Association of Cortical Superficial Siderosis with Post-Stroke Epilepsy.

OBJECTIVE: To assess whether post-stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case-control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE. METHODS: We performed a post-hoc analysis of the PROgnosis of POST-Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient-echo T2*-weighted images. A logistic regression model with ridge penalties was tuned using 10-fold cross-validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models. RESULTS: The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT-S and CAVE-S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT-S and 0.88 [p = 0.001] for CAVE-S at the testing data). INTERPRETATION: Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2023;93:357-370.

Targeted autophagy disruption reveals the central role of macrophage iron metabolism in systemic iron homeostasis.

Iron homeostasis depends on both intracellular control through iron-responsive proteins and the systemic level of iron through hepcidin-ferroportin axis. Indeed, the hormone hepcidin downregulates the ferroportin iron exporter to control iron recycling from macrophages and iron uptake from enterocytes. Here, we focused on the role of autophagy in macrophage iron metabolism and systemic iron homeostasis. Mice deficient for autophagy in macrophages (LysM-Atg5-/-) mimicked a primary iron overload phenotype, resulting in high ferroportin expression in both macrophages and enterocytes that correlated with marked parenchymal iron overload. Furthermore, LysM-Atg5-/- mice exhibited increased hematopoietic activity with no sign of anemia but correlating with rather high plasma iron level. Compared with wild-type cells, bone marrow-derived macrophages from LysM-Atg5-/- mice had significantly increased ferroportin expression and decreased iron content, confirming high iron export. In erythrophagocytic macrophages, autophagy regulates hemosiderin storage mechanisms as well as degradation of ferroportin and subsequently its plasma membrane localization and iron export; furthermore, ferroportin colocalization with hepcidin indicates hepcidin autocrine activity. Relatively high hepatic hepcidin expression and decreased hepcidin level in the spleen of LysM-Atg5-/- mice, correlating with low hemosiderin iron storage, as well as in erythrophagocytic Atg5-/- macrophages were evidenced. Therefore, our results highlight the critical role of autophagy in macrophages for iron trafficking and systemic iron homeostasis. We propose that in macrophages, autophagy restricts ferroportin level and iron export, resulting in hepcidin expression with an autocrine-paracrine effect that plays a role in the regulation of ferroportin expression in duodenal enterocytes.

Hemosiderin-Laden Macrophages in Bronchoalveolar Lavage Samples of Children with Bronchopulmonary Dysplasia.

OBJECTIVES: To evaluate the prevalence of hemosiderin-laden macrophages in children with bronchopulmonary dysplasia (BPD) and assess for an association between hemosiderin-laden macrophages and pulmonary arterial hypertension. STUDY DESIGN: Retrospective case-control study of infants and children with and without BPD who underwent bronchoscopy with bronchoalveolar lavage (BAL) the at Children's Hospital of Philadelphia between 2012 and 2021. RESULTS: BAL from 205 children with BPD and 106 controls without BPD matched for tracheostomy, infection, and age were reviewed for hemosiderin-laden macrophages. Seventy-one individuals (34.6%) with BPD had a BAL with 10% or more hemosiderin-laden macrophages compared with 3 (2.8%) controls (P < .0001; OR, 18.19; 95% CI, 5.57-59.41). Patients with pulmonary hypertension by echocardiogram (P = .04; OR, 3.69; 95% CI, 1.05-12.96) or an elevated mean pulmonary artery pressure during cardiac catheterization, rs (14) = 0.56, P = .04, were more likely to have elevated hemosiderin-laden macrophages on BAL samples less than 60 days from bronchoscopy. After adjusting for birth weight, gestational age, BPD grade, and age at the time of bronchoscopy using logistic regression, pulmonary hypertension was associated with a higher odds of hemosiderin-laden macrophages of 10% or more (P = .02; OR, 6.37; 95% CI, 1.28-31.87). No association was observed between hemosiderin-laden macrophages and sex, race, gestational age, birth weight, tracheostomy, or infectious studies. CONCLUSIONS: This retrospective study revealed increased hemosiderin-laden macrophages in BAL samples from patients with BPD and a significant association with pulmonary arterial hypertension. It is unclear whether elevated hemosiderin-laden macrophages within BPD contributes to the pathogenesis of lung and pulmonary vascular disease or is simply a biomarker of pulmonary arterial hypertension.

Low-temperature Mössbauer spectroscopy of organs from 57Fe-enriched HFE(-/-) hemochromatosis mice: an iron-dependent threshold for generating hemosiderin.

Hereditary hemochromatosis is an iron-overload disease most often arising from a mutation in the Homeostatic Fe regulator (HFE) gene. HFE organs become overloaded with iron which causes damage. Iron-overload is commonly detected by NMR imaging, but the spectroscopic technique is insensitive to diamagnetic iron. Here, we used Mössbauer spectroscopy to examine the iron content of liver, spleen, kidney, heart, and brain of 57Fe-enriched HFE(-/-) mice of ages 3-52 wk. Overall, the iron contents of all investigated HFE organs were similar to the same healthy organ but from an older mouse. Livers and spleens were majorly overloaded, followed by kidneys. Excess iron was generally present as ferritin. Iron-sulfur clusters and low-spin FeII hemes (combined into the central quadrupole doublet) and nonheme high-spin FeII species were also observed. Spectra of young and middle-aged HFE kidneys were dominated by the central quadrupole doublet and were largely devoid of ferritin. Collecting and comparing spectra at 5 and 60 K allowed the presence of hemosiderin, a decomposition product of ferritin, to be quantified, and it also allowed the diamagnetic central doublet to be distinguished from ferritin. Hemosiderin was observed in spleens and livers from HFE mice, and in spleens from controls, but only when iron concentrations exceeded 2-3 mM. Even in those cases, hemosiderin represented only 10-20% of the iron in the sample. NMR imaging can identify iron-overload under non-invasive room-temperature conditions, but Mössbauer spectroscopy of 57Fe-enriched mice can detect all forms of iron and perhaps allow the process of iron-overloading to be probed in greater detail.

The Acute Superficial Siderosis Syndrome - Clinical Entity, Imaging Findings, and Histopathology.

Superficial siderosis is a consequence of repetitive bleeding into the subarachnoid space, leading to toxic iron and hemosiderin deposits on the surface of the brain and spine. The clinical and radiological phenotypes of superficial siderosis are known to manifest over long time intervals. In contrast, this study defines the "acute superficial siderosis syndrome" and illustrates typical imaging and histopathological findings of this entity. We describe the case of a 61-year-old male patient who was diagnosed with a melanoma metastasis in the right frontal cortex in February 2019. Within a few weeks he developed a progressive syndrome characterized by cerebellar ataxia, gait disturbance, signs of myelopathy, and radiculopathy. MRI revealed ongoing hemorrhage from the metastasis into the lateral ventricle and the subarachnoid space. A semiquantitative assessment of three subsequent MRI within an 8-week period documented the rapid development of superficial siderosis along the surface of the cerebellum, the brain stem, and the lower parts of the supratentorial regions on T2*-weighted sequences. The diagnosis of a superficial siderosis was histopathologically confirmed by identifying iron and hemosiderin deposits on the cortex along with astrogliosis. The recognition of this "acute superficial siderosis syndrome" triggered surgical removal of the hemorrhagic metastasis. Based on a single case presentation, we define the "acute superficial siderosis syndrome" as a clinical entity and describe the radiological and histopathological characteristics of this entity. Early recognition of this syndrome may allow timely elimination of the bleeding source, in order to prevent further clinical deterioration.

Clinical characteristics and risk factors of cerebral cavernous malformation-related epilepsy.

PURPOSE: This study aimed to summarize the clinical characteristics and explore the risk factors for cerebral cavernous malformation (CCM)-related epilepsy (CRE). METHODS: We retrospectively analyzed the clinical data of patients with CCM in our cerebral vascular malformations database. Descriptive statistics were used to present the clinical characteristics of CRE patients. Patients were divided into a CRE and a non-CRE group according to clinical presentation. Binary logistic regression analysis was used to analyze the risk factors of CRE. RESULTS: A total of 199 patients with CCM confirmed by postoperative pathological examination were enrolled, 93 of whom were diagnosed with CRE, and 34 patients had drug-resistant epilepsy. The most common seizure type of CRE patients was focal to bilateral tonic-clonic seizure (FBTCS), followed by focal impaired awareness motor seizure. All CCM lesions were supratentorial, 97.8% of which involved the cerebral cortex, 86.0% of lesions had hemosiderin rim, and 50.5% of lesions were located in the temporal lobe. Binary logistic regression analysis indicated that CCM diagnosis age ≤ 44 years (odds ratio [OR] 2.79, p = 0.010), temporal lobe lesion location (OR = 9.07, p = 0.042), medial temporal lobe lesion (OR = 14.09, p = 0.002), cortical involvement of the lesion (OR = 32.77, p = 0.010), and hemosiderin rim around the lesion (OR = 16.48, p = 0.001) significantly increased the risk of CRE. CONCLUSIONS: The most common seizure type of CRE was FBTCS. Those whose CCM diagnosis age was ≤ 44 years, having a temporal lobe lesion location, especially the medial temporal lobe lesion, cortical involvement, and hemosiderin rim around the lesion had a higher risk of developing CRE.

An old thrombus may potentially identify patients at higher risk of poor outcome in anterior circulation stroke undergoing thrombectomy.

PURPOSE: To investigate thrombus age and its association with clinical and procedural parameters in patients with acute ischemic stroke (AIS) due to anterior circulation occlusions. METHODS: The thrombi of 107 consecutive AIS patients with occlusions in anterior circulation large-arteries were collected during mechanical recanalization. By hematoxylin-eosin staining analysis, thrombi were classified as fresh (< 3 days) or old (≥ 3 days) according to the hemosiderin positivity. Old thrombi were further classified as thrombi with focal hemosiderin or diffuse hemosiderin according to their predominant distribution. Neuro-interventional data and clinical outcomes were compared based on thrombus age. RESULTS: We identified fresh thrombi in 29 patients and old thrombi in 78 patients. Compared with patients with fresh thrombi, patients with old thrombi were associated with (i) a longer mechanical recanalization time (p = 0.027), (ii) a higher percentage of fibrin/platelets and leukocytes (all p = 0.02) and a lower percentage of erythrocytes (p = 0.001), and (iii) less favorable clinical outcomes at discharge (p = 0.019) and 90 days later (OR = 2.76, 95% CI = 1.09-6.99, p = 0.032). Furthermore, 18 (16.8%) of all patients had focal hemosiderin in old thrombi, which was independently linked to a poor clinical outcome 90 days later (adjusted OR = 5.37, 95% CI = 1.14-25.28, p = 0.034). CONCLUSION: The presence of old thrombi, particularly those with focal hemosiderin, may aid in identifying patients with acute ischemic anterior circulation stroke who are at a higher risk of poor clinical outcome at 3-month follow-up.

Chronic kidney disease in a giant panda (Ailuropoda melanoleuca): a case report.

BACKGROUND: Chronic kidney disease (CKD) is a common cause of morbidity and mortality in captive wildlife species. However, CKD has been rarely documented in giant pandas. CASE PRESENTATION: The following report describes a case of an eight-year-old female giant panda showing clinical signs of epistaxis, bloody diarrhea, polyuria, azotemia and anemia. The animal died despite of supportive treatments. Necropsy was performed. Grossly, both kidneys were shrunken and scarred with pallor. Subcutis edema and petechia on the epicardium of the heart were observed. The tissue samples were made into paraffin sections and stained by H.E and special staining including Periodic Acid-Schiff (PAS), von Kossa, Masson's trichrome, Phosphotungstic acid-hematoxylin (PTAH), and Congo red. Histopathology examination revealed severe chronic tubulointerstitial nephritis with marked interstitial fibrosis, glomerulosclerosis, tubular atrophy and calcification in kidneys, and acute necrotizing hemorrhagic myocarditis with calcification in heart. Other lesions included intestinal hemorrhage, hepatic fatty degeneration and necrosis with hemosiderin, and splenic hemosiderin. CONCLUSIONS: In summary, chronic kidney disease was finally diagnosed based on the association of clinical, gross, and histopathological findings. Heart failure secondary to CKD is the leading cause of death in this giant panda. The potential cause of CKD in this animal is possibly due to long term and uncontrolled hypertension. Blood pressure monitoring is essential in establishing the diagnosis and management of hypertension in giant panda.

Cytologic scoring of equine exercise-induced pulmonary hemorrhage: Performance of human experts and a deep learning-based algorithm.

Exercise-induced pulmonary hemorrhage (EIPH) is a relevant respiratory disease in sport horses, which can be diagnosed by examination of bronchoalveolar lavage fluid (BALF) cells using the total hemosiderin score (THS). The aim of this study was to evaluate the diagnostic accuracy and reproducibility of annotators and to validate a deep learning-based algorithm for the THS. Digitized cytological specimens stained for iron were prepared from 52 equine BALF samples. Ten annotators produced a THS for each slide according to published methods. The reference methods for comparing annotator's and algorithmic performance included a ground truth dataset, the mean annotators' THSs, and chemical iron measurements. Results of the study showed that annotators had marked interobserver variability of the THS, which was mostly due to a systematic error between annotators in grading the intracytoplasmatic hemosiderin content of individual macrophages. Regarding overall measurement error between the annotators, 87.7% of the variance could be reduced by using standardized grades based on the ground truth. The algorithm was highly consistent with the ground truth in assigning hemosiderin grades. Compared with the ground truth THS, annotators had an accuracy of diagnosing EIPH (THS of < or ≥ 75) of 75.7%, whereas, the algorithm had an accuracy of 92.3% with no relevant differences in correlation with chemical iron measurements. The results show that deep learning-based algorithms are useful for improving reproducibility and routine applicability of the THS. For THS by experts, a diagnostic uncertainty interval of 40 to 110 is proposed. THSs within this interval have insufficient reproducibility regarding the EIPH diagnosis.

Tenosynovial giant cell tumors of digits: MRI differentiation between localized types and diffuse types with pathology correlation.

OBJECTIVE: To compare the MRI findings between the localized- and diffuse-type tenosynovial giant cell tumors (TSGCTs) of digits with pathology correlation. METHODS: Twenty-eight patients with newly diagnosed TSGCTs of digits (22 localized and 6 diffuse types) who underwent preoperative MRI and surgical excision were included from Jan. 2015 to September 2021. MRI findings regarding nodularity, margins, morphology of hypointensity with pathology correlation, and disease extent (bone erosion, articular involvement, muscle involvement, tendon destruction, and neurovascular encasement) were assessed. RESULTS: Diffuse type was significantly larger (P = 0.006), more multinodular on both MRI and pathology (P = 0.038, both) with significant agreement, and infiltrative on both MRI and pathology (P < 0.001, both) with substantial agreement, and showed central granular on MRI and strong hemosiderin deposition on pathology (P = 0.022 and P = 0.021) with moderate agreement than localized type. Localized type showed significantly more frequent peripheral capsules on both MRI and pathology (P < 0.001, both) with moderate agreement than diffuse type. However, the septum on both MRI and pathology showed no statistically significant difference between the two groups (P = 0.529 and P = 0.372) without significant agreement. The disease extent was more severe in the diffuse type than the localized type regarding articular involvement (P < 0.001), muscle involvement (P < 0.001), and tendon destruction (P = 0.010). No statistically significant differences were found between the two groups regarding bone erosion (P = 0.196) or neurovascular bundle encasement (P = 0.165). CONCLUSIONS: Diffuse-type TSGCTs of digits presented as locally aggressive lesions with larger, multinodular, infiltrative masses exhibiting stronger hemosiderin deposition and more severe disease extents of articular, muscle, and tendon involvement than the localized type.

Corneal Perforation as a Rare and Late Manifestation of Choroidal Melanoma.

PURPOSE: To report a case of corneal perforation as a rare and late manifestation of choroidal melanoma and to highlight the major histopathological findings of this unusual combined clinical presentation. METHODS: A 74-year-old male patient presented to our department due to corneal perforation of the right eye with the absence of light perception for 6 months. The intraocular pressure was hard on palpation. Because of the protracted finding and reduced visual prognosis, primary enucleation was performed. RESULTS: The histopathological examination revealed choroidal melanoma with epithelioid and spindle cell components at the posterior pole, which was positive for Melan-A, Human Melanoma Black 45 (HMB45), BAP1, and SOX10. The anterior segment showed complete anterior chamber hemorrhage and blood remnants in the trabecular meshwork. The cornea displayed diffuse blood staining with hemosiderin and hemosiderin-loaded macrophages and keratocytes. No inflammatory cells were present near the corneal perforation, which had a width of 3 mm. Intraocular heterotopic ossification was indicative of a long-standing condition. Postoperative cancer staging was normal. CONCLUSION: Corneal perforation should be considered as a very rare and late manifestation of advanced choroidal melanoma and may result from interaction between intraocular hemorrhage, elevated IOP, and its secondary signs such as corneal blood staining.

Assessment of Imaging Findings of Renal Carcinoma Subtypes with 3.0T MRI.

BACKGROUND: The prevalence of renal masses has escalated as a result of the augmented utilization of cross-sectional imaging techniques. The approach to managing renal masses may exhibit variability contingent upon the subtype of renal cell carcinoma (RCC). AIM: This research aimed to distinguish between clear cell and papillary RCCs, utilizing dynamic contrast magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI). MATERIALS AND METHODS: The study assessed the MR images of 112 patients with RCC. Two radiologists independently analyzed tumor size, vascular involvement, signal characteristics in T1- and T2-weighted sequences, the presence of hemosiderin, both microscopic and macroscopic fat content, enhancement patterns, and apparent diffusion coefficient (ADC) values derived from b-values of 1000 s/mm². RESULTS: Seventy patients had clear cell RCC, and 42 had papillary. In the clear cell RCC, microscopic fat content was significantly higher than the papillary RCC (P < 0.001). However, in papillary RCC, hemosiderin content was substantially greater (P = 0.001). On T2-weighted MR images, clear cell RCCs were usually hyperintense, while papillary RCCs were hypointense (P < 0.001). Even though the rapid enhancement pattern was observed in clear cell RCCs, the progressive enhancement pattern was more prevalent in papillary RCCs (P < 0.001). CONCLUSION: Hyperintensity on T2-weighted images, microscopic fat content, and rapid enhancement pattern may be indicative of clear cell RCC, whereas hypointensity on T2-weighted images, hemosiderin content, and a progressive contrast pattern may be diagnostic for papillary RCC.

Xanthogranulomatous epithelial tumors and keratin-positive giant cell-rich soft tissue tumors: two aspects of a single entity with frequent HMGA2-NCOR2 fusions.

Xanthogranulomatous epithelial tumor (XGET) and keratin-positive giant cell-rich soft tissue tumor with HMGA2-NCOR2 fusion (KPGCT) are two recently described neoplasms with both distinct and overlapping clinical and histopathologic features. We hypothesized that XGET and KPGCT may be related and represent a histologic spectrum of a single entity. To test this, we sought to characterize the clinical, radiographic, immunohistochemical, ultrastructural and molecular features of additional tumors with features of XGET and/or KPGCT, which we refer to descriptively as keratin-positive xanthogranulomatous/giant cell-rich tumors (KPXG/GCT). The archives were searched for potential cases of KPXG/GCT. Clinical and imaging features were noted. Slides were assessed for histologic and immunohistochemical findings. Ultrastructural and next generation RNA sequencing-based analysis were also performed. Nine cases were identified arising in seven women and two men [median age of 33 years (range: 12-87)]. Median tumor size was 4 cm (range: 2.4-14.0 cm) and tumors presented in the thigh (2), buttock (1), forearm (2), groin (1), cranial fossa (1), ilium (1), and tibia (1). Morphologically, tumors were most frequently characterized by a fibrous capsule, with associated lymphoid reaction, enclosing a polymorphous proliferation of histiocytes, giant cells (Touton and osteoclast-types), mixed inflammatory infiltrate, hemorrhage and hemosiderin deposition, which imparted a variably xanthogranulomatous to giant cell tumor-like appearance. One case clearly showed mononuclear cells with eosinophilic cytoplasm characteristic of XGET. All cases expressed keratin and 7 of 9 were found to harbor HMGA2-NCOR2 fusions including cases with xanthogranulomatous appearance. One patient developed local recurrence and multifocal pulmonary lesions, which were radiographically suspicious for metastases. Shared clinical, histologic and immunohistochemical features, and the shared presence of HMGA2-NCOR2 fusions supports interpretation of KPXG/GCT as a single entity which includes XGET and KPGCT. Given limited clinical follow-up to date and rare cases with apparently aggressive findings, we provisionally regard these tumors as having uncertain biologic potential.

Superficial Siderosis: A Clinical Review.

Superficial siderosis of the central nervous system results from subpial hemosiderin deposition due to chronic low-grade bleeding into the subarachnoid space. The confluent and marginal subpial hemosiderin is best appreciated on iron-sensitive magnetic resonance imaging sequences. With widespread use of magnetic resonance imaging, the disorder is increasingly being recognized, including in asymptomatic individuals. Gait ataxia, often with hearing impairment is a common clinical presentation. A clinical history of subarachnoid hemorrhage is generally not present. A macrovascular pathology is generally not causative. The most common etiology is dural disease, often dural tears. Prior or less commonly ongoing symptoms of craniospinal hypovolemia may be present. Common etiologies for dural tears include disc disease and trauma, including surgical trauma. Patients with dural tears due to herniated and calcified discs often have a ventral intraspinal fluid collection due to cerebrospinal fluid leak. A precise identification of the dural tear relies on multimodality imaging. It has been speculated that chronic bleeding from fragile blood vessels around the dural tear may be the likely underlying mechanism. Surgical correction of the bleeding source is a logical therapeutic strategy. Clinical outcomes are variable, although neuroimaging evidence of successful dural tear repair is noted. The currently available data regarding use of deferiprone in patients with superficial siderosis is insufficient to recommend its routine use in patients. ANN NEUROL 2021;89:1068-1079.

Interval appendicitis shows histological differences from acute appendicitis and may mimic Crohn disease and other forms of granulomatous appendicitis.

AIMS: While patients presenting with clinical signs and symptoms of acute appendicitis (AA) often receive surgical intervention shortly after presentation, certain patients may instead receive non-operative management initially, with appendectomy later. The histology of such interval appendicitis (IA) has only been described in small series. Also, we have noticed a recent increase in the incidence of IA specimens at our institution. METHODS AND RESULTS: We identified appendectomy specimens in our department during 2018 with available haematoxylin and eosin slides and electronic clinical data, and evaluated multiple histological findings. Cases were then divided into AA and IA, based on clinical history (AA if the patient presented to the hospital within 1 week of symptom onset and underwent appendectomy within 48 h; IA if appendectomy was delayed at least 1 week). Changes between groups were compared. The cohort included 165 cases (125 AA, 40 IA). Findings significantly more common in AA included mucosal acute inflammation, mural acute inflammation and acute serositis. Findings significantly more common in IA included Crohn-like mural inflammation, mural fibrosis, goblet cell hyperplasia, granulomas, xanthogranulomatous inflammation, haemosiderin-laden macrophages and granulation tissue. The rate of IA in 2018 (24%) was noticeably higher than in previous years. CONCLUSION: Acute inflammatory changes are more common in AA but can remain present in IA. Mural fibrosis, serosal adhesions, haemosiderin-laden macrophages and granulation tissue suggest IA. Granulomas and xanthogranulomatous inflammation can also be seen in IA, and Crohn-like mural inflammation is not uncommon. These histological patterns can guide signout and prevent diagnostic errors, particularly when clinical information is unavailable.

Obsessive-compulsive symptoms in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome.

Symptoms of obsessive-compulsive disorder (OCD) may rarely occur in the context of genetic syndromes. So far, an association between obsessive-compulsive symptoms (OCS) and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome has not been described as yet. A thoroughly phenotyped patient with OCS and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome is presented. The 25-year-old male patient was admitted to in-patient psychiatric care due to OCD. A whole-exome sequencing analysis was initiated as the patient also showed an autistic personality structure, below average intelligence measures, craniofacial dysmorphia signs, sensorineural hearing loss, and sinus cavernoma as well as subtle cardiac and ophthalmological alterations. The diagnosis of Baraitser-Winter cerebrofrontofacial syndrome type 2 was confirmed by the detection of a heterozygous likely pathogenic variant in the ACTG1 gene [c.1003C > T; p.(Arg335Cys), ACMG class 4]. The automated analysis of magnetic resonance imaging (MRI) revealed changes in the orbitofrontal, parietal, and occipital cortex of both sides and in the right mesiotemporal cortex. Electroencephalography (EEG) revealed intermittent rhythmic delta activity in the occipital and right temporal areas. Right mesiotemporal MRI and EEG alterations could be caused by a small brain parenchymal defect with hemosiderin deposits after a cavernomectomy. This paradigmatic case provides evidence of syndromic OCS in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. The MRI findings are compatible with a dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD. If a common pathophysiology is confirmed in future studies, corresponding patients with Baraitser-Winter cerebrofrontofacial syndrome type 2 should be screened for OCS. The association may also contribute to a better understanding of OCD pathophysiology.

Percutaneous Radiofrequency Ablation to Occlude the Thoracic Duct: Preclinical Studies in Swine for a Potential Alternative to Embolization.

PURPOSE: To investigate the feasibility of percutaneous radiofrequency (RF) ablation to occlude the thoracic duct (TD) in a swine model with imaging and histologic correlation. MATERIALS AND METHODS: Six swine underwent TD RF ablation. Two terminal (4 hours, 1 open and 1 percutaneous) and 4 survival (30 days, all percutaneous) studies were performed. Two 20-gauge needles were placed adjacent to the TD under direct visualization after right thoracotomy or under fluoroscopic guidance using a percutaneous transabdominal approach after intranodal lymphangiography. RF electrodes were advanced through the needles, and ablation was performed at 90°C for 90 seconds. Lymphangiography was performed, and the TD and adjacent structures were resected and examined microscopically at the end of each study period. RESULTS: Four of 6 subjects survived the planned study period and underwent follow-up lymphangiography. Two subjects in the survival group were euthanized early-1 after developing an acute chylothorax and 1 because of gastric volvulus 14 days after ablation. Occlusion of the targeted TD segment was noted on lymphangiography in 3 of the 4 remaining subjects (2 acute and 1 survival). Histology 4 hours after RF ablation demonstrated necrosis of the TD wall and hemorrhage within the lumen. Histology at 14 and 30 days revealed fibrosis with hemosiderin-laden macrophages replacing the ablated TD. Collagen degeneration within the aortic wall involving a maximum of 60% thickness was noted in 5 of the 6 subjects. CONCLUSIONS: Percutaneous RF ablation can achieve short-segment TD occlusion. Further study is needed to improve safety and demonstrate clinical efficacy in treating TD leaks.

Protective activity of purpurin against d-galactosamine and lipopolysaccharide-induced hepatorenal injury by upregulation of heme oxygenase-1 in the RBC degradation cycle.

Acute liver failure, associated with oxidative stress and sustained inflammation is the major clinical manifestation of liver diseases with a high mortality rate due to limited therapeutic options. Purpurin is a bioactive compound of Rubia cordifolia that has been used in textile staining, as a food additive, and as a treatment of multiple chronic and metabolic diseases associated with inflammation and oxidative stress. The present work aimed to investigate the protective efficacy of purpurin against hepatorenal damage. Thirty-six female albino rats were equally assigned into six groups. Purpurin was administered orally once a day for 6 days at doses of 05, 10, and 20 mg/kg, respectively. Intraperitoneal injection of lipopolysaccharide (50 µg/kg) was administered to the animals on 6th day evening, 1 h after d-galactosamine (300 mg/kg) administration to induce hepatorenal injury. The results revealed that purpurin alleviated alterations in serological and hematological parameters as well as restored histoarchitectural and cellular integrity of the liver and kidney. Purpurin restored superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and glutathione content in hepatorenal tissues. Accompanied by the diminution of increased bilirubin and biliverdin, purpurin also diminished total cholesterol, triglyceride, and lipid peroxidation in hepatorenal tissues. Purpurin markedly attenuated the elevation of CYP2E1, restored glutathione-S-transferase, and prevented DNA damage in hepatorenal tissues. Purpurin reduced iron overload by reducing heme depletion and recycling of ferritin and hemosiderin. It also reinforced biliverdin reductase, heme oxygenase-1 to employ hepatorenal protection by regulating antioxidant enzymes and other pathways that produced NADPH. Thus, it may be concluded that purpurin has protective potential against acute hepatorenal injury.

No differences in histopathological degenerative changes found in acute, trauma-related rotator cuff tears compared with chronic, nontraumatic tears.

PURPOSE: Acute trauma-related rotator cuff tears are believed to have better healing potential than chronic tears due to less degenerative changes of the tendons. However, the histopathological condition of tendons from trauma-related tears is not well investigated. The purpose of this study was to explore specific histopathological features in tendons from acute trauma-related full-thickness rotator cuff tears and to compare them to findings in tendons from nontraumatic, chronic tears. METHODS: In a prospective cohort study, 62 previously asymptomatic patients [14 women, median age 61 years (range 42-75)] with trauma-related full-thickness rotator cuff tears were consecutively included. Arthroscopic repair was performed within 30 (median, IQR 25-37) days after the injury. During surgery, tissue biopsies were harvested from the supraspinatus tendons in 53 (86%) of the patients. In addition, similar biopsies were harvested from 10 patients undergoing surgery for chronic tears without history of trauma. All tissue samples were examined by a well-experienced pathologist under light microscope. Tendon degeneration was determined using the Bonar score whereas immunostaining was used for proliferation (Ki67), inflammation (CD45), apoptosis (p53) and haemosiderin staining to study traces of bleeding. RESULTS: The median (IQR) Bonar score for the acute trauma-related biopsies was 10.5 (7.5-14.5) compared to 11 (5-12.8) for the control group with no statistically significant difference between the groups. No statistically significant between-group difference was found for the inflammatory index whereas tendons from patients with trauma-related full-thickness rotator cuff tears had statistically significantly higher apoptosis [3.1 (0.5-8.9) vs. 0.1 (0-1.5), p = 0.003] and proliferation [4.0 (1.8-6.9) vs. 0.4 (0-2.0), p = 0.001) indices than those undergoing surgery for chronic tears. Positive haemosiderin staining was found in 34% of tissue samples from patients with trauma-related tears compared to 10% in the control group (n.s). CONCLUSION: This study suggests that there is no difference with regard to degenerative changes between supraspinatus tendons harvested from patients with acute, trauma-related rotator cuff tears and patients with nontraumatic, chronic tears. LEVEL OF EVIDENCE: II.

Hemosiderin Accumulation in Liver Decreases Iron Availability in Tachycardia-Induced Porcine Congestive Heart Failure Model.

Despite advances in the management of iron deficiency in heart failure (HF), the mechanisms underlying the effects of treatment remain to be established. Iron distribution and metabolism in HF pathogenesis need to be clarified. We used a porcine tachycardia-induced cardiomyopathy model to find out how HF development influences hepatic and myocardial iron storing, focusing on ferritin, the main iron storage protein. We found that cumulative liver congestion (due to the decrease of heart function) overwhelms its capacity to recycle iron from erythrocytes. As a consequence, iron is trapped in the liver as poorly mobilized hemosiderin. What is more, the ferritin-bound Fe3+ (reflecting bioavailable iron stores), and assembled ferritin (reflecting ability to store iron) are decreased in HF progression in the liver. We demonstrate that while HF pigs show iron deficiency indices, erythropoiesis is enhanced. Renin-angiotensin-aldosterone system activation and hepatic hepcidin suppression might indicate stress erythropoiesisinduced in HF. Furthermore, assembled ferritin increases but ferritin-bound Fe3+ is reduced in myocardium, indicating that a failing heart increases the iron storage reserve but iron deficiency leads to a drop in myocardial iron stores. Together, HF in pigs leads to down-regulated iron bioavailability and reduced hepatic iron storage making iron unavailable for systemic/cardiac needs.