Pub Date : 2024-01-02eCollection Date: 2023-01-01DOI: 10.48101/ujms.v128.10241
Kajsa Björner, Wei-Na Chen, Venkata Ram Gannavarapu, Fredrik Axling, Miklos Gulyas, Mohammad Abdul Halim, Dominic-Luc Webb, Per M Hellström
Background: Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn's disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown.
Aim: The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC.
Methods: Immunohistochemistry was performed on tissue sections as follows: CAC (n = 59); sporadic CRC (sCRC) (n = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (n = 22); paracancerous IBD (pIBD) (n = 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases.
Results: Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (P < 0.01) and IL-1β (P < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (P < 0.001), whereas IL-1β was higher (P < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases.
Conclusion: Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward.
{"title":"High iNOS and IL-1β immunoreactivity are features of colitis-associated colorectal cancer tumors, but fail to predict 5-year survival.","authors":"Kajsa Björner, Wei-Na Chen, Venkata Ram Gannavarapu, Fredrik Axling, Miklos Gulyas, Mohammad Abdul Halim, Dominic-Luc Webb, Per M Hellström","doi":"10.48101/ujms.v128.10241","DOIUrl":"10.48101/ujms.v128.10241","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory bowel disease (IBD; mainly ulcerative colitis and Crohn's disease) is associated with the development of colorectal cancer (CRC) referred to as colitis-associated colorectal cancer (CAC). In inflammatory flares of IBD, the production of luminal nitric oxide (NO) increases due to the increased inducible nitric oxide synthase (iNOS) activity in inflamed tissue. It is believed that iNOS parallels pro-inflammatory interleukin-1β (IL-1β). How these biomarkers relate to CAC pathogenesis or survival is unknown.</p><p><strong>Aim: </strong>The primary aim of this study was to investigate iNOS and IL-1β immunoreactivity in CAC tumors in comparison with CRC and normal colonic mucosa, and the secondary aim was to determine if immunoreactivity correlates with 5-year survival of CAC.</p><p><strong>Methods: </strong>Immunohistochemistry was performed on tissue sections as follows: CAC (<i>n</i> = 59); sporadic CRC (sCRC) (<i>n</i> = 12); colonic mucosa >2 cm outside sCRC margin (normal mucosa) (<i>n =</i> 22); paracancerous IBD (pIBD) (<i>n =</i> 12). The expression of iNOS and IL-1β was quantified separately for epithelium and stroma. Data were evaluated using the Mann-Whitney U-test and the log-rank test for 5-year Kaplan-Meier survival curves. Results were compared with online mRNA databases.</p><p><strong>Results: </strong>Immunoreactivity occurred predominantly in epithelial cells and to lesser extent in stroma. Compared with normal mucosa, immunoreactivity for iNOS (<i>P</i> < 0.01) and IL-1β (<i>P</i> < 0.005) was higher in CAC epithelium. In CAC stroma, iNOS immunoreactivity was lower than normal mucosa (<i>P</i> < 0.001), whereas IL-1β was higher (<i>P</i> < 0.05). Immunoreactivity differences of iNOS or IL-1β among CAC patients failed to correlate with 5-year survival. These findings were supported by online mRNA databases.</p><p><strong>Conclusion: </strong>Consistent with high NO production in IBD, there is more iNOS in CAC epithelium, albeit not in stroma. This immunoreactivity difference exists for IL-1β in both epithelium and stroma. The intervention of arginine or iNOS activity for CAC chemotherapy is not straightforward.</p>","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"28 ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10770641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139378250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-31eCollection Date: 2023-01-01DOI: 10.48101/ujms.v128.10033
Karl-Mikael Kälkner, Anders Sundström, Maria Juhasz Haverinen, Kenneth Nordback, Veronica Arthurson, Björn Zethelius, Rickard Ljung
Background: Chloroquine and hydroxychloroquine (C/HC) received considerable international media attention due to anticipated treatment effect in COVID-19. This led to increased prescriptions threatening to generate product shortages for patients prescribed within approved indications.We evaluated effects of a temporary regulation mandating pharmacies to only dispense C/HC prescribed by physicians with defined specialties.
Methods: Data from Region Stockholm, which include 2.4 out of 10 million Sweden's population, were used. Weekly time trends of prescriptions and requisitions of C/HC by prescriber's workplace during January to April 2020 were followed.
Results: Numbers of unique individuals with filled prescriptions of chloroquine increased tenfold and of hydroxychloroquine more than threefold from January to March. In the first week of April, filled prescriptions of C/HC dropped. In the later weeks of April, the number of filled prescriptions was back at similar levels as before the SARS-CoV-2 outbreak.During January and February, specialists in rheumatology accounted for 686 out of all 979 prescriptions dispensed (70.1%) of C/HC. In March, a large proportion of prescriptions dispensed were from specialists not usually prescribing C/HC, and rheumatology accounted for 628 out of all 1,639 prescriptions (38.3%). In April, specialists in rheumatology accounted for 386 out of all 641 prescriptions dispensed (60.0%).
Conclusion: After an observed increase in prescriptions of C/HC, a temporary regulation was introduced on 2nd April 2020 to reduce prescriptions from specialists not usually prescribing C/HC to avoid shortages for patients within approved indications. Subsequently, dispensed prescriptions decreased from April and remained at pre-COVID-19 levels thereafter.
{"title":"A temporary regulation to manage an impending shortage due to extraordinary prescribing patterns of chloroquines observed during early phase of COVID-19 epidemic.","authors":"Karl-Mikael Kälkner, Anders Sundström, Maria Juhasz Haverinen, Kenneth Nordback, Veronica Arthurson, Björn Zethelius, Rickard Ljung","doi":"10.48101/ujms.v128.10033","DOIUrl":"10.48101/ujms.v128.10033","url":null,"abstract":"<p><strong>Background: </strong>Chloroquine and hydroxychloroquine (C/HC) received considerable international media attention due to anticipated treatment effect in COVID-19. This led to increased prescriptions threatening to generate product shortages for patients prescribed within approved indications.We evaluated effects of a temporary regulation mandating pharmacies to only dispense C/HC prescribed by physicians with defined specialties.</p><p><strong>Methods: </strong>Data from Region Stockholm, which include 2.4 out of 10 million Sweden's population, were used. Weekly time trends of prescriptions and requisitions of C/HC by prescriber's workplace during January to April 2020 were followed.</p><p><strong>Results: </strong>Numbers of unique individuals with filled prescriptions of chloroquine increased tenfold and of hydroxychloroquine more than threefold from January to March. In the first week of April, filled prescriptions of C/HC dropped. In the later weeks of April, the number of filled prescriptions was back at similar levels as before the SARS-CoV-2 outbreak.During January and February, specialists in rheumatology accounted for 686 out of all 979 prescriptions dispensed (70.1%) of C/HC. In March, a large proportion of prescriptions dispensed were from specialists not usually prescribing C/HC, and rheumatology accounted for 628 out of all 1,639 prescriptions (38.3%). In April, specialists in rheumatology accounted for 386 out of all 641 prescriptions dispensed (60.0%).</p><p><strong>Conclusion: </strong>After an observed increase in prescriptions of C/HC, a temporary regulation was introduced on 2nd April 2020 to reduce prescriptions from specialists not usually prescribing C/HC to avoid shortages for patients within approved indications. Subsequently, dispensed prescriptions decreased from April and remained at pre-COVID-19 levels thereafter.</p>","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"128 ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10770639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139378249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-21DOI: 10.48101/ujms.v128.10312
Ebba Sivertsson, Amanda Balboa, Tomas A. Schiffer, P. Hansell, M. Friederich‐Persson, P. Persson, Fredrik Palm
Background: Intrarenal hypoxia has been suggested a unifying pathway to chronic kidney disease (CKD) and increased mitochondria leak respiration, which increases mitochondrial oxygen usage and is one important mechanism contributing to the development of the hypoxia. Previous studies indicate that angiotensin II (Ang II) effects on mitochondria function could be dose dependent. We investigated how moderate and high levels of Ang II affect kidney mitochondria function and pathways of leak respiration. Methods: C57 black 6 mice were treated with either vehicle or Ang II in low dose (400 ng/kg/min) or high dose (1,000 ng/kg/min) for 4 weeks. The function of kidney cortex mitochondria was measured by high-resolution respirometry. Ang II effects on gene expression in kidney tissue were measured by quantitative real-time PCR. Thiobarbituric acids reactive substances were determined as a marker of oxidative stress, and urinary protein excretion was measured as a maker of kidney injury. Results: Low-dose Ang II induced overall mitochondria respiration, without compromising capacity of ATP production. Mitochondrial leak respiration was increased, and levels of oxidative stress were unchanged. However, high-dose Ang II decreased overall mitochondria respiration and reduced mitochondrial capacity for ATP production. Mitochondrial leak respiration was decreased, and oxidative stress increased in kidney tissue. Furthermore, gene expression of mediators that stimulate vasoconstriction and ROS production was increased, while components of counteracting pathways were decreased. Conclusions: In conclusion, Ang II dose-dependently affects mitochondrial function and leak respiration. Thus, Ang II has the potential to directly affect cellular metabolism during conditions of altered Ang II signaling.
背景:肾小球内缺氧被认为是慢性肾脏病(CKD)的一个统一途径,线粒体漏式呼吸增加,线粒体耗氧量增加,是导致缺氧发生的一个重要机制。先前的研究表明,血管紧张素 II(Ang II)对线粒体功能的影响可能与剂量有关。我们研究了中等和高浓度的 Ang II 如何影响肾脏线粒体功能和泄漏呼吸途径。研究方法用低剂量(400 纳克/千克/分钟)或高剂量(1,000 纳克/千克/分钟)的药物或 Ang II 治疗 C57 black 6 小鼠 4 周。通过高分辨率呼吸测定法测量肾皮质线粒体的功能。血管紧张素 II 对肾脏组织基因表达的影响通过实时定量 PCR 进行测量。测定硫代巴比妥酸活性物质作为氧化应激的标志,测定尿蛋白排泄量作为肾损伤的标志。结果小剂量 Ang II 可诱导线粒体的整体呼吸,但不影响 ATP 的生成能力。线粒体漏呼吸增加,氧化应激水平保持不变。然而,大剂量 Ang II 降低了线粒体的整体呼吸,并降低了线粒体产生 ATP 的能力。在肾组织中,线粒体泄漏呼吸减少,氧化应激增加。此外,刺激血管收缩和 ROS 生成的介质基因表达增加,而抵消途径的成分减少。结论总之,Ang II 会对线粒体功能和泄漏呼吸产生剂量依赖性影响。因此,在 Ang II 信号改变的条件下,Ang II 有可能直接影响细胞代谢。
{"title":"Dose-dependent regulation of kidney mitochondrial function by angiotensin II","authors":"Ebba Sivertsson, Amanda Balboa, Tomas A. Schiffer, P. Hansell, M. Friederich‐Persson, P. Persson, Fredrik Palm","doi":"10.48101/ujms.v128.10312","DOIUrl":"https://doi.org/10.48101/ujms.v128.10312","url":null,"abstract":"Background: Intrarenal hypoxia has been suggested a unifying pathway to chronic kidney disease (CKD) and increased mitochondria leak respiration, which increases mitochondrial oxygen usage and is one important mechanism contributing to the development of the hypoxia. Previous studies indicate that angiotensin II (Ang II) effects on mitochondria function could be dose dependent. We investigated how moderate and high levels of Ang II affect kidney mitochondria function and pathways of leak respiration. \u0000Methods: C57 black 6 mice were treated with either vehicle or Ang II in low dose (400 ng/kg/min) or high dose (1,000 ng/kg/min) for 4 weeks. The function of kidney cortex mitochondria was measured by high-resolution respirometry. Ang II effects on gene expression in kidney tissue were measured by quantitative real-time PCR. Thiobarbituric acids reactive substances were determined as a marker of oxidative stress, and urinary protein excretion was measured as a maker of kidney injury. \u0000Results: Low-dose Ang II induced overall mitochondria respiration, without compromising capacity of ATP production. Mitochondrial leak respiration was increased, and levels of oxidative stress were unchanged. However, high-dose Ang II decreased overall mitochondria respiration and reduced mitochondrial capacity for ATP production. Mitochondrial leak respiration was decreased, and oxidative stress increased in kidney tissue. Furthermore, gene expression of mediators that stimulate vasoconstriction and ROS production was increased, while components of counteracting pathways were decreased. \u0000Conclusions: In conclusion, Ang II dose-dependently affects mitochondrial function and leak respiration. Thus, Ang II has the potential to directly affect cellular metabolism during conditions of altered Ang II signaling.","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"8 4","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138948568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Movérare, Eilif Persson, A. Malinovschi, Christer Janson
Background Total immunoglobulin E (IgE) analysis is a common tool in allergy diagnosis. Suggested reference values for IgE are divergent and sometimes based on outdated assay methods. We aimed to validate the published reference values (geometric mean [GM]: 13.2 kU/L, upper limit of normal [ULN], 114 kU/L) shown in an Uppsala cohort from 1974 using Phadebas IgE PRIST, and the suggested clinical threshold of 100 kU/L (Zetterström and Johansson 1981). Methods Immunoglobulin E was measured in two Uppsala cohorts from 1997 (Blood bank) and 2011 to 2013 (the European community respiratory health survey part III [ECRHS III]) using ImmunoCAP™ Total IgE. For the reference value calculations, exclusion criteria were atopy (both cohorts), doctor’s diagnosis of asthma and self-reported allergy (hay fever, rhinitis, rash) (only ECRHS III). Upper limit of normal was defined as mean + 2 standard deviations (SD) calculated using log-transformed values and back-transformation of the ULN prior to presentation. Common imputation methods for results below the assay range were evaluated. Results The average GM was 14.2 kU/L (Blood bank, n = 63; imputation method range: 16.9–17.4 kU/L; ECRHS III, n = 113: 10.7–11.6 kU/L) and the overall mean ULN was 118 kU/L (Blood bank: 113–130 kU/L; ECRHS III: 104–128 kU/L). The clinical sensitivity and specificity of the 100 kU/L IgE threshold were 37.8 and 94.3% for atopy, 34.9 and 89.5% for doctor’s diagnosis of asthma, and 24.5 and 97.3% for any self-reported allergy (ECRHS III). Conclusion The calculated ULN values were similar between the cohorts. We conclude that the total IgE reference values shown for Uppsala subjects from 1974 are still valid and suitable also for the ImmunoCAP Total IgE assay. The 100 kU/L threshold for total IgE had a low sensitivity but high specificity for atopy, asthma, and allergy.
{"title":"Reference values of serum total IgE in Uppsala – comparison over four decades","authors":"R. Movérare, Eilif Persson, A. Malinovschi, Christer Janson","doi":"10.48101/ujms.v128.9892","DOIUrl":"https://doi.org/10.48101/ujms.v128.9892","url":null,"abstract":"Background Total immunoglobulin E (IgE) analysis is a common tool in allergy diagnosis. Suggested reference values for IgE are divergent and sometimes based on outdated assay methods. We aimed to validate the published reference values (geometric mean [GM]: 13.2 kU/L, upper limit of normal [ULN], 114 kU/L) shown in an Uppsala cohort from 1974 using Phadebas IgE PRIST, and the suggested clinical threshold of 100 kU/L (Zetterström and Johansson 1981). Methods Immunoglobulin E was measured in two Uppsala cohorts from 1997 (Blood bank) and 2011 to 2013 (the European community respiratory health survey part III [ECRHS III]) using ImmunoCAP™ Total IgE. For the reference value calculations, exclusion criteria were atopy (both cohorts), doctor’s diagnosis of asthma and self-reported allergy (hay fever, rhinitis, rash) (only ECRHS III). Upper limit of normal was defined as mean + 2 standard deviations (SD) calculated using log-transformed values and back-transformation of the ULN prior to presentation. Common imputation methods for results below the assay range were evaluated. Results The average GM was 14.2 kU/L (Blood bank, n = 63; imputation method range: 16.9–17.4 kU/L; ECRHS III, n = 113: 10.7–11.6 kU/L) and the overall mean ULN was 118 kU/L (Blood bank: 113–130 kU/L; ECRHS III: 104–128 kU/L). The clinical sensitivity and specificity of the 100 kU/L IgE threshold were 37.8 and 94.3% for atopy, 34.9 and 89.5% for doctor’s diagnosis of asthma, and 24.5 and 97.3% for any self-reported allergy (ECRHS III). Conclusion The calculated ULN values were similar between the cohorts. We conclude that the total IgE reference values shown for Uppsala subjects from 1974 are still valid and suitable also for the ImmunoCAP Total IgE assay. The 100 kU/L threshold for total IgE had a low sensitivity but high specificity for atopy, asthma, and allergy.","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"40 9","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138588489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-08DOI: 10.48101/ujms.v128.10281
Lee Ti Davidson
Nitrous oxide, commonly known as ‘laughing gas’, has become a popular recreational drug. Whippets, small canisters containing gas in pressurized form, can be easily obtained from a food store. However, inhaling nitrous oxide from these canisters, which contain a 100% concentration, can lead to hypoxia, resulting in seizures or even death. Inhalation of nitrous oxide rarely causes pneumothorax, pneumomediastinum, and pneumopericardium. This case study highlights the potential dangers of recreational abuse of nitrous oxide.
{"title":"Recreational use of nitrous oxide causes seizure, pneumothorax, pneumomediastinum, and pneumopericardium: nitrous oxide and its harm, a case report","authors":"Lee Ti Davidson","doi":"10.48101/ujms.v128.10281","DOIUrl":"https://doi.org/10.48101/ujms.v128.10281","url":null,"abstract":"Nitrous oxide, commonly known as ‘laughing gas’, has become a popular recreational drug. Whippets, small canisters containing gas in pressurized form, can be easily obtained from a food store. However, inhaling nitrous oxide from these canisters, which contain a 100% concentration, can lead to hypoxia, resulting in seizures or even death. Inhalation of nitrous oxide rarely causes pneumothorax, pneumomediastinum, and pneumopericardium. This case study highlights the potential dangers of recreational abuse of nitrous oxide.","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"24 8","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138589925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-28eCollection Date: 2023-01-01DOI: 10.48101/ujms.v128.10316
Lars Lannfelt
Recent advances have driven the development of immunotherapies that act by either promoting or suppressing a patient's immune system to treat inflammation, autoimmune disease, cardiovascular disease, infectious diseases, and several cancers. In addition, research conducted over the past 25 years has identified therapeutic targets and indicated that immunotherapy could be used to treat Alzheimer's disease (AD). Despite a number of setbacks, this approach has now led to the development of the first disease-modifying treatments for this devastating disease. A key neuropathological feature of AD is the accumulation of a ~40-amino acid peptide known as amyloid β (Aβ) in the brain and cerebrovasculature. Our detection of an Aβ precursor protein mutation that caused early-onset AD in a Swedish family by enhancing Aβ protofibril formation sharpened the focus on soluble Aβ aggregates (oligomers and protofibrils) as viable therapeutic targets. Initial studies developed and tested a mouse monoclonal antibody (mAb158) with specific conformation-dependent binding to these soluble Aβ aggregates. Treatment with mAb158 selectively reduced Aβ protofibrils in the brain and cerebrospinal fluid of a transgenic mouse model of AD. A humanized version of mAb158 (lecanemab) subsequently entered clinical trials. Based on promising Phase 2 data showing plaque clearance and reduced cognitive decline, a Phase 3 trial found that lecanemab slowed decline on the primary cognitive endpoint by 27% over 18 months and also produced positive effects on secondary clinical endpoints and key biomarkers. In July 2023, the FDA granted lecanemab a full approval, and this therapeutic antibody will be marketed as Leqembi®. This represents a significant advance for patients with AD, although many challenges remain. In particular, it is now more important than ever to identify individuals who are vulnerable to AD, so that treatment can be initiated at an early stage in the disease process.
{"title":"A light at the end of the tunnel - from mutation identification to a potential treatment for Alzheimer's disease.","authors":"Lars Lannfelt","doi":"10.48101/ujms.v128.10316","DOIUrl":"https://doi.org/10.48101/ujms.v128.10316","url":null,"abstract":"<p><p>Recent advances have driven the development of immunotherapies that act by either promoting or suppressing a patient's immune system to treat inflammation, autoimmune disease, cardiovascular disease, infectious diseases, and several cancers. In addition, research conducted over the past 25 years has identified therapeutic targets and indicated that immunotherapy could be used to treat Alzheimer's disease (AD). Despite a number of setbacks, this approach has now led to the development of the first disease-modifying treatments for this devastating disease. A key neuropathological feature of AD is the accumulation of a ~40-amino acid peptide known as amyloid β (Aβ) in the brain and cerebrovasculature. Our detection of an Aβ precursor protein mutation that caused early-onset AD in a Swedish family by enhancing Aβ protofibril formation sharpened the focus on soluble Aβ aggregates (oligomers and protofibrils) as viable therapeutic targets. Initial studies developed and tested a mouse monoclonal antibody (mAb158) with specific conformation-dependent binding to these soluble Aβ aggregates. Treatment with mAb158 selectively reduced Aβ protofibrils in the brain and cerebrospinal fluid of a transgenic mouse model of AD. A humanized version of mAb158 (lecanemab) subsequently entered clinical trials. Based on promising Phase 2 data showing plaque clearance and reduced cognitive decline, a Phase 3 trial found that lecanemab slowed decline on the primary cognitive endpoint by 27% over 18 months and also produced positive effects on secondary clinical endpoints and key biomarkers. In July 2023, the FDA granted lecanemab a full approval, and this therapeutic antibody will be marketed as Leqembi®. This represents a significant advance for patients with AD, although many challenges remain. In particular, it is now more important than ever to identify individuals who are vulnerable to AD, so that treatment can be initiated at an early stage in the disease process.</p>","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"128 ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10710852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138809772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-22eCollection Date: 2023-01-01DOI: 10.48101/ujms.v128.9888
Hans J Arnqvist, Per Leanderson, Anna Spångeus
Background: Patients with type 1 diabetes have a high prevalence of upper extremity impairments (UEIs), such as frozen shoulder, carpal tunnel syndrome, and trigger finger. The UEIs are strongly associated with activity limitations and impaired quality of life. The etiology of the UEI is not clear. Vitamin D deficiency has been considered to play a role in the pathogenesis of type 1 diabetes and in the development of macro- and microvascular complications in diabetes.
Aim: To characterize vitamin D status in a large population of patients with type 1 diabetes, if vitamin D deficiency is associated with metabolic factors and possible association with UEI.
Material and methods: Patients who diagnosed before 35 years of age, whose diabetes duration >20 years, and who are not older than 65 years were invited to participate in this cross-sectional case-control, multicenter study. Controls matched for age and sex were obtained from the national population registry. Fasting blood samples were collected and stored at -80°C until analyzed regarding 25-hydroxy-vitamin D (25(OH)D3) by a liquid chromatographic-mass spectrometric method (LC-MS/MS).
Results: Vitamin D levels varied with season as expected in the northern hemisphere. The association between 25(OH)D3 and clinical variables was analyzed in a univariate general linear model, which indicated no difference in 25(OH)D3 in men with and without diabetes but higher values in women with diabetes. About 30% of both patients and controls had vitamin D deficiency (≤50 nmol/L). Analyzed by binary logistic regression UEIs was not associated with 25(OH)D3 levels. In both patients and controls, 25(OH)D3 was correlated to apolipoprotein A1 (r = 0.153; 0.220, P < 0.001).
Conclusion: In patients with type 1 diabetes and a duration of 20 years or more, vitamin D level is not lower than in nondiabetic controls and is not associated with UEIs.
{"title":"Vitamin D status in longstanding type 1 diabetes and controls. Association with upper extremity impairments.","authors":"Hans J Arnqvist, Per Leanderson, Anna Spångeus","doi":"10.48101/ujms.v128.9888","DOIUrl":"10.48101/ujms.v128.9888","url":null,"abstract":"<p><strong>Background: </strong>Patients with type 1 diabetes have a high prevalence of upper extremity impairments (UEIs), such as frozen shoulder, carpal tunnel syndrome, and trigger finger. The UEIs are strongly associated with activity limitations and impaired quality of life. The etiology of the UEI is not clear. Vitamin D deficiency has been considered to play a role in the pathogenesis of type 1 diabetes and in the development of macro- and microvascular complications in diabetes.</p><p><strong>Aim: </strong>To characterize vitamin D status in a large population of patients with type 1 diabetes, if vitamin D deficiency is associated with metabolic factors and possible association with UEI.</p><p><strong>Material and methods: </strong>Patients who diagnosed before 35 years of age, whose diabetes duration >20 years, and who are not older than 65 years were invited to participate in this cross-sectional case-control, multicenter study. Controls matched for age and sex were obtained from the national population registry. Fasting blood samples were collected and stored at -80°C until analyzed regarding 25-hydroxy-vitamin D (25(OH)D3) by a liquid chromatographic-mass spectrometric method (LC-MS/MS).</p><p><strong>Results: </strong>Vitamin D levels varied with season as expected in the northern hemisphere. The association between 25(OH)D3 and clinical variables was analyzed in a univariate general linear model, which indicated no difference in 25(OH)D3 in men with and without diabetes but higher values in women with diabetes. About 30% of both patients and controls had vitamin D deficiency (≤50 nmol/L). Analyzed by binary logistic regression UEIs was not associated with 25(OH)D3 levels. In both patients and controls, 25(OH)D3 was correlated to apolipoprotein A1 (<i>r</i> = 0.153; 0.220, <i>P</i> < 0.001).</p><p><strong>Conclusion: </strong>In patients with type 1 diabetes and a duration of 20 years or more, vitamin D level is not lower than in nondiabetic controls and is not associated with UEIs.</p>","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"128 ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10710851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138809802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-13eCollection Date: 2023-01-01DOI: 10.48101/ujms.v128.9805
Edvin Svedberg, Curt Ekström
Background: Increased cup-disc ratio (CDR) is a hallmark of open-angle glaucoma (OAG), an age-related neurodegenerative disease of significant importance for public health. There are few studies on the distribution of CDR in the Nordic populations.
Methods: The distribution of CDR was studied in 749 subjects aged 65-74 years in a population survey in the rural district of Tierp, Sweden, from 1984 to 86. The optic discs were assessed with binocular ophthalmoscopy at a slit lamp. Drawings of the discs were made in the protocol and used for the calculation of vertical CDRs. Odds ratios, adjusted for age and sex, according to Mantel-Haenszel (ORMH), were determined to estimate predictors of increased CDR, defined as a ratio in the upper quartile. For these analyses, the eye with the most advanced OAG or the highest pressure was chosen. Automated perimetry was used to identify OAG.
Results: The distribution of vertical CDR was fairly close to that of other European-derived populations. The mean CDR was 0.45 in both eyes, with no difference between women and men. An increased ratio was associated with the age ≥70 years, a positive family history of OAG and intraocular pressure ≥20 mmHg. OAG increased the risk 8-fold (ORMH 8.06; 95% CI 4.12-15.8).
Conclusions: In this study, the distribution of CDR was fairly close to that of other European-derived populations. As expected, OAG increased the risk of having a CDR in the upper quartile. The CDR increased with age.
{"title":"Distribution of cup-disc ratio in a Swedish population.","authors":"Edvin Svedberg, Curt Ekström","doi":"10.48101/ujms.v128.9805","DOIUrl":"10.48101/ujms.v128.9805","url":null,"abstract":"<p><strong>Background: </strong>Increased cup-disc ratio (CDR) is a hallmark of open-angle glaucoma (OAG), an age-related neurodegenerative disease of significant importance for public health. There are few studies on the distribution of CDR in the Nordic populations.</p><p><strong>Methods: </strong>The distribution of CDR was studied in 749 subjects aged 65-74 years in a population survey in the rural district of Tierp, Sweden, from 1984 to 86. The optic discs were assessed with binocular ophthalmoscopy at a slit lamp. Drawings of the discs were made in the protocol and used for the calculation of vertical CDRs. Odds ratios, adjusted for age and sex, according to Mantel-Haenszel (OR<sub>MH</sub>), were determined to estimate predictors of increased CDR, defined as a ratio in the upper quartile. For these analyses, the eye with the most advanced OAG or the highest pressure was chosen. Automated perimetry was used to identify OAG.</p><p><strong>Results: </strong>The distribution of vertical CDR was fairly close to that of other European-derived populations. The mean CDR was 0.45 in both eyes, with no difference between women and men. An increased ratio was associated with the age ≥70 years, a positive family history of OAG and intraocular pressure ≥20 mmHg. OAG increased the risk 8-fold (OR<sub>MH</sub> 8.06; 95% CI 4.12-15.8).</p><p><strong>Conclusions: </strong>In this study, the distribution of CDR was fairly close to that of other European-derived populations. As expected, OAG increased the risk of having a CDR in the upper quartile. The CDR increased with age.</p>","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"128 ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10619472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71427253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-11eCollection Date: 2023-01-01DOI: 10.48101/ujms.v128.9807
Lisa Faxén, Marie Edvinsson
Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunocompromised patients remains a major medical challenge. Diagnosing the syndrome is difficult as symptoms may mimic other diseases and treatment guidelines are lacking. We describe a case series of four patients with persistent SARS-CoV-2 infection that all had an underlying B-cell deficiency due to rituximab treatment (in one case in combination with epcoritamab). In all four patients, it was initially difficult to recognize the persistent disease, leading to a duration of illness between 45 and 242 days. Two patients were only positive for SARS-CoV-2 by polymerase chain reaction (PCR) in the nasopharynx at the beginning of the disease but were later repeatedly negative. However, when bronchoalveolar lavage was performed, a positive SARS-CoV-2 PCR was revealed from the lower airways in both patients. The difficulties establishing diagnosis contributed to these two patients' long disease course. The longest disease duration was in the patient treated with rituximab and epcoritamab, who also responded poorly to single standard antiviral treatment. This patient ultimately cleared the infection after administering a combination treatment with remdesivir and nirmatrelvir/ritonavir. After a confirmed diagnosis, the other three patients cleared the infection when they were finally treated with antivirals. Increasing clinicians' awareness of this condition is important as it might be treatable once diagnosed. Further studies are warranted to define the condition and treatment strategy with greater precision.
{"title":"Persistent SARS-CoV-2 infection in patients with B-cell deficiency: a case series of successful antiviral treatment of four patients.","authors":"Lisa Faxén, Marie Edvinsson","doi":"10.48101/ujms.v128.9807","DOIUrl":"10.48101/ujms.v128.9807","url":null,"abstract":"<p><p>Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunocompromised patients remains a major medical challenge. Diagnosing the syndrome is difficult as symptoms may mimic other diseases and treatment guidelines are lacking. We describe a case series of four patients with persistent SARS-CoV-2 infection that all had an underlying B-cell deficiency due to rituximab treatment (in one case in combination with epcoritamab). In all four patients, it was initially difficult to recognize the persistent disease, leading to a duration of illness between 45 and 242 days. Two patients were only positive for SARS-CoV-2 by polymerase chain reaction (PCR) in the nasopharynx at the beginning of the disease but were later repeatedly negative. However, when bronchoalveolar lavage was performed, a positive SARS-CoV-2 PCR was revealed from the lower airways in both patients. The difficulties establishing diagnosis contributed to these two patients' long disease course. The longest disease duration was in the patient treated with rituximab and epcoritamab, who also responded poorly to single standard antiviral treatment. This patient ultimately cleared the infection after administering a combination treatment with remdesivir and nirmatrelvir/ritonavir. After a confirmed diagnosis, the other three patients cleared the infection when they were finally treated with antivirals. Increasing clinicians' awareness of this condition is important as it might be treatable once diagnosed. Further studies are warranted to define the condition and treatment strategy with greater precision.</p>","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"128 ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41238906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-09-15eCollection Date: 2023-01-01DOI: 10.48101/ujms.v128.9785
Muhammad Naeem, Till Ittermann, Marcello Ricardo Paulista Markus, Mohammed Farah Mahmoud Mousa, Laura von Heder, Robin Bülow, Marcus Dörr, Matthias Nauck, Ali Agdassi, Florian H Heidel, Henry Völzke
Background: The aim of our study was to investigate associations of spleen volume with blood count markers and lipid profile in the general population.
Materials & methods: Cross-sectional data from 1,106 individuals aged 30-90 years from the population-based Study of Health in Pomerania (SHIP-START-2) were analyzed. Blood count markers included red blood cell (RBC) counts, hemoglobin, platelet count, and white blood cell (WBC) counts. Lipid profile included total-cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) as well as triglycerides. Linear regression models adjusted for age, sex, body height, and weight were used to associate standardized spleen volume with blood counts and lipid profile markers.
Results: Spleen volume was positively associated with RBC (β = 0.05; 95% confidence interval [CI] = 0.03 to 0.08) and hemoglobin (β = 0.05; 95% CI = 0.01 to 0.09) but inversely with platelet count (β = -16.3; 95% CI = -20.5 to -12.1) and WBC (β = -0.25; 95% CI = -0.37 to -0.14). Furthermore, spleen volume showed inverse associations with total cholesterol (β = -0.17; 95% CI = -0.24 to -0.09), HDL-C (β = -0.08; 95% CI = -0.10 to -0.05), and LDL-C (β = -0.12; 95% CI = -0.17 to -0.06). There was no significant association of spleen volume with triglycerides.
Conclusion: Our study showed that the spleen volume is associated with markers of the blood count and lipid profile in the general population.
{"title":"Associations of spleen volume with markers of blood count and lipid profile in a large population-based study.","authors":"Muhammad Naeem, Till Ittermann, Marcello Ricardo Paulista Markus, Mohammed Farah Mahmoud Mousa, Laura von Heder, Robin Bülow, Marcus Dörr, Matthias Nauck, Ali Agdassi, Florian H Heidel, Henry Völzke","doi":"10.48101/ujms.v128.9785","DOIUrl":"10.48101/ujms.v128.9785","url":null,"abstract":"<p><strong>Background: </strong>The aim of our study was to investigate associations of spleen volume with blood count markers and lipid profile in the general population.</p><p><strong>Materials & methods: </strong>Cross-sectional data from 1,106 individuals aged 30-90 years from the population-based Study of Health in Pomerania (SHIP-START-2) were analyzed. Blood count markers included red blood cell (RBC) counts, hemoglobin, platelet count, and white blood cell (WBC) counts. Lipid profile included total-cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) as well as triglycerides. Linear regression models adjusted for age, sex, body height, and weight were used to associate standardized spleen volume with blood counts and lipid profile markers.</p><p><strong>Results: </strong>Spleen volume was positively associated with RBC (<i>β</i> = 0.05; 95% confidence interval [CI] = 0.03 to 0.08) and hemoglobin (β = 0.05; 95% CI = 0.01 to 0.09) but inversely with platelet count (β = -16.3; 95% CI = -20.5 to -12.1) and WBC (β = -0.25; 95% CI = -0.37 to -0.14). Furthermore, spleen volume showed inverse associations with total cholesterol (β = -0.17; 95% CI = -0.24 to -0.09), HDL-C (β = -0.08; 95% CI = -0.10 to -0.05), and LDL-C (β = -0.12; 95% CI = -0.17 to -0.06). There was no significant association of spleen volume with triglycerides.</p><p><strong>Conclusion: </strong>Our study showed that the spleen volume is associated with markers of the blood count and lipid profile in the general population.</p>","PeriodicalId":23458,"journal":{"name":"Upsala journal of medical sciences","volume":"128 ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10552697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41180054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}