Histopathology of persistent long COVID toe: A case report.

During the 2020 coronavirus (SARS-CoV-2) pandemic, several cutaneous lesions were identified, including pseudo-chilblain, vesicular, urticarial, maculopapular, and livedo/necrosis. A 59-year-old obese man with probable COVID-19 developed painful cyanosis with histopathologic capillary thrombosis of toes, and the cyanosis persisted for nearly 22 months. Shortly after initial exposure to family members with documented SARS-CoV-2, he developed upper respiratory symptoms, yet his anti-SARS-CoV-2 antibody and nasal swab RT-PCR tests were repeatedly negative. Two family members were hospitalized and one of them succumbed with documented SARS-CoV-2 pneumonia within 10 days of exposure. Biopsy specimen of the distal toe 16 weeks after initial exposure showed papillary dermal capillary thrombosis with endothelial swelling, telangiectasia, and peri-eccrine lymphocytic infiltrates resembling pernio. Overall, this is the first case of biopsy specimen of "long COVID toe" following presumed SARS-CoV-2 exposure, with a demonstration of thrombotic vasculopathy, toe cyanosis, and pernio-like pathology.

Knockdown of Long Noncoding RNA SNHG14 Protects H9c2 Cells Against Hypoxia-induced Injury by Modulating miR-25-3p/KLF4 Axis in Vitro.

ABSTRACT: Cyanotic congenital heart disease (CCHD) is the main cause of death in infants worldwide. Long noncoding RNAs (lncRNAs) have been pointed to exert crucial roles in development of CHD. The current research is designed to illuminate the impact and potential mechanism of lncRNA SNHG14 in CCHD in vitro. The embryonic rat ventricular myocardial cells (H9c2 cells) were exposed to hypoxia to establish the model of CCHD in vitro. Quantitative real-time polymerase chain reaction was conducted to examine relative expressions of SNHG14, miR-25-3p, and KLF4. Cell viability was determined by the MTT assay. Lactate dehydrogenase (LDH) was measured by an LDH assay kit. Apoptosis-related proteins (Bax and Bcl-2) and KLF4 were detected by Western Blot. The targets of SNHG14 and miR-25-3p were verified by the dual-luciferase reporter assay. SNHG14 and KLF4 were upregulated, whereas miR-25-3p was downregulated in hypoxia-induced H9c2 cells and cardiac tissues of patients with CCHD compared with their controls. Knockdown of SNHG14 or overexpression of miR-25-3p facilitated cell viability, while depressing cell apoptosis and release of LDH in hypoxia-induced H9c2 cells. MiR-25-3p was a target of SNHG14 and inversely modulated by SNHG14. MiR-25-3p could directly target KLF4 and negatively regulate expression of KLF4. Repression of miR-25-3p or overexpression of KLF4 reversed the suppression impacts of sh-SNHG14 on cell apoptosis and release of LDH as well as the promotion impact of sh-SNHG14 on cell viability in hypoxia-induced H9c2 cells. Sh-SNHG14 protected H9c2 cells against hypoxia-induced injury by modulating miR-25-3p/KLF4 axis in vitro.

First Observation of HbM-Saskatoon at the Origin of Neonatal Cyanosis in a Tunisian Baby.

Several causes are known to be at the origin of neonatal cyanosis among them methemoglobinemia is by inheritance of an hemoglobin (Hb) M variant. This is a rare condition never been reported in Tunisia so far. Here, we report a Tunisian newborn with refractory cyanosis since birth. As cardiac and respiratory diseases were ruled out, methemoglobinemia was suspected. Hematological parameters, concentration of methemoglobin, capillary electrophoresis, and amplification sequencing of the HBB gene were performed. Computational analysis was achieved by different in silico tools to investigate the mutation effect. The diagnosis was established by a raised MetHb, confirmed by the presence HbM-Saskatoon [Beta63 (E7) His>Tyr] by capillary electrophoresis and molecular analysis. The identified mutation occurred as a de novo mutation. In silico analysis confirmed the pathogenicity of the mutation. To our knowledge, this is the first time that this mutation has been reported in the Tunisian population. In view of its low incidence rate, clinicians might misdiagnose cyanosis caused by HbM, which can lead to inappropriate treatment and clinical complications. An up-to-date literature review of HbM disease is presented in this study.

Cyanosis Due to Methemoglobinemia as the Presenting Sign of Glucose-6-Phosphate Dehydrogenase Deficiency in a Child: Diagnostic and Clinical Implications.

A previously healthy 3-year-old boy presented with pallor, jaundice, cyanosis, and a 24-hour history of vomiting and anorexia following fava bean ingestion. Clinical examination and laboratory findings were consistent with severe nonimmune hemolytic anemia with methemoglobinemia. Given the patient's history, a previously unrecognized glucose-6-phosphate dehydrogenase deficiency was suspected and diagnosed. The aim of this article is to delineate the possible coexistence of methemoglobinemia and glucose-6-phosphate dehydrogenase deficiency in children presented with acute hemolysis and discuss its management while reviewing the existing literature.

IDDCA syndrome in a Chinese infant due to GNB5 biallelic mutations.

Herein, we present a Chinese infant with an early-onset intellectual developmental disorder with cardiac arrhythmia syndrome. A 6-month-old boy visited our hospital because of convulsions and paroxysmal cyanosis for 1 day. Mental development analysis showed that the patient had a neurodevelopmental delay. Frequent seizures occurred, and ECG monitoring demonstrated severe cardiac arrhythmia. Whole-exome sequencing showed that the infant had two compound heterozygous variants, NM_016194:c.458G>A/p.Cys153Tyr and NM_016194:c.1032C>A/p.Tyr344*, in GNB5. The first variant was inherited from his mother, while the other one was a de novo variant. Haplotype analysis indicated that the de novo variant was located in the paternal chromosome. Structural modeling indicated that both mutations could influence the interaction of GNB5 with its binding protein. Our study expanded the known genetic and phenotypic spectrum of GNB5-associated diseases, by presenting a Chinese male infant with IDDCA.

Positional asphyxia in a work-related fatality.

Positional or postural asphyxia occurs when a particular body position interferes with adequate respiratory movements for a lengthy period of time. Death is usually accidental and associated with alcohol or drug intoxication, disability, or restraint. We report on the case of a 42-year-old man found unresponsive while working on farmland. The upper part of his body (head and upper limbs) was trapped in the highest and largest opening of the atomizer of a high-volume sprayer tank while his legs were hanging down. Bruises and abrasions were found on both suprascapular regions. Tramline bruises encircled the body between the abdominal and thoracic regions in line with the morphology of the tank's opening where the body was found. Cyanosis and petechial hemorrhages were found on his face, conjunctives, neck, and superior chest; the lungs were edematous. Toxicological analyses of body fluids were negative. The cause of death was postural asphyxia, and the manner of death was certified as a fatal accident at work. Work-related postural asphyxia has rarely been described in the literature. Scene investigation, autopsy, and toxicological analyses play a key role in the reconstruction of the dynamics involved in occupational events, in turn allowing the identification of any legal responsibilities of the worker or the employer.

Medical and pathologic characteristics of fatal anaphylaxis: a Spanish nationwide 17-year series.

Forensic series on fatal anaphylaxis are scarce, probably because the diagnosis of anaphylaxis is often complex and the incidence is low. We report on the medicolegal, demographic and histopathological characteristics of a series of sudden deaths which were investigated for anaphylaxis at the Spanish National Institute of Toxicology and Forensic Sciences (INTCF) over a 17-year period (1998-2015). A total of 122 undetermined sudden deaths from a high percentage of Spanish regions (81.5% of the total population) were sent to the INTCF with anaphylaxis as the suspected cause of death for histological, biochemical, and medicolegal investigation. Two certified allergists confirmed that 46 of the 122 cases were fatal anaphylaxis. The results indicated a median age of 51 years (IQR = 29) and a male predominance (76%). The main causes of anaphylaxis were drugs (41%), hymenoptera stings (33%), and food (13%). A previous allergic event had been reported in both food anaphylaxis (67%) and drug anaphylaxis (53%). The deaths occurred in health care settings (37%), at home (22%), and outside the home (26.09%). Histopathology data were available for 40 individuals. The most frequent autopsy findings were angioedema of the upper airways (50%), pulmonary edema (47.5%), atheromatosis of coronary vessels (32.5%), and pulmonary congestion (27.5%). Our findings for fatal anaphylaxis indicated a predominance of men, older age (≥50 years) and death in a health care setting (one-third of cases). Previous episodes had occurred in two-thirds of cases of food-induced anaphylaxis and in half of the cases of drug-induced anaphylaxis.

[BLUE BABY, PINK FUTURE].

Neonatal cyanosis is relatively common. It is usually a consequence of cyanotic heart disease or a pulmonary disorder, and warrants a thorough and quick investigation. Mutations causing decreased affinity of hemoglobin to oxygen may change α1 to ß2 binding. We describe a new mutation (asp 102 serine), in the γ chain of hemoglobin, causing neonatal cyanosis which resolves as the baby matures. In this case we would like to emphasize the importance of early diagnosis in order to avoid unnecessary disease workup.

Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India.

We report the clinical features and molecular characterization of 23 patients with cyanosis due to NADH-cytochrome b5 reductase (NADH-CYB5R) deficiency from India. The patients with type I recessive congenital methemoglobinemia (RCM) presented with mild to severe cyanosis only whereas patients with type II RCM had cyanosis associated with severe neurological impairment. Thirteen mutations were identified which included 11 missense mutations causing single amino acid changes (p.Arg49Trp, p.Arg58Gln, p.Pro145Ser, p.Gly155Glu, p.Arg160Pro, p.Met177Ile, p.Met177Val, p.Ile178Thr, p.Ala179Thr, p.Thr238Met, and p.Val253Met), one stop codon mutation (p.Trp236X) and one splice-site mutation (p.Gly76Ser). Seven of these mutations (p.Arg50Trp, p.Gly155Glu, p.Arg160Pro, p.Met177Ile, p.Met177Val, p.Ile178Thr, and p.Thr238Met) were novel. Two mutations (p.Gly76Ser and p.Trp236X) were identified for the first time in the homozygous state globally causing type II RCM. We used the three-dimensional (3D) structure of human erythrocyte NADH-CYB5R to evaluate the protein structural context of the affected residues. Our data provides a rationale for the observed enzyme deficiency and contributes to a better understanding of the genotype-phenotype correlation in NADH-CYB5R deficiency.

Lesson of the month 1: sudden onset postural livedo reticularis, cyanotic toes and multiorgan failure.

Cholesterol embolisation syndrome (CES) is a rare but serious disease with high mortality caused by the formation of an embolus made up of cholesterol crystals from atherosclerotic plaques. Its clinical presentation is usually initially insidious and it often remains unrecognised because of its non-specific clinical presentation, which can cause delays in treatment and high mortality. The most common physical symptoms are cutaneous. We present a lethal case of CES to increase the awareness about this serious condition.

[Nail-fold capillaroscopy in dermatology]. / La capillaroscopie péri-unguéale en dermatologie.

Nail-fold capillaroscopy is a non-invasive tool to study the microcirculation and is increasingly being used in dermatology, angiology and rheumatology. More recently, the use of video-capillaroscopy has allowed computer storage of capillaroscopic images (video-capillaroscopy), enabling evaluation of changes in capillaroscopic abnormalities during the follow-up of patients with systemic sclerosis or mixed connective tissue disease. Qualitative and quantitative assessment of the nail-fold dermal capillaries and of their organization can readily distinguish between a normal capillaroscopic pattern in primary Raynaud phenomenon and a specific sclerodermic pattern in secondary Raynaud phenomenon carrying a very high risk of systemic sclerosis. Apart from its important role as a diagnostic tool for distinguishing between primary and secondary Raynaud phenomenon, capillaroscopy is now used to predict the risk of development of digital ulcers and of future visceral complications in patients with systemic sclerosis. Moreover, nail-fold capillaroscopy is essential for differential diagnosis between connective tissue diseases, for the etiologic diagnosis of digital necrosis and diffuse interstitial lung disease, and in sclerodermiform syndromes.

[Clinical characteristics of 6 children with idiopathic interstitial pneumonia].

Objective: To analyze the clinical characteristics and prognosis of 6 children with idiopathic interstitial pneumonia (IIP). Methods: This retrospective study analyzed the clinical manifestations, examinations, treatment and prognosis of 6 children with IIP who were hospitalized in Children's Hospital of Nanjing Medical University from January 2015 to March 2020. Results: Of the 6 children, 2 were males and 4 were females, aged 4.8 to10.6 years. All children had a subacute onset, and presented with cough, shortness of breath and cyanosis. The lung high-resolution CT (HRCT) showed diffuse patchiness in bilateral lung fields in all the children and reticular pattern in 2 cases. Pulmonary function test found moderate to severe mixed defect in 5 children. Lung biopsy was performed in 4 children. All of the 6 children were treated with systemic glucocorticoids, of whom 2 cases had additional inhaled glucocorticoids. Four children were finally diagnosed as cryptogenic organizing pneumonia (COP), whose lung HRCT return to normal in 1-11 months. Two children were finally diagnosed as nonspecific interstitial pneumonia (NSIP), and had long-term residual fibrosis on lung HRCT. The 6 children were followed up for 1 year to 6 years and 5 months after discontinuation of systemic glucocorticoids, and all had no recurrence. Conclusions: The clinical characteristics of IIP in children are subacute onset presented with cough, shortness of breath, cyanosis and diffuse patchiness in bilateral lungs on HRCT. The common subtypes of IIP in children are COP and NSIP. Systemic glucocorticoid is effective for IIP in children and there is a good prognosis overall.

Developing and optimizing a chronic cyanotic swine model.

BACKGROUND: Pulmonary artery (PA)-left atrial (LA) shunt models in piglets have been described, but technical details critical to limit morbidity/mortality and promote study of chronic cyanosis are lacking. Accordingly, we describe our experience with an optimized technique. MATERIALS AND METHODS: In 25 6- to 8-wk-old Yorkshire piglets, a beveled, 8 mm, polytetrafluoroethylene tube graft was anastomosed to the PA and LA. Systemic pressure was maintained at >60 mmHg. Saturation targets were met by adjusting a Teflon band on the graft and distal PA. The target oxygen saturation (SO(2)) was 85% on a 50% fraction of inspired oxygen (FiO(2)). If the SO(2) was <75% on a 50% FiO(2), the graft was constricted to achieve a SO(2) ≥ 90% on a 100% FiO(2) and 75%-80% on a 21% FiO(2). Complications affecting mortality were neutralized with a stepwise strategy to minimize risk. RESULTS: Thrombosis, blood loss, and arrhythmia were determinants of survival. Protocol optimization over time increased survival while assuring chronic cyanosis. Survival approached 90%, with a SO(2) of 80% to 90%, 3 to 5 wk postoperatively. Complications included bleeding, excessive hypoxemia, uncontrolled shunt flow, arrhythmias, and thrombosis. CONCLUSIONS: Refinement of surgical technique, shunt adjustment via graft banding, and thrombotic and arrhythmia prophylaxis are the keys to success with this model.

Single ventricle cardiac defect.

Single ventricle heart is defined as a rare cardiac abnormality with a single ventricle chamber involving diverse functional and physiological defects. Our case is of a ten month-old baby boy who died shortly after admission to the hospital due to vomiting and diarrhoea. Autopsy findings revealed cyanosis of finger nails and ears. Internal examination revealed; large heart, weighing 60 grams, single ventricle, without a septum and upper membranous part. Single ventricle is a rare pathology, hence, this paper aims to discuss this case from a medico-legal point of view.

Congenital cyanotic heart disease with situs inversus totalis: an autopsy case report.

Sudden deaths because of congenital heart diseases are infrequently referred to the forensic pathologist for autopsy. Many of such deaths, if already diagnosed are released directly from the hospital without autopsy. Even forensic pathologists face a few difficulties in performing the autopsy on such infrequent cases, as they are not always updated with the anatomy of anomalies. While dealing with such cases, the concerned forensic pathologist is compelled to refer literature and textbooks again to understand the nature of developmental defects. This is especially so when dealing with cases of situs inversus accompanied by transposition of great arteries and other congenital cardiac abnormalities and variants such as single ventricle, double outlet right ventricle, Taussig-Bing variety etc. In the present case also, situs inversus with transposition of great vessels and other anomalies have been noted and studied.

Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress.

Sirtuin 1 (Sirt1) exerts its cardioprotective effects in various cardiovascular diseases via multiple cellular activities. However, the therapeutic implications of Sirt1 in hypoxic cardiomyocytes and the underlying mechanisms remain elusive. The present study investigated whether Sirt1 regulates autophagy and apoptosis in hypoxic H9C2 cardiomyocytes and in an experimental hypoxic mouse model. Right ventricular outflow tract biopsies were obtained from patients with cyanotic or acyanotic congenital heart diseases. Adenovirus Ad­Sirt1 was used to activate Sirt1 and Ad­Sh­Sirt1 was used to inhibit Sirt1 expression in H9C2 cells, in order to investigate the effect of Sirt1 on cellular autophagy and apoptosis. SRT1720, a pharmacological activator of Sirt1 and EX­527, a Sirt1 antagonist, were administered to mice to explore the role of Sirt1 in hypoxic cardiomyocytes in vivo. The levels of autophagy and apoptosis­related proteins were evaluated using western blotting. Apoptosis was investigated by TUNEL staining and Annexin V/7­aminoactinomycin D flow cytometry analysis. Heart tissue samples from cyanotic patients exhibited increased autophagy and apoptosis, as well as elevated Sirt1 levels, compared with the noncyanotic control samples. The data from the western blot analysis revealed that Sirt1 promoted autophagic flux and reduced apoptosis in hypoxic H9C2 cells. In addition, Sirt1 activated AMP­activated protein kinase (AMPK), and the AMPK inhibitor Compound C abolished the effect of Sirt1 on autophagy activation. Further exploration of the mechanism revealed that Sirt1 protects hypoxic cardiomyocytes from apoptosis, at least in part, through inositol requiring kinase enzyme 1α (IRE1α). Consistent with the in vitro results, treatment with the Sirt1 activator SRT1720 activated AMPK, inhibited IRE1α, enhanced autophagy, and decreased apoptosis in the heart tissues of normoxic mice compared with the hypoxia control group. Opposite changes were observed in hypoxic mice treated with the Sirt1 inhibitor EX­527. These results suggested that Sirt1 promoted autophagy via AMPK activation and reduced hypoxia­induced apoptosis via the IRE1α pathway, to protect cardiomyocytes from hypoxic stress.

The potentially lethal nature of bronchial casts: plastic bronchitis.

The gross and microscopic findings from 2 fatal cases of plastic bronchitis (PB) in children, a rare entity characterized by the formation of large mucous casts in the bronchial tree, are presented. These casts differ from ordinary mucus because of their increased cohesiveness and consistency, resulting in solid structures that model the respiratory airway tree. PB usually presents as a complication of underlying diseases, which determine the prognosis of the afflicted patients. Conditions commonly associated with PB include congenital cardiopathies, lymph vessel malformations, asthma, and sickle cell disease. The first case is a typical example of PB following surgical treatment of a cyanotic cardiopathy, with very characteristic and illustrative morphology. The second case describes the fatal course of PB in a patient with sickle cell disease, which has never been reported to the best of the authors' knowledge; in this case, an overlooked association with asthma could have contributed to the fatal outcome.