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Globally, adverse drug reactions (ADRs) are the foremost cause of morbidity as well as mortality. This necessitates a system of surveillance that can effectively and efficiently monitor the effect of drugs on the general population. The role of pharmacovigilance (PV) is paramount in ensuring drug safety through spontaneous ADR reporting. Data collection in the current research was carried out by an anonymous, online 36-item self-report questionnaire amongst a sample of 351 working healthcare professionals (HCPs) across different regions of Jazan Province, Kingdom of Saudi Arabia (KSA). The current sample comprised 54.4% males and 45.6% females, having an age range of 26–57 years, and was conducted between August 21 and October 21, 2022. Participants were recruited using the convenience snowball sampling technique. The participants' awareness of PV as well as spontaneous ADR reporting, had a significant association with having <40 years of age (χ2 = 27.40 ; p < 0.001), being pharmacists (χ2 = 212.20; p < 0.001), with more than five years of experience (χ2 = 40.80 ; p < 0.001), having Masters (or) Doctorate/Fellowship (χ2 = 171.94; p < 0.001), and having their practice located in an urban area (χ2 = 50.30 ; p < 0.001). It was also observed that most participants with excellent awareness of PV and spontaneous ADR reporting also demonstrated excellent attitudes (χ2 = 147.70; p < 0.001). Similarly, it was also seen that almost all (97%) of the study sample with excellent attitudes towards PV and spontaneous ADR reporting also demonstrated excellent practices (χ2 = 250.73; p < 0.001). Our results demonstrate a need for designing and conducting educational programs, providing training and conducting workshops for all the HCPs to improve their awareness towards PV and spontaneous ADR reporting while also highlighting the need and importance of having positive attitudes towards spontaneous ADR reporting. Cooperation between different HCPs should be encouraged to improve their practices towards spontaneous ADR reporting. [ABSTRACT FROM AUTHOR]

Manzala Lake was sampled to assess the concentrations and possible ecological risks of heavy metals. The mean heavy metal levels in the muscles of Nile tilapia, Flathead grey mullets and African catfish were 0.01, 0.15 and 0.29 mg/kg, respectively, for mercury; 3.16, 4.25 and 4.74 mg/kg for arsenic; 1.01, 0.87 and 0.95 mg/kg for lead; and 0.05, 0.12 and 0.06 mg/kg for cadmium. The levels of heavy metals exceeded their maximum permissible limits in most samples. The EDIs of some metals were higher than their PTDIs or BMDLs. The THQs and TTHQs from metal intake were >1 for Hg and Cd. In addition, the TCR values of As in all fish species were higher than 1.0 × 10−4 indicating a potential health risks from consumption of fish species which need strict hygienic procedures to prevent fish contamination with heavy metals and ensure that their levels did not exceed the maximum permissible limits. [Display omitted] • The pollution of Manzala Lake with heavy metals increased after recent cleanup and dredging operations. • Heavy metals in most tested samples exceeded their Egyptian legal limits. • The EDIs of some metals were higher than PTDIs or BMDLs. • The THQ and TTHQ values of both Hg and Cd in most samples were >1 suggesting public health risks. • The TCR values of As in all tested fishes were higher than 1.0 × 10−4 indicating carcinogenic health risks. [ABSTRACT FROM AUTHOR]

G protein-coupled estrogen receptor (GPER) activation by G1 attenuates diastolic dysfunction from estrogen loss, which may be partly due to suppression of angiotensin II pathological actions. We aimed to determine the independent effects of 8 weeks of G1 (100 µg/kg/d, subcutaneous pellet), ACE-inhibition (ACEi; lisinopril 10 mg/kg, drinking water), or combination therapy versus vehicle in the ovariectomized (OVX) spontaneously hypertensive rat (SHR) on cardiac function and morphometrics (echocardiography), serum equilibrium of angiotensins (mass spectroscopy) and cardiac components of the RAS (Western blotting). G1 alone and when combined with ACEi enhanced myocardial relaxation (é: 30 and 17%) and diastolic wall strain (DWS: 76 and 68%) while reducing relative wall thickness (RWT: 20 and 33%) and filling pressures (E/é: 30 and 37%). Cardiac expression levels of Mas receptor (Mas-R) and ACE2 also increased in the presence of G1. Strong antihypertensive effects of lisinopril monotherapy were associated with reductions in RWT, collagen deposition and E/é without overtly altering é or DWS. Chronic ACEi also increased cardiac levels of Mas-R and AT1-R and tilted the circulating RAS toward the formation of Ang-(1-7), which was amplified in the presence of G1. In vitro studies further revealed that an inhibitor to prolyl endopeptidase (PEP), but not to neprilysin, significantly reduced serum Ang-(1-7) levels in G1-treated rats, suggesting that G1 might be increasing Ang-(1-7) formation via PEP. We conclude that activating GPER with G1 augments components of the cardiac RAS and improves diastolic function without lowering blood pressure, and that lisinopril-induced blood pressure control and cardiac alterations in OVX SHR are permissive in facilitating G1 to augment Ang-(1-7) in serum, thereby strengthening its cardioprotective benefits. [ABSTRACT FROM AUTHOR]

Resumo Justificativa e objetivos O manejo de vias aéreas em contratura de pescoço após queimadura sempre foi um desafio para os anestesiologistas, pois a contratura limita o alinhamento do eixo orofaringolaríngeo devido às deformidades funcionais e anatômicas que ocorrem como resultado de contraturas de longa duração. Relato de caso Paciente do sexo masculino, 35 anos de idade, com contratura do pescoço após queimadura foi programado para liberação da contratura. Como estava com deformidade fixa em flexão no pescoço, não tentamos a laringoscopia convencional e optamos por usar o videolaringoscópio King Vision . Conclusão O videolaringoscópio King Vision pode ser usado em situações de via aérea difícil como a contratura de pescoço após queimadura. Background and objectives Managing the airway of post burn contracture of the neck has always been challenging to anesthesiologists as it limits the alignment of oro‐pharyngo‐laryngeal axes because of functional and anatomical deformities that occur as a result of long standing contractures. Here the role of the King Vision video laryngoscope which is the latest in the series of video laryngoscope has been evaluated for such patients. Case report A 35 year old male patient with post burn contracture of neck was scheduled for release of the contracture. As the patient had had fixed flexion deformity of the neck we did not attempt the conventional laryngoscopy. Instead we opted for King Vision video laryngoscope. Conclusion We therefore conclude that King Vision videolaryngoscope can be used for difficult airway situations like post burn contracture of neck. [ABSTRACT FROM AUTHOR]

Abstract: Identification of angiotensin-(1-12) [Ang-(1-12)] in forming angiotensin II (Ang II) by a non-renin dependent mechanism has increased knowledge on the paracrine/autocrine mechanisms regulating cardiac expression of Ang peptides. This study now describes in humans the identity of the enzyme accounting for Ang-(1-12) metabolism in the left ventricular (LV) tissue of normal subjects. Reverse phase HPLC characterized the products of 125I-Ang-(1-12) metabolism in plasma membranes (PMs) from human LV in the absence and presence of inhibitors for chymase (chymostatin), angiotensin-converting enzyme (ACE) 1 (lisinopril) and 2 (MLN-4760), and neprilysin (SHC39370). In the presence of the inhibitor cocktail, ≥98% ± 2% of cardiac 125I-Ang-(1-12) remained intact, whereas exclusion of chymostatin from the inhibitor cocktail led to significant conversion of Ang-(1-12) into Ang II. In addition, chymase-mediated hydrolysis of 125I-Ang I was higher compared with Ang-(1-12). Negligible Ang-(1-12) hydrolysis occurred by ACE, ACE2, and neprilysin. A high chymase activity was detected for both 125I-Ang-(1-12) and 125I-Ang I substrates. Chymase accounts for the conversion of Ang-(1-12) and Ang I to Ang II in normal human LV. These novel findings expand knowledge of the alternate mechanism by which Ang-(1-12) contributes to the production of cardiac angiotensin peptides. [Copyright &y& Elsevier]

Abstract: The environmental carcinogen 5-methylchrysene (5MC) can be activated to mutagenic metabolites by several isozymes of cytochrome P-450 (CYP). The resulting reactive diol-epoxides can be detoxified via conjugation by glutathione S-transferases (GST). We investigated whether expression of human glutathione S-transferase P1 (hGSTP1) would differentially protect cells against the cytotoxicity or mutagenicity of 5MC or its 1,2-dihydrodiol intermediate (5MC-1,2-diol) in V79MZ cells with activation via stably transfected human CYP1B1 (hCYP1B1) as compared to activation by human CYP1A1 (hCYP1A1). The parent compound 5MC was only 2-fold more cytotoxic in the CYP-expressing cell lines than in the V79MZ parental cell line, while 5MC-1,2-dihydrodiol was more than 30-fold more cytotoxic in CYP-transfected cells compared to V79MZ cells. Cells co-expressing either hCYP1B1 or hCYP1A1 together with hGSTP1 were 2-fold less sensitive to 5MC or 5MC-1,2-diol cytotoxicity than their CYP-only parent lines. The 5MC was highly mutagenic with similar potency in both hCYP-transfected cell lines, while 5MC-1,2-diol was 2-fold more mutagenic in hCYP1B1-transfected cells as compared to hCYP1A1 cells. Coexpression of hGSTP1 with either hCYP reduced 5MC or 5MC-1,2-diol mutagenicity by 1.4–4.5-fold compared to the corresponding hCYP-only expressing cell lines. The greater protection against mutagenicity of 5MC is in contrast to our previous studies in which we found greater protection by hGSTP1 against cytotoxicity than mutagenicity of benzo[a]pyrene in cells co-expressing hCYP1A1. Protection against mutagenicity by hGSTP1 was greater with activation of either compound by hCYP1B1 than with hCYP1A1 activation. These studies show that the relative efficacy of protection by hGSTP1 against mutagenicity of 5MC or 5MC-1,2-diol is in part determined by the specific CYP pathway that catalyzes activation to the toxic or mutagenic metabolites. [Copyright &y& Elsevier]

Background. The activity of the organic anion transporter 1 (OAT1) has been implicated recently in the basolateral uptake of thiol conjugates of inorganic mercury in renal proximal tubular cells. However, very little is known about the role of OAT1 in the renal epithelial transport of organic forms of mercury, such as methylmercury (CH3Hg+), especially when it is in the form of the cysteine (Cys) S-conjugate of methylmercury (CH3Hg-Cys), which is believed to be a biologically relevant form of mercury. Methods. Accordingly, the present study, was designed to characterize the transport of CH3Hg-Cys in Madin-Darby canine kidney (MDCK) cells transfected stably with the human isoform of OAT1 (hOAT1) and in proximal tubular–derived NRK-52E cells. Results. Data on saturation kinetics, time dependency, substrate specificity, and temperature dependency demonstrate that CH3Hg-Cys is transported by hOAT1. Substrate-specificity data from the control cells also show that CH3Hg-Cys is a substrate of one or more transporter(s) that is/are not hOAT1. Additional findings indicate that at least one amino acid transport system is involved in the uptake of CH3Hg-Cys in MDCK cells. Furthermore, in the presence of cytotoxic concentrations of CH3Hg-Cys, rates of survival were lower in hOAT1-transfected cells than in wild-type control cells. Conclusion. The present data demonstrate clearly that CH3Hg-Cys is indeed a transportable substrate of OAT1. Moreover, the collective findings from the MDCK cells and NRK-52E cells infer that CH3Hg-Cys is a likely transportable mercuric species in proximal tubular epithelial cells that is taken up in vivo by both OAT1 and amino acid transporters. [ABSTRACT FROM AUTHOR]

Many modes of action for arsenic carcinogenesis have been proposed, but few theories have a substantial mass of supporting data. Three stronger theories of arsenic carcinogenesis are production of chromosomal abnormalities, promotion of carcinogenesis and oxidative stress. This article presents the oxidative stress theory along with some supporting experimental data. In the area of which arsenic species is causually active, recent data have suggested that trivalent methylated arsenic metabolites, particularly monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), have a great deal of biological activity. Some evidence now indicates that these trivalent, methylated, and relatively less ionizable arsenic metabolites may be unusually capable of interacting with cellular targets such as proteins and even DNA. Thus for inorganic arsenic, oxidative methylation followed by reduction to trivalency may be a activation, rather than a detoxification pathway. This would be particularly true for arsenate. In forming toxic and carcinogenic arsenic species, reduction from the pentavalent state to the trivalent state may be as or more important than methylation of arsenic. [Copyright &y& Elsevier]

Both dimethylarsinic acid (DMA(V)) and dimethylarsinous acid (DMA(III)) release iron from human liver ferritin (HLF) with or without the presence of ascorbic acid. With ascorbic acid the rate of iron release from HLF by DMA(V) was intermediate (3.37 nM/min, P<0.05) and by DMA(III) was much higher (16.3 nM/min, P<0.001). No pBR322 plasmid DNA damage was observed from in vitro exposure to arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)) or DMA(V) alone. DNA damage was observed following DMA(III) exposure; coexposure to DMA(III) and HLF caused more DNA damage; considerably higher amounts of DNA damage was caused by coexposure of DMA(III), HLF and ascorbic acid. Diethylenetriaminepentaacetic acid (an iron chelator), significantly inhibited DNA damage. Addition of catalase (which can increase Fe2+ concentrations) further increased the plasmid DNA damage. Iron-dependent DNA damage could be a mechanism of action of human arsenic carcinogenesis. [Copyright &y& Elsevier]

The dodecapeptide angiotensin-(1–12) [Ang-(1–12)] functions as an intracrine/paracrine substrate for local production of angiotensin II. We developed a reliable and specific radioimmunoassay (RIA) method for the measurement of Ang-(1–12) in human plasma and urine using an affinity purified antibody fraction directed towards the C-terminus of the human Ang-(1–12) sequence. The RIA method was applied to quantify the Ang-(1–12) in plasma and urine collected from thirty-four human subjects (29 treated with antihypertensive medicines and 5 untreated patients). Plasma Ang-(1–12) level was significantly higher (P < 0.05) in patients with systolic blood pressure ≥140 mm Hg (n = 10) compared to the group with systolic blood pressure <140 mm Hg (n = 24). No significant difference (P = 0.22) was found in spot urine between the groups. Our study also shows that the polyclonal antibody neutralizes the cleavage sites of the human Ang-(1–12) from recombinant human chymase (rhChymase) and serum angiotensin converting enzyme (ACE) mediated Ang II generating hydrolysis. Overall, this newly developed RIA method is reliable and applicable to accurately quantify the Ang-(1–12) level in clinical samples (plasma and urine). Further, our in vitro neutralization study suggests that the anti-Ang-(1–12)-antibody might be used as an in vivo therapeutic agent for preventing Ang-(1–12)/Ang II-mediated hypertension and organ damage. [ABSTRACT FROM AUTHOR]

Abstract: Under optimized reaction conditions, an efficient synthetic method has been developed to afford the functionalized flavone-triazole-tetrahydropyran conjugates via click reactions. The Cu-catalyzed 1,3-dipolar cycloaddition reaction gave the pure products, 5-iodo- and 5-H-1-(tetrahydropyran)-1,2,3-triazol-4-(3-methoxylflavone) derivatives in excellent yield (90–98%) within 1–3 h. Further, Pd-catalyzed Suzuki coupling of 5-iodo-1,2,3-triazoles with phenylboronic acids afforded 5-phenyl-1-(tetrahydropyran)-1,2,3-triazol-4-(3-methoxylflavone) derivatives in excellent yield (93–95%) in 4–5 h. Products (3a–l, 4a–j) were screened in vitro for their anti-proliferative activity against three human cancer cell lines (MDA-MB 231, KCL22 and Hela). Compounds 3c, 3g, 3i, 3j, 4c and 4h have shown better cytotoxicity (IC50 0.61–1.68 μM) than the reference drugs. Compounds 4e (IC50 0.70 μM), 3j (IC50 0.61 μM) and 4d (IC50 0.65 μM) exhibited anti-proliferative activity better than the reference drugs against the MDA-MB 231 cells, KCL22 cells and HeLa cells respectively. [Copyright &y& Elsevier]

Following our previously reported Prins cyclization strategy, a series of novel and highly functionalized flavonoid based THPs (Prins products) were designed, synthesized and evaluated for their antiproliferative activity. Novel products were afforded in excellent yields (72–96%) within 20–90 min at 62 °C using flavonoid aldehydes, homoallylic alcohols, p-TSA·H2O (catalyst and reagent) and MS 4 Å in CHCl3. Deprotection of tosyl group was achieved with TFA (catalyst and solvent) at 140 °C to obtain 4-hydroxytetrahydropyrans and further reaction of 4-hydroxytetrahydropyrans with cinnamoyl chloride afforded 4-cinnamate tetrahydropyrans under neat condition. Synthesized compounds evaluated against human cancer cell lines (Hep3β, MCF-7 and Hela), have shown moderate to good antiproliferative activity in vivo. Compounds 3q and 3zb exhibited similar cytotoxicity (IC50 6.6 ± 1.4, 6.9 ± 1.0 μM, respectively) to the reference drug doxorubicin (IC50 7.6 ± 0.9 μM) against the MCF-7 cancer cell line. Compound 3zb was found equally active as the standard drug (IC50 4.48 ± 2.1 μM) against the Hep3β cell line and compounds 3c and 3q showed moderate cytotoxicity (IC50 10.40 ± 1.1, 12.9 ± 1.7 μM, respectively) against the HeLa cell line. [ABSTRACT FROM AUTHOR]

Abstract: We have used V79MZ hamster lung fibroblasts stably transfected with human cytochrome P450-1A1 (hCYP1A1; cell line designated V79MZh1A1) or P450-1B1 (hCYP1B1; cell line designated V79MZh1B1) alone, or in combination with human glutathione-S-transferase (GST) alpha-1 (hGSTA1), in order to examine GST protection against cytotoxicity and mutagenicity of dibenzo[a,l]pyrene (DBP) and the intermediate dihydrodiol metabolite (±)-DBP-11,12-dihydrodiol (DBPD). At comparable expression levels of hCYP1A1 and hCYP1B1, both DBP and DBPD were more cytotoxic in V79MZ1A1 (IC50 =2.7 and 0.7nM, respectively) than in V79MZh1B1 (IC50 =6.0 and 4.8nM, respectively). In contrast, both DBP and DBPD were two- to four-fold more mutagenic in V79MZh1B1 than in V79MZ1A1. Co-expression of hGSTA1 with hCYP1A1 decreased DBP cytotoxicity two-fold compared to V79MZh1A1 with hCYP1A1 alone, and provided a small, yet still statistically significant, 1.3-fold protection against DBPD. Protection against mutagenicity of these compounds was comparable to that for cytotoxicity in cells expressing hCYP1A1. In V79MZh1B1 cells, co-expression of hGSTA1 conferred up to five-fold protection against DBP cytotoxicity, and up to nine-fold protection against the (±)-DBP-dihydrodiol cytotoxicity relative to the cells expressing hCYP1B1 alone. Co-expression of hGSTA1 also reduced mutagenicity of DBP or its dihydrodiol to a lesser extent (1.3–1.8-fold) than the protection against cytotoxicity in cells expressing hCYP1B1. These findings demonstrate that the protective efficacy of hGSTA1 against DBP and DBPD toxicity is variable, depending on the compound or metabolite present, the specific cytochrome P450 isozyme expressed, and the specific cellular damage endpoint examined. [Copyright &y& Elsevier]

Human organic anion transporter 1 mediates cellular uptake of cysteine- S conjugates of inorganic mercury. Background. The epithelial cells lining the renal proximal tubule have been shown to be the primary cellular targets where mercuric ions gain entry, accumulate, and induce pathologic effects in vivo. Recent data have implicated at least one of the organic anion transport systems in the basolateral uptake of inorganic mercury (Hg2+). Methods. Using a line of Madin-Darby canine kidney (MDCK) II cells transfected stably with the human organic anion transporter 1 (hOAT1), and oocytes from Xenopus laevis microinjected with cRNA for hOAT1, we tested the hypothesis that hOAT1 can transport biologically relevant mercuric conjugates of cysteine (Cys). Results. Indeed, MDCK II cells expressing a functional form of hOAT1 gained the ability to transport the mercuric conjugate 2-Amino-3-(2-amino-2-carboxy-ethylsulfanyl-mercuricsulfanyl)-propionic acid (Cys- S-Hg- S-Cys), but not the corresponding di-glutathione S-conjugate of Hg2+ (G- S-Hg- S-G). Moreover, p-aminohippurate (PAH), adipate, and glutarate (but not succinate or malonate) inhibited individually the uptake of Cys- S-Hg- S-Cys in a dose-dependent manner. Uptake of Cys- S-Hg- S-Cys, but not G- S-Hg- S-G, was also documented in Xenopus oocytes expressing hOAT1. Conclusion. These data represent ostensibly the most direct line of evidence implicating a specific membrane protein (i.e., hOAT1) in the transport of a biologically relevant molecular species of Hg2+ in a mammalian cell. Moreover, these data indicate that the organic anion transporter(s) likely play a prominent role in the basolateral transport of mercuric ions by proximal tubular cells and in the nephropathy induced by Hg2+. [ABSTRACT FROM AUTHOR]

Angiotensin-(1–12) [Ang-(1–12)] is a renin-independent precursor for direct angiotensin-II production by chymase. Substantial evidence suggests that heart failure (HF) may alter cardiac Ang-(1–12) expression and activity; this novel Ang-(1–12)/chymase axis may be the main source for angiotensin-II deleterious actions in HF. We hypothesized that HF alters cardiac response to Ang-(1–12). Its stimulation may produce cardiac negative modulation and exacerbate left ventricle (LV) systolic and diastolic dysfunction. We assessed the effects of Ang-(1–12) (2 nmol/kg/min, iv, 10 min) on LV contractility, LV diastolic filling, and LV-arterial coupling (AVC) in 16 SD male rats with HF-induced by isoproterenol (3 mo after 170 mg/kg sq. for 2 consecutive days) and 10 age-matched male controls. In normal controls, versus baseline, Ang-(1–12) increased LV end-systolic pressure, without altering heart rate, arterial elastance (E A), LV end-diastolic pressure (P ED), the time constant of LV relaxation (τ) and ejection fraction (EF). Ang-(1–12) significantly increased the slopes (E ES) of LV end-systolic pressure (P)-volume (V) relations and the slopes (M SW) of LV stroke wok-end-diastolic V relations, indicating increased LV contractility. AVC (quantified as E ES /E A) improved. In contrast, in HF, versus HF baseline, Ang-(1–12) produced a similar increase in P ES , but significantly increased τ, E A , and P ED. The early diastolic portion of LV P V loop was shifted upward with reduced in EF. Moreover, Ang-(1–12) significantly decreased E ES and M SW , demonstrating decreased LV contractility. AVC was decreased by 43%. In both normal and HF rats, Ang-(1–12) causes similar vasoconstriction. In normal, Ang-(1–12) increases LV contractile function. In HF, Ang-(1–12) has adverse effects and depresses LV systolic and diastolic functional performance. • Ang-(1–12) augments LV contractile performance of the normal heart. • In heart failure, Ang-(1–12) depresses LV systolic and diastolic functional performance. • Ang-(1–12) inotropic responses on LV functional performance are mediated by the activation of Ang II AT 1 receptors • Cardiac chymase may account for Ang II generation from Ang-(1–12). [ABSTRACT FROM AUTHOR]

Activation of the intracrine renin angiotensin systems (RAS) is increasingly recognized as contributing to human pathologies, yet non-canonical renin-independent mechanisms for angiotensin II (Ang II) biosynthesis remain controversial. Direct Ang II generation from angiotensin-(1–12) [Ang-(1–12)] by chymase is an essential intracrine source for regulation of cardiac function. Using a transgenic rat model that overexpresses the human angiotensinogen gene [TGR(hAGT)L1623] and displays increased cardiac Ang II levels, this study aimed to provide evidence for intracrine activation of L-type calcium currents (I Ca-L) mediated by the Ang-(1–12)/chymase axis. On patch clamp, I Ca-L density was significantly higher in TGR(hAGT)L1623 (−6.4 ± 0.3 pA/pF) compared to Sprague Dawley (SD) cardiomyocytes (−4.8, ± 0.5 pA/pF). Intracellular administration of Ang II and Ang-(1–12) elicited a I Ca-L increase in both SD and TGR(hAGT)L1623 cardiomyocytes, albeit blunted in transgenic cells. I Ca-L activation by intracellular Ang II and Ang-(1–12) was abolished by the specific Ang II type 1 receptor blocker E−3174. Co-administration of a chymase inhibitor prevented activation of I Ca-L by Ang-(1–12). Confocal micrographs revealed abundant chymase (mast cell protease 5) immunoreactive protein in SD and TGR(hAGT)L1623 cardiomyocytes. Our data demonstrate the existence in cardiomyocytes of a calcium channel modulatory activity responsive to Ang II generated by the Ang-(1–12)/chymase axis that signals via intracellular receptors. Chronically elevated Ang II in TGR(hAGT)L1623 hearts leading to increased intracellular calcium through I Ca-L suggests that activation of this Ang-(1–12)/chymase-governed cardiac intracrine RAS may contribute to the pathological phenotypes observed in the humanized model of chronic hypertension and cardiac hypertrophy. • Ang-(1–12)/chymase axis is active in cardiomyocytes of Ang II-mediated heart disease model. • Intracellular Ang II and Ang-(1–12) control L-type calcium currents. • Chymase inhibition prevents Ang-(1–12) L-type calcium channel activation. • Ang II formed by Ang-(1–12)/chymase axis acts via AT 1 receptors. • Targeting Ang-(1–12)/chymase axis in cardiac tissue may add benefit to current care. [ABSTRACT FROM AUTHOR]

[Display omitted] • Ang-(1–12) is an endogenous Ang II-forming substrate that contributes to the maintenance of arterial pressure. • Immunoneutralization of human Ang-(1–12) employing a selective mAb blocks the vasoconstrictor activity of this Ang II-generating substrate. • The h-Ang-(1–12) mAb has antihypertensive actions when given into the circulation of transgenic rats expressing the human AGT gene. • Ang-(1–12) mAbs may be facilitate long-term therapeutic control of blood pressure alone or combined with other antihypertensive medications. We engineered a monoclonal antibody (mAb) against the human C-terminus of angiotensin-(1–12) [h-Ang-(1–12)] and performed a biochemical characterization in concert with direct in vivo and ex vivo (carotid artery strips) assessments of h-Ang-(1–12) vasoconstrictor activity in 78 (36 females) transgenic rats expressing the human angiotensinogen gene [TGR(hAGT)L1623] and 26 (10 female) Sprague Dawley (SD) controls. The mAb shows high specificity in neutralizing angiotensin II formation from h-Ang-(1–12) and did not cross-react with human and rat angiotensins. Changes in arterial pressure and heart rate in Inactin® hydrate anesthetized rats were measured before and after h-Ang-(1–12) injections [dose range: 75–300 pmol/kg i.v.] prior to and 30–60 minutes after administration of the h-Ang-(1–12) mAb. Neutralization of circulating Ang-(1–12) inhibited the pressor action of h-Ang-(1–12), prevented Ang-(1–12) constrictor responses in carotid artery rings in both SD and TGR(hAGT)L1623 rats, and caused a fall in the arterial pressure of male and female transgenic rats. The Ang-(1–12) mAb did not affect the response of comparable dose-related pressor responses to Ang II, pre-immune IgG, or the rat sequence of Ang-(1–12). This h-Ang-(1–12) mAb can effectively suppress the pressor actions of the substrate in the circulation of hypertensive rats or in carotid artery strips from both SD and transgenic rats. The demonstration that this Ang-(1–12) mAb by itself, induced a fall in arterial pressure in transgenic hypertensive rats supports further exploring the potential abilities of Ang-(1–12) mAb in the treatment of hypertension. [ABSTRACT FROM AUTHOR]

Although they correspond to an important fraction of the total area of mountain glaciers (33,000 km2 out of 546,000 km2), Himalayan glaciers and their mass balance are poorly sampled. For example, between 1977 and 1999, the average area surveyed each year on the field was 6.8 km2 only. No direct mass balance measurement is available after 1999. To contribute to fill this gap, we use remote sensing data to monitor glacier elevation changes and mass balances in the Spiti/Lahaul region (32.2°N, 77.6°E, Himachal Pradesh, Western Himalaya, India). Our measurements are obtained by comparing a 2004 digital elevation model (DEM) to the 2000 SRTM (Shuttle Radar Topographic Mission) topography. The 2004 DEM is derived from two SPOT5 satellite optical images without any ground control points. This is achieved thanks to the good on-board geolocation of SPOT5 scenes and using SRTM elevations as a reference on the ice free zones. Before comparison on glaciers, the two DEMs are analyzed on the stable areas surrounding the glaciers where no elevation change is expected. Two different biases are detected. A long wavelength bias affects the SPOT5 DEM and is correlated to an anomaly in the roll of the SPOT5 satellite. A bias is also observed as a function of altitude and is attributed to the SRTM dataset. Both biases are modeled and removed to permit unbiased comparison of the two DEM on the 915 km2 ice-covered area digitized from an ASTER image. On most glaciers, a clear thinning is measured at low elevations, even on debris-covered tongues. Between 1999 and 2004, we obtain an overall specific mass balance of −0.7 to −0.85 m/a (water equivalent) depending on the density we use for the lost (or gained) material in the accumulation zone. This rate of ice loss is twice higher than the long-term (1977 to 1999) mass balance record for Himalaya indicating an increase in the pace of glacier wastage. To assess whether these ice losses are size-dependant, all glaciers were classified into three samples according to their areal extent. All three samples show ice loss, the loss being higher for glaciers larger than 30 km2. In the case of the benchmark Chhota Shigri glacier, a good agreement is found between our satellite observations and the mass balances measured on the field during hydrological years 2002–2003 and 2003–2004. Future studies using a similar methodology could determine whether similar ice losses have occurred in other parts of the Himalaya and may allow evaluation of the contribution of this mountain range to ongoing sea level rise. [Copyright &y& Elsevier]

The identification of an alternate extended form of angiotensin I composed of the first twelve amino acids at the N-terminal of angiotensinogen has generated new knowledge of the importance of noncanonical mechanisms for renin independent generation of angiotensins. The human sequence of the dodecapeptide angiotensin-(1–12) [N-Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8-His9-Leu10-Val1-Ile12-COOH] is an endogenous substrate that in the rat has been documented to be present in multiple organs including the heart, brain, kidney, gut, adrenal gland, and the bone marrow. Newer studies have confirmed the existence of Ang-(1–12) as an Ang II-forming substrate in the blood and heart of normal and diseased patients. Studies to-date document that angiotensin II generation from angiotensin-(1–12) does not require renin participation while chymase rather than angiotensin converting enzyme shows high catalytic activity in converting this tissue substrate into angiotensin II directly. [Display omitted] [ABSTRACT FROM AUTHOR]