Clinical outcomes, time span for healing of various ocular surface disorders with amniotic membrane: A prospective, an Indian study

Purpose: To study the clinical outcomes, time span of healing of various ocular surface disorders with amniotic membrane graft. Methods: A total of 41 patients, presenting to cornea clinic were included in the study and divided into five groups depending on the type of diagnosis: Group 1, with either >2 weeks of Persistent epithelial defect following cataract/retinal/glaucoma surgeries or Shield ulcers, Group 2 with >4 weeks of Non healing corneal ulcers, Group 3 with chemical injuries, Group 4 with Epithelial defects following keratoplasty, and Group 5 is the miscellaneous group. Results: The mean age of the study subjects was 50.0 years. Overall mean duration between clinical presentation and AMT was 23.59 (30.7) days, a median 16 days (IQR; 2?26 days). Failure rate was high in Group 5 (n = 3: 30.0%) and Group 2 (n = 3: 27.3%). Time taken for epithelial closure was slower in groups 1 and 5 patients. The average time taken for reabsorption of AMG was 14.98 days. The complications included repeat AMG was in four eyes (9.75%), and graft displacement was noted in four eyes (9.75%) required resuturing, three eyes required TPK (7.31%), and one eye underwent evisceration (2.43%) following severe corneal melt secondary to neurotropic ulcer. The mean log MAR visual acuity improved from 1.52 to 1.26 at the 3 months. Conclusion: Understanding on timespan for healing of ocular surface disorders with AMG is needed to assess the prognosis of the disease, preoperative counselling for repeat procedures, and the compliance with regard to follow up.

Safety and efficacy of omecamtiv mecarbil for heart failure: A systematic review and meta-analysis

Aim: To assess the safety and efficacy of omecamtiv mecarbil compared with placebo in heart failure (HF) patients. Methods: We searched PubMed, Web of Science, Cochrane Library, and SCOPUS until August 15th, 2021. We included all randomized controlled studies comparing omecamtiv mecarbil with placebo in heart failure patients. The meta-analysis was carried out using Rev Man software V5.4. Results: A total of eight studies were included in our systematic review. Pooled analysis showed that omecamtiv mecarbil is not associated with increased incidence of death, any adverse events, hypotension, heart failure, ventricular tachyarrhythmia, dyspnea, dizziness, and serious adverse events. Regarding the efficacy, omecamtiv mecarbil significantly reduced heart rate with some studies demonstrating its significant improvement in left ventricular ejection fraction and systolic function. Conclusion: Omecamtiv mecarbil is a well-tolerated drug in heart failure patients. The limited data regarding the efficacy suggested that it may improve ejection fraction and systolic function

AMG-102 inhibits proliferation and induces apoptosis of laryngeal squamous cell carcinoma cells by regulating c-Met/PI3K/Akt pathway / 中华肿瘤杂志

Objective@#To investigate the effects of c-Met inhibitor AMG-102 on the proliferation and apoptosis of laryngeal squamous carcinoma Hep-2 cells and the underlying mechanism.@*Methods@#Laryngeal squamous carcinoma cell line Hep-2 cells were treated with 2.5, 5 and 10 μmol/L AMG-102, respectively. The proliferation activities of Hep-2 cells were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT). The apoptotic rate of Hep-2 cells was detected by flow cytometry analysis and Hoechst staining. The mRNA expression levels of apoptosis-related genes were detected by real-time quantitative polymerase Chain reaction (RT-qPCR), and the protein expressions of c-Met/PI3K/AKT pathway were detected by western blot.@*Results@#Compared with the control group, the proliferation rates of Hep-2 cells treated with 2.5, 5 and 10 μmol/L AMG-102 for 24 hours were (89.8±1.1)%, (79.8±1.0)% and (69.1±1.2)%, respectively; for 48 hours were (76.8±2.0)%, (60.2±1.1)% and (49.8±1.2)%, respectively; for 72 hours were (50.1±2.0)%, (41.5±1.1)% and (33.6±1.0), respectively, with significant differences (all P<0.05). The apoptotic rates of Hep-2 cells treated with 2.5, 5 and 10 μmol/L AMG-102 for 48 hours were (16.09±1.53)%, (27.51±2.02)% and (36.57±1.42)%, respectively, which were significantly higher than (3.62±0.10) % in the control group (all P<0.05). After treated with 2.5, 5 and 10 μmol/L AMG-102 for 48 hours, the relative expression levels of Bcl-2 mRNA in Hep-2 cells were 0.58±0.13, 0.38±0.12 and 0.20±0.13, respectively; the relative protein expression of p-Met were 80.0±3.8, 50.6±4.2 and 28.5±1.3, respectively; the relative protein expression of p-PI3K were 87.1±0.9, 54.2±1.2 and 21.0±1.2, respectively; the relative protein expression of p-AKT were 98.7±5.6, 56.9±3.2 and 32.2±4.3, respectively; which were significantly lower than those in the control group (all P<0.05). The relative expression levels of Bax mRNA were 1.78±0.13, 2.37±0.14 and 3.05±0.13, respectively, and the relative expression levels of caspase-3 mRNA were 1.98±0.14, 2.47±0.14 and 3.15±0.13, respectively, which were significantly higher than those in the control group (all P<0.05).@*Conclusion@#c-Met inhibitor AMG-102 could inhibit the proliferation and induce apoptosis of laryngeal squamous carcinoma Hep-2 cells by regulating the c-Met/PI3K/Akt pathway.

Efficacy and safety of abrilumab, an α4β7 integrin inhibitor, in Japanese patients with moderate-to-severe ulcerative colitis: a phase II study

BACKGROUND/AIMS: Inhibition of α4β7 integrin has been shown to be effective for induction and maintenance therapy in patients with ulcerative colitis (UC). We investigated the effects of varying doses of the α4β7 inhibitor abrilumab in Japanese patients with moderate-to-severe UC despite conventional treatments. METHODS: In this randomized, double-blind, placebo-controlled study, 45 UC patients were randomized to abrilumab 21 mg (n=11), 70 mg (n=12), 210 mg (n=9), or placebo (n=13) via subcutaneous (SC) injection for 12 weeks. The double-blind period was followed by a 36-week open-label period, in which all patients received abrilumab 210 mg SC every 12 weeks, and a 28-week safety follow-up period. The primary efficacy variable was clinical remission at week 8 (total Mayo score ≤2 points with no individual subscore >1 point). RESULTS: Clinical remission at week 8 was 4 out of 31 (12.9%) overall in the abrilumab groups versus 0 out of 13 in the placebo group (abrilumab 21 mg, 1/10 [10.0%]; 70 mg, 2/12 [16.7%]; 210 mg, 1/9 [11.1%]). In both the double-blind and open-label periods, fewer patients in the abrilumab groups experienced ≥1 adverse event compared with those in the placebo group. There were no cases of progressive multifocal leukoencephalopathy and no deaths. CONCLUSIONS: Abrilumab 70 mg and 210 mg yielded numerically better results in terms of clinical remission rate at Week 8 than placebo, with the 210 mg dose showing more consistent treatment effects. Abrilumab was well tolerated in Japanese patients with UC.

Effect of c-Met inhibitor AMG-102 on radiosensitivity in laryngeal squamous carcinoma cells / 中华肿瘤杂志

Objective@#To investigate the effect of c-Met inhibitor AMG-102 on proliferation and radiosensitivity in laryngeal squamous carcinoma cells.@*Methods@#The effects of AMG-102 on proliferation and radiosensitivity of laryngeal squamous carcinoma cell lines Hep-2 and KBV200 were detected by 3-(4, 5-dimethy-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay and colony formation assay, respectively. The apoptosis of Hep-2 and KBV200 cells was detected by flow cytometry. The expression levels of c-Met, phospho-Met (p-Met), cleaved caspase-3 and Akt/p-Akt, Erk/p-Erk were detected by Western blot. Specific small interfering RNA targeting c-Met or plasmid of c-Met were transfected into Hep-2 and KBV200 cells to investigate the cell sensitivity to AMG-102.@*Results@#Compared with KBV200 cells, Hep-2 cells were more sensitive to AMG-102 with IC50 of 14 and 9 μmol/L, respectively. The relative expression levels of c-Met and p-Met proteins in Hep-2 cells were 194.48±0.57 and 177.76±1.53, respectively, which were significantly higher than those in KBV200 cells (171.24±1.00 and 115.37±0.56, respectively, P<0.001 for both). Exogenous hepatocyte growth factor (HGF) was added to increase the expression level of p-Met protein in KBV200 cells. The results showed that AMG-102 significantly reduced the expression of p-Met in KBV200 cells treated with HGF (P<0.001). Compared with the dimethyl sulfoxide (DMSO) group, AMG-102 treatment combined with radiotherapy significantly increased the radiosensitivity of Hep-2 cells (SER=1.28, P<0.001). However, AMG-102 had little effect on the radiosensitivity of KBV200 cells (SER=1.18, P=0.002). Compared with the 4 Gy radiotherapy alone group and the 5 μmol/L of AMG-102 alone treatment group, the apoptosis rate of Hep-2 cells in the combined treatment group was significantly increased. Meanwhile, the expression level of cleaved caspase-3 protein was also markedly increased. However, there were no significant changes in the apoptotic rate and cleaved caspase-3 expression in each treatment group of KBV200 cells. Compared with DMSO treatment group, the expression levels of p-Met, p-Akt and p-Erk were significantly decreased in the 4 Gy radiotherapy group, 5 μmol/L of AMG-102 treatment group and combined treatment group of Hep-2 cells. And the levels of p-Met, p-Akt and p-Erk in the combined treatment group were significantly lower than those in the 4 Gy radiotherapy alone group and 5 μmol/L of AMG-102 treatment alone group. By contrast, in KBV200 cells, the expression of p-Met, p-Akt and p-Erk in each group was not changed. The relative expression of p-Met in Hep-2 cells before and after radiotherapy at 30 min, 1 h, 4 h, 8 h, 24 h were 99.89±0.61, 138.62±1.00, 163.07±5.00, 87.80±1.85, 90.67±0.65 and 94.09±1.41, respectively. The level of p-Met was slightly increased after radiotherapy at 30 min and 1 h (P<0.001 for all), whereas it was significantly decreased from 4 h to 24 h after radiotherapy (P<0.05 for all). By contrast, the expression of p-Met in KBV200 cells did not change with time after radiotherapy (P>0.05). The sensitivity of Hep-2 cells to AMG-102 was decreased after silencing of c-Met, while the sensitivity of KBV200 cells to AMG-102 was not significantly changed (P>0.05). Moreover, the radiosensitivity of Hep-2 cells in c-Met knockdown group had a slightly increasing trend (SER=1.07, P=0.068). After the treatment with 10 μmol/L of AMG-102, the proliferation rate of c-Met ectopically expressed KBV200 cells was 60.05%±3.23%, It was significantly lower than that of the blank control 90.08%±1.04% and siRNA negative control (90.12%±1.01%, P<0.001). The results suggested that the overexpression of c-Met in KBV200 cells increased the radiosensitivity to AMG-102, whereas depletion of c-Met resulted in resistance to AMG-102 in Hep-2 cells. Furthermore, the radiosensitivity of KBV200 cells that overexpressed c-Met showed a decreased trend (SER=0.7, P=0.005).@*Conclusions@#c-Met inhibitor AMG-102 has a significant inhibitory effect on the proliferation of c-Met overexpressing laryngeal squamous carcinoma cells, leading to increased radiosensitivity. It suggests that molecular targeted therapy against c-Met receptor is more effective in c-Met overexpressed subtype of laryngeal squamous cell carcinoma.

AMG – SIGA - Cadastro e Acompanhamento de Portadores de Diabetes mellitus em SMS SP

Em agosto de 2005, a Secretaria Municipal da Saúde – SMS SP iniciou o atendimento a 3.000 munícipes em cinco Unidades de Referência para atender a Lei Estadual 10.782/01 e CIB 57/05, que determinavam a disponibilização de insumos para portadores de Diabetes mellitus. A pactuação entre Estado e municípios estabelecia repasse de 75% dos gastos por paciente cadastrado no Sistema de Insumos Estratégicos da Secretaria de Estado de Saúde – SIE SES.Com a publicação da Lei Federal 11.347 de 2006, e da Portaria 2.583 de 2007, as responsabilidades e atribuições dos entes federativos do SUS foram definidas quanto ao atendimento aos portadores de Diabetes mellitus Insulinodependentes, que necessitam de automonitoramento glicêmico, isto é, realizam a verificação de glicemia capilar.O desenvolvimento e implantação do sistema municipal de cadastro para o Automonitoramento Glicêmico – AMG, no Sistema Integrado de Gestão da Assistência à Saúde – SIGA, em 2009, viabilizou avaliações mais abrangentes e a gestão completa dos dados destes portadores de Diabetes mellitus.

AMG – SIGA - Cadastro e Acompanhamento de Portadores de Diabetes mellitus em SMS SP / AMG – SIGA - Registration and Monitoring of Patients with Diabetes mellitus in SMS SP

Em agosto de 2005, a Secretaria Municipal da Saúde – SMS SP iniciou o atendimento a 3.000 munícipes em cinco Unidades de Referência para atender a Lei Estadual 10.782/01 e CIB 57/05, que determinavam a disponibilização de insumos para portadores de Diabetes mellitus. A pactuação entre Estado e municípios estabelecia repasse de 75% dos gastos por paciente cadastrado no Sistema de Insumos Estratégicos da Secretaria de Estado de Saúde – SIE SES.Com a publicação da Lei Federal 11.347 de 2006, e da Portaria 2.583 de 2007, as responsabilidades e atribuições dos entes federativos do SUS foram definidas quanto ao atendimento aos portadores de Diabetes mellitus Insulinodependentes, que necessitam de automonitoramento glicêmico, isto é, realizam a verificação de glicemia capilar.O desenvolvimento e implantação do sistema municipal de cadastro para o Automonitoramento Glicêmico – AMG, no Sistema Integrado de Gestão da Assistência à Saúde – SIGA, em 2009, viabilizou avaliações mais abrangentes e a gestão completa dos dados destes portadores de Diabetes mellitus.

Flavonoids of Lonchocarpus montanus A.M.G. Azevedo and biological activity

The analysis of root extracts from Lonchocarpus montanus A.M.G. Azevedo resulted in the isolation of twenty three compounds chiefly flavonoids of which five (four flavonoids and one benzophenone) are described for the first time. The molecular structures of the new compounds (1-5) were determined through spectral analysis (UV, IR, MS and NMR) as being: 2'-hydroxy-8-(a,a-dimethylallyl)-2", 2"-dimethylpyrano-(5",6":3',4')-dibenzoylmethane (1), 2'-methoxy-8-(a, a-dimethylallyl)-2", 2"-dimethylpyrano-(5",6":3',4')-dibenzoylmethane (2), 4'-methoxy-2",2"-dimethylpyrano-(5",6":8,7)-flavone (3), 2"-(1-hydroxy-1-methylethyl)-furano-(4",5":8,7)-flavone (4) and [2'-methoxy-furano-(4",5":3',4')-phenyl]-phenylmethanone (5). Additionally, fifteen fatty acids were detected through GC-MS analysis of the corresponding methyl esters [(CH3)2CH(CH2)8COOH and CH3(CH2)nCOOH (n = 6, 12-24)]. Quantitative RP-HPLC showed that the most abundant flavonoids in the petroleum ether and dichloromethane extracts were pongamol (19 percent) and lanceolatine B (8.0 percent), respectively. In the bioautography assay, the extracts, pongamol (9), lanceolatine B (10), isolonchocarpin (14), derriobtusone A (17) and medicarpine (18) were active against Staphilococus aureus whereas 9 also against Bacillus subtilis and Cladosporium cladosporioides. Compound 1, 2",2"-dimethylpyrano-(5",6":8,7)-flavone (11) and furano-(1200,1300:7,8)- 4'-methoxy flavone (12) were active against Fusarium oxysporium whereas 11 also against Rhizopus orizae. The extracts, compounds 9, 10, 17 and (E)-7-O-methoxypongamol (23) displayed high toxicity in the brine shrimp lethality assay.

A análise dos extratos das raízes de L. montanus A.M.G. Azevedo resultou no isolamento de vinte e três compostos principalmente flavonóides dos quais cinco são descritos pela primeira vez. As estruturas moleculares dos novos compostos (1-5) foram propostas através da análise dos espectros de UV, IV, EM e RMN como sendo: 2'-hidroxi-8-(a, a-dimetilalil)-2", 2"-dimetilpirano-(5", 6":3',4')-dibenzoilmetano (1), 2'-metoxi-8-(a,a-dimetilalil)-2", 2"-dimetilpirano-(5", 6":3',4')-dibenzoilmetano (2), 4'-metoxi-2", 2"-dimetilpirano-(5", 6":8,7)-flavona (3), 2"-(1-hidroxi-1-metiletil)-furano-(4", 5":8,7)-flavona (4) e [2'-metoxi-furano(4", 5":3',4')-fenil]-fenilmetanona (5). Adicionalmente quinze ácidos graxos foram detectados através da análise de CG-EM dos ésteres metílicos correspondentes [(CH3)2CH(CH2)8COOH e CH3(CH2)nCOOH (n = 6, 12-24)]. A análise quantitativa por CLAE mostrou que os flavonóides mais abundantes nos extratos éter de petróleo e diclorometânico foram pongamol (19 por cento) e lanceolatina B (8.0 por cento), respectivamente. Nos ensaios de bioautografia, os extratos, pongamol (9), laceolatina B (10), isolonchocarpina (14), derriobtusona A (17) e medicarpina (18) foram ativos contra Staphilococcus aureus enquanto 9, também contra Bacillus subtilis e Cladosporium cladosporióides. O composto 1, 2", 2"-dimetilpirano-(5", 6":8,7)-flavona (11) e furano-(2", 3":7,8)-4'-metoxiflavona (12) foram ativos contra Fusarium oxysporium, enquanto 11, também contra Rhizopus oryzae. Os extratos assim como os compostos 9, 10, 17 e (E)-7-O-metoxipongamol (23) apresentaram alta toxicidade no ensaio de letalidade com Artemia salina.

Alteration of Ionic Zinc Distribution in Rat Spinal Ganglion by Inflammatory Pain Stimulus: Autometallography / 대한해부학회지

This study was designed to investigate any correlation between the mechanism of pain development and changes of histochemically reactive zinc contents in the rat spinal ganglion following complete Freund's Adjuvant (CFA) injection, as an inflammatory pain model. Male Sprague-Dawley rats (270~290 g) were used for this study. Surgeries were done under anesthesia using pentobarbital (30 mg/kg). we injected 200 microliter of CFA subcutaneously in the dorsal aspect of one hind paw using a 30- gauge needle and an 1 mL syringe. Semmes-Weinstein monofilaments was used to test for mechanical hyperalgesia. Finally, zinc selenite autometallography (AMG) was done by Danscher's method. The rat suffered from severe painful swelling of the hindpaw 1 day after a CFA inoculation. Changes in pain threshold were significantly changed on 1 day, and lasted during experiment period of 3 weeks after the CFA inoculation. In control group, ganglion cells vary in size from 15 to 100 micrometer. The smaller neurons are strongly stained with AMG, whereas the larger cells are not almostly stained. Each large ganglion cell is surrounded by perineuronal satellite cells, showing apparent AMG stainity. In experiment group, AMG-positive small ganglion cells increased on 1 day after CFA inoculation, and showed a peak in cell number at 3days group, and decreased gradually after 7 days. We found a small number of large-sized ganglion cells with AMG stainity 7 days and 3 weeks after CFA inoculation. Our results indicate that zinc may be involved in pain mechanism in the spinal ganglion level.

Decrease in Zinc Concentration in the Rat Spinal Gray Matter Induced by Peripheral Nerve Ligation, and its Relations with Increased Pain Threshold / 대한해부학회지

This study was designed to investigate any correlation between the mechanism of pain development and changes of histochemically-reactive zinc contents in the rat spinal cords following peripheal nerve ligation. Male Sprague-Dawley rats (270 ~290 g) were used for this study. We ligated a left-sided lumbar spinal nerve with silk under anesthesia using pentobarbital (50 mg/kg). Semmes-Weinstein monofilaments (Stoelting Company, Wood Dale, IL) was used to test for mechanical hyperalgesia. 30 micrometer-thick spinal cord cryosections were stained by automet-allography (Danscher, 1981). The density of zinc was significantly decreased in zinc concentration in the dorsal horn of 4th, 5th and 6th lumbar segments at 5 and 10 days after the spinal nerve ligation. Here, zinc depletion was apparent in superficial gray matter, especially layer III-IV. In addition the nerve ligated rats showed lower pain threshold. This increased pain sensation might be related with lowered vesicular zinc level in the superficial gray matter in the spinal cord. The present findings offer a proposed link between zinc and pain. Our interpretation is that there may be an extension of fine primary afferent fibers into lamina III and possibly lamina IV following peripheral nerve ligation. If further work bears out this conclusion, this would provide a possible explanation for the chronic pain states that sometimes follow peripheral nerve damage.

The Effect of Amniotic Membrane Gra ft on the Inhibition of Corneal Haze in Rabbit

This study was performed to investigate histopathologically the effect of amniotic membrane graft (AMG)on haze in deep stromal wound of cornea. The excimer laser phototherapeutic keratectomy (PTK)was used to create the wound model of 150 micrometerdepth, 6.0 mmdiameter area in 72 white rabbitsbilaterally.Each eye was randomized to three groups: control (topical antibiotic alone), contact lens application and AMG. Corneal haze,the number of anterior stromal keratocytes and thickness of the regenerated stroma were evaluated after treatments in corneal wound, and also the morphological changes of anterior stroma connected with corneal haze were analyzed. The score of corneal haze in AMG group was significantly lower than those in the others at postoperative 3 days, 2, 4, 6 and 8 weeks. The anterior stromal keratocytes in AMG group significantly remained more than those in the others at postoperative 3 days. The number of keratocytes and thickness of regenerated stromal tissue in wound area of AMG group were statistically lower as compared with those of the other groups at postoperative 4 weeks. The architecture of stromal lamella was most reg-ular in AMG group. Transmission electron microscopic observation demonstrated that the cells in anterior stroma were the active fibroblastic cells with prominent rough endoplasmic reticulum at postoperative 8 weeks. These findings indicate that corneal haze is closely connected with proliferation of corneal stroma , suggesting that AMG on deep corneal stromal wound reduces corneal haze by preventing proliferation of abnormal collagen and fibroblasts at the anterior stroma of the wound area.