Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a life-threatening adverse reaction to certain drugs. The pathogenesis of DRESS is poorly understood, but genetic factors and viral reactivation may play a role. DRESS is associated with reactivation of herpesviruses like EBV and HHV-6, which can trigger a massive anti-viral immune response involving cytokines that cause systemic inflammation and organ damage. Recent research has identified HLA genetic variants that increase susceptibility to DRESS from specific drugs like carbamazepine and allopurinol. Screening patients for these HLA types before prescribing high-risk drugs could help reduce DRESS cases. The exact mechanisms linking drugs, genetics, viruses
This study aimed to determine the incidence of intraoperative hypersensitivity reactions at a large U.S. surgical center. The researchers developed a novel methodology using electronic search strategies and clinical adjudication to identify potential cases. Among 178,746 surgical procedures, 4,008 charts were identified by the search and 264 cases of hypersensitivity reactions were confirmed after adjudication. The overall incidence of hypersensitivity reactions was 1 in 677 procedures. The incidence of severe, life-threatening reactions was 1 in 4,583 procedures. This incidence of severe reactions was similar to previous reports, but the overall incidence of hypersensitivity reactions was much higher than reported elsewhere, likely due to the comprehensive search methodology.
This document provides an overview of multi-target drugs (MTDs) or designed multi-target ligands (DMLs) as a potential approach for treating Alzheimer's disease (AD). AD has a complex pathophysiology involving multiple factors. While previous drug candidates have targeted single factors, MTDs/DMLs aim to target multiple relevant factors simultaneously through a single compound in order to achieve synergistic effects. The document discusses advantages and limitations of the MTD/DML approach for AD treatment and provides recommendations for rational design of effective MTDs/DMLs, including consideration of physicochemical properties, pharmacokinetics, toxicity, and the blood-brain barrier. To date, clinical trials of MTDs
The document provides an introduction to the Buck Institute's Alzheimer's/Mild Cognitive Impairment Program. It summarizes that the program aims to develop novel therapeutic candidates for Alzheimer's disease by identifying compounds that interact with the amyloid precursor protein (APP) or other members of the underlying biological network. Three classes of drug candidates are being researched: 1) the endogenous protein netrin-1, 2) several small molecule compounds identified in screens, including a lead candidate called F03, and 3) analogs of F03 and other hits with improved properties. The Buck Institute is pursuing clinical development of F03 and seeking partners to collaborate on additional candidate drugs.
This document discusses the potential for using genetic biomarkers to improve treatment for psychiatric disorders. It notes that while the causes of psychiatric disorders are still unclear, identifying genetic markers that predict treatment response could help tailor medication selection. The document outlines several studies that have identified candidate genes associated with response to antidepressants and other psychotropic drugs. It acknowledges limitations but argues that further research in pharmacogenetics, using larger, more standardized studies, could help incorporate genetic testing into clinical practice to select safer, more effective treatments for individual patients.
Presentation entitled "Drug Allergy: what have we learned from immunogenetics?", updated and published in Portuguese as an open access full-text "Santos N, Cernadas J. Imunogenética das reacções alérgicas a fármacos. Rev Port Imunoalergologia 2013;23(4):247-258."
A Pilot Study on the Drug-Drug interactions among the Schizophrenia Patients ...pharmaindexing
The study assessed prescriptions of 35 schizophrenia patients for potential drug-drug interactions (DDIs). 19 prescriptions were found to have DDIs, with 12 in male patients and 7 in females. More interactions (7) occurred in patients aged 19-29. The DDIs were classified as major (16%), moderate (58%), or minor (26%). Over half (53%) had a rapid onset, while 37% had a delayed onset. Common moderate interactions involved haloperidol combined with dicyclomine or alprazolam, which can worsen symptoms or increase haloperidol levels. The study highlights the need for assessing prescriptions with multiple drugs to prevent serious DDI
This document summarizes a talk on adverse reactions to oral contraceptives (birth control pills). It discusses how third generation oral contraceptives with modern progesterone types have a higher risk of venous thromboembolism than second generation pills. It also notes that the new progesterone drospirenone seems to increase the risk compared to older pills. While risks exist, the overall benefits of oral contraceptives in preventing pregnancy and some cancers outweigh the risks. The talk aims to examine the evidence behind controversies on health risks and discuss implications for the growing number of potential oral contraceptive users in India.
This case report describes a 28-year-old female patient who presented with hypersensitivity reactions after being treated with ceftriaxone (a third-generation cephalosporin antibiotic) for a bacterial infection. The patient developed urticaria (hives) after a few days of ceftriaxone therapy. Tests ruled out other potential causes, and causality assessment scales determined the reactions were probably caused by ceftriaxone. The antibiotic was stopped and the patient recovered from the hypersensitivity reactions after 10 days. The report discusses how cephalosporins can rarely cause immediate IgE-mediated allergic reactions like urticaria.
This study aimed to determine the incidence of intraoperative hypersensitivity reactions at a large U.S. surgical center. The researchers developed a novel methodology using electronic search strategies and clinical adjudication to identify potential cases. Among 178,746 surgical procedures, 4,008 charts were identified by the search and 264 cases of hypersensitivity reactions were confirmed after adjudication. The overall incidence of hypersensitivity reactions was 1 in 677 procedures. The incidence of severe, life-threatening reactions was 1 in 4,583 procedures. This incidence of severe reactions was similar to previous reports, but the overall incidence of hypersensitivity reactions was much higher than reported elsewhere, likely due to the comprehensive search methodology.
This document provides an overview of multi-target drugs (MTDs) or designed multi-target ligands (DMLs) as a potential approach for treating Alzheimer's disease (AD). AD has a complex pathophysiology involving multiple factors. While previous drug candidates have targeted single factors, MTDs/DMLs aim to target multiple relevant factors simultaneously through a single compound in order to achieve synergistic effects. The document discusses advantages and limitations of the MTD/DML approach for AD treatment and provides recommendations for rational design of effective MTDs/DMLs, including consideration of physicochemical properties, pharmacokinetics, toxicity, and the blood-brain barrier. To date, clinical trials of MTDs
The document provides an introduction to the Buck Institute's Alzheimer's/Mild Cognitive Impairment Program. It summarizes that the program aims to develop novel therapeutic candidates for Alzheimer's disease by identifying compounds that interact with the amyloid precursor protein (APP) or other members of the underlying biological network. Three classes of drug candidates are being researched: 1) the endogenous protein netrin-1, 2) several small molecule compounds identified in screens, including a lead candidate called F03, and 3) analogs of F03 and other hits with improved properties. The Buck Institute is pursuing clinical development of F03 and seeking partners to collaborate on additional candidate drugs.
This document discusses the potential for using genetic biomarkers to improve treatment for psychiatric disorders. It notes that while the causes of psychiatric disorders are still unclear, identifying genetic markers that predict treatment response could help tailor medication selection. The document outlines several studies that have identified candidate genes associated with response to antidepressants and other psychotropic drugs. It acknowledges limitations but argues that further research in pharmacogenetics, using larger, more standardized studies, could help incorporate genetic testing into clinical practice to select safer, more effective treatments for individual patients.
Presentation entitled "Drug Allergy: what have we learned from immunogenetics?", updated and published in Portuguese as an open access full-text "Santos N, Cernadas J. Imunogenética das reacções alérgicas a fármacos. Rev Port Imunoalergologia 2013;23(4):247-258."
A Pilot Study on the Drug-Drug interactions among the Schizophrenia Patients ...pharmaindexing
The study assessed prescriptions of 35 schizophrenia patients for potential drug-drug interactions (DDIs). 19 prescriptions were found to have DDIs, with 12 in male patients and 7 in females. More interactions (7) occurred in patients aged 19-29. The DDIs were classified as major (16%), moderate (58%), or minor (26%). Over half (53%) had a rapid onset, while 37% had a delayed onset. Common moderate interactions involved haloperidol combined with dicyclomine or alprazolam, which can worsen symptoms or increase haloperidol levels. The study highlights the need for assessing prescriptions with multiple drugs to prevent serious DDI
This document summarizes a talk on adverse reactions to oral contraceptives (birth control pills). It discusses how third generation oral contraceptives with modern progesterone types have a higher risk of venous thromboembolism than second generation pills. It also notes that the new progesterone drospirenone seems to increase the risk compared to older pills. While risks exist, the overall benefits of oral contraceptives in preventing pregnancy and some cancers outweigh the risks. The talk aims to examine the evidence behind controversies on health risks and discuss implications for the growing number of potential oral contraceptive users in India.
This case report describes a 28-year-old female patient who presented with hypersensitivity reactions after being treated with ceftriaxone (a third-generation cephalosporin antibiotic) for a bacterial infection. The patient developed urticaria (hives) after a few days of ceftriaxone therapy. Tests ruled out other potential causes, and causality assessment scales determined the reactions were probably caused by ceftriaxone. The antibiotic was stopped and the patient recovered from the hypersensitivity reactions after 10 days. The report discusses how cephalosporins can rarely cause immediate IgE-mediated allergic reactions like urticaria.
#APM16 - A Toolkit for Social and Digital Media Policies in Field EducationLaurel Hitchcock
Social Work field directors are increasingly dealing with ethical and practical issues related to the use of social and digital media in field education. This workshop will provide information and tools to help field directors raise awareness with students and field supervisors.
The document provides details about an agronomy internship at Deseret Farms of California during the summer of 2016. It includes background information about the intern, Cody Deitz, and outlines several projects he worked on, including new orchard development, GPS work, tree evaluations, well testing, and sand testing. It discusses specific tasks like creating tree arrays, evaluating tree growth, and measuring tree trunk diameters to compare trees that were replanted after fumigation to those that were not.
Blake Lemoi is a hands-on business development leader with extensive experience in sales, marketing, and operations. He has worked in various industries, holding titles such as Director of Sales and Marketing, Business Development Consultant, and Sales Manager. Lemoi strives to implement strategic approaches to optimize operations and improve sales through innovative customer-focused solutions. He aims to establish winning teams by reducing risk and creating digital assets to generate qualified leads.
El documento contiene varios ejercicios de álgebra sobre ecuaciones de primer grado. En la primera sección, se pide identificar cuales expresiones son ecuaciones y resolver algunas ecuaciones de primer grado. La segunda sección contiene más ejercicios de resolución de ecuaciones con una o más variables. La tercera sección presenta ejercicios adicionales sobre ecuaciones con denominadores.
This document discusses how Softbridge Smart Monitoring Engine can help companies monitor critical business processes end-to-end. It detects incidents in real-time, identifies the root cause instantly, and enables companies to resolve incidents before customers are impacted. The document claims Softbridge can reduce incidents by 80% in 6 months, diagnose issues in under 5 minutes, and save companies over 1 million euros per year while also reducing complaints by 30%. It promotes learning more about Softbridge's monitoring capabilities by visiting their website.
1) DRESS syndrome is a severe cutaneous drug reaction characterized by fever, lymphadenopathy, hematologic abnormalities, multisystem involvement, and viral reactivation. It has a delayed onset of 2-3 weeks after starting the culprit drug.
2) The skin manifestations are typically a polymorphous maculopapular eruption and facial edema. Systemic involvement can include the liver, kidneys, lungs and other organs.
3) Diagnosis is based on clinical criteria including the RegiSCAR scoring system which evaluates morphology, timing of onset, organ involvement, hematologic abnormalities and viral reactivation.
This document discusses the association between HLA alleles and susceptibility to disease. It notes that HLA allelic diversity helps the immune system recognize pathogens, but some alleles may recognize self-molecules and cause autoimmune diseases. Most disease associations are with Class I or Class II HLA alleles. Specific examples discussed include associations between HLA-B27 and various conditions like ankylosing spondylitis, HLA-DQ genes and celiac disease, and HLA-DRB1 alleles and rheumatoid arthritis. The document hypothesizes that HLA molecules play a key role in thymic selection of T-cells and presentation of peptides to initiate or propagate immune responses, providing a basis for HLA-associated disease susceptibility.
Sometimes it is difficult & even problem to deal with patient with refractory LN, so we are in need for expert perspectives as a guide to treat those cases.
Association of the HLA-B alleles with carbamazepine-induced Stevens–Johnson s...UniversitasGadjahMada
Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN.We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sundanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2–33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78; 95% CI: 1.96– 23.38). These findings support the involvement of HLA-B*15:02 in CBZ-induced SJS/TEN reported in other Asian populations. Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90–75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83–40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.
Systemic lupus erythematosus (SLE) is an autoimmune disease and as we know immune
system is vast and complex and presents an enormous challenge to scientists working in this field as well as presents a challenge to anyone seeking to explain where pathogenesis research stands at the end of 2011
Stability criterion of periodic oscillations in a (1)Alexander Decker
This document summarizes a mathematical model of the interaction between HIV, immune cells (CTLs), and antiretroviral drug treatment. The model accounts for time delays between viral infection of cells and viral production. It consists of 4 equations tracking healthy CD4+ T-cells, latently infected cells, productively infected cells, and free virus over time. The paper analyzes the model's equilibrium states and how time delays impact the stability of periodic oscillations. It finds that oscillations are stable if the time delay is within certain bounds, and drug efficacy can lead to oscillation death at a critical delay value. This threshold could help control HIV dynamics through treatment intervention.
This study analyzed the properties of the novel Class 1 HDAC inhibitor MC2625 and its ability to reactivate HIV-1 latency. Experiments using the J-Lat 10.6 model of latency found that while MC2625 was able to potently reactivate HIV-1 at concentrations around 700 nM, it also showed some toxicity at higher concentrations above 2000 nM. Western blot analysis confirmed the compound induced production of viral proteins. Though MC2625 shows potential as a latency-reversing agent, more research is needed to better understand its effects and how to optimize its ability to reduce the HIV reservoir.
Psychiatric treatment considerations with direct acting antivirals in hepatit...Enrique Moreno Gonzalez
Despite recent advances in hepatitis C (HCV) treatment, specifically the addition of direct
acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of HCV therapy.
Therefore, the impact of DAAs on the management of co-morbid psychiatric illness and
neuropsychiatric sequalae remains an ongoing concern during HCV therapy. This paper
provides a review of the neuropsychiatric adverse effects of DAAs and drug-drug interactions
(DDIs) between DAAs and psychiatric medications.
This study examined the association between HLA-B*1502 and carbamazepine-induced Stevens-Johnson syndrome (SJS) in North Indians. The study found that HLA-B*1502 was present in 2 of 9 (22.2%) patients with carbamazepine-induced SJS but in none of 37 carbamazepine-tolerant controls, suggesting HLA-B*1502 is a risk factor. HLA-B*1502 was not associated with phenytoin-induced SJS. The results provide evidence that HLA-B*1502 testing should be performed before initiating carbamazepine treatment in North Indian patients.
Rheumatoid arthritis is an autoimmune disease characterized by inflammation of the joints. Genetic and environmental factors contribute to its pathogenesis. Genome-wide analyses have identified genes related to immune regulation that increase the risk of developing rheumatoid arthritis. Environmental triggers such as smoking can interact with genetic susceptibility factors like HLA-DRB1 alleles to further increase the risk. This leads to a breakdown of self-tolerance and production of autoantibodies against citrullinated proteins. While the cause is unknown, it is believed that citrullination of proteins by enzymes like peptidyl arginine deiminase 4 results in the formation of neo-epitopes that elicit an autoimmune response. This prearthritis phase
TB is a major worldwide disease with new cases arising at an alarmin.pdfinfo961251
TB is a major worldwide disease with new cases arising at an alarming rate, What factors can
account for this and what lays behind the trend of multidrug resistant strains of mycobacterium?
please cite reference.
Solution
Tuberculosis is caused by mycobacteriam tuberculosis. TB is one of the most common cause of
death due to infection of the mycobacteriam species.various factor have been found to develop
resistance against M. tuberculosis. resistance means simply afterwards that drug potency in terms
of pharmacological response will be decresed gradually and at certain level it will not active
against the strain. There are two types of resistance 1. natural resistance and second is aquired
resistance. natural resistance is found on wild strain. multidrug resistance is the phase in which
strain is not responsive against primary line therapy of disease.
factor which induced resistance
gene factor
In a recent year study suggest that the patient who shows the presence of HLA -DRB1 13 and
HLA-DRB 1 14 has two fold risk to develop resistance against strain.(Park et al.)
Incomplete and inadequate mangment Review of literature suggests that the most powerful
factor of MDR-TB is a history of treatment of tuberculosis(diagnosis). TB patients get treated
with DOTS regimens not only through the Revised National Tuberculosis Control Programme
(RNTCP), but also receive treatment from private medical doctors. Irregular, incomplete,
inadequate treatment is the commonest mean of acquiring drug resistant due to improper
mangment of drug mostly organism develop the resistnacce against drug eg. use of single drug to
treat tb is the fetal cause to develope resistance against organisms.it may be due to ignorance.
anothe common error in prescription error it may like additions syndromes.
Inadequate treatment compliance : the change over form has complied a significant effece in
development of drug resistance it was observed that only 44 per cent of the patients receiving
short-course treatment (n=2300) and 36 per cent of those receiving standard chemotherapy
(n=1000) completed 81 per cent or more of their treatment.
Noncompliance with prescribed treatment is often underestimated by the physician and is
difficult to predict. On the other hand, certain factors such as psychiatric illness, alcoholism, drug
addiction and homelessness do predict noncompliance .The drug defaulter, just like placebo
reactor is not a consistent or readily identified person demographic factors such as ,sex, age,
marital status,socio-economic status and education levelhave not been found to correlate with the
degree of compliance..
This document summarizes research on regulatory T cells (Tregs) and their implications in graft-versus-host disease (GVHD). It discusses:
1) Tregs play an important role in maintaining immune homeostasis and preventing autoimmune diseases like GVHD.
2) Preclinical studies show that Treg depletion leads to worse GVHD in mice, while Treg adoptive transfer mitigates GVHD.
3) Clinical trials testing Treg immunotherapy for GVHD prevention and treatment have shown promising results, but more research is still needed to fully understand Treg subsets and develop effective Treg-based therapies.
This document discusses genetic polymorphisms and summarizes several research studies. It begins by defining genetic polymorphisms as variations in regulatory DNA. It then summarizes three key points:
1) A study that used a cross-species strategy to identify 6 causal genes for Alzheimer's disease by studying interactions between human genes and neurotoxicity in the fly model.
2) Research confirming the association between a genetic variant in the PLA2R gene and membranous nephropathy through genome-wide association studies and previous Asian studies.
3) The potential medical benefits of these discoveries such as earlier diagnosis, improved treatment, and further genetic research.
#APM16 - A Toolkit for Social and Digital Media Policies in Field EducationLaurel Hitchcock
Social Work field directors are increasingly dealing with ethical and practical issues related to the use of social and digital media in field education. This workshop will provide information and tools to help field directors raise awareness with students and field supervisors.
The document provides details about an agronomy internship at Deseret Farms of California during the summer of 2016. It includes background information about the intern, Cody Deitz, and outlines several projects he worked on, including new orchard development, GPS work, tree evaluations, well testing, and sand testing. It discusses specific tasks like creating tree arrays, evaluating tree growth, and measuring tree trunk diameters to compare trees that were replanted after fumigation to those that were not.
Blake Lemoi is a hands-on business development leader with extensive experience in sales, marketing, and operations. He has worked in various industries, holding titles such as Director of Sales and Marketing, Business Development Consultant, and Sales Manager. Lemoi strives to implement strategic approaches to optimize operations and improve sales through innovative customer-focused solutions. He aims to establish winning teams by reducing risk and creating digital assets to generate qualified leads.
El documento contiene varios ejercicios de álgebra sobre ecuaciones de primer grado. En la primera sección, se pide identificar cuales expresiones son ecuaciones y resolver algunas ecuaciones de primer grado. La segunda sección contiene más ejercicios de resolución de ecuaciones con una o más variables. La tercera sección presenta ejercicios adicionales sobre ecuaciones con denominadores.
This document discusses how Softbridge Smart Monitoring Engine can help companies monitor critical business processes end-to-end. It detects incidents in real-time, identifies the root cause instantly, and enables companies to resolve incidents before customers are impacted. The document claims Softbridge can reduce incidents by 80% in 6 months, diagnose issues in under 5 minutes, and save companies over 1 million euros per year while also reducing complaints by 30%. It promotes learning more about Softbridge's monitoring capabilities by visiting their website.
1) DRESS syndrome is a severe cutaneous drug reaction characterized by fever, lymphadenopathy, hematologic abnormalities, multisystem involvement, and viral reactivation. It has a delayed onset of 2-3 weeks after starting the culprit drug.
2) The skin manifestations are typically a polymorphous maculopapular eruption and facial edema. Systemic involvement can include the liver, kidneys, lungs and other organs.
3) Diagnosis is based on clinical criteria including the RegiSCAR scoring system which evaluates morphology, timing of onset, organ involvement, hematologic abnormalities and viral reactivation.
This document discusses the association between HLA alleles and susceptibility to disease. It notes that HLA allelic diversity helps the immune system recognize pathogens, but some alleles may recognize self-molecules and cause autoimmune diseases. Most disease associations are with Class I or Class II HLA alleles. Specific examples discussed include associations between HLA-B27 and various conditions like ankylosing spondylitis, HLA-DQ genes and celiac disease, and HLA-DRB1 alleles and rheumatoid arthritis. The document hypothesizes that HLA molecules play a key role in thymic selection of T-cells and presentation of peptides to initiate or propagate immune responses, providing a basis for HLA-associated disease susceptibility.
Sometimes it is difficult & even problem to deal with patient with refractory LN, so we are in need for expert perspectives as a guide to treat those cases.
Association of the HLA-B alleles with carbamazepine-induced Stevens–Johnson s...UniversitasGadjahMada
Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN.We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sundanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2–33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78; 95% CI: 1.96– 23.38). These findings support the involvement of HLA-B*15:02 in CBZ-induced SJS/TEN reported in other Asian populations. Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90–75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83–40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.
Systemic lupus erythematosus (SLE) is an autoimmune disease and as we know immune
system is vast and complex and presents an enormous challenge to scientists working in this field as well as presents a challenge to anyone seeking to explain where pathogenesis research stands at the end of 2011
Stability criterion of periodic oscillations in a (1)Alexander Decker
This document summarizes a mathematical model of the interaction between HIV, immune cells (CTLs), and antiretroviral drug treatment. The model accounts for time delays between viral infection of cells and viral production. It consists of 4 equations tracking healthy CD4+ T-cells, latently infected cells, productively infected cells, and free virus over time. The paper analyzes the model's equilibrium states and how time delays impact the stability of periodic oscillations. It finds that oscillations are stable if the time delay is within certain bounds, and drug efficacy can lead to oscillation death at a critical delay value. This threshold could help control HIV dynamics through treatment intervention.
This study analyzed the properties of the novel Class 1 HDAC inhibitor MC2625 and its ability to reactivate HIV-1 latency. Experiments using the J-Lat 10.6 model of latency found that while MC2625 was able to potently reactivate HIV-1 at concentrations around 700 nM, it also showed some toxicity at higher concentrations above 2000 nM. Western blot analysis confirmed the compound induced production of viral proteins. Though MC2625 shows potential as a latency-reversing agent, more research is needed to better understand its effects and how to optimize its ability to reduce the HIV reservoir.
Psychiatric treatment considerations with direct acting antivirals in hepatit...Enrique Moreno Gonzalez
Despite recent advances in hepatitis C (HCV) treatment, specifically the addition of direct
acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of HCV therapy.
Therefore, the impact of DAAs on the management of co-morbid psychiatric illness and
neuropsychiatric sequalae remains an ongoing concern during HCV therapy. This paper
provides a review of the neuropsychiatric adverse effects of DAAs and drug-drug interactions
(DDIs) between DAAs and psychiatric medications.
This study examined the association between HLA-B*1502 and carbamazepine-induced Stevens-Johnson syndrome (SJS) in North Indians. The study found that HLA-B*1502 was present in 2 of 9 (22.2%) patients with carbamazepine-induced SJS but in none of 37 carbamazepine-tolerant controls, suggesting HLA-B*1502 is a risk factor. HLA-B*1502 was not associated with phenytoin-induced SJS. The results provide evidence that HLA-B*1502 testing should be performed before initiating carbamazepine treatment in North Indian patients.
Rheumatoid arthritis is an autoimmune disease characterized by inflammation of the joints. Genetic and environmental factors contribute to its pathogenesis. Genome-wide analyses have identified genes related to immune regulation that increase the risk of developing rheumatoid arthritis. Environmental triggers such as smoking can interact with genetic susceptibility factors like HLA-DRB1 alleles to further increase the risk. This leads to a breakdown of self-tolerance and production of autoantibodies against citrullinated proteins. While the cause is unknown, it is believed that citrullination of proteins by enzymes like peptidyl arginine deiminase 4 results in the formation of neo-epitopes that elicit an autoimmune response. This prearthritis phase
TB is a major worldwide disease with new cases arising at an alarmin.pdfinfo961251
TB is a major worldwide disease with new cases arising at an alarming rate, What factors can
account for this and what lays behind the trend of multidrug resistant strains of mycobacterium?
please cite reference.
Solution
Tuberculosis is caused by mycobacteriam tuberculosis. TB is one of the most common cause of
death due to infection of the mycobacteriam species.various factor have been found to develop
resistance against M. tuberculosis. resistance means simply afterwards that drug potency in terms
of pharmacological response will be decresed gradually and at certain level it will not active
against the strain. There are two types of resistance 1. natural resistance and second is aquired
resistance. natural resistance is found on wild strain. multidrug resistance is the phase in which
strain is not responsive against primary line therapy of disease.
factor which induced resistance
gene factor
In a recent year study suggest that the patient who shows the presence of HLA -DRB1 13 and
HLA-DRB 1 14 has two fold risk to develop resistance against strain.(Park et al.)
Incomplete and inadequate mangment Review of literature suggests that the most powerful
factor of MDR-TB is a history of treatment of tuberculosis(diagnosis). TB patients get treated
with DOTS regimens not only through the Revised National Tuberculosis Control Programme
(RNTCP), but also receive treatment from private medical doctors. Irregular, incomplete,
inadequate treatment is the commonest mean of acquiring drug resistant due to improper
mangment of drug mostly organism develop the resistnacce against drug eg. use of single drug to
treat tb is the fetal cause to develope resistance against organisms.it may be due to ignorance.
anothe common error in prescription error it may like additions syndromes.
Inadequate treatment compliance : the change over form has complied a significant effece in
development of drug resistance it was observed that only 44 per cent of the patients receiving
short-course treatment (n=2300) and 36 per cent of those receiving standard chemotherapy
(n=1000) completed 81 per cent or more of their treatment.
Noncompliance with prescribed treatment is often underestimated by the physician and is
difficult to predict. On the other hand, certain factors such as psychiatric illness, alcoholism, drug
addiction and homelessness do predict noncompliance .The drug defaulter, just like placebo
reactor is not a consistent or readily identified person demographic factors such as ,sex, age,
marital status,socio-economic status and education levelhave not been found to correlate with the
degree of compliance..
This document summarizes research on regulatory T cells (Tregs) and their implications in graft-versus-host disease (GVHD). It discusses:
1) Tregs play an important role in maintaining immune homeostasis and preventing autoimmune diseases like GVHD.
2) Preclinical studies show that Treg depletion leads to worse GVHD in mice, while Treg adoptive transfer mitigates GVHD.
3) Clinical trials testing Treg immunotherapy for GVHD prevention and treatment have shown promising results, but more research is still needed to fully understand Treg subsets and develop effective Treg-based therapies.
This document discusses genetic polymorphisms and summarizes several research studies. It begins by defining genetic polymorphisms as variations in regulatory DNA. It then summarizes three key points:
1) A study that used a cross-species strategy to identify 6 causal genes for Alzheimer's disease by studying interactions between human genes and neurotoxicity in the fly model.
2) Research confirming the association between a genetic variant in the PLA2R gene and membranous nephropathy through genome-wide association studies and previous Asian studies.
3) The potential medical benefits of these discoveries such as earlier diagnosis, improved treatment, and further genetic research.
Pharmacogenomics shows promise for improving patient outcomes and safety by enabling more personalized treatment approaches based on a patient's genetics. However, fully realizing its benefits faces several challenges, including the need for healthcare stakeholders to coordinate effectively, securing adequate resources, and educating physicians on pharmacogenomics. Additionally, drug interactions and environmental factors can complicate the relationship between genetics and drug response, requiring more research before pharmacogenomic testing can be widely implemented in clinical practice.
This document defines adverse drug reactions and discusses their epidemiology, classification, detection, and monitoring. It provides definitions of adverse drug reactions from WHO and other organizations. It describes the incidence, costs, and preventability of ADRs. It classifies ADRs into types A-F based on mechanisms and discusses methods to determine causality, including the Naranjo algorithm. It outlines the pharmacovigilance system in India including monitoring centers coordinated by AIIMS.
This document discusses genetic polymorphisms and summarizes several articles on related topics. It begins by defining genetic polymorphisms as variations in regulatory DNA. It then summarizes findings from articles on using cross-species strategies to study human disease like Alzheimer's, identifying genes linked to membranous nephritis and autoantibodies, and discusses the medical utility of early diagnosis and improved treatment from genetic studies.
This document discusses genetic polymorphisms and summarizes several research articles. It begins by defining genetic polymorphisms as variations in regulatory DNA. It then summarizes a study that used a cross-species strategy to identify genes involved in Alzheimer's disease by comparing human and fly genomes. Another section summarizes findings from a study linking certain genes to membranous nephritis. Specifically, it discusses the association between this disease and the PLA2R receptor gene. The document concludes by discussing the medical utility of these findings, such as enabling early diagnosis and treatment.
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
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Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
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Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
1. Drug Reaction with Eosinophilia and Systemic Symptoms: an
update on pathogenesis
Xavier Camous1
, Sebastien Calbo1
, Damien Picard2
and Philippe Musette2
The syndrome termed ‘Drug Reaction with Eosinophilia and
Systemic Symptoms’ (DRESS) is an unpredictable, life-
threatening condition associated with adverse reactions to
therapy. Although the etiology of DRESS is poorly understood,
genetic susceptibility markers have been identified within the
HLA complex and there are several prevailing models of
pathogenesis. Modification of host antigens by haptens (drugs
or their metabolites), or non-covalent drug binding to
endogenous proteins (the p-i concept), may drive pro-
inflammatory immune responses in patients. Alternatively, a
viral trigger for DRESS has been proposed based on the
concomitant detection of herpesviruses and the recent
demonstration of Epstein–Barr virus-specific immune
responses in DRESS patients. In the present review, we
discuss the latest findings concerning the pathogenesis of drug
reactions and known risk factors for DRESS.
Addresses
1
Biomedical Sciences Institutes, Singapore Immunology Network
(SIgN), A*STAR, 8A Biomedical Grove #4 Immunos Building, Singapore
138648, Singapore
2
INSERM U905, Rouen University Hospital, Rouen 76000, France
Corresponding author: Musette, Philippe (philippe.musette@chu-
rouen.fr)
Current Opinion in Immunology 2012, 24:730–735
This review comes from a themed issue on Allergy and hypersensitivity
Edited by Hans-Uwe Simon and Steven F Ziegler
For a complete overview see the Issue and the Editorial
Available online 11th October 2012
0952-7915/$ – see front matter, # 2012 Elsevier Ltd. All rights
reserved.
http://dx.doi.org/10.1016/j.coi.2012.07.010
Introduction
Drug Reaction with Eosinophilia and Systemic Symp-
toms (DRESS) is a type of severe cutaneous drug erup-
tion (DE), being a class of adverse reactions to therapies
that also includes Steven–Johnson Syndrome (SJS) and
Toxic Epidermal Necrolysis (TEN). The initial
sequence of events that drives the pathogenesis of DE
may be consistent between the three different forms of
severe DE, while specific outcomes and clinical manifes-
tations are influenced by patient-intrinsic factors that
have yet to be identified. DRESS is a disease difficult
to diagnose since the symptoms mimic those of several
other pathologies and can appear a long time after initial
drug exposure. A diagnostic tool known as the RegiSCAR
criteria grid was thus created to better diagnose DRESS
in drug-treated patients [1]. RegiSCAR is based on seven
parameters and mandates three or more primary symp-
toms (fever >38 8C, acute skin rash, lymphadenopathy,
internal organ involvement, blood count abnormalities)
for a diagnosis of DRESS. An update to this approach was
subsequently developed and named the ‘Japanese con-
sensus group diagnostic criteria for DIHS’ (drug-induced
hypersensitivity syndrome) [2]. This diagnostic tool
requires that at least seven of nine patient symptoms
must be present to identify DRESS (rash development
more than three weeks after starting medication, symp-
toms not stopped by drug discontinuation, fever, liver
abnormalities, leukocyte abnormalities, leukocytosis, aty-
pical lymphocytosis, lymphadenopathy and re-activation
of human herpesvirus 6 (HHV-6). In DRESS, the liver,
kidneys and lungs are the organs most often involved in
the disease process, and the most common blood abnorm-
alities include atypical lymphocytes, eosinophilia and
lymphocytopenia. Affected patients are usually treated
with immunosuppressive drugs including corticosteroids,
and full recovery is achieved in up to 90% of cases.
Drug-specific T-cells have been identified as the primary
effectors of disease in DE patients [3]. However, T-cells
from healthy donors can also efficiently respond to drugs,
despite a lack of previous drug exposure [4–6]. These data
predict a far higher incidence of DE than observed in
human patients. DE is rather a rare disease, and factors
that effectively identify ‘at-risk’ individuals within a
population of patients receiving a given drug have yet
to be determined. While some genetic susceptibility of
DE is associated with the HLA loci [7–11], these findings
alone cannot account for DE prevalence, since the ident-
ified HLA susceptibility alleles are neither necessary nor
sufficient for disease development [12]. More recently, a
link was established between drug re-activation of
endogenous herpesvirus and presentation of DRESS in
treated patients [2]. However, there is as yet no evidence
that re-activation of dormant viruses can occur in SJS and
TEN. The present review focuses on the latest advances
in our understanding of the pathogenesis of DRESS.
The hapten theory and p-i concept
To better understand the role of HLA molecules in
severe cutaneous drug reactions, a brief description of
the hapten theory and p-i concept is necessary (Figure 1)
[3]. Haptenation is a process whereby a small and immu-
nologically neutral molecule becomes antigenic when
bound to a protein [13,14
]. Pro-hapten molecules must
Available online at www.sciencedirect.com
Current Opinion in Immunology 2012, 24:730–735 www.sciencedirect.com
2. first be metabolized by detoxification enzymes to become
able to bind to proteins. Since haptens cannot discrimi-
nate between individual patients, and detoxification
enzymes are expressed by all drug recipients, it has been
proposed that polymorphisms in the genes that encode
detoxification enzymes may be responsible for the de-
velopment of DRESS in only a subset of patients. How-
ever, no such polymorphism has been identified that
correlates with the occurrence of patient drug reactions
[9,15,16]. Indeed, the majority of drugs studied can be
recognized by patient T-cells despite lacking hapten-like
features [17]. Labile binding of drugs or their metabolites
to MHC molecules that induce T-cell responses has been
termed the ‘p-i’ concept (pharmacological interaction of
drugs with immune receptor) [18]. The fact remains that
T-cells in healthy donors have the capacity to be stimu-
lated by drugs just as potently as T-cells in patients,
thereby indicating the involvement of additional
susceptibility factors [4–6].
Drug interactions with HLA type
In the hapten-driven and p-i models of DRESS patho-
genesis, drugs or their metabolites bind to host proteins to
induce immune responses. Assuming that the protein
involved is not unique to affected patients, these models
predict that any treated individual may be at risk of
DRESS whenever a new medication is administered.
However, very promising results have been obtained
indicating that specific HLA variants may be partially
responsible for increased risk of DRESS. The first study
to describe a relationship between drug susceptibility and
HLA type was conducted by Mallal et al. in 2002 [8], and
identified a link between HLA type in HIV-positive
Caucasians and development of hypersensitivity to aba-
cavir (a nucleotide analog that acts as a HIV reverse
transcriptase inhibitor). Mallal and colleagues showed
that expression of HLA-B*5701 was strongly associated
( p 0.0001) with abacavir hypersensitivity. The mech-
anism of T-cell activation by abacavir was subsequently
elucidated by Illing et al. in 2012 [19
], and confirmed by
other investigators [20,21]; abacavir is able to bind non-
covalently to the peptide-binding groove of the HLA-
B*5701 molecule (but not to the related HLA-B*5703)
and thereby induces a T-cell response against the modi-
fied MHC/self peptide complex. This modification of
endogenous proteins effectively renders the involved
tissues ‘allogeneic’, which may explain the particular
magnitude of the inflammatory response induced. Impor-
tantly, the authors also showed that non-covalent drug
binding in the MHC groove altered the self-peptide
repertoire, thus also providing a possible explanation
for cases of autoimmunity that can occur following DE
DRESS Camous et al. 731
Figure 1
T cell
TCR
Peptide
Drug
HLA
(I or II)
APC
A B C
IMMUNE RESPONSE
Current Opinion in Immunology
Models of drug-specific T-cell activation. Drugs can bind covalently to the MHC (a) and to peptides (b), or can become non-covalently embedded
within the MHC groove. Drug binding may expose peptide residues not usually displayed for TCR binding, or could perhaps modify the repertoire of
peptides presented by a given MHC molecule. If the drug-modified structure is subsequently recognized by a T-cell in the context of co-stimulation, T-
cell responses will then be initiated.
www.sciencedirect.com Current Opinion in Immunology 2012, 24:730–735
3. [22,23]. However, we know that not all HLA-B*5701
positive patients will develop a DE in response to aba-
cavir [12], suggesting other risk factors.
Carbamazepine is an anti-convulsant drug and well-estab-
lished inducer of hypersensitivity reactions. Suscepti-
bility to carbamazepine has been linked to patients
that carry the HLA-B*1502 variant [9]. The proposed
mechanism of T-cell activation by carbamazepine is
similar to that described above for abacavir [19
].
HLA-B*1502 is very commonly expressed in South East
Asia population and is almost exclusive of this region. In
contrast, carbamazepine responses in Europeans descent
are associated with the expression of HLA-B*3101 [11].
Similarly, gout medication allopurinol is known to induce
reactions in HLA-B*5801 carriers [10]. All of these associ-
ations are likely to share a comparable mechanism of
patient T-cell activation that depends on drug modu-
lation of the host MHC/peptide repertoire, although
rigorous proof of this mechanism is currently lacking.
The identification of DE risk-associated HLA variants
has opened new doors for healthcare practitioners by
enabling patient stratification for DE susceptibility using
simple HLA typing techniques. A Taiwanese study of
almost 5000 patients categorized their cohort according to
HLA haplotype [24
], and administered a substitute for
carbamazepine in patients carrying the HLA-B*1502
variant. By conducting HLA typing before drug prescrip-
tion, the incidence of drug disorders was dramatically
reduced, and none of the patients developed either SJS or
TEN (despite a predicted incidence of 0.23%, equivalent
to 10 cases of SJS or TEN among the 4120 study subjects
who took carbamazepine). Mild rash was observed in only
6% of non-HLA-B*1502 patients, and 0.1% of these
patients required hospitalization, implicating additional
risk factors for drug reactions in this population. Screen-
ing patients’ HLA haplotype before administering medi-
cations could therefore be a very efficient method of
reducing the number of severe drug reactions. For a
complete review of HLA associations with drug hyper-
sensitivities, please refer to Bharadwaj et al. [25].
Anti-viral responses
The observation that DRESS can re-activate dormant
viruses in affected patients, especially in individuals
infected with members of the human herpesviridae
family [26–29], has led to the hypothesis that viruses
may play a key role in DRESS pathogenesis. The first
virus shown to be re-activated in DRESS patients was
human HHV-6 [30]. This double-stranded DNA virus,
first discovered in 1986 [31], infects most humans in the
first year of life and induces roseola infantum, a disease
associated with fever and skin rash. HHV-6 involvement
has been reported in a large number of different pathol-
ogies including AIDS [32], multiple sclerosis [33], chronic
fatigue syndrome [34], graft complications [35], epilepsy
[36] and cancers [37]. The main feature of HHV-6 is the
virus’ capacity to infect T-cells [31] and to dysregulate
CD8+
lymphocytes by inducing ectopic expression of
CD4 [38]. In 2010, Marviridin et al., by showing that
HHV-6 replication can be induced in vitro by amoxillicin,
hypothesized that this antibiotic induces DRESS by
promoting viral reactivation [39]. Now, it has been estab-
lished that nearly every member of the herpesviridae
family can be re-activated by DRESS-inductive medi-
cation, including Epstein–Barr Virus [28], Cytomegalo-
virus [40], Varicella Zoster Virus [41] and HHV-7 [27]. We
demonstrated that a massive, system-wide, anti-viral T-
cell response is ongoing in DRESS patients [42
]. In this
study of 40 cases of DRESS, we showed that EBV-
specific CD8+
T-cells were substantially over-
represented within the T-cell pool, comprising up to
21% of total cytotoxic T-cells in DRESS patients com-
pared with 0.1% in control patients. Activated T-cells
were producing large quantities of TNFa, IL-2 and
IFNg, which are key mediators of the ‘cytokine storm’
that can promote the characteristic symptoms of DRESS
syndrome (Figure 2). Moreover, EBV-specific T-cells
were also detected in the liver, skin and lungs, which
are the most commonly affected organs in DRESS
patients. Interestingly, we also showed that the culprit
drug was able to promote viral reactivation [42]. In this
respect, re-activation of herpesvirus followed by broad,
uncontrolled anti-viral T-cell responses that lead to a
state of generalized inflammation (with associated organ
failure), may be a unique feature of DRESS. Indeed,
evidence of herpesvirus re-activation during SJS and
TEN is still a matter of debate [43,44]. Further investi-
gation will now be required to elucidate the nature of the
drug-specific T-cell response in DRESS patients, and to
better understand the influence of drugs on the course of
human anti-viral immune responses. Intriguingly, since
DRESS induces inflammation, this syndrome can also
promote the expansion of regulatory T-cell populations
(T-reg) [45] that are susceptible to infection by viruses
such as HHV-6 [46]. Altered function of virus-infected T-
reg may therefore contribute to the dysregulated immune
response observed in DRESS.
Toward a unified theory of DRESS
pathogenesis?
Sulfamethoxazole (SMX) is an antibiotic which can be
processed into the metabolite N-acetyl-SMX by the
enzymes cytochrome P450 [47] and myeloperoxidase
[48] in detoxification organs. While the bulk of N-
acetyl-SMX is excreted in urine, a small part is further
metabolized into SMX-hydroxylamine (SMX-HA) which
can autoxidize to form SMX-NO and stimulate immune
cells [49]. In 2009, a study from Lavergne et al. showed
that ‘danger signals’ can lead to an increase in protein-
SMX adducts in peripheral blood mononuclear cells and
dendritic cells [50], revealing an alternative route by
which DRESS could be induced in drug-treated patients.
Under these conditions, SMX-NO binds preferentially to
732 Allergy and hypersensitivity
Current Opinion in Immunology 2012, 24:730–735 www.sciencedirect.com
4. cysteine residues, and Callan et al. showed that optimal
binding was obtained when those amino acids were oxi-
dized as sulfenic acids [51]. Several factors have been
shown to modify cysteine oxidation levels, including oxi-
dative stress and various pathological conditions [50,52,53].
By mimicking several pathogenic conditions in turn (using
lipopolysaccharides, staphylococcal enterotoxin B, and
inactivated H2N2 flu virus), Lavergne et al. showed that
key cytokines involved in the induction of immunological
stress (IL-1b, IL-6, IFN-g, TNF-a) or mediators of inflam-
mation and hyperthermia (prostaglandin E2, activated
protein C and human serum complement) promote
accumulation of oxidized cysteines and thus an increase
in adduct formation. In vivo, ‘danger’ signals such as these
may well be expressed following the re-activation of
endogenous viruses, leading to increased cysteine oxi-
dation and accompanying adduct formation. This
sequence of events could also explain why HIV patients
receiving tritherapy are particularly susceptible to devel-
opment of DE, since ongoing inflammation in these
patients coupled with the daily administration of drugs
may facilitate adduct formation. It is thus increasingly clear
that the hapten model, p-i concept and viral hypothesis can
be unified into a single model of DE pathogenesis that is
critically influenced by patient HLA type.
Conclusion
Despite considerable advances in our understanding of the
mechanisms that promote DRESS, many unanswered
questions remain regarding the pathogenesis of this syn-
drome. Critically, the relative scarcity of DRESS cannot be
explained by existing data. Virtually all human adults have
been infected by several herpesviruses, and all HLA hap-
lotypes are capable of binding to drug metabolites and
haptenated peptides. We hypothesize that the location and
orientation of hapten binding is an important determinant
of DRESS susceptibility, or alternatively, that only rare
drug-modified peptides are capable of eliciting a T-cell
response. In addition, future studies will need to evaluate
DRESS Camous et al. 733
Figure 2
CLA4+
CCR4
CCR10
Cutaneous eruption
Antiviral response
B cell
HLA-I
EBV-specific
CD8 T cells
IFNγ
TNFα
Drug
T cell
TCR
Virus
production
Systemic
effects
Antidrug response
T cell
Naïve B cells Dendritic cells Monocytes Keratinocytes
EBV virus
Current Opinion in Immunology
DRESS pathogenesis. In this model, drugs re-activate EBV within the B cell reservoir. Virus re-activation increases MHC presentation of virus peptides
to EBV-specific memory T-cells, which provides the necessary co-stimulation for activation of drug-specific T-cells by the same antigen presenting
cell. Cytolysis then releases new virions to infect nearby host cells and further stimulate EBV-specific T-cell responses, thereby establishing a pro-
inflammatory environment which supports the activation of additional drug-specific T-cell clones. This sequence of events will gradually generate a
‘cytokine storm’ which leads to the systemic effects observed in DRESS patients.
www.sciencedirect.com Current Opinion in Immunology 2012, 24:730–735
5. the influence of drug metabolites and drug-specific T-cells
responses on anti-viral immunity in treated patients.
Acknowledgement
We thank Neil McCarthy of Insight Editing London for proof-reading the
manuscript.
References and recommended reading
Papers of particular interest, published within the period of review,
have been highlighted as:
of special interest
of outstanding interest
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