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Lobar cerebral microbleeds are a characteristic neuroimaging finding in cerebral amyloid angiopathy (CAA) but can also be found in hypertensive arteriolosclerosis. We aimed to investigate whether CAA is more associated with intracortical lobar microbleeds than hypertensive arteriosclerosis. Ninety-one survivors of spontaneous intracerebral hemorrhage with at least one lobar microbleed were included and underwent brain MRI and amyloid PET. We categorized lobar microbleeds as intracortical, juxtacortical, or subcortical. We assessed the associations between the lobar microbleed categories and microangiopathy subtypes or cerebral amyloid load based on the Pittsburgh Compound-B PET standardized uptake value ratio (SUVR). Patients with CAA had a higher prevalence of intracortical lobar microbleeds (80.0% vs. 50.8%, P = 0.011) and lower prevalence of subcortical lobar microbleeds (13.3% vs. 60.1%, P < 0.001) than patients with hypertensive arteriolosclerosis. Strictly intracortical/juxtacortical lobar microbleeds were associated with CAA (OR 18.9 [1.9-191.4], P = 0.013), while the presence of subcortical lobar microbleeds was associated with hypertensive arteriolosclerosis (OR 10.9 [1.8-68.1], P = 0.010). Amyloid retention was higher in patients with strictly intracortical/juxtacortical CMBs than those without (SUVR = 1.15 [1.05-1.52] vs. 1.08 [1.02-1.19], P = 0.039). Amyloid retention positively correlated with the number of intracortical lobar microbleeds (P < 0.001) and negatively correlated with the number of subcortical lobar microbleeds (P = 0.018). CAA and cortical amyloid deposition are more strongly associated with strictly intracortical/juxtacortical microbleeds than subcortical lobar microbleeds. Categorization of lobar microbleeds based on anatomical location may help differentiate the underlying microangiopathy and potentially improve the accuracy of current neuroimaging criteria for cerebral small vessel disease., (© 2024. The Author(s).)

Background: The aim was to study clinicopathological characteristics, risk factors and renal outcome in IgA nephropathy (IgAN) patients with vascular lesions., Methods: We enrolled a Chinese cohort with 458 biopsy-confirmed primary IgAN patients for a retrospective analysis. They were divided into three groups according to vascular lesions: no vascular lesions (n = 239), arterio-/arteriolosclerosis (n = 181) and microangiopathic lesions (n = 38). The clinicopathological features and renal outcome were recorded. In univariate and multivariate models, association between vascular lesions and renal outcome and vascular lesions associated clinical factors were analyzed., Results: Patients with vascular lesions presented worse clinical characteristics with regard to blood pressure and kidney function, and segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1/2) and lymphocytes and monocytes infiltration were more common. Furthermore, older age, hyperuricemia, proteinuria, global glomerulosclerosis and endocapillary hypercellularity (E1) were more severe in patients with simple arterio-/arteriolosclerosis. By multivariate logistic regression, age, MAP and eGFR were significantly associated with vascular lesions. Vascular lesions, especially arterio-/arteriolosclerosis, were significantly associated with poorer renal survival in IgAN patients, and renal survival was similar whether patients with arterio-/arteriolosclerosis received immunosuppressive therapy. In addition to eGFR, arterio-/arteriolosclerosis, along with arterial intimal fibrosis, was an independent predictor for renal survival in multivariate Cox analyses., Conclusion: IgAN patients with vascular lesions, especially with arterio-/arteriolosclerosis, presented more severe clinicopathological features. Renal function, blood pressure and age contributed to distinguishing patients with vascular lesions. Arterio-/arteriolosclerosis lesions were associated with poorer renal survival., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest., (Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Objective: A definite diagnosis of cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid β in walls of cerebral small vessels, can only be obtained through pathological examination. A diagnosis of probable CAA during life relies on the presence of hemorrhagic markers, including lobar cerebral microbleeds (CMBs). The aim of this project was to study the histopathological correlates of lobar CMBs in false-positive CAA cases., Methods: In 3 patients who met criteria for probable CAA during life, but showed no CAA upon neuropathological examination, lobar CMBs were counted on ex vivo 3T magnetic resonance imaging (MRI) and on ex vivo 7T MRI. Areas with lobar CMBs were next sampled and cut into serial sections, on which the CMBs were then identified., Results: Collectively, there were 25 lobar CMBs on in vivo MRI and 22 on ex vivo 3T MRI of the analyzed hemispheres. On ex vivo MRI, we targeted 12 CMBs for sampling, and definite histopathological correlates were retrieved for 9 of them, of which 7 were true CMBs. No CAA was found on any of the serial sections. The "culprit vessels" associated with the true CMBs instead showed moderate to severe arteriolosclerosis. Furthermore, CMBs in false-positive CAA cases tended to be located more often in the juxtacortical or subcortical white matter than in the cortical ribbon., Interpretation: These findings suggest that arteriolosclerosis can generate lobar CMBs and that more detailed investigations into the exact localization of CMBs with respect to the cortical ribbon could potentially aid the diagnosis of CAA during life. ANN NEUROL 2023;94:856-870., (© 2023 American Neurological Association.)

Introduction: We investigated the link between locus coeruleus (LC) pathology and cerebral microangiopathy in two large neuropathology datasets., Methods: We included data from the National Alzheimer's Coordinating Center (NACC) database (n = 2197) and Religious Orders Study and Rush Memory and Aging Project (ROSMAP; n = 1637). Generalized estimating equations and logistic regression were used to examine associations between LC hypopigmentation and presence of cerebral amyloid angiopathy (CAA) or arteriolosclerosis, correcting for age at death, sex, cortical Alzheimer's disease (AD) pathology, ante mortem cognitive status, and presence of vascular and genetic risk factors., Results: LC hypopigmentation was associated with higher odds of overall CAA in the NACC dataset, leptomeningeal CAA in the ROSMAP dataset, and arteriolosclerosis in both datasets., Discussion: LC pathology is associated with cerebral microangiopathy, independent of cortical AD pathology. LC degeneration could potentially contribute to the pathways relating vascular pathology to AD. Future studies of the LC-norepinephrine system on cerebrovascular health are warranted., Highlights: We associated locus coeruleus (LC) pathology and cerebral microangiopathy in two large autopsy datasets. LC hypopigmentation was consistently related to arteriolosclerosis in both datasets. LC hypopigmentation was related to cerebral amyloid angiopathy (CAA) presence in the National Alzheimer's Coordinating Center dataset. LC hypopigmentation was related to leptomeningeal CAA in the Religious Orders Study and Rush Memory and Aging Project dataset. LC degeneration may play a role in the pathways relating vascular pathology to Alzheimer's disease., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: Assessing the risk of recurrent intracerebral hemorrhage (ICH) is of high clinical importance. MRI-based cerebral small vessel disease (SVD) markers may help establish ICH etiologic subtypes (including cryptogenic ICH) relevant for recurrence risk., Methods: We investigated the risk of recurrent ICH in a large cohort of consecutive ICH survivors with available MRI at baseline. Patients with macrovascular, structural, or other identified secondary causes (other than SVD) were excluded. Based on MRI findings, ICH etiology was defined as probable cerebral amyloid angiopathy (CAA) according to the Boston 2.0 criteria, arteriolosclerosis (nonlobar ICH and additional markers of arteriolosclerosis, absent lobar hemorrhagic lesions), mixed SVD (mixed deep and lobar hemorrhagic changes), or cryptogenic ICH (no MRI markers of SVD). Recurrent ICH was determined using electronic health records and confirmed by neuroimaging. Data from an independent multicenter cohort (CROMIS-2 ICH) were used to confirm core findings., Results: Of 443 patients with ICH (mean age 67 ± 13 years, 41% female), ICH etiology was mixed SVD in 36.7%, arteriolosclerosis in 23.6%, CAA in 23.0%, and cryptogenic ICH in 16.7%. During a median follow-up period of 5.7 years (interquartile range 2.9-10.0, 2,682 patient-years), recurrent ICH was found in 59 individual patients (13.3%). The highest recurrence rate per 100 person-years was detected in patients with CAA (8.5, 95% CI 6.1-11.7), followed by that in those with mixed SVD (1.8, 95% CI 1.1-2.9) and arteriolosclerosis (0.6, 95% CI 0.3-1.5). No recurrent ICH occurred in patients with cryptogenic ICH during 510 person-years follow-up (97.5% CI 0-0.7); this finding was confirmed in an independent cohort (CROMIS-2 ICH, n = 216), in which also there was no recurrence in patients with cryptogenic ICH. In patients with CAA, cortical superficial siderosis was the imaging feature strongest related to ICH recurrence (hazard ratio 5.7, 95% CI 2.4-13.6)., Discussion: MRI-based etiologic subtypes are helpful in determining the recurrence risk of ICH; while the highest recurrence risk was found in CAA, recurrence risk was low for arteriolosclerosis and negligible for cryptogenic ICH., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: VERTIS CV was a randomised, double-blind, placebo-controlled, parallel-group, multicentre cardiovascular outcomes trial that evaluated the cardiovascular efficacy and safety of ertugliflozin in adults with type 2 diabetes and atherosclerotic cardiovascular disease. The primary objective of VERTIS CV was to show non-inferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke). The analyses reported here aimed to assess cardiorenal outcomes, kidney function, and other safety outcomes with ertugliflozin in older adults with type 2 diabetes and atherosclerotic cardiovascular disease compared with younger participants., Methods: VERTIS CV was done at 567 centres in 34 countries. Participants (aged ≥40 years) with type 2 diabetes and atherosclerotic cardiovascular disease were randomly assigned (1:1:1) to once-daily ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo in addition to background standard-of-care treatment. Random assignment was done with the use of an interactive voice-response system. The study outcomes were major adverse cardiovascular events, hospitalisation for heart failure or cardiovascular death, cardiovascular death, hospitalisation for heart failure, prespecified kidney composite outcomes, kidney function, and other assessments of safety. Cardiorenal outcomes, kidney function, and safety outcomes were evaluated by baseline age (≥65 years and <65 years [prespecified] and ≥75 years and <75 years [post hoc]). The study is registered with ClinicalTrials.gov, NCT01986881., Findings: Between Dec 13, 2013, and July 31, 2015, and between June 1, 2016, and April 14, 2017, 8246 adults with type 2 diabetes and atherosclerotic cardiovascular disease were recruited to the study and randomly assigned. 2752 patients were assigned to ertugliflozin 5 mg, 2747 patients to ertugliflozin 15 mg, and 2747 patients to placebo. 8238 participants received at least one dose of ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo. 4145 (50·3%) of 8238 participants were aged 65 years and older, including 903 (11·0%) participants aged 75 years and older. 5764 (70·0%) of 8238 participants were male and 2474 (30·0%) were female, and 7233 (87·8%) of 8238 participants were White, 497 (6·0%) were Asian, 235 (2·9%) were Black, and 273 (3·3%) were classified as other. The mean estimated glomerular filtration rate (eGFR) was lower and the type 2 diabetes duration longer for those aged 65 years and older versus those younger than 65 years, and for those aged 75 years and older versus those younger than 75 years. Cardiovascular outcomes were more common in the older age subgroups than in the younger age subgroups. Similar to the overall VERTIS CV cohort, ertugliflozin did not increase the risk of major adverse cardiovascular events, cardiovascular death or hospitalisation for heart failure, cardiovascular death alone, or the kidney composite outcome (using doubling of serum creatinine, dialysis or transplantation, or kidney death), and reduced the risk of hospitalisation for heart failure and the exploratory kidney composite outcome (using a 40% sustained eGFR decrease, dialysis or transplantation, or kidney death) in the older age subgroups (p interaction >0·05 for outcomes assessed). A slower decline in eGFR and a smaller increase in the urine albumin-to-creatinine ratio were observed over time in all age subgroups taking ertugliflozin compared with placebo. Across age subgroups, safety outcomes were consistent with the known profile of ertugliflozin., Interpretation: The effects of ertugliflozin on cardiorenal outcomes, kidney function, and safety outcomes were generally similar across age subgroups. These results have the potential to help clinical decision making by providing a longer-term evaluation of the cardiorenal safety and overall tolerability of ertugliflozin in a large population of older adults., Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA in collaboration with Pfizer Inc, New York, NY, USA., Competing Interests: Declaration of interests REP reports consulting fees from Bayer, Corcept Therapeutics, Dexcom, Hanmi Pharmaceutical, Merck, Novo Nordisk, Pfizer, Sanofi, Scohia Pharma, and Sun Pharmaceutical Industries, and grants or research support from Hanmi Pharmaceutical, Janssen, Metavention, Novo Nordisk, Poxel, and Sanofi. All funds were paid directly to REP's employer, AdventHealth, a non-profit organisation that supports education and research. CPC has received research grants from Amgen, Better Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Merck, Novo Nordisk, and Pfizer; fees from Aegerion-Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, and Sanofi; and serves on data and safety monitoring boards for the Veteran's Administration, Applied Therapeutics, and Novo Nordisk. DZIC has received consulting fees or speaking honoraria or both from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck & Co, Inc, Mitsubishi-Tanabe, Novo Nordisk, Prometic, and Sanofi, and has received operating funds from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck & Co, Inc, and Sanofi. FC has received fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck Sharp & Dohme, Novo Nordisk, and Pfizer, and research grants from the King Gustav V and Queen Victoria Foundation, the Swedish Heart & Lung Foundation, and the Swedish Research Council. DKM has received consulting fees from Afimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Esperion, Lexicon, Lilly USA, Merck Sharp & Dohme, Metavant, Novo Nordisk, Pfizer, and Sanofi US, and has received payment for expert testimony from Kirkland & Ellis on behalf of Boehringer Ingelheim. MNE, DL, and PLSJ are employees and shareholders of Pfizer. JL was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, who owned stock in Merck & Co, Inc, Rahway, NJ, USA at the time of the submission. IA is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, who owns stock in Merck & Co, Inc, Rahway, NJ, USA. SD-J has led clinical trials for AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; has received consulting fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck & Co, and Sanofi; and has equity interests in Jana Care and Aerami Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Arteriolosclerosis is common in older brains and related to cognitive and motor impairment. We compared the severity of arteriolosclerosis and its associations with cerebrovascular disease risk factors (CVD-RFs) in multiple locations in the brain and spinal cord. Participants (n = 390) were recruited in the context of a longitudinal community-based clinical-pathological study, the Rush Memory and Aging Project. CVD-RFs were assessed annually for an average of 8.7 (SD = 4.3) years before death. The annual assessments included systolic (SBP) and diastolic (DBP) blood pressure, diabetes mellitus (DM), low- and high-density lipoprotein cholesterol, triglyceride, body mass index, and smoking. Postmortem pathological assessments included assessment of arteriolosclerosis severity using the same rating scale in three brain locations (basal ganglia, frontal, and parietal white matter regions) and four spinal cord levels (cervical, thoracic, lumbar and sacral levels). A single measure was used to summarize the severity of spinal arteriolosclerosis assessments at the four levels due to their high correlations. Average age at death was 91.5 (SD = 6.2) years, and 73% were women. Half showed arteriolosclerosis in frontal white matter and spinal cord followed by parietal white matter (38%) and basal ganglia (27%). The severity of arteriolosclerosis in all three brain locations showed mild-to-moderate correlations. By contrast, spinal arteriolosclerosis was associated with brain arteriolosclerosis only in frontal white matter. Higher DBP was associated with more severe arteriolosclerosis in all three brain locations. DM was associated with more severe arteriolosclerosis only in frontal white matter. Controlling for DBP, higher SBP was inversely associated with arteriolosclerosis in parietal white matter. Blood cholesterol and triglyceride, high body mass index, or smoking were not related to the severity of arteriolosclerosis in any brain region. None of the CVD-RFs were associated with the severity of spinal arteriolosclerosis. These data indicate that severity of arteriolosclerosis and its associations with CVD-RFs may vary in different CNS locations., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Determining the underlying causes of intracerebral hemorrhage (ICH) is of major importance, because risk factors, prognosis, and management differ by ICH subtype. We developed a new causal CLASsification system for ICH Subtypes, termed CLAS-ICH, based on recent advances in neuroimaging., Methods: CLAS-ICH defines 5 ICH subtypes: arteriolosclerosis, cerebral amyloid angiopathy, mixed small vessel disease (SVD), other rare forms of SVD (genetic SVD and others), and secondary causes (macrovascular causes, tumor, and other rare causes). Every patient is scored in each category according to the level of diagnostic evidence: (1) well-defined ICH subtype; (2) possible underlying disease; and (0) no evidence of the disease. We evaluated CLAS-ICH in a derivation cohort of 113 patients with ICH from Massachusetts General Hospital, Boston, USA, and in a derivation cohort of 203 patients from Inselspital, Bern, Switzerland., Results: In the derivation cohort, a well-defined ICH subtype could be identified in 74 (65.5%) patients, including 24 (21.2%) with arteriolosclerosis, 23 (20.4%) with cerebral amyloid angiopathy, 18 (15.9%) with mixed SVD, and 9 (8.0%) with a secondary cause. One or more possible causes were identified in 42 (37.2%) patients. Interobserver agreement was excellent for each category (kappa value ranging from 0.86 to 1.00). Despite substantial differences in imaging modalities, we obtained similar results in the validation cohort., Interpretation: CLAS-ICH is a simple and reliable classification system for ICH subtyping, that captures overlap between causes and the level of diagnostic evidence. CLAS-ICH may guide clinicians to identify ICH causes, and improve ICH classification in multicenter studies. ANN NEUROL 2023;93:16-28., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Importance: Scam susceptibility is associated with adverse financial and health outcomes, including an increased risk of cognitive decline and dementia. Very little is known about the role of cerebrovascular pathologies with scam susceptibility., Objective: To examine the association of diverse cerebrovascular pathologies (globally and regionally) with scam susceptibility., Design, Setting, and Participants: This clinical-pathological cohort study included participants from 2 ongoing studies of aging that began enrollment in 1994 and 1997. In 2010, participants were enrolled in the decision-making and behavioral economics substudy and were followed up for a mean (SD) of 3.4 (2.6) years prior to death. From 1365 older persons with clinical evaluations, 69 were excluded for having dementia at baseline. From 538 older persons who died, 408 had annual assessments for scam susceptibility, cardiovascular risk burden, and cognitive function and consented to brain donation for detailed neuropathologic examination. Data were analyzed from June 2021 through September 2022., Exposures: Neuropathologic examination identified the presence of macroscopic and microscopic infarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, and common neurodegenerative pathologies (Alzheimer disease, limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy, and Lewy bodies)., Results: There was a total of 408 participants. The mean (SD) age at death was 91 (6.1) years, the mean (SD) amount of education was 15.6 (3.1) years, and 297 (73%) were women. Participants included 4 Latino individuals (1%), 7 non-Latino Black individuals (2%), and 397 non-Latino White individuals (97%). The frequency of participants with macroscopic infarcts was 38% (n = 154), microinfarcts was 40% (n = 163), and moderate to severe vessel disease; specifically, atherosclerosis was 20% (n = 83), arteriolosclerosis was 25% (n = 100), and cerebral amyloid angiopathy was 35% (n = 143). In linear regression models adjusted for demographics and neurodegenerative pathologies, macroscopic infarcts were associated with greater scam susceptibility (estimate [SE], 0.18 [0.07]; P = .009). This association persisted after adjusting for cardiovascular risk burden and global cognition. Regionally, infarcts localized to the frontal, temporal, and occipital lobes and thalamus were associated with greater scam susceptibility. Neither arteriosclerosis, atherosclerosis, cerebral amyloid angiopathy, nor microinfarcts were associated with scam susceptibility., Conclusions and Relevance: Cerebrovascular pathologies, specifically cerebral infarcts, is linked with greater scam susceptibility in older adults, independent of common neurodegenerative diseases such as Alzheimer disease. Future studies examining in vivo magnetic resonance imaging markers of cerebrovascular pathologies with scam susceptibility and related decision-making outcomes will be important.

Background and Objectives: Topographical distribution of white matter hyperintensities (WMH) are hypothesized to vary by cerebrovascular risk factors. We used an unbiased pattern discovery approach to identify distinct WMH spatial patterns and investigate their association with different WMH etiologies., Methods: We performed a cross-sectional study on participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify spatially distinct WMH distribution patterns using voxel-based spectral clustering analysis of aligned WMH probability maps. We included all participants from the ADNI Grand Opportunity/ADNI 2 study with available baseline 2D-FLAIR MRI scans, without history of stroke or presence of infarction on imaging. We evaluated the associations of these WMH spatial patterns with vascular risk factors, amyloid-β PET, and imaging biomarkers of cerebral amyloid angiopathy (CAA), characterizing different forms of cerebral small vessel disease (CSVD) using multivariable regression. We also used linear regression models to investigate whether WMH spatial distribution influenced cognitive impairment., Results: We analyzed MRI scans of 1,046 ADNI participants with mixed vascular and amyloid-related risk factors (mean age 72.9, 47.7% female, 31.4% hypertensive, 48.3% with abnormal amyloid PET). We observed unbiased partitioning of WMH into 5 unique spatial patterns: deep frontal, periventricular, juxtacortical, parietal, and posterior. Juxtacortical WMH were independently associated with probable CAA, deep frontal WMH were associated with risk factors for arteriolosclerosis (hypertension and diabetes), and parietal WMH were associated with brain amyloid accumulation, consistent with an Alzheimer disease (AD) phenotype. Juxtacortical, deep frontal, and parietal WMH spatial patterns were associated with cognitive impairment. Periventricular and posterior WMH spatial patterns were unrelated to any disease phenotype or cognitive decline., Discussion: Data-driven WMH spatial patterns reflect discrete underlying etiologies including arteriolosclerosis, CAA, AD, and normal aging. Global measures of WMH volume may miss important spatial distinctions. WMH spatial signatures may serve as etiology-specific imaging markers, helping to resolve WMH heterogeneity, identify the dominant underlying pathologic process, and improve prediction of clinical-relevant trajectories that influence cognitive decline., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Aim: We investigated whether retinal arteriolosclerosis (RA) could be used for cardiovascular disease (CVD) risk stratification of individuals categorized according to the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) Blood Pressure (BP) guideline., Methods: We studied 291,522 participants without a history of CVD and not taking any BP-lowering medications from the JMDC Claims Database. RA was defined as Keith-Wagener-Barker system grade ≥ 1. Each participant was classified into one of the six groups: (1) normal or elevated BP without RA, (2) normal or elevated BP with RA, (3) stage 1 hypertension without RA, (4) stage 1 hypertension with RA, (5) stage 2 hypertension without RA, and (6) stage 2 hypertension with RA., Results: Median (interquartile range) age was 46 (40-53) years, and 141,397 (48.5%) of the participants were men. During a mean follow-up of 1,223±830 days, 527 myocardial infarction (MI), 5,718 angina pectoris, 2,890 stroke, and 5,375 heart failure (HF) events occurred. Multivariable Cox regression analyses revealed that the risk of CVD increased with BP category, and this association was pronounced by the presence of RA. Compared with normal or elevated BP without RA, the hazard ratios (HRs) for MI (HR 1.17, 95% CI 0.93-1.47) were higher in stage 1 hypertension without RA. The HRs for MI further increased in stage 1 hypertension with RA (1.86 [1.17-2.95]). This association was present in stroke and HF., Conclusion: Incorporation of the assessment for RA may facilitate the CVD risk stratification of people classified based on the 2017 ACC/AHA BP guideline, particularly for those categorized in stage 1 hypertension.

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is most often seen in the oldest-old (≥ 90 years of age) but can also be present in the younger-old (< 90 years of age). In this study, we compared the neuropathological associations of LATE-NC and contribution of LATE-NC to cognitive impairment between the oldest-old and younger-old. We observed significant differences in the prevalence of LATE-NC and its association with other co-pathologies in these two age groups. LATE-NC was present in 30.9% (34/110) of the oldest-old but only 9.4% (19/203) of the younger-old. Participants of the oldest-old with LATE-NC were more likely to have hippocampal sclerosis (HS) (55.9% vs. 10.5%, p < 0.001) and moderate to severe arteriolosclerosis (82.4% vs. 50%, p = 0.007), but not intermediate to high Alzheimer's disease neuropathologic change (ADNC) (70.6% vs. 59.2%, p = 0.486) or Lewy body disease (LBD) (20.6% vs. 26.3%, p = 0.793). Participants of the younger-old with LATE-NC were more likely to have intermediate to high ADNC (94.7% vs. 55.4%, p < 0.001) and LBD (63.2% vs. 28.8%, p = 0.013) in addition to hippocampal sclerosis (42.1% vs. 6.5%, p < 0.001), and moderate to severe arteriolosclerosis (42.1% vs. 15.2%, p = 0.020). Of note, participants with LATE-NC and no to low ADNC were very rare in the younger-old (< 1%) but relatively common in the oldest-old (9.1%). Logistic regression modeling showed that in the oldest-old, both intermediate to high ADNC and LATE-NC were independently associated with higher odds of having dementia (OR: 5.09, 95% CI [1.99, 13.06], p < 0.001 for ADNC; OR: 3.28, 95% CI [1.25, 8.57], p = 0.015 for LATE-NC). In the younger-old, by contrast, intermediate to high ADNC and LBD were independently associated with higher odds of having dementia (OR: 4.43, 95% CI [2.27, 8.63], p < 0.001 for ADNC; OR: 2.55, 95% CI [1.21, 5.35], p < 0.014 for LBD), whereas LATE-NC did not show an independent association with dementia. Overall, LATE-NC is strongly associated with arteriolosclerosis and HS in both groups; however, in the younger-old, LATE-NC is associated with other neurodegenerative pathologies, such as ADNC and LBD; whereas in the oldest-old, LATE-NC can exist independent of significant ADNC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Arteriolosclerotic ulcers of Martorell are histologically characterized by hyaline arteriolosclerosis resulting in concentric occlusion of the arteriolar lumina. Although several authors have previously reported on hyaline changes in hypertensive arteriolopathies, so far, little information is available on the molecular composition of hyaline wall depositions., Objectives: This study aimed at the molecular characterization of hyaline arteriolar deposits in patients with hypertensive arteriolopathy using confocal Raman spectroscopy., Methods: Samples of patients diagnosed with arteriolosclerotic ulcers of Martorell were analysed using confocal Raman spectroscopy. The findings were correlated with histological analyses. Skin samples from healthy, non-hypertensive patients served as controls., Results: Confocal Raman spectroscopy analysis revealed that subendothelial hyaline deposits in arteriolosclerotic ulcers are mainly composed of collagen and phospholipids, in particular phosphatidylcholine. The presence of collagen within hyaline deposits was confirmed by Masson's Trichrome and Picrosirius Red staining. Additionally, the presence of collagen could also be shown for hypertensive nephrosclerosis. Actin was markedly decreased in hyalinized compared to control vessels, corresponding to the loss of smooth muscle cells in the process of hyalinization. This was confirmed by immunofluorescence staining for α-smooth muscle actin and desmin., Conclusion: The present findings suggest that arteriolar hyaline deposits in hypertensive arteriolopathy are mainly composed of collagen and phospholipids, in particular phosphatidylcholine. Together with the concurrent absence of actin, these findings suggest that potentially critical disease mechanisms involve pressure-induced vascular smooth muscle cell apoptosis with subsequent deposition of collagen., (© 2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Charcot neuropathic arthropathy is a debilitating, rapidly destructive degenerative joint disease that occurs in diabetic, neuropathic midfoot. Clinicoradiologic assessment for Charcot neuropathic arthropathy previously relied on Eichenholtz stage. There is limited histopathologic data on this entity. We wanted to independently develop a histopathologic scoring system for Charcot neuropathic arthropathy., Design: Retrieval of surgical pathology midfoot specimens from Charcot patients (2012-2019) were analyzed to evaluate joint soft tissue and bone. Considering progression from large (≥half 40× hpf) to small (

Background: We aimed to evaluate the relationship between biopsy-proven kidney lesions, subclinical markers of atherosclerosis and intrarenal resistive index (RRI) in chronic kidney disease (CKD) patients. Methods: This cross-sectional, single-center study prospectively enrolled 44 consecutive CKD patients (57% male gender, 54.1 (95%CI, 49.7-58.6) years, median eGFR 28.1 (15.0-47.7) mL/min) diagnosed by renal biopsy during 6 months in our clinic. RRI, carotid intima-media thickness (IMT), Kauppila score for abdominal aortic calcification (AACs) were assessed. Traditional and nontraditional atheroscleosis risk factors were also evaluated. Results: Most of the patients had a diagnosis of glomerular nephropathy, with IgA nephropathy and diabetic nephropathy being the most frequent. RRI increased proportionally with CKD stages. Patients with RRI >0.7 (39%) were older, had diabetic and vascular nephropathies more frequently, higher mean arterial blood pressure, increased systemic atherosclerosis burden (IMT and AACs), higher percentage of global glomerulosclerois, GBM thickness, arteriolosclerosis and interstitial fibrosis/tubular atrophy. RRI directly correlated with age (rs = 0.55, p  < 0.001) and with all the studied atherosclerosis markers (clinical atherosclerosis score rs = 0.50, p  = 0.02; AACs rs = 0.50, p  < 0.01; IMT rs = 0.34, p  = 0.02). Also, global glomerulosclerosis (rs = 0.31, p  = 0.03) and interstitial fibrosis/tubular atrophy (rs = 0.35, p  = 0.01) were directly correlated with RRI. In multivariable adjusted binomial logistic regression models, only arteriolosclerosis was retained as independent predictor of RRI >0.7. Conclusion: The analysis of RRI may be useful in the evaluation of the general vascular condition of the patient with CKD, supplying information about both microvascular and macrovascular impairment. Moreover, RRI correlates well with renal histopathologic characteristics, particularly with arteriolosclerosis.

Alzheimer's dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer's disease (AD) and other brain pathologies. We leveraged postmortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. Linear and logistic regressions examined the association of sex with each of the pathologic measures. Two-thirds of subjects were women (n = 971; 67%), with a mean age at death of 89.8 (SD = 6.6) years in women and 87.3 (SD = 6.6) in men. Adjusted for age and education, women had higher levels on a global measure of AD pathology (estimate = 0.102, SE = 0.022, p < 0.001), and tau tangle density in particular (estimate = 0.334, SE = 0.074, p < 0.001), and there was a borderline difference between women and men in amyloid-β load (estimate = 0.124, SE = 0.065, p = 0.056). In addition, compared to men, women were more likely to have more severe arteriolosclerosis (OR = 1.28, 95% CI:1.04-1.58, p = 0.018), and less likely to have gross infarcts (OR = 0.78, 95% CI:0.61-0.98, p = 0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors. These data help elucidate the neuropathologic footprint of sex difference in AD and other common brain pathologies of aging.

Background: The histological characteristic of hypertensive leg ulcers (HLU) is the presence of "arteriolosclerosis." The pertinence of performing a skin biopsy to diagnose HLU is questionable, as cutaneous arteriolosclerosis may be related to patient comorbidities. The objective here was to evaluate the frequency of arteriolosclerosis in skin leg biopsies performed in patients without ulcer and in control patients with HLU., Methods: We performed a retrospective study between January 2013 and July 2014. Patients were included if they had undergone a deep skin biopsy on the lower limbs, in the absence of any leg ulcer. Controls were patients with typical HLU., Results: Fifty-eight patients and 6 controls were included. Hypertension was present in 25 patients (43%). Arteriolosclerosis, defined as fibrous endarteritis, was present in 35 out of 58 patients (60%) and in all of the controls. No hyalinosis or hyperplastic proliferative arteriolosclerosis was observed in the patients or controls. Only age was an independent factor associated with the presence of cutaneous arteriolosclerosis (p &x#3c; 0.0001)., Conclusion: Cutaneous arteriolosclerosis is significantly and independently associated with age. Thus, skin biopsy seems not to be necessary for the diagnosis of HLU but only for a differential diagnosis., (© 2018 S. Karger AG, Basel.)

Background: Our objective is to investigate whether C-reactive protein (CRP) and homocysteine (Hcy) levels in the acute phase of large-artery atherosclerotic stroke predict long-term functional disability and recurrent vascular events., Methods: Patients with first-ever large-artery atherosclerotic ischemic stroke were prospectively registered in the Nanjing Stroke Registry Program between January 2012 and June 2014. Venous blood samples were collected within 2 weeks after the index stroke. Patients were followed up for 1 year. The Kaplan-Meier method was performed in survival analysis. Multiple logistic regression analysis and Cox proportional hazard model were applied to identify predictors of functional disability and recurrent vascular events, respectively., Results: A total of 625 eligible patients (458 males) were evaluated. During the 1-year follow-up period, 63 patients suffered recurrent vascular events. An elevated CRP level is an independent predictor of poor functional disability at 1 year (P for trend = .002), in both males (P for trend = .017) and females (P for trend = .042). Hcy showed no relationship with functional disability. No significant relationship between CRP and Hcy levels and recurrent vascular events was found in total patients in multiple models. Stratified by sex, high Hcy levels were associated with recurrent vascular events in females (P for trend = .036) but not in males., Conclusions: Elevated CRP levels are associated with poor functional disability in patients with large-artery atherosclerotic stroke at 1 year, and Hcy is a relatively moderate predictor of recurrent vascular events in female patients with large-artery atherosclerotic stroke at 1 year., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer's Disease Centre, Nun Study, and National Alzheimer's Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case-control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P < 0.001). This enables informative evaluation of anatomical regions outside of the hippocampus. To assess the morphology of brain microvasculature far more rigorously than what is possible using semi-quantitative pathological scoring, we applied digital pathological (Aperio ScanScope) methods on a subsample of frontal cortex sections from hippocampal sclerosis of ageing (n = 15) and control (n = 42) cases. Following technical studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin-immunoreactive arterioles had thicker walls (P < 0.05), larger perimeters (P < 0.03), and larger vessel areas (P < 0.03) than controls. Unlike the arterioles, CD34-immunoreactive capillaries had dimensions that were unchanged in cases with hippocampal sclerosis of ageing versus controls. Arteriolosclerosis appears specific to hippocampal sclerosis of ageing brains, because brains with Alzheimer's disease pathology did not show the same morphological alterations. We conclude that there may be a pathogenetic change in aged human brain arterioles that impacts multiple brain areas and contributes to hippocampal sclerosis of ageing.

Context: Evaluating nontumor portions of tumor nephrectomies is useful to diagnose nonneoplastic renal disease., Objective: To determine the medical renal disease frequency and to assess the prognostic significance of the various renal pathologic variables with long-term follow-up in tumor nephrectomy patients., Design: We reviewed nonneoplastic kidney sections of 456 consecutive cases from 1998 to 2008. Seventy-five cases were excluded (19 tumor compression, 25 no nonneoplastic tissue, 22 embolized kidneys, 9 end stage). Special staining, immunofluorescence, and/or electron microscopy was performed where appropriate. Vascular sclerosis was scored from mild to severe; interstitial fibrosis/tubular atrophy and global glomerulosclerosis (GS) were expressed as percentages. Follow-up, minimum 12 months, was evaluated in 156 cases. All renal pathologic variables were compared with regard to change in creatinine level from preoperative assessment to follow-up., Results: Of 381 cases, 57 had additional medical renal disease (15%), most frequently diabetic nephropathy (28) and hypertensive nephropathy (11). Postoperative creatinine levels increased significantly in patients with severe arteriosclerosis or arteriolosclerosis, >5% GS, and >10% interstitial fibrosis/tubular atrophy. Seventy-four percent of cases with additional nonneoplastic diagnoses showed severe arteriolosclerosis. Higher corresponding GS was seen in the more affected vascular cases: mean, 5.56% GS for mild versus 23% GS for severe. Three patients progressed to renal failure 1 to 4 years after nephrectomy, 2 with hypertensive nephrosclerosis and 1 with diabetic nephropathy., Conclusions: Medical renal disease was identified in 15% of tumor nephrectomy specimens. The degrees of vascular sclerosis, GS, and interstitial fibrosis/tubular atrophy are predictive of elevated creatinine levels in postnephrectomy patients. Prognostic implications of the nontumor pathology are important in nephrectomized patients.

Renal artery stenosis is found in 2% and 40% of general and high cardiovascular risk populations, respectively. Atherosclerotic renal artery stenosis (ARAS) has become an increasingly recognized clinical condition, especially in older or otherwise atherosclerosis-prone populations. This increase in prevalence has led to a dramatically increased use of percutaneous transluminal renal angioplasty. Randomized trials have failed to demonstrate any superiority of renal revascularization over medical therapy as far as control of hypertension, mortality or cardiovascular events is concerned. However, in this report we present two cases in which rescue endovascular revascularization in patients affected by bilateral ARAS permitted withdrawal from hemodialysis treatment and the restoration of a certain degree of renal function. In conclusion, for certain carefully-selected high-risk patients, renal revascularization may still have an important role. The two cases presented in this article are good examples of the extraordinary benefit that endovascular revascularization can bestow.

Background: Little is known about the relationship between splenic arteriolar hyaline and cause of death. The purpose of this retrospective study was to evaluate the clinicopathological significance of splenic arteriolar hyaline in autopsy cases and estimate the applicability of hyaline for diagnosing the cause and rapidity of death., Methods: Archival data and histological slides from 82 cases were reviewed retrospectively. One section of each spleen was evaluated microscopically. The tinctorial pattern of splenic arteriolar hyaline was examined with Heidenhain's Azan trichrome stain, and the relationships between this pattern and age, cause of death, and rapidity of death were investigated., Results: Fifty-four cases demonstrated hyaline change, with 3 different tinctorial patterns: red, blue, and a combination of red and blue. The 3 patterns coexisted in various proportions in each tissue section. Frequency of the blue pattern increased with age (P < 0.01) and was unrelated to cause of death. By contrast, the red pattern was unrelated to age and appeared with different frequency according to cause of death. The red pattern appeared with significantly higher frequency in the circulatory disease group and the drowning and asphyxia group (both P < 0.01). Moreover, the presence of the red pattern had high specificity for the detection of rapidly fatal cases. The combination of the 2 colors was excluded from clinicopathological analyses due to its admixed nature., Conclusions: Estimation of splenic arteriolar hyaline with Heidenhain's Azan trichrome stain is useful for assessment of the cause and rapidity of death., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1132441651796836.

Atypical wounds are probably the most delicate modern medicine topics as well as the most demanding surgical issue. Recently, we submitted an original report of two similar atypical vascular cases at our surgery department. Both presented a rare type of atypical, potentially fatal, vascular illness due to acute ischemic subcutaneous arteriolosclerosis. Because of the strikingly similar common pathophysiological features, Martorell hypertensive ischemic leg ulcer (HYTILU) and calciphylaxis require identical approach and therapy, both systemic and surgical. Even an experienced clinician can easily confuse it with other atypical wounds, namely pyoderma gangrenosum, which due to the corticosteroid induced immunodeficiency can be detrimental, since the two different approach strategies are required. Based on typical localization, necrotic painful skin necroses, progressive local deterioration, often difficult secondary infections along with long term hypertension and diabetes history could elucidate suspicion of ischemic subcutaneous arteriosclerosis. Hypertension (and often diabetes), local findings and histologically proven subcutaneous arteriolosclerosis are mandatory to make the diagnosis. Rapid local amelioration following correct treatment approach additionally confirms the presumed diagnosis. Besides the minutely repetitive surgical debridement, negative wound pressure therapy and split skin transplantation, one should consider systemic medication (analgesics, antioxidants, LMWH, sodium thiosulfate and antibiotics). Considering the cases presented, opportune decisions along with moderate aggressive and modern holistic surgical approach should inevitably resolve hard to heal atypical wounds.

Background: MELAS syndrome (MIM ID#540000), an acronym for Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with protean manifestations and occasional kidney involvement. Interest in the latter is rising due to the identification of cases with predominant kidney involvement and to the hypothesis of a link between mitochondrial DNA and kidney neoplasia., Case Presentation: We report the case of a 41-year-old male with full blown MELAS syndrome, with lactic acidosis and neurological impairment, affected by the "classic" 3243A > G mutation of mitochondrial DNA, with kidney cancer. After unilateral nephrectomy, he rapidly developed severe kidney functional impairment, with nephrotic proteinuria. Analysis of the kidney tissue at a distance from the two tumor lesions, sampled at the time of nephrectomy was performed in the context of normal blood pressure, recent onset of diabetes and before the appearance of proteinuria. The morphological examination revealed a widespread interstitial fibrosis with dense inflammatory infiltrate and tubular atrophy, mostly with thyroidization pattern. Vascular lesions were prominent: large vessels displayed marked intimal fibrosis and arterioles had hyaline deposits typical of hyaline arteriolosclerosis. These severe vascular lesions explained the different glomerular alterations including ischemic and obsolescent glomeruli, as is commonly observed in the so-called "benign" arteriolonephrosclerosis. Some rare glomeruli showed focal segmental glomerulosclerosis; as the patient subsequently developed nephrotic syndrome, these lesions suggest that silent ischemic changes may result in the development of focal segmental glomerulosclerosis secondary to nephron loss., Conclusions: Nephron loss may trigger glomerular sclerosis, at least in some cases of MELAS-related nephropathy. Thus the incidence of kidney disease in the "survivors" of MELAS syndrome may increase as the support therapy of these patients improves.

Background: Shortening of red blood cell (RBC) survival contributes to the anemia of chronic kidney disease. The toxic uremic environment accounts for the decreased RBC life span. The contribution of mechanical damage caused by hemodialysis to the shortened life span is unclear. Reductions up to 70% in RBC survival have been reported in uremic patients. To date, no accurate well-controlled RBC survival data exist in dialysis patients treated using different dialysis modalities and receiving erythropoiesis-stimulating agent (ESA) therapy. The aim of this study was to determine RBC survival in hemodialysis (HD) and peritoneal dialysis (PD) patients compared with healthy persons., Study Design: Observational study., Setting & Participants: 14 HD patients and 5 PD patients were recruited from the dialysis unit. Healthy volunteers (n = 14) age- and sex-matched to HD participants were included. All dialysis patients received either ESA therapy or regular iron supplementation., Predictor: Dialysis patients versus age- and sex-matched healthy controls., Outcomes: RBC survival., Measurements: RBC survival was determined using radioactive chromium labeling., Results: More than 85% of dialysis patients were anemic (hemoglobin, 12.0 ± 1.1 g/dL); hemoglobin concentrations were not significantly different between HD and PD patients. Median RBC survival was significantly decreased by 20% in HD patients compared with healthy controls: 58.1 (25th-75th percentile, 54.6-71.2) versus 72.9 (25th-75th percentile, 63.4-87.8) days (P = 0.02). No difference was shown between the PD and HD groups: 55.3 (25th-75th percentile, 49.0-60.2) versus 58.1 (25th-75th percentile, 54.6-71.2) days (P = 0.2)., Limitations: Label loss from RBCs associated with the chromium 51 labeling technique needs to be accounted for in the interpretation of RBC survival data., Conclusions: Despite current ESA therapy, decreased RBC survival contributes to chronic kidney disease-related anemia, although the reduction is less than previously reported. There does not appear to be net mechanical damage associated with HD therapy resulting in decreased RBC life span., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To better define the diagnosis and treatment of Martorell hypertensive ischemic leg ulcer (HYTILU) and to compare Martorell HYTILU with calciphylaxis (calcific uremic arteriolopathy) and nonuremic forms of calciphylaxis., Design: Retrospective study from 1999 through 2007., Setting: Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland., Participants: Of 330 patients with leg ulcers, 31 had a clinical diagnosis of Martorell HYTILU confirmed by dermatopathologic examination., Main Outcome Measures: Clinical features, suspected diagnosis at initial presentation, cardiovascular risk factors, findings from vascular examination and histologic analysis, specific medical and surgical management, and outcome., Results: Of the 31 patients, all presented with 1 or multiple painful necrotic skin ulcers on the laterodorsal part of the leg, with bilateral involvement in 16 of 31 cases (52%), and 16 were referred with suspected pyoderma gangrenosum. All patients had arterial hypertension, and 18 (58%) had diabetes. All patients had subcutaneous stenotic arteriolosclerosis on histologic analysis, with medial calcification in 22 of 31 of cases (71%). Martorell HYTILU, calciphylaxis, and nonuremic forms of calciphylaxis shared identical histologic features. Of the 31 patients, 29 (94%) were successfully treated with surgical debridement and split-thickness skin grafting. Three patients (9%) died of sepsis, 2 of whom were undergoing immunosuppressive treatment for wrongly diagnosed pyoderma gangrenosum., Conclusions: Ischemic subcutaneous arteriolosclerosis is the hallmark of Martorell HYTILU, calciphylaxis, and the nonuremic forms of calciphylaxis. All patients are hypertensive and approximately 60% are diabetic. Martorell HYTILU can easily be confused with pyoderma gangrenosum, which can be detrimental, since the 2 diseases require a completely different treatment strategy.

Hypertension has an important function in the formation of renal arterio-arteriolosclerosis. However, renal arterio-arteriolosclerosis is sometimes found in biopsy specimens of normotensive patients, which indicates unknown factors may contribute to renal arterio-arteriolosclerosis. In this study, we aimed to evaluate the effects of glucose metabolism/insulin resistance on renal arterio-arteriolosclerosis. Forty-eight patients with biopsy-proven non-diabetic chronic glomerular disease were included. Renal arterio-arteriolosclerosis was evaluated as the percentage of vessels showing hyaline changes or wall thickening. We correlated renal arterio-arteriolosclerosis with clinical parameters including indices obtained by 75 g oral glucose tolerance test. Of the 48 patients, 30 had hypertension. The results of univariate analysis showed significant association of renal arterio-arteriolosclerosis with hypertension, increased serum creatinine (S-Cr), hypertriglyceridemia, increased 2-h plasma glucose (PG) and increased 2-h plasma insulin (PI). In stepwise multiple regression analysis, hypertension (beta=0.344, P=0.009), S-Cr (beta=0.287, P=0.03) and 2-h PG (beta=0.274, P=0.03) were independently associated with renal arterio-arteriolosclerosis. Eleven of the 30 hypertensive patients did not have renal arterio-arteriolosclerosis. The hypertensive patients with renal arterio-arteriolosclerosis showed significantly higher 2-h PG (134+/-25 vs. 106+/-26 mg per 100 ml, P=0.008) and higher 2-h PI (67.7+/-34.9 vs. 48.3+/-30.0 microU ml(-1), P=0.04) compared with those without renal arterio-arteriolosclerosis, but the difference in S-Cr was not significant. Postprandial hyperglycemia and hyperinsulinemia may contribute to the formation of renal arterio-arteriolosclerosis independently of hypertension.

A 63-year-old woman was referred to the dermatology outpatient department with extremely painful ulcers on the right lower leg. Medical history listed hypertension, diabetes mellitus and chronic obstructive pulmonary disease. Intensive analgesia was insufficient. Blood analysis, microbial cultures and venous ultrasound did not reveal a cause. At histopathologic examination of an ulcer, arteriolosclerosis was revealed. The patient was treated for Martorell arteriolosclerotic ulcer with nifedipine, acenocoumarol and split-thickness skin grafts followed by vacuum-assisted closure therapy. Two weeks postoperative, analgesia was discontinued and all ulcers were healed. Nifedipine and acenocoumarol were continued in the outpatient setting to prevent relapses. Patients with long-standing hypertension are particularly prone to cutaneous arteriolosclerosis. Thrombosis of the cutaneous arterioles results in painful ischemic ulcers. This disease probably frequently goes unrecognised.

Idiopathic nodular glomerulosclerosis is an enigmatic condition closely resembling diabetic nodular glomerulosclerosis without evidence of diabetic mellitus or other specific disease. Idiopathic nodular glomerulosclerosis remains a rare disease entity with an unclear pathogenesis. Clinicopathologic features of 15 patients with idiopathic nodular glomerulosclerosis were evaluated in a retrospective review of renal biopsies between 1998 and 2007. Our study cohort consisted predominantly of older (mean age, 64.2 years) white (73%) women (67%). Fourteen patients (93%) had a history of hypertension, and 10 (67%) were active smokers at the time of biopsy. Nine patients (60%) were obese (body mass index, >30 kg/m(2)) and 4 (27%) were overweight (body mass index, 25-29.9 kg/m(2)). Fourteen patients (93%) presented with renal insufficiency with mean serum creatinine level of 2.8 mg/dL. All 15 patients presented with proteinuria (mean urinary protein excretion, 5.6 g/24 h). Eleven patients (73%) presented with nephrotic-range proteinuria and 8 (53%) with nephrotic syndrome. Histopathologic findings showed nodular glomerulosclerosis (100%), moderate to severe arterio-arteriolosclerosis (100%), and glomerular basement membrane thickening (100%). Immunofluorescence and electron microscopy studies had no other specific findings. Our results confirm previous studies of a close association of hypertension and smoking with idiopathic nodular glomerulosclerosis. A significantly higher incidence of obesity and overweight in patients with idiopathic nodular glomerulosclerosis suggests that increased body mass index may also contribute to the development and progression of idiopathic nodular glomerulosclerosis.