An Anthranilate Derivative Inhibits Glutamate Release and Glutamate Excitotoxicity in Rats

The neurotransmitter glutamate plays an essential role in excitatory neurotransmission; however, excessive amounts of glutamate lead to excitotoxicity, which is the most common pathogenic feature of numerous brain disorders. This study aimed to investigate the role of butyl 2-[2-(2-fluorophenyl)acetamido]benzoate (HFP034), a synthesized anthranilate derivative, in the central glutamatergic system. We used rat cerebrocortical synaptosomes to examine the effect of HFP034 on glutamate release. In addition, we used a rat model of kainic acid (KA)-induced glutamate excitotoxicity to evaluate the neuroprotective potential of HFP034. We showed that HFP034 inhibits 4-aminopyridine (4-AP)-induced glutamate release from synaptosomes, and this inhibition was absent in the absence of extracellular calcium. HFP034-mediated inhibition of glutamate release was associated with decreased 4-AP-evoked Ca2+ level elevation and had no effect on synaptosomal membrane potential. The inhibitory effect of HFP034 on evoked glutamate release was suppressed by blocking P/Q-type Ca2+ channels and protein kinase C (PKC). Furthermore, HFP034 inhibited the phosphorylation of PKC and its substrate, myristoylated alanine‐rich C kinase substrate (MARCKS), in synaptosomes. We also observed that HFP034 pretreatment reduced neuronal death, glutamate concentration, glial activation, and the levels of endoplasmic reticulum stress-related proteins, calpains, glucose-regulated protein 78 (GRP 78), C/EBP homologous protein (CHOP), and caspase-12 in the hippocampus of KA-injected rats. We conclude that HFP034 is a neuroprotective agent that prevents glutamate excitotoxicity, and we suggest that this effect involves inhibition of presynaptic glutamate release through the suppression of P/Q‐type Ca2+ channels and PKC/MARCKS pathways.

Anthranilate Derivative Inhibits Glutamate Release and Glutamate Excitotoxicity In Rats

The neurotransmitter glutamate plays an essential role in excitatory neurotransmission; however, excessive glutamate leads to excitotoxicity, which is the most common pathogenic feature of numerous brain disorders. This study aimed to investigate the role of butyl 2-[2-(2-fluorophenyl)acetamido]benzoate (HFP034), a synthesized anthranilate derivative, in the central glutamatergic system. We used rat cerebrocortical synaptosomes to examine the effect of HFP034 on glutamate release. In addition, we used a rat model of kainic acid (KA)-induced glutamate excitotoxicity to evaluate the neuroprotective potential of HFP034. We showed that HFP034 inhibited 4-aminopyridine (4-AP)-induced glutamate release from the synaptosomes, and this inhibition was abolished in the absence of extracellular calcium. HFP034-mediated inhibition of glutamate release was associated with a decreased 4-AP-evoked Ca2+ level elevation, and had no effect on synaptosomal membrane potential. The inhibitory effect of HFP034 on evoked glutamate release was suppressed by blocking P/Q-type Ca2+ channels and protein kinase C (PKC). Furthermore, HFP034 inhibited the phosphorylation of PKC and its substrate, myristoylated alanine-rich C kinase substrate (MARCKS), in the synaptosomes. We also observed that HFP034 pretreatment reduced neuronal death, glutamate concentration, glial activation, and the levels of endoplasmic reticulum stress-related proteins, calpains, glucose-regulated protein 78 (GRP 78), C/EBP homologous protein (CHOP), and caspase-12 in the hippocampus of KA-injected rats. We concluded that HFP034 is a neuroprotective agent that prevents glutamate excitotoxicity, and we suggest that this effect involves the inhibition of presynaptic glutamate release by suppressing P/Q‐type Ca2+ channels and PKC/MARCKS pathways.

Orissa super cyclone – A Synopsis

lkj & 29 vDrwcj 1999] dks ikjknhi ds fudV vk, egkpØokrh; rwQku us mM+hlk dks rgl ugl dj Mkyk ftlds dkj.k ikjknhi ds fudV ,d ySUMQky cu x;k blds dkj.k van:uh {ks=ksa esa yxHkx 260 ls 270 fd-eh- izfr?kaVk dh rhozxfr ls gok,¡ pyus ls leqnz esa Å¡ph&Å¡ph rjaxsa mBha vkSj leqnz ds ty dk Lrj 20 QhV ls Hkh vf/kd c<+ x;kA bl egkpØokrh; rwQku ds dkj.k yxHkx 10]000 yksxksa dks vius cgqewY; thou ls gkFk /kksuk iM+kA blds lkFk&lkFk vlk/kkj.k Hkkjh o"kkZ gqbZ ftlds dkj.k izy;adkjh ck<+ vkus ls jkT; dk lewps ns’k ls laidZ dV x;kA bl 'kks/k&i= esa jsMkj vkSj mixzg ds fp=ksa] ikjEifjd vk¡dM+ksa] la[;kRed ekWMyksa ls bl pØokr ds mRiUu gksus vkSj mlds vkxs c<+us ds fofHkUu y{k.kksa dk foospu fd;k x;k gSA bl 'kks/k&i= esa pØokr ls gq, fouk’k ds fy, jkT; vkSj dsUnzh; vfHkdj.kksa }kjk vkink izca/ku ds :Ik esa okLrfod le; ij fd, x, jkgr dk;ksZa ij fo’ks"k cy fn;k x;k gSA ABSTRACT. Orissa was battered by a Super Cyclonic Storm on 29 October, 1999 that made landfall near Paradip (43976). The estimated maximum wind speed reached 260-270 kmph in the core area which produced a huge storm surge that led to sea-level elevation of more than 20 feet and took away valuable lives of nearly 10,000 people. It was accompanied with exceptionally heavy rains which led to devastating floods and cut off the State from the rest of the country. An attempt is made to describe the various features of development and movement of this cyclone through radar and satellite imageries, conventional data and numerical models. Emphasis is laid on the real-time handling of this event, impacts made by the cyclone and the services rendered in relation to disaster management by the State and Central Agencies.

Atmospheric Stilling Promotes Summer Algal Growth in Eutrophic Shallow Lakes

Algal blooms are environmental challenges confronting lakes worldwide and are significantly influenced by chlorophyll a yields per unit phosphorus (Chla/TP), or nitrogen (Chla/TN). Here, the influence of inter-annual hydrometeorological variations on Chla/TP and Chla/TN were evaluated in eutrophic shallow Lake Taihu, China. Our results demonstrated significant increases (p < 0.001) in both Chla/TN and Chla/TP from 2005 to 2017, and increased Chla yields during the winter months were mainly correlated with higher water temperature and longer sunshine hours, which may cause severer blooms in winter and spring. In remaining months from 2005 to 2017, typical associations between atmospheric stilling (or water level elevation) and higher Chla yields were observed. The results also indicate that atmospheric stilling and water level elevation significantly (p < 0.001) decreased background turbidity and promoted buoyant cyanobacterial biomass, alleviating phytoplankton light limitation. Given the subtropical location, eutrophic status, and high background turbidity of Lake Taihu, light may be the critical limiting factor for summer phytoplankton growth; thus, improved light availability would promote Chla yields until self-shading caused further light limitations. If the mechanism is general, promoting the effect of atmospheric stilling on annual peak Chla in shallow lakes may be greatly underestimated, and our finding will affect future bloom mitigation efforts in such systems.

Nintedanib-Induced Renal Thrombotic Microangiopathy

Nintedanib is a unique tyrosine kinase inhibitor used to suppress fibrosis in patients with idiopathic pulmonary fibrosis (IPF). Nintedanib has been shown to suppress multiple processes of fibrosis, thereby reducing the rate of lung function decline in patients with IPF. Since vascular endothelial growth factor is one of this agent’s targets, nephrotoxicity, including renal thrombotic microangiopathy (TMA), is a possible major adverse effect. However, only 2 previous cases of nintedanib-induced renal TMA have been published. Our patient was an 83-year-old man with IPF. As adverse effects including liver enzyme level elevation, diarrhoea, anorexia, and nephrotoxicity developed, the nintedanib dosage was reduced after 9 months. The digestive symptoms resolved promptly, but the proteinuria and reduced kidney function remained. Although the kidney injury had improved to some extent, we performed a percutaneous renal biopsy. The biopsy revealed typical TMA findings such as microaneurysms filled with pale material, segmental double contours of glomerular basement membranes, and intracapillary foam cells. After discontinuation of nintedanib, the patient’s nephrotoxicity improved. Nintedanib-induced renal TMA is reversible and is possibly dose-dependent. Here, we report the clinical course of our case and review the characteristics of nintedanib-induced renal TMA.

Soluble Neuropilin-1 Response to Hypoglycemia in Type 2 Diabetes: Increased Risk or Protection in SARS-CoV-2 Infection?

IntroductionNeuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection.MethodsA case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(&lt;40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9).ResultsBaseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p&lt;0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p&lt;0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia.ConclusionHypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear.Clinical Trial Registrationhttps://clinicaltrials.gov, identifier NCT03102801.

A new opilioacarid species (Parasitiformes: Opilioacarida) from Crete (Greece) with notes on its karyotype

A new species of opilioacarid mite, Opilioacarus thaleri n. sp., is described from mid-level elevation close to the seashore in Crete (Greece). It was found on moister sites, under stones or inside stone accumulations in phrygana vegetation. The peak of activity was found to be in early May. The diagnostic morphological characters include 7–8 eugenital setae (female), 5/7 setae on each sclerite at pregenital and genital areas, 11 setae on genital area (male), anterior dorsal shield with two pairs of eyes and 60–70 stout, ribbed setae, 5 (female) or 6 (male) leaf setae plus one pectinate seta on the palp tarsus, and the "simple" type of ovipositor with two pairs of glands, a pair of ducts plus a basal structure. The female karyotype comprises 16 monocentric chromosomes, predominantly with acrocentric morphology. Comparison with data of the ixodids and mesostigmatids indicates that a low number of chromosomes and predomination of acrocentric chromosomes could be plesiomorphies of the parasitiform mites.

Development and validation of the State Moral Elevation Scale: Assessing state-level elevation across nonclinical and clinical samples

Research on moral elevation has steadily increased and identified several psychosocial benefits that bear relevance to both the general population and people with psychological distress. However, elevation measurement is inconsistent, and few state-level measures have been created and critically evaluated to date. To address this gap, the State Moral Elevation Scale (SMES) was developed and tested using an online sample (N = 930) including subsamples of general participants (nonclinical) and those who screened positive for mental health symptoms (clinical). Factor analysis indicated a single factor structure with nine items that demonstrated excellent reliability. Multigroup confirmatory factor analysis indicated good fit statistics and strict measurement invariance across clinical and nonclinical subsamples. Last, correlational analyses with related constructs provided evidence of construct validity for both subsamples. Thus, the SMES is a psychometrically valid and reliable assessment tool for state-level elevation which can be used in both general and clinical populations.

Predictors of Brain Natriuretic Peptide Serum Level Elevation in Patients with Symptomatic Chronic Subdural Hematoma: A Prospective Study

Background: Brain natriuretic peptide serum levels (BNP) on admission are frequently elevated in patients with symptomatic chronic subdural hematoma (cSDH) and predict unfavorable long-term functional outcomes. However, the reasons for these elevated levels remain unclear. Therefore, we aimed to identify the predictors of BNP elevation. Methods: Patients with unilateral symptomatic cSDH who were surgically treated in our department between November 2016 and May 2020 were enrolled. Patients’ symptoms and neurological deficits were prospectively assessed using a study questionnaire. On initial computer tomography, hematoma volumes and midline shift (MLS) values were measured to analyze the degree of brain compression. Results: In total, 100 patients were analyzed. Linear regression analysis showed that higher BNP levels were significantly associated with smaller hematoma volumes (p = 0.003) and littler MLS values (p = 0.022). Multivariate analysis revealed that presence of a neurological deficit (p = 0.041), a hematoma volume < 140 mL (p = 0.047), advanced age (p = 0.023), and head trauma within 24 h of admission (p = 0.001) were independent predictors of BNP elevation. Conclusion: In symptomatic cSDH, BNP elevation is related, among others, to the presence of neurological deficits and smaller hematoma volumes. Whether BNP elevation may coincide with the early stage of hematoma growth, i.e., immaturity of cSDH neomembrane, requires further investigations.