treated with carvedilol, the vasoconstrictor responses to all the vasoactive agents were enhanced compared with those in SHR with intact renal nerves treated with carvedilol. Intact SHR given both losartan and carvedilol showed greater renal vasoconstrictor responses to the vasoactive agents than when given either losartan or carvedilol alone (all P < 0.05). Conclusion: Carvedilol reduced the vasoconstrictor response to Ang II and all the adrenergic agonists in the presence of the renal nerves, but, following the removal of renal sympathetic activity, carvedilol enhanced the sensitivity of both renal α₁‐adrenoceptors and AT₁ receptors to the vasoactive agents. Co‐treatment with losartan and carvedilol reduced the renal vasoconstrictor responses to exogenously administered vasoactive agents but to a lesser extent than losartan or carvedilol alone. The results obtained demonstrate an interaction between Ang II receptors and adrenergic neurotransmission in the SHR.     

Changes of vitamin D levels and bone turnover markers after CPAP therapy: a randomized sham‐controlled trial

The aim was to investigate whether continuous positive airway pressure treatment could modulate serum vitamin D (25‐hydroxyvitamin D) and bone turnover markers (collagen‐type 1 cross‐linked C‐telopeptide, osteocalcin and N‐terminal propeptide of type 1 collagen) in secondary analysis from a randomized controlled trial. Sixty‐five continuous positive airway pressure‐naïve male patients with obstructive sleep apnea (age = 49 ± 12 years, apnea–hypopnea index = 39.9 ± 17.7 events h^?1, body mass index = 31.3 ± 5.2 kg m^?2) were randomized to receive either real (n  = 34) or sham (n  = 31) continuous positive airway pressure for 12 weeks. At 12 weeks, all participants received real continuous positive airway pressure for an additional 12 weeks. After 12 weeks of continuous positive airway pressure (real versus sham), there were no between‐group differences for any of the main outcomes [Δ25‐hydroxyvitamin D: ?0.80 ± 5.28 ng mL ^?1 (mean ± SE ) versus 3.08 ± 3.66 ng mL ^?1, P  = 0.42; Δcollagen‐type 1 cross‐linked C‐telopeptide: 0.011 ± 0.014 ng mL ^?1 versus ?0.004 ± 0.009 ng mL ^?1, P  = 0.48; Δosteocalcin: 1.13 ± 1.12 ng mL ^?1 versus 0.46 ± 0.75 ng mL ^?1, P  = 0.80; ΔN‐terminal propeptide of type 1 collagen: 2.07 ± 3.05 μ g L^?1 versus ?1.05 ± 2.13 μ g L^?1, P  = 0.48]. There were no further differences in subgroup analyses (continuous positive airway pressure‐compliant patients, patients with severe obstructive sleep apnea or sleepy patients). However, after 24 weeks irrespective of initial randomization, vitamin D increased in patients with severe obstructive sleep apnea (9.56 ± 5.51 ng mL ^?1, P  = 0.045) and in sleepy patients (14.0 ± 4.69 ng mL ^?1, P  = 0.007). Also, there was a significant increase in osteocalcin at 24 weeks (3.27 ± 1.06 ng mL ^?1, P  = 0.01) in compliant patients. We conclude that 12 weeks of continuous positive airway pressure did not modulate vitamin D or modulate any of the bone turnover markers compared with sham. However, it is plausible that continuous positive airway pressure may have late beneficial effects on vitamin D levels and bone turnover markers in selected groups of patients with obstructive sleep apnea.     

Dose‐dependent effects of continuous positive airway pressure for sleep apnea on weight or metabolic function: Individual patient‐level clinical trial meta‐analysis

Therapeutic‐continuous positive airway pressure seems to increase weight compared with placebo‐continuous positive airway pressure. It is not known whether weight gain with therapeutic‐continuous positive airway pressure dose is dependent or whether it causes metabolic dysfunction. Data synthesis of three randomised placebo‐continuous positive airway pressure‐controlled trials (2–3 months) was performed to test whether there is a dose‐dependent effect of continuous positive airway pressure on weight. Fasting glucose, insulin, insulin resistance (homeostatic model assessment), lipids and visceral abdominal fat were also tested to determine any effect on metabolic function. Mixed‐model analysis of variance was used to quantify these effects. One‐hundred and twenty‐eight patients were analysed. Overall there was a small increase in weight with therapeutic‐continuous positive airway pressure use compared with placebo‐continuous positive airway pressure (difference: 1.17 kg; 0.37–1.97, p = 0.005), which was greater with high‐use therapeutic‐continuous positive airway pressure compared with high‐use placebo‐continuous positive airway pressure (1.45 kg; 0.10–2.80, p = 0.04). Continuous positive airway pressure use as a continuous variable was also significantly associated with weight change in continuous positive airway pressure users (0.30 kg hr^?1 night^?1; 0.04–0.56, p = 0.001), but not in placebo users (0.04 kg hr^?1 night^?1; ?0.22 to 0.26, p = 0.76). Neither therapeutic‐continuous positive airway pressure nor the dose of therapeutic‐continuous positive airway pressure caused any changes to metabolic outcomes. The weight gain effects of medium‐term therapeutic‐continuous positive airway pressure appear modest and are not accompanied by any adverse metabolic effects.     

Renal medullary effects of transient prehypertensive treatment in young spontaneously hypertensive rats

Aim: Transient angiotensin II receptor blockade (ARB) leads to prolonged blood pressure (BP) lowering, but the underlying mechanism remains uncertain. Long‐term BP control is regulated by the medullary microcirculation with the pericyte as contractile cell. We hypothesize that the prolonged BP effect is caused by increased medullary blood flow (MBF) associated with structural alterations based on reduced medullary pericyte number. Methods: Four‐week‐old spontaneously hypertensive rats (SHR) were treated for 4 weeks with losartan (SHR‐Los: 20 mg kg^?1 day^?1), hydralazine (SHR‐Hyd: 15 mg kg^?1 day^?1), losartan and pan‐caspase inhibitor zVAD (SHR‐Los + 1 mg kg^?1 day^?1 zVAD), losartan and glycogen synthase kinase‐3β (GSK) inhibitor valproate (SHR‐Los + 10 mg kg^?1 day^?1 Val) or placebo. BP, MBF and pericyte number were determined under and after treatment (8 and 12 weeks). Apoptotic pericytes were determined with α‐actin and TUNEL double staining. Sodium concentration was determined in renal medulla and urine. Results: Antihypertensive treatment equipotently reduced BP at 8 weeks of age. After drug withdrawal (12 weeks of age) BP reduction was restricted to SHR‐Los (SHR‐Los: 153 ± 5, SHR‐Hyd: 177 ± 2, SHR: 184 ± 3 mmHg). Simultaneously, MBF was increased and pericyte number reduced, while medullary and urinary sodium concentration increased. Transient ARB in combination with zVAD or valproate resulted in more medullary pericytes and higher BP (SHR‐Los/zVAD: 164 ± 7; SHR‐Los/Val: 168 ± 6 mmHg) compared with transient ARB alone. Conclusion: After drug withdrawal, transient ARB leads to increased MBF and is associated with a reduction in medullary pericytes. This may be associated with pericyte apoptosis as anti‐apoptosis during transient ARB increases pericyte number and BP.     

Anti‐Asthma Simplified Herbal Medicine Intervention‐induced long‐lasting tolerance to allergen exposure in an asthma model is interferon‐γ, but not transforming growth factor‐β dependent

Background Chronic allergic asthma is the result of a T‐helper type 2 (Th2)‐biased immune status. Current asthma therapies control symptoms in some patients, but a long‐lasting therapy has not been established. Anti‐Asthma Simplified Herbal Medicine Intervention (ASHMI^?), a Chinese herbal formula improved symptoms and lung function, and reduced Th2 responses in a controlled trial of patients with persistent moderate to severe asthma. Objective We evaluated the persistence of ASHMI^? beneficial effects following therapy in a murine model of chronic asthma and the immunological mechanisms underlying such effects. Methods BALB/c mice sensitized intraperitoneally with ovalbumin (OVA) received 3 weekly intratracheal OVA challenges to induce airway hyper‐reactivity (AHR) and inflammation (OVA mice). Additionally, OVA mice were treated with ASHMI^? (OVA/ASHMI^?) or water (OVA/sham) for 4 weeks, and then challenged immediately and 8 weeks post‐therapy. In other experiments, OVA mice received ASHMI^? treatment with concomitant neutralization of IFN‐γ or TGF‐β. Effects on airway responses, cytokine‐ and OVA‐specific IgE levels were determined 8 weeks post‐therapy. Results Before treatment, OVA mice exhibited AHR and pulmonary eosinophilic inflammation following OVA challenge, which was almost completely resolved immediately after completing treatment with ASHMI^? and did not re‐occur following OVA re‐challenge up to 8 weeks post‐therapy. Decreased allergen‐specific IgE and Th2 cytokine levels, and increased IFN‐γ levels also persisted at least 8 weeks post‐therapy. ASHMI^? effects were eliminated by the neutralization of IFN‐γ, but not TGF‐β, during therapy. Conclusion ASHMI^? induced long‐lasting post‐therapy tolerance to antigen‐induced inflammation and AHR. IFN‐γ is a critical factor in ASHMI^? effects. Cite this as: K. Srivastava, T. Zhang, N. Yang, H. Sampson and X. M. Li, Clinical & Experimental Allergy, 2010 (40) 1678–1688.     

Exercise and myocardial tolerance to ischaemia‐reperfusion

It is well established that both short‐term (1–5 days) and long‐term (weeks to months) high intensity exercise (i.e. 70–75%VO_2max) provides cardioprotection against ischaemia‐reperfusion injury. However, it is unclear if moderate intensity exercise will also provide cardioprotection. Aim: Therefore, these experiments compared the protective effects of moderate vs. high intensity exercise in providing defense against ischaemia‐reperfusion injury. Methods: Male Sprague–Dawley rats were randomly assigned to one of three‐experimental groups: (1) sedentary (control); (2) moderate intensity treadmill exercise (60 min day^?1 at ～55%VO_2max); or (3) high intensity treadmill exercise (60 min day^?1 at ～75%VO_2max). Hearts were exposed to 20 min of global ischaemia followed by 30 min reperfusion in an isolated working heart preparation. Results: Compared with sedentary rats, both moderate and high intensity exercised rats maintained a higher (P < 0.05) percentage of pre‐ischaemia cardiac output and cardiac work (cardiac output × systolic blood pressure) during reperfusion. No differences in the percent recovery of cardiac output and heart work existed (P > 0.05) between the two exercise groups. Conclusions: These data reveal that both moderate and high intensity exercise training provide equivalent protection against ischaemia‐reperfusion injury.     

Oral pre‐treatment with rosuvastatin protects porcine myocardium from ischaemia/reperfusion injury via a mechanism related to nitric oxide but not to serum cholesterol level

Aims: The aim of this study was to test whether oral pre‐treatment with rosuvastatin at a dosage giving clinically relevant plasma concentrations protects the myocardium against ischaemia/reperfusion injury and to investigate the involvement of nitric oxide (NO) and neutrophil infiltration. Methods: Pigs were given placebo (n = 7), rosuvastatin (80 mg day^?1, n =7), rosuvastatin (160 mg day^?1, n = 7) or pravastatin (160 mg day^?1, n = 7) orally for 5 days before being subjected to coronary artery ligation and reperfusion. An additional group was given rosuvastatin 160 mg day^?1 and a nitric oxide synthase (NOS) inhibitor. Results: Rosuvastatin 80 and 160 mg day^?1 resulted in plasma concentrations of 2.6 ± 0.7 and 5.6 ± 1.0 ng mL^?1, respectively. Serum cholesterol was not affected. Rosuvastatin 160 mg day^?1 and pravastatin limited the infarct size from 82 ± 3% of the area at risk in the placebo group to 61 ± 3% (P < 0.05), and to 61 ± 2% (P < 0.05) respectively. Rosuvastatin 80 mg day^?1 limited the infarct size to 69 ± 2%, however, this effect was not statistically significant. Rosuvastatin 160 mg day^?1 attenuated neutrophil infiltration in the ischaemic/reperfused myocardium. The protective effect of rosuvastatin 160 mg day^?1 was abolished by NOS inhibition. The expression of NOS2 and NOS3 in the myocardium did not differ between the groups. Conclusions: Oral pre‐treatment with rosuvastatin limited infarct size following ischaemia/reperfusion without affecting cholesterol levels. The cardioprotective effect is suggested to be dependent on maintained bioactivity of NO, without influencing NOS expression.     

Cantú syndrome: Findings from 74 patients in the International Cantú Syndrome Registry

Cantú syndrome (CS), first described in 1982, is caused by pathogenic variants in ABCC9 and KCNJ8, which encode the regulatory and pore forming subunits of ATP‐sensitive potassium (K_ATP) channels, respectively. Multiple case reports of affected individuals have described the various clinical features of CS, but systematic studies are lacking. To define the effects of genetic variants on CS phenotypes and clinical outcomes, we have developed a standardized REDCap‐based registry for CS. We report phenotypic features and associated genotypes on 74 CS subjects, with confirmed ABCC9 variants in 72 of the individuals. Hypertrichosis and a characteristic facial appearance are present in all individuals. Polyhydramnios during fetal life, hyperflexibility, edema, patent ductus arteriosus (PDA), cardiomegaly, dilated aortic root, vascular tortuosity of cerebral arteries, and migraine headaches are common features, although even with this large group of subjects, there is incomplete penetrance of CS‐associated features, without clear correlation to genotype.     

Integration of Pig-a, micronucleus, chromosome aberration, and Comet assay endpoints in a 28-day rodent toxicity study with 4-nitroquinoline-1-oxide

As part of the Stage III Pig‐a multilaboratory validation trial, we examined the induction of CD59‐negative reticulocytes and total red blood cells (RET^CD59? and RBC^CD59?, respectively) in male Sprague Dawley® rats treated with 4‐nitroquinoline‐1‐oxide (4NQO), for 28 consecutive days by oral gavage, at doses of 1.25, 2.50, 3.75, 5.00, and 7.50 mg kg^?1 day^?1 (the high dose group was sacrificed on Day 15 due to excessive morbidity/mortality). Animals also were evaluated for: micronucleated reticulocytes (mnRET) by flow cytometry; DNA damage in peripheral blood, liver, and stomach using the Comet assay; and chromosome aberrations (CAb) in peripheral blood lymphocytes (PBL). All endpoints were analyzed at two or more timepoints where possible. Mortality, body and organ weights, food consumption, and clinical pathology also were evaluated, and demonstrated that the maximum tolerated dose was achieved at 5.00 mg kg^?1 day^?1. The largest increases observed for the genetic toxicology endpoints (fold‐increase compared to control, where significant; all at 5.00 mg kg^?1 day^?1 on Day 29) were: RET^CD59? (21X), RBC^CD59? (9.0X), and mnRET (2.0X). In contrast, no significant increases were observed for the CAb or Comet response, in any tissue analyzed, at any timepoint. Because 4NQO is a well known mutagen, clastogen, and carcinogen, the lack of response for these latter endpoints was unexpected. These results emphasize the extreme care that must betaken in dose and endpoint selection when incorporating genotoxicity endpoints into routine toxicity studies as has been recommended or is under consideration by various regulatory and industrial bodies. Environ. Mol. Mutagen., 2011. © 2011 Wiley‐Liss, Inc.     

Genomics‐based treatment in a patient with two overlapping heritable skin disorders: Epidermolysis bullosa and acrodermatitis enteropathica

Next‐generation sequencing (NGS) is helpful in diagnosing complex genetic disorders and phenotypes, particularly when more than one overlapping condition is present. From a large cohort of 362 families with clinical manifestations of skin and mucosal fragility, referred by several major medical centers, one patient was found by NGS to have two overlapping heritable skin diseases, recessive dystrophic epidermolysis bullosa (RDEB; COL7A1 mutations) and acrodermatitis enteropathica (AE; SLC39A4 mutations). The pathogenicity of the variants was studied at gene expression as well as ultrastructural and tissue levels. Although there is no specific treatment for RDEB except avoiding trauma, supplementation with oral zinc (3 mg·kg^?1·day^?1) for the AE resulted in rapid amelioration of the skin findings. This case demonstrates the power of NGS in identifying two genetically unlinked diseases that led to effective treatment with major clinical benefits as an example of genomics‐guided treatment.     

Nerve growth factor increases airway responses and decreases levels of exhaled nitric oxide during histamine challenge in an in vivo guinea‐pig model

There is a growing body of evidence supporting the idea that nerve growth factor (NGF) may be involved in the development of asthma‐associated symptoms, such as airway hyper‐responsiveness. Increased levels of NGF have recently been described in serum and in the airways of asthmatics. We have examined whether exhaled nitric oxide (NO) levels might be altered during the increased airway responses upon NGF treatment in guinea‐pigs in vivo. Intravenous (i.v.) administration of histamine normally elicits a rapid peak in insufflation pressure (IP) and in exhaled NO, followed by a period of decreased concentrations of exhaled NO. Anaesthetized guinea‐pigs were pre‐treated intravenously with either saline, 4 or 80 ng kg^–1 NGF 30 min before i.v. challenge with 16 μg kg^–1 histamine. At 80 ng kg^–1 NGF significantly enhanced the airway obstruction caused by histamine, whereas the peak acute increase in exhaled NO was not enhanced. Following the increase, came a rapid drop, an effect enforced in the NGF treated animals. Subsequently, the time to return to 90% of resting exhaled NO was increased, from 12 min in saline‐treated animals to 48 min in NGF‐treated animals. Our data confirm that NGF can enhance airway responses to histamine. Moreover, our study shows a decrease in exhaled NO following a histamine challenge, an effect enhanced by NGF. A reduced ability to release exhaled NO may be a mechanism for increased airway responses during elevated NGF levels. The interaction between NGF and airway NO formation, and its relation to airway responses, merit further investigation.     

Additive hypothermic effects of the 5‐HT1A receptor agonist 8‐OH‐DPAT and the dopamine D2/3 receptor agonist 7‐OH‐DPAT in the rat

The objective of this study was to examine possible interactions between serotonergic and dopaminergic agents lowering core temperature via stimulation of 5‐HT_1A and dopamine (DA) D₂ receptors, respectively. The effects of the 5‐HT_1A receptor agonist (±)‐8‐hydroxy‐2‐(di‐n‐propylamino)tetralin HBr (8‐OH‐DPAT) and the DA D_2/3 receptor agonist 7‐OH‐DPAT on core temperature was monitored in adult male Wistar rats, approximately 300 g body weight. The temperature probe was connected to a PC‐assisted temperature instrument, and an automated printer device was activated when the temperature reading had stabilized (±0.1 °C) for 10 s. As expected, 7‐OH‐DPAT [0.5 and 2.0 μmol kg^–1 subcutaneous (s.c.)] as well as 8‐OH‐DPAT (0.15–2.4 μmol kg^–1 s.c.), produced a dose‐dependent hypothermia. When combined, there were additive effects of the two compounds, although the effects of 7‐OH‐DPAT were attenuated by 8‐OH‐DPAT at the higher doses (0.6–2.4 μmol kg^–1), in all probability because of emerging DA D₂ receptor blocking properties of the latter compound.     

B2 kinin receptors mediate the Indian red scorpion venom‐induced augmentation of visceral reflexes via the nitric oxide cyclic guanosine monophosphate pathway

Aim: This study was performed to delineate the kinin (receptor)‐dependent pathways in the Indian red scorpion (Mesobuthus tamulus; MBT) venom‐induced pulmonary oedema as well as the augmentation of cardio‐pulmonary reflexes evoked by phenyldiguanide (PDG). Methods: In urethane‐anaesthetized adult rats, the effect of venom on the PDG reflex responses (blood pressure, heart rate and respiration rate) and the pulmonary water content was ascertained using various antagonists(des‐ Arg, B₁ receptor antagonist; Hoe 140, B₂ receptor antagonist; N^ω‐nitro‐l ‐arginine methyl ester (l ‐NAME), nitric oxide (NO) synthase inhibitor; methylene blue, soluble guanylate cyclase inhibitor; and glibenclamide, K⁺_ATP channel blocker). The effect of phosphodiesterase V inhibitor (sildenafil citrate) on the reflex response and the pulmonary water content was also examined and compared with venom‐induced responses. Results: Intravenous injection of PDG (10 μg kg^?1) evoked apnoea, bradycardia and hypotension lasting >60 s. Exposure to MBT venom (100 μg kg^?1) for 30 min augmented the PDG reflex responses by two times and increased the pulmonary water content, significantly. Hoe 140 blocked the venom‐induced responses (augmentation of PDG reflex and increased pulmonary water content) whereas des‐Arg did not. l ‐NAME, methylene blue or glibenclamide also blocked the venom‐induced responses. Furthermore, sildenafil citrate (that increases cGMP levels) produced augmentation of PDG reflex response and increased the pulmonary water content as seen with venom. Conclusion: The results indicate that venom‐induced responses involve B₂ kinin receptors via the NO‐dependent guanylate cyclase‐cGMP pathway involving K⁺_ATP channels.     

Effects of N‐nitro l‐arginine methyl ester (l‐NAME), a potent nitric oxide synthase inhibitor,on visual evoked potentials of rats exposed to different experimental stress models

Aim: The aim of our study was to investigate the effects of the nitric oxide synthase inhibitor, N‐nitro l ‐arginine methyl ester (l ‐NAME, 10 mg kg^?1 day^?1 i.p.), on visual evoked potentials (VEPs) and lipid peroxidation expected to occur during chronic stress (15 days). Methods: Eight experimental groups, each consisting of 10 rats, were formed: control group (C), the group injected with l ‐NAME (L), groups exposed to cold stress (CS), immobilization stress (IS), and both cold and immobilization stress (CIS), groups exposed to stress and injected with l ‐NAME (CSL, ISL, CISL). Results: l ‐NAME decreased brain and retina nitrite levels in all experimental groups compared with their corresponding control groups. l ‐NAME decreased glutathione peroxidase (GSH‐Px) activity in the brain and retina in the L group, but increased it in the CSL and CISL groups compared with the C group. Lipid peroxidation was increased in the brain and retina tissues of all stress groups with respect to the C group. l ‐NAME markedly increased brain thiobarbituric acid reactive substances (TBARS) levels in the L group, while significantly decreasing brain and retina TBARS levels in all stress groups in comparison with their respective control groups. l ‐NAME caused a significant delay in all components of VEPs in the L group compared with the C group. However, l ‐NAME significantly decreased latencies of P₁, N₁, P₂ and P₃ components in the CSL group and all components in the ISL and CISL groups with respect to their corresponding control groups. Conclusion: This study clearly indicated that lipid peroxidation may be one possible factor affecting VEP components.     

Does central nitric oxide chronically modulate the acute hypoxic ventilatory response in conscious rats?

Aim: Hypoxia initiates an increase in ventilation (V_E) through a cascade of events of which central nitric oxide (NO) has been implicated as an important neuromodulator. There have not been any reports describing the consequences of long‐term imbalances in the central NO pathways on the modulation of the acute hypoxic ventilatory response (HVR). Chronic hypoxia (CH) can potentially modify the HVR, and so we hypothesized that central NO may be involved. In this study we describe the long‐term role of central NO in the modulation of HVR before and after CH. Methods: Male Sprague–Dawley rats (BW c. 200–320 g; n = 21) were implanted with an osmotic pump for continuous intracerebroventricular administration of either artificial cerebrospinal fluid (control), N^ω‐nitro‐l ‐arginine methyl ester (l ‐NAME) (150 μg kg^?1 day^?1) or the NO‐donor, 3‐[4‐morpholinyl]‐sydnonimine‐hydrochloride (SIN‐1) (100 μg kg^?1 day^?1). The V_E response to acute poikilocapnic hypoxia (8% O₂ for 20 min) was measured by plethysmography seven days after surgery, in normoxia, and again after 14 days of exposure to CH (CH = 12% O₂). Results: The magnitude of the HVR (c. 230% increase in V_E) was unaltered by centrally infusing either l ‐NAME or SIN‐1 for 1 week. CH did not modify the HVR, although baseline V_E and HVR were shifted downward by l ‐NAME during CH – because of a reduction in the frequency component. Conclusions: These results suggest that long‐term alterations in central NO levels may not alter the HVR under moderate CH, presumably because of the onset/development of compensatory mechanisms. However, NO appears to be an important component of the HVR following CH.     

Enzyme activity of rat tibialis anterior muscle differs between treatment with triamcinolone and prednisolone and nutritional deprivation

The maximal activity of a selection of enzymes involved in muscle carbohydrate handling, citric acid cycle and fatty acyl β-oxidation were studied after treatment with the fluorinated corticosteroid triamcinolone and compared to a similar treatment of the non-fluorinated corticosteroid prednisolone in an equipotent anti-inflammatory dose. Furthermore, because triamcinolone causes loss of body mass and muscle wasting, the effects of triamcinolone were investigated relative to a control group, with the same loss of body mass, due to nutritional deprivation. The study was performed in male Wistar rats in the following treatment groups: TR, triamcinolone treatment (0.25?mg?·?kg^?1?· day^?1 for 2 weeks), which resulted in a reduction of body mass (24%); ND, nutritional deprivation (30% of normal daily food intake for 2 weeks) resulting in a similar (24%) decrease of body mass as TR; PR, prednisolone treatment (0.31?mg?·?kg^?1?·?day^?1 for 2 weeks), with a 10% increase in body mass; FF, free-fed control group, with a 12% increase in body mass in 2 weeks. Compared to FF, TR induced an increase in phosphofructokinase (PFK) activity (P?P?P?P?P?P?P?P?P?P?P?相似文献   

Three‐dimensional facial morphology in Cantú syndrome

Cantú syndrome (CS) was first described in 1982, and is caused by pathogenic variants in ABCC9 and KCNJ8 encoding regulatory and pore forming subunits of ATP‐sensitive potassium (K_ATP) channels, respectively. It is characterized by congenital hypertrichosis, osteochondrodysplasia, extensive cardiovascular abnormalities and distinctive facial anomalies including a broad nasal bridge, long philtrum, epicanthal folds, and prominent lips. Many genetic syndromes, such as CS, involve facial anomalies that serve as a significant clue in the initial identification of the respective disorder before clinical or molecular diagnosis are undertaken. However, an overwhelming number of CS patients receive misdiagnoses based on an evaluation of coarse facial features. By analyzing three‐dimensional images of CS faces, we quantified facial dysmorphology in a cohort of both male and female CS patients with confirmed ABCC9 variants. Morphometric analysis of different regions of the face revealed gender‐specific significant differences in face shape. Moreover, we show that 3D facial photographs can distinguish between CS and other genetic disorders with specific facial dysmorphologies that have been mistaken for CS‐associated anomalies in the past, hence assisting in an earlier clinical and molecular diagnosis. This optimizes genetic counseling and reduces stress for patients and parents by avoiding unnecessary misdiagnosis.     

Differential expression of androgen and estrogen receptors in PCB (Aroclor 1254)-exposed rat ventral prostate: Impact of alpha-tocopherol

Polychlorinated biphenyls (PCBs) are environmental toxicants, which affect male fertility by altering the androgen and estrogen levels. PCB-induced toxic manifestations are associated with the production of reactive oxygen species. Vitamin E (α-tocopherol) is a major lipophilic chain breaking antioxidant, which protects polyunsaturated fatty acids in tissues against peroxidation, a property that could be beneficial in the male reproductive biology. The purpose of this study was to determine the impact of α-tocopherol on PCB (Aroclor 1254)-induced changes in androgen receptor (AR) and estrogen receptors (ERs) expression in Wistar rat ventral prostate. Rats were divided into 3 groups of 6 animals each. Group I rats were administered corn oil (vehicle) intraperitoneally (i.p.); Group II rats were treated with 2 mg kg^?1 day^?1 of PCB (i.p.); Group III rats were treated with 2 mg kg^?1 day^?1 of PCB (i.p.) along with simultaneous oral supplementation of 50 mg kg^?1 day^?1 of α-tocopherol. Serum testosterone and estradiol titers were assayed. Prostatic acid phosphatase activity (PAcP), citric acid concentration, generation of hydrogen peroxide (H₂O₂) and lipid peroxides (LPO) were estimated. mRNA and protein expression of AR, ER-α and ER-β in ventral prostate were quantified. Serum testosterone, estradiol, PAcP, citric acid levels, AR and ER-α expressions were significantly decreased while H₂O₂ generation, LPO, ER-β were increased in PCB-exposed animals. Simultaneous supplementation of α-tocopherol in PCB-exposed rats resulted in significant restoration of all the parameters to the control. The results suggest that α-tocopherol has definite protective effect against PCB-induced toxicity in ventral prostatic dysfunction.     

Novel ABCC8 (SUR1) Gene Mutations in Asian Indian Children with Congenital Hyperinsulinemic Hypoglycemia

Congenital hyperinsulinemic hypoglycemia (HI) is a heterogeneous genetic disorder of insulin secretion characterized by persistent hypoglycemia, most commonly associated with inactivating mutations of the β‐cell ATP‐sensitive K⁺ channel (K^ATP channel) genes ABCC8 (encoding SUR1) and KCNJ11(encoding Kir6.2). This study aimed to screen the mutations in the genes associated with congenital HI in Asian Indian children. Recessive mutations of these genes cause hyperinsulinism that is unresponsive to treatment with channel agonists like diazoxide. Dominant K^ATP mutations have been associated with diazoxide‐responsive disease. The KCNJ11, ABCC8, GCK, HNF4A, and GLUD1 genes were analyzed by sequence analysis in 22 children with congenital HI. We found 10 novel mutations (c.1delA, c.61delG, c.267delT, c.619–629delCCCGAGGACCT, Gln444*, Leu724Pro, Ala847Thr, Trp898*, IVS30–2A>C, and Leu1454Arg) and two known mutations (Gly111Arg and Arg598*) in the ABCC8 gene. This study describes novel and known ABCC8 gene mutations in children with congenital HI. This is the first large genetic screening study on HI in India and our results will help clinicians in providing optimal treatment for patients with hyperinsulinemia and in assisting affected families with genetic counseling.     

Emulsion Self‐Assembly Synthesis of Chitosan/Poly(lactic‐co‐glycolic acid) Stimuli‐Responsive Amphiphiles

An amphiphilic graft copolymer using chitosan (CS) as a hydrophilic main chain and poly(lactic‐co‐glycolic acid) (PLGA) as a hydrophobic side chain is prepared through an emulsion self‐assembly synthesis. CS aqueous solution is used as a water phase and PLGA in chloroform is served as an oil phase. A water‐in‐oil (W/O) emulsion is fabricated in the presence of the surfactant span‐80. The self‐assembly reaction is performed between PLGA and CS under the condensation of EDC. Fourier transform IR (FTIR) spectroscopy reveals that PLGA is grafted onto the backbone of CS through the interactions between end carboxyl and amino groups of the two components. ¹H NMR spectroscopy directly indicates the grafting content of PLGA in the CS‐graft‐PLGA (CS‐g‐PLGA) copolymer is close to 25%. X‐ray diffraction (XRD) confirms that the copolymer exhibits an amorphous structure. The CS‐g‐PLGA amphiphile can self‐assemble to form micelles with size in the range of ≈100–300 nm, which makes it easy to apply in various targeted‐drug‐release and biomaterial fields.