Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer’s disease and other neurological disorders. However, whether and how centra...Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer’s disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance my lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.展开更多
Beneficial effects of dietary energy restriction (DER), including extension of life-span, reduction in cancer risk, anti-cancer effects and decrease in age related neurodegenerative diseases have been well established...Beneficial effects of dietary energy restriction (DER), including extension of life-span, reduction in cancer risk, anti-cancer effects and decrease in age related neurodegenerative diseases have been well established. Given that DER is difficult to implement in humans due to practical constraints, development of energy restriction mimetics (ERMs) is considered as a suitable alternative. Our recent studies have established the anti-tumor effects of the dietary administration of the glycolytic inhibitor 2-deoxy-D-glucose, a potential ERM, an alternative to DER;without any adverse effects on general physiology. Since functioning of the brain is critically dependent on glucose, we investigated the effects of chronic dietary 2-DG administration on the behavioural outcome in mice. Our findings based on a battery of neuro-behavioural tests clearly suggest that the chronic dietary administration of 2-DG that appreciably impairs the process of tumorigenesis has no adverse effect on the cognitive, affective and sensory-motor functions. Together with the maintenance of normal physiology reported by us earlier, these observations strengthen the potential of dietary 2-DG as a safe cancer preventive strategy.展开更多
Background:Trichomoniasis,a sexually transmitted disease(STD),is caused by Trichomonas vaginalis in both men and women.Screening of trichomoniasis is problematic in resource challenged settings as currently available,...Background:Trichomoniasis,a sexually transmitted disease(STD),is caused by Trichomonas vaginalis in both men and women.Screening of trichomoniasis is problematic in resource challenged settings as currently available,inexpensive diagnostic methods are of low sensitivity and/or specificity.In India,National AIDS Control organization(NACO)recommended syndromic case management(SCM)for treatment.The objective of the present study was to compare the utility of the NACO-NACP III Algorithms for STI/RTI treatment used by clinicians with PCR based diagnosis.Methods:Patients visiting Department of Obstetrics&Gynecology,Vardhman Mahavir Medical College and Safdarjung Hospital,New Delhi from January 2011 to June 2014 were enrolled in the study to compare the diagnostic efficiency of PCR-based assays against SCM.Based on SCM,patients(n=820)were treated with antibiotics using pre-packed STI/RTI kits(sexually transmitted infection/reproductive tract infection;procured by National AIDS Control/State AIDS Control Society(NACO/SACS),Ministry of Health and Family Welfare,Govt of India.)under National AIDS Control Programme(NACP III)for syndromic case management(SCM).Ectocervical dry swab samples were also obtained from these patients and out of that 634 samples were tested by PCR.Total genomic DNA was extracted from these samples and used as template for PCR amplification using pfoB,gyrA and orf1 gene specific primers for diagnosis of T.vaginalis(TV),Chlamydia trachomatis(CT)and Neisseria gonorrhoeae(NG)respectively.Results:Out of 6000 patients who visited OPD,820(14%)female patients reported vaginal discharge and were recommended antibiotic treatment for one or more pathogens namely,TV,CT,NG and Candida or for co-infection.On the basis of signs&symptoms and NACO guidelines,the following distribution of various infections was observed:TV(46%),CT(20%),coinfection with TV and CT(12%),coinfection with CT and NG(11%),coinfection with TV,CT and Candida(7%)and coinfection with TV and NG(2%).Others were infected with NG alone(1%),coinfected with TV and Candida(0.4%)and 0.3%were coinfected with CT,NG and Candida.Based on PCR method,110(17%)women tested positive for one or more of these three pathogens while 524(83%)women were negative for any of these three pathogens but could be positive for other STIs not tested in this study.Since all the patients(634)were given antibiotics,we estimate that the over-treatment was 85%while 524(83%)patients were also misdiagnosed by SCM.Conclusions:The over-treatment and inaccurate diagnosis of pathogens due to subjective judgment based on syndromic approach in symptomatic women is a large economic wastage and may also contribute towards increased resistance.The misdiagnosed patients will also serve as a reservoir for transmission of pathogens to their sexual partner.展开更多
基金supported by a grant from All India Institute of Medical Sciences,New Delhi (to RD and TD)Indian Council of Medical Research,Senior Research Fellowship Grant (3/1/2(24)/oph-2009-NCD-II,to MAF)+1 种基金Feldstein Medical Foundation Research Grant (to KCC)unrestricted fund from Research to Prevent Blindness to NYU Langone Health Department of Ophthalmology (to KCC)。
文摘Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer’s disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance my lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.
文摘Beneficial effects of dietary energy restriction (DER), including extension of life-span, reduction in cancer risk, anti-cancer effects and decrease in age related neurodegenerative diseases have been well established. Given that DER is difficult to implement in humans due to practical constraints, development of energy restriction mimetics (ERMs) is considered as a suitable alternative. Our recent studies have established the anti-tumor effects of the dietary administration of the glycolytic inhibitor 2-deoxy-D-glucose, a potential ERM, an alternative to DER;without any adverse effects on general physiology. Since functioning of the brain is critically dependent on glucose, we investigated the effects of chronic dietary 2-DG administration on the behavioural outcome in mice. Our findings based on a battery of neuro-behavioural tests clearly suggest that the chronic dietary administration of 2-DG that appreciably impairs the process of tumorigenesis has no adverse effect on the cognitive, affective and sensory-motor functions. Together with the maintenance of normal physiology reported by us earlier, these observations strengthen the potential of dietary 2-DG as a safe cancer preventive strategy.
基金supported by funds from University of Delhi(DST-PURSE grant 2011–2013)to DS.supported by grants from Indian.Indian Council of Medical Research(ICMR),Government of India,to DS and PM.
文摘Background:Trichomoniasis,a sexually transmitted disease(STD),is caused by Trichomonas vaginalis in both men and women.Screening of trichomoniasis is problematic in resource challenged settings as currently available,inexpensive diagnostic methods are of low sensitivity and/or specificity.In India,National AIDS Control organization(NACO)recommended syndromic case management(SCM)for treatment.The objective of the present study was to compare the utility of the NACO-NACP III Algorithms for STI/RTI treatment used by clinicians with PCR based diagnosis.Methods:Patients visiting Department of Obstetrics&Gynecology,Vardhman Mahavir Medical College and Safdarjung Hospital,New Delhi from January 2011 to June 2014 were enrolled in the study to compare the diagnostic efficiency of PCR-based assays against SCM.Based on SCM,patients(n=820)were treated with antibiotics using pre-packed STI/RTI kits(sexually transmitted infection/reproductive tract infection;procured by National AIDS Control/State AIDS Control Society(NACO/SACS),Ministry of Health and Family Welfare,Govt of India.)under National AIDS Control Programme(NACP III)for syndromic case management(SCM).Ectocervical dry swab samples were also obtained from these patients and out of that 634 samples were tested by PCR.Total genomic DNA was extracted from these samples and used as template for PCR amplification using pfoB,gyrA and orf1 gene specific primers for diagnosis of T.vaginalis(TV),Chlamydia trachomatis(CT)and Neisseria gonorrhoeae(NG)respectively.Results:Out of 6000 patients who visited OPD,820(14%)female patients reported vaginal discharge and were recommended antibiotic treatment for one or more pathogens namely,TV,CT,NG and Candida or for co-infection.On the basis of signs&symptoms and NACO guidelines,the following distribution of various infections was observed:TV(46%),CT(20%),coinfection with TV and CT(12%),coinfection with CT and NG(11%),coinfection with TV,CT and Candida(7%)and coinfection with TV and NG(2%).Others were infected with NG alone(1%),coinfected with TV and Candida(0.4%)and 0.3%were coinfected with CT,NG and Candida.Based on PCR method,110(17%)women tested positive for one or more of these three pathogens while 524(83%)women were negative for any of these three pathogens but could be positive for other STIs not tested in this study.Since all the patients(634)were given antibiotics,we estimate that the over-treatment was 85%while 524(83%)patients were also misdiagnosed by SCM.Conclusions:The over-treatment and inaccurate diagnosis of pathogens due to subjective judgment based on syndromic approach in symptomatic women is a large economic wastage and may also contribute towards increased resistance.The misdiagnosed patients will also serve as a reservoir for transmission of pathogens to their sexual partner.
