Efficacy of Botulinum Type A Injection for the Treatment of Postherpetic Neuralgia and Pruritus Persisting for More Than Four Years-A Case Report.

Background: Postherpetic neuralgia (PHN) and postherpetic pruritus (PHP) are common complications of shingles that affect patients' quality of life. PHN and PHP can be managed using various medications and interventional procedures; however, complications persisting for at least six months may hamper recovery. Subcutaneous injections of botulinum toxin type A (BTX-A) can control persistent PHN and PHP. Case presentation: A 71-year-old man presented at our hospital with itching and pain. He had been diagnosed with shingles in the ophthalmic branch of the trigeminal nerve one year previously. As the pain and itching persisted despite medication, a supraorbital nerve block, Gasserian ganglion block, epidural nerve block, and radiofrequency thermocoagulation were performed. A subcutaneous injection of BTX-A was administered into the ophthalmic area of the trigeminal nerve three years after the initial presentation. A decrease of >80% in pain and itching was reported after the injection; however, the left eyelid drooped and the eyeball shifted downward and outward immediately after the injection. No deterioration in vision or pupil dilation was observed, and almost complete resolution of these symptoms occurred spontaneously three months after the injection. Pain and itching continued to improve without further side-effects until six months after the injection. Conclusions: The subcutaneous injection of BTX-A may be an alternative treatment option for chronic and refractory neurological diseases such as PHN and PHP, which persist for four years and are resistant to conventional treatments. Nevertheless, care must be taken to minimize the risk of ptosis.

Push-Pull Mechanism of Attention and Emotion in Children with Attention Deficit Hyperactivity Disorder.

Background/Objectives: While deficits in executive attention and alerting systems in children with attention deficit hyperactivity disorder (ADHD) are well-documented, findings regarding orienting attention in ADHD have been inconsistent. The current study investigated the mechanism of attentional orienting in children with ADHD by examining their attentional bias towards threatening stimuli. Furthermore, we explored the modulating role of anxiety levels in ADHD on this attentional bias. Methods: In Experiment 1, 20 children with ADHD and 26 typically developing children (TDC) performed a continuous performance task that included task-irrelevant distractions consisting of angry faces and neutral places. In Experiment 2, 21 children with ADHD and 25 TDC performed the same task, but with angry and neutral faces as distractors. To measure children's anxiety levels, the State-Trait Anxiety Inventory was administered before each experiment. Results: In Experiment 1, results revealed no attentional bias effects in children with ADHD, whereas TDC exhibited attentional capture effects by both types of distractors. However, in Experiment 2, ADHD children demonstrated an attentional bias towards angry faces, which revealed a significant positive correlation with their trait anxiety levels (r = 0.61, p < 0.05). Further analyses combining all ADHD children showed that trait anxiety levels in Experiment 2 were significantly higher than those in Experiment 1. Finally, a significant positive correlation was found between anxiety levels and attentional bias towards angry faces in all ADHD children (r = 0.36, p < 0.01). Conclusions: Children with ADHD exhibited atypical attentional-orienting effects to threats, and their levels of trait anxiety appeared to modulate such attentional-orienting mechanisms.

Novel germline JAK2R715T mutation causing PV-like erythrocytosis in 3 generations. Amelioration by Ropeg-Interferon.

Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the JAK2 gene, including JAK2V617F or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for JAK2V617F and exon 12 mutations. Next generation sequencing revealed a novel mutation: JAK2R715T in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a JAK2R715T mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The in vitro reporter assay confirmed increased activity of the JAK2R715T kinase. Similar to PV, the JAK2R715T native cells have increased STAT5 phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased KLF2 transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated; however, Ropeginterferon-alfa-2b (Ropeg-IFN-α) induced a remission. Ropeg-IFN-α treatment also reduced JAK2 activity in the propositus, her mother and JAK2V617F PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline JAK2R715T gain-of-function mutation with many but not all comparable molecular features to JAK2V617F PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-α.

Impact of Guideline-Directed Management Strategies for Low-Density Lipoprotein Cholesterol Control in Patients Who Underwent Percutaneous Coronary Intervention.

There are little direct comparative evidences of strategies between ≥50% and the absolute target goal of low-density lipoprotein cholesterol (LDL-C) level <55 mg/100 ml for the patients who underwent percutaneous coronary intervention (PCI). This study aimed to investigate the clinical impact of different strategies between 2 groups of patients who underwent PCI. A total of 3,104 patients with previous PCI were retrospectively enrolled from 2014 to 2020 at Yeungnam University Medical Center. The study population was stratified into 2 groups based on whether the LDL-C level was <55 mg/100 ml at the 1-year mark or not. Furthermore, the 50% reduction rate of LDL-C was also categorized based on whether it had decreased by ≥50% from the initial LDL-C level at the 1-year mark. The primary end point was 3-year major adverse cardiovascular events (MACEs) which were defined as a composite of cardiovascular death, nonfatal myocardial infarction, target lesion revascularization, hospitalization for heart failure, or nonfatal stroke. There was no significant difference between the LDL <55 mg/100 ml group and the LDL ≥55 mg/100 ml group in the risk of MACEs (hazard ratio 1.06, 95% confidence interval 0.81 to 1.38, p = 0.690) after propensity score matching. However, the group that achieved ≥50% reduction of LDL-C from baseline LDL-C level showed a significant reduction in the occurrence of MACEs in the subgroup of LDL-C level ≥55 mg/100 ml (hazard ratio 0.41, 95% confidence interval 0.19 to 0.89, p = 0.025) compared with the group with <50% reduction of LDL-C. In all patients, the achievement rate of target LDL-C <55 mg/100 ml and more than 50% reduction from baseline was 17.2%. In conclusion, guideline-directed management strategy of ≥50% reduction of LDL-C from the baseline will be needed to reduce the incidence of MACEs in patients with LDL-C ≥55 mg/100 ml who underwent PCI. Additional efforts to increase the target goal achievement rate of LDL-C are warranted.

Gene expression changes in sickle cell reticulocytes and their clinical associations.

Transcriptional changes in compensatory erythropoiesis in sickle cell anemia (SCA) and their disease modulation are unclear. We detected 1226 differentially expressed genes in hemoglobin SS reticulocytes compared to non-anemic hemoglobin AA controls. Assessing developmental expression changes in hemoglobin AA erythroblasts for these genes suggests heightened terminal differentiation in early erythroblasts in SCA that diminishes toward the polychromatic to orthochromatic stage transition. Comparison of reticulocyte gene expression changes in SCA with that in Chuvash erythrocytosis, a non-anemic disorder of increased erythropoiesis due to constitutive activation of hypoxia inducible factors, identified 453 SCA-specific changes attributable to compensatory erythropoiesis. Peripheral blood mononuclear cells (PBMCs) in SCA contain elevated proportions of erythroid progenitors due to heightened erythropoiesis. Deconvolution analysis in PBMCs from 131 SCA patients detected 54 genes whose erythroid expression correlated with erythropoiesis efficiency, which were enriched with SCA-specific changes (OR = 2.9, P = 0.00063) and annotation keyword "ubiquitin-dependent protein catabolic process", "protein ubiquitination", and "protein polyubiquitination" (OR = 4.2, P = 7.5 × 10-5). An erythroid expression quantitative trait locus of one of these genes, LNX2 encoding an E3 ubiquitin ligase, associated with severe pain episodes in 774 SCA patients (OR = 1.7, P = 3.9 × 10-5). Thus, erythroid gene transcription responds to unique conditions within SCA erythroblasts and these changes potentially correspond to vaso-occlusive manifestations.

Increased blood reactive oxygen species and hepcidin in obstructive sleep apnea precludes expected erythrocytosis.

Obstructive sleep apnea (OSA) causes intermittent hypoxia during sleep. Hypoxia predictably initiates an increase in the blood hemoglobin concentration (Hb); yet in our analysis of 527 patients with OSA, >98% did not have an elevated Hb. To understand why patients with OSA do not develop secondary erythrocytosis due to intermittent hypoxia, we first hypothesized that erythrocytosis occurs in these patients, but is masked by a concomitant increase in plasma volume. However, we excluded that explanation by finding that the red cell mass was normal (measured by radionuclide labeling of erythrocytes and carbon monoxide inhalation). We next studied 45 patients with OSA before and after applying continuous positive airway pressure (CPAP). We found accelerated erythropoiesis in these patients (increased erythropoietin and reticulocytosis), but it was offset by neocytolysis (lysis of erythrocytes newly generated in hypoxia upon return to normoxia). Parameters of neocytolysis included increased reactive oxygen species from expanded reticulocytes' mitochondria. The antioxidant catalase was also downregulated in these cells from hypoxia-stimulated microRNA-21. In addition, inflammation-induced hepcidin limited iron availability for erythropoiesis. After CPAP, some of these intermediaries diminished but Hb did not change. We conclude that in OSA, the absence of significant increase in red cell mass is integral to the pathogenesis, and results from hemolysis via neocytolysis combined with inflammation-mediated suppression of erythropoiesis.

"What We Know and What We Do Not Know about Evolutionary Genetic Adaptation to High Altitude Hypoxia in Andean Aymaras".

Three well-studied populations living at high altitudes are Tibetans, Andeans (Aymaras and Quechuas), and Ethiopians. Unlike Tibetans and Ethiopians who have similar hemoglobin (Hb) levels as individuals living at sea level, Aymara Hb levels increase when living at higher altitudes. Our previous whole genome study of Aymara people revealed several selected genes that are involved in cardiovascular functions, but their relationship with Hb levels was not elucidated. Here, we studied the frequencies of known evolutionary-selected variants in Tibetan and Aymara populations and their correlation with high Hb levels in Aymara. We genotyped 177 Aymaras at three different altitudes: 400 m (Santa Cruz), 4000 m (La Paz), and 5000 m (Chorolque), and correlated the results with the elevation of residence. Some of the Tibetan-selected variants also exist in Aymaras, but at a lower prevalence. Two of 10 Tibetan selected variants of EPAS1 were found (rs13005507 and rs142764723) and these variants did not correlate with Hb levels. Allele frequencies of 5 Aymara selected SNPs (heterozygous and homozygous) at 4000 m (rs11578671_BRINP3, rs34913965_NOS2, rs12448902_SH2B1, rs10744822_TBX5, and rs487105_PYGM) were higher compared to Europeans. The allelic frequencies of rs11578671_BRINP3, rs34913965_NOS2, and rs10744822_SH2B1 were significantly higher for Aymaras living at 5000 m than those at 400 m elevation. Variant rs11578671, close to the BRINP3 coding region, correlated with Hb levels in females. Variant rs34913965 (NOS2) correlated with leukocyte counts. Variants rs12448902 (SH2B1) and rs34913965 (NOS2) associated with higher platelet levels. The correlation of these SNPs with blood cell counts demonstrates that the selected genetic variants in Aymara influence hematopoiesis and cardiovascular effects.

Downregulated KLF2 in polycythemia vera and essential thrombocythemia induces prothrombotic gene expression.

Thromboses are major causes of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET) diseases associated with JAK2V617F mutation. However, the molecular mechanism(s) of increased thrombosis in PV and ET remain unknown. Kruppel-like factor 2 (KLF2) is a transcription factor that regulates expression of genes associated with inflammation and thrombosis; the absence of KLF2 in neutrophils causes thrombosis by inducing tissue factor. We studied the role of KLF2 in regulating prothrombotic gene expression in PV and ET. Neutrophils and platelets KLF2 expression in PV and ET was lower than the controls. Furthermore, in patients with thromboses, KLF2 transcripts were lower in platelets than those without thromboses. JAK2V617F allelic burden was inversely correlated with KLF2 transcript levels, suggesting JAK-STAT pathway may downregulate KLF2 expression. Whole transcriptome analyses of neutrophils and platelets showed that a lower KLF2 expression was associated with an upregulation of KLF2-regulated thrombotic genes. In addition, low KLF2 expression in platelets positively correlated with thrombotic events. In patients with PV and ET, KLF2 expression was induced by pegylated interferon alfa (PegINF-α) but not by hydroxyurea treatments. These data suggest that KLF2 may be a regulator of PV and ET thrombosis and a novel therapeutic target to prevent thrombosis.

Risk Assessment of Perioperative Respiratory Adverse Events and Validation of the COLDS Score in Children with Upper Respiratory Tract Infection.

Background and objectives: Children are at greater risk of upper respiratory tract infection (URTI), which can pose a higher risk of perioperative respiratory adverse events (PRAEs), than adults. The purpose of this study was to validate the COLDS score as a pre-anesthetic risk assessment tool for predicting the possibility of PRAEs. Materials and methods: Children aged under 18 years and undergoing elective surgery were retrospectively included. Logistic regression analysis and the area under the receiver-operating characteristic (ROC) curve (AUC) were used to estimate the ability of the COLDS score to predict PRAEs. Propensity-matched comparison was evaluated using the cut-off value from the ROC curve. Results: Among the 6252 children, 158 children had a recent URTI and 34 cases of PRAEs were reported. Age, current symptoms, and COLDS score were found to be significant variables in predicting PRAEs. From the ROC curve, values of 0.652 (p = 0.007) for AUC and 12.5 for the cut-off value of the COLDS score were calculated. Propensity-matched comparison revealed that each and every component of COLDS contributed to the higher COLDS score group. In addition to higher COLDS score, younger age and current URTI symptoms were found to be significant risk factors for PRAEs. Conclusions: This study validated the predictive power of COLDS score as a risk assessment tool for children with URTI undergoing elective surgery under general anesthesia.