Anti-TNF Thioester Glucocorticoid Antibody-Drug Conjugate Fully Inhibits Inflammation with Minimal Effect on Systemic Corticosterone Levels in a Mouse Arthritis Model.

We describe the discovery of a thioester-containing glucocorticoid receptor modulator (GRM) payload and the corresponding antibody-drug conjugate (ADC). Payload 6 was designed for rapid hepatic inactivation to minimize systemic exposure of nonconjugated GRM. Mouse PK indicated that 6 is cleared 10-fold more rapidly than a first-generation GRM payload, resulting in 10-fold lower exposure and 3-fold decrease in Cmax. The anti-mTNF conjugate ADC5 fully inhibited inflammation in mouse contact hypersensitivity with minimal effects on corticosterone, a biomarker for systemic GRM effects, at doses up to and including 100 mg/kg. Concomitant inhibition of P1NP suggests potential delivery to cells involved in the remodeling of bone, which may be a consequence of TNF-targeting or bystander payload effects. Furthermore, ADC5 fully suppressed inflammation in collagen-induced arthritis mouse model after one 10 mg/kg dose for 21 days. The properties of the anti-hTNF conjugate were suitable for liquid formulation and may enable subcutaneous dosing.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Long-term risk of glaucoma after cataract surgery in childhood.

PURPOSE: To examine the long-term risk of glaucoma after cataract surgery in childhood. METHODS: This study took place from January 2022 until December 2022 and included patients from a large family with hereditary childhood cataract who had cataract surgery before 18 years of age. Patients underwent an ophthalmologic examination to determine the presence of glaucoma or ocular hypertension (OHT). Patients who did not want to participate in the examination could contribute with a medical journal from their treating ophthalmologist. The risk of long-term glaucoma was determined using survival analysis, and risk factors were assessed using a Cox proportional hazards regression model. RESULTS: We included 68 patients (133 eyes) with a median age at cataract surgery of 7 years (IQR: 5-10). The median follow-up time after cataract surgery to glaucoma/OHT or the latest ophthalmologic examination was 35 years (IQR: 15-48). Twelve patients (18 eyes) had glaucoma, and five patients (eight eyes) had OHT, resulting in 15 patients with glaucoma/OHT. The long-term risk of glaucoma/OHT diagnosed in adulthood was 47.7% (CI: 21.8-70.9) at the age of 70 years of patients who were free of glaucoma before their 18th year. We could not confirm or dismiss an association between glaucoma/OHT and sex, age at surgery, number of ocular interventions before 18 years of age or glaucoma after cataract surgery in a first-degree relative. CONCLUSION: Cataract surgery in childhood is associated with a high risk of late-onset glaucoma. Regular lifelong follow-up is important to ensure early diagnosis and prevent extensive vision loss.

Which rehabilitation initiatives can effectively improve participation in an educational setting for visually impaired and blind adolescents? A systematic review.

BACKGROUND: Visually impaired and blind adolescents fare poorly in educational attainment compared to adolescents without vision impairment. Rehabilitation holds the potential to compensate for the hindrances that the impairment causes. Many rehabilitation initiatives exist. However, the efficacy of these initiatives remains uncertain. This systematic review assessed which rehabilitation initiatives improve participation in an educational setting for visually impaired and blind adolescents. METHODS: PubMed, Embase, Scopus, Cinahl, and Cochrane library databases were searched. Only primary studies as randomized controlled trial (parallel group or crossover), cohort studies, case-control studies, qualitative studies, and case-studies were included. Data on the study characteristics, visual impairment, type of intervention, research question, main findings, and implications for practice were extracted from the papers. Critical appraisal was performed using the Critical Appraisal Checklist for Qualitative Research and the Checklist for Quasi-Experimental Studies both from the Joanna Briggs Institute. The data extraction and the critical appraisal were performed independently by two reviewers. RESULTS: A total of 10 studies with visually impaired and blind adolescents were considered eligible, from an original search result of 3210 studies. In the thematic analysis we identified a heightened focus on different means for studying by making the curriculum content more accessible by applying different audio, tactile, or electronic devices (n = 8). A minor focus in the identified studies (n = 2) was placed on the impact of support from the environment on the development of literacy, for example the support from teachers or parents. Outcome parameters representing more diverse rehabilitation initiatives have not been adequately investigated in the literature. The scientific evidence that we identified was based on few publications with contradictory results and some studies were of questionable quality, limiting the applicability of their findings. CONCLUSIONS: Overall, the review identified a gap in the evidence regarding rehabilitation initiatives for visually impaired and blind adolescents that enables participation in an educational setting. The overall quality assessment of the 10 studies identified several risks of bias, for which reason the current scientific evidence does not qualify as a basis for decision making, leaving the adolescents in a heightened risk to fall even further behind in the educational system. Further high quality randomized controlled trials are required to establish high-quality evidence.

At-Home Trial of Four Different Head-Mounted Displays in Visual Rehabilitation of People with Stargardt Disease.

Purpose: To examine the potential of different head-mounted displays in the rehabilitation of individuals with visual impairment. Methods: This prospective explorative study conducted between September 2019 and August 2020 included participants with Stargardt disease with moderate to severe visual impairment and a relatively preserved peripheral visual field. AceSight, eSight 3, IrisVision Live, and Jordy were tested. After instruction and training, participants chose two head-mounted displays for home use for two weeks per device. The Canadian Occupational Performance Measure was used for evaluation. Results: Twelve participants (aged 16-53 years) tested all head-mounted displays in the clinic. Distance visual acuity and reading distance improved with all head-mounted displays and eSight and Irisvision improved near visual acuity. Six participants decided not to test the head-mounted display at home due to lack of time or energy, dizziness and discomfort, double vision and peripheral visual field limitation, or aesthetics. After home use, the participants reported improved visual function at a distance with IrisVision, AceSight, and e-Sight, whereas only AceSight improved vision during near tasks. IrisVision and eSight improved reading ability, and none of the devices improved vision during tasks involving computers. Five participants used the devices sparingly, and five avoided public use owing to aesthetics. Conclusion: We found an improvement in distance visual acuity and increased reading distance for all tested head-mounted displays. Additionally, IrisVision and eSight improved visual function at near and eSight also improved contrast vision at distance. Despite the possibility of improving vision, social stigma and device aesthetics kept the participants from using head-mounted displays in public and limited their use at home.

Optic Disc Drusen Prevalence in Patients With Retinitis Pigmentosa: A Cross-Sectional Study.

BACKGROUND: Studies of patients with retinitis pigmentosa (RP) have reported an increased prevalence of optic disc drusen (ODD) compared with the ODD prevalence in the general population. The diagnostic gold standard method for identifying ODD is enhanced depth imaging optical coherence tomography (EDI-OCT), but this modality has not previously been used systematically for identifying ODD in patients with RP. This study aimed to estimate the prevalence of ODD in patients with RP using EDI-OCT. METHODS: In this cross-sectional study, 40 patients with clinically diagnosed RP aged 18 years or older were included. All patients underwent an ophthalmic examination, including kinetic perimetry, EDI-OCT of the optic nerve head, and fundus photography. Genetic testing with a next-generation sequencing panel of retinal dystrophy genes was performed on the RP patients without a prior genetic diagnosis. RESULTS: Twelve patients (30.0%) had at least one ODD. Six patients had bilateral ODD. No significant differences between patients with and without ODD were found according to age, refraction, best-corrected visual acuity, Bruch membrane opening, or visual field. The genetic variation causing RP was found in 11 of 12 cases in the ODD group and in 17 of 28 cases in the group without ODD. CONCLUSIONS: We found the prevalence of ODD in patients with RP to be 30.0%. This is 15 times higher than in the general population and much higher than previously estimated in most studies, potentially indicating that the 2 conditions might be pathogenically related.

Endoplasmic reticulum protein 5 attenuates platelet endoplasmic reticulum stress and secretion in a mouse model.

Extracellular protein disulfide isomerases (PDIs), including PDI, endoplasmic reticulum protein 57 (ERp57), ERp72, ERp46, and ERp5, are required for in vivo thrombus formation in mice. Platelets secrete PDIs upon activation, which regulate platelet aggregation. However, platelets secrete only ∼10% of their PDI content extracellularly. The intracellular role of PDIs in platelet function is unknown. Here, we aim to characterize the role of ERp5 (gene Pdia6) using platelet conditional knockout mice, platelet factor 4 (Pf4) Cre+/ERp5floxed (fl)/fl. Pf4Cre+/ERp5fl/fl mice developed mild macrothrombocytopenia. Platelets deficient in ERp5 showed marked dysregulation of their ER, indicated by a twofold upregulation of ER proteins, including PDI, ERp57, ERp72, ERp46, 78 kilodalton glucose-regulated protein (GRP78), and calreticulin. ERp5-deficient platelets showed an enhanced ER stress response to ex vivo and in vivo ER stress inducers, with enhanced phosphorylation of eukaryotic translation initiation factor 2A and inositol-requiring enzyme 1 (IRE1). ERp5 deficiency was associated with increased secretion of PDIs, an enhanced response to thromboxane A2 receptor activation, and increased thrombus formation in vivo. Our results support that ERp5 acts as a negative regulator of ER stress responses in platelets and highlight the importance of a disulfide isomerase in platelet ER homeostasis. The results also indicate a previously unanticipated role of platelet ER stress in platelet secretion and thrombosis. This may have important implications for the therapeutic applications of ER stress inhibitors in thrombosis.

Prevalence and risk factors for hypothalamus-pituitary-adrenal axis suppression in infants receiving glucocorticoid eye drops after ocular surgery.

PURPOSE: To examine the prevalence and risk factors for hypothalamus-pituitary-adrenal axis suppression (HPA axis suppression) in infants receiving glucocorticoid (GC) eye drops after ocular surgery. METHODS: This was a clinical observational cohort study. Children under the age of two receiving GC eye drops after cataract or glaucoma surgery between 1 January 2017 and 31 December 2021 were included at one centre. Medical history and results of the adrenocorticotropic hormone (ACTH) stimulation tests were obtained through patient charts. RESULTS: Forty-nine infants were included in the study. Ten out of 22 patients (45.5%) tested during treatment and two out of 27 patients (7.4%) tested after treatment cessation were diagnosed with HPA axis suppression. The duration of HPA axis suppression extended beyond 3 months in 8 out of 12 patients. Logistic regression showed that infants with HPA axis suppression had received a higher GC dose/body weight/day before the first ACTH test (p < 0.001). There was a 79% (95% CI:1.28;2.50) increase in the odds of having HPA axis suppression for a 0.01 mg GC increase/kg/day corresponding to an additional daily eye drop for an infant weighing 5 kg. There was an association between HPA axis suppression and number of days from surgery to test (p = 0.003), age at surgery (p = 0.035) and cumulated GC dose (p = 0.005). Three infants with HPA axis suppression had affected growth and one had Cushing-like features, but there were no cases of Addisonian crisis. CONCLUSION: Infants are at risk of having hypothalamus-pituitary-adrenal axis suppression if they receive a high daily glucocorticoid dose per weight by topical ocular administration. Infants receiving glucocorticoids after ocular surgery should be monitored clinically or by ACTH testing.

Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure-activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

Cataract Surgery with or without Intraocular Lens Implantation in Pediatric Uveitis: A Systematic Review with Meta-Analyses.

PURPOSE: To systematically review the results of comparative studies of modern cataract surgery in pediatric uveitis with or without intraocular lens (IOL) implantation and to perform comparative meta-analyses to compare visual acuity outcomes and complication rates. METHODS: On 12 November 2020, we systematically searched the Cochrane Central, PubMed/MEDLINE, EMBASE, ClinicalTrials.gov, and all affiliated databases of the Web of Science. Two authors independently reviewed studies and extracted data. Studies were reviewed qualitatively in text and quantitatively with meta-analyses. Outcome measures were preoperative and postoperative best-corrected visual acuity (BCVA), inflammation control, and rates of postoperative complications. RESULTS: Ten studies of 288 eyes were eligible for review of which the majority were eyes with juvenile idiopathic arthritis-associated uveitis. Summary estimates revealed that the BCVA was better in pseudophakic eyes vs. aphakic eyes (1-year postoperative: -0.23 logMAR, 95% CI: -0.43 to -0.03 logMAR, P=0.027; 5-year postoperative: -0.35 logMAR, 95% CI: -0.51 to -0.18 logMAR, P=0.000036). Pseudophakic eyes had more visual axis opacification (OR 6.76, 95% CI: 2.73 to 16.8, P=0.000036) and less hypotony (OR 0.19, 95% CI: 0.04 to 0.95, P=0.044). CONCLUSIONS: In modern era cataract surgery on eyes with pediatric uveitis with IOL implantation leads to satisfactory and superior visual outcomes and no differences in complication rates apart from an increased prevalence of visual axis opacification and a decreased prevalence of hypotony when compared to aphakia. However, limitations of the retrospective design and the presence of selection bias necessitate a careful interpretation.

Pars plana vitrectomy combined with hyaloido-zonula-iridectomy in treatment of patients with chronic aqueous misdirection: A systematic literature review and case series.

PURPOSE: To evaluate the efficacy of vitrectomy combined with hyaloido-zonula-iridectomy from an anterior or a posterior approach in patients with treatment-resistant aqueous misdirection (chronic aqueous misdirection) by systematically reviewing existing literature in combination with presentation of a case series. METHODS: A systematic literature review was performed in PubMed, EMBASE and Cochrane Library databases using search terms: malignant glaucoma, ciliary block, ciliolenticular block and aqueous misdirection. A consecutive series of three pseudophakic patients (5 eyes) diagnosed with chronic aqueous misdirection after cataract surgery is presented. RESULTS: A literature search identified 31 articles describing treatment of chronic aqueous misdirection with vitrectomy and a hyaloido-zonula-iridectomy. Studies, where patients were treated with a complete vitrectomy from pars plana in combination with a hyaloido-zonula-iridectomy, reported low relapse rates. Studies describing a surgical approach with vitrectomy performed from the anterior chamber, followed by a hyaloido-zonula-iridectomy, also reported low relapse rates except for one reporting relapse in nearly half of the patients. In our case series, a complete vitrectomy combined with a hyaloido-zonula-iridectomy resolved the chronic aqueous misdirection in all five eyes after one procedure except one eye where the hyaloido-zonula-iridectomy was repeated due to an insufficient opening. Some of the eyes still needed antiglaucomatous treatment due to chronic angle closure. CONCLUSION: In treatment-resistant malignant glaucoma, vitrectomy combined with a hyaloido-zonula-iridectomy should be considered performed to ensure communication between the anterior chamber and the vitreous cavity. If the condition has been unresolved for a long time, extensive synechiae of the angle may decrease the success rate due to chronic angle closure.

Prevalence of Charles Bonnet syndrome in patients with glaucoma: a systematic review with meta-analyses.

Glaucoma is a widespread sight-threatening condition often only recognized when very pronounced. It is initially characterized by peripheral visual field losses, while advanced stages also affect the central vision. Some of these patients may experience visual hallucinations, the Charles Bonnet syndrome (CBS). In this systematic review and meta-analysis, we provide an overview of the literature dealing with the prevalence of CBS in patients with glaucoma. We searched the databases PubMed/MEDLINE, Embase, Web of Science, the Cochrane Central and PsycInfo on 22 March 2020. Eight studies (n = 827 patients) were identified and included for a qualitative and quantitative analysis. No studies included a representative sample of patients with only glaucoma. In patients with glaucoma in different stages and with ocular comorbidities, prevalence of CBS was 2.8% (CI95%: 0.7-6.1%). Among patients with glaucoma where all had bilateral low visual acuity, prevalence of CBS was 13.5% (CI95%: 8.4-19.6%). In patients with glaucoma who visited vision rehabilitation clinics, presumably due to an extensive vision impairment, prevalence of CBS was 20.1% (CI95%: 16.8-23.6%). Risk factors of CBS besides low vision were high age, female gender, reduced contrast sensitivity and not living alone. Taken together, we find that CBS may not be rare in patients with advanced glaucoma with and without ocular comorbidities. However, limitations of the current literature should be highlighted and careful approach towards conclusions is important. More studies are needed to better understand the prevalence and risk factors among different populations of patients with glaucoma.

Diagnostic Test Accuracy of the Red Reflex Test for Ocular Pathology in Infants: A Meta-analysis.

Importance: Red reflex testing is a simple and inexpensive method implemented in many countries as an important part of infant screening for ocular pathologies. Objectives: To review the literature on the diagnostic accuracy of the red reflex test in infant screening for ocular pathologies and to perform meta-analyses to provide summary estimates. Data Sources: The following literature databases were searched for English-language, peer-reviewed literature, published until April 19, 2020: Cochrane Central, PubMed/MEDLINE, Embase, Web of Science Core Collection, BIOSIS Previews, Current Contents Connect, Data Citation Index, Derwent Innovations Index, KCI-Korean Journal Database, Russian Science Citation Index, SciELO Citation Index, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and ClinicalTrials.gov. Study Selection: Eligibility criteria were defined according to population (studies of consecutively screened infants), exposure (red reflex or Brückner test as the index test), comparator (any ophthalmological examination), and study type (any study with diagnostic test accuracy data). Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines were followed. Data were extracted independently by 2 authors. For summary estimates of diagnostic test accuracy, the hierarchical summary receiver operating characteristics curve was used. Prevalence of ocular pathologies was introduced for a prevalence meta-analysis, which was then used in calculations of diagnostic accuracy of the red reflex test when applied in infant screening. Main Outcomes and Measures: True-positive, false-positive, true-negative, and false-negative findings; sensitivity; specificity; and positive and negative predictive values. Results: In this meta-analysis, 8713 unique infants from 5 unique studies were eligible for qualitative and quantitative review. All studies used the red reflex test without pupillary dilation and were compared with a reference test performed with pupillary dilation. For any ocular pathology, an estimated sensitivity of 7.5% (95% CI, 7.4%-7.5%) and specificity of 97.5% (95% CI, 97.5%-97.5%) was found. Focusing on ocular pathologies that required a medical or surgical intervention, sensitivity improved to 17.5% (95% CI, 0.8%-84.8%) and specificity remained high at 97.6% (95% CI, 87.7%-99.6%). Conclusions and Relevance: These findings suggest that an abnormal red reflex finding most likely reflects an underlying ocular pathology. However, a normal red reflex finding during screening does not exclude ocular disease.

Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: A Danish population-based study.

BACKGROUND: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but it may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine can be best used as a predictor for severely delayed MTX elimination, thus providing a guide for therapeutic interventions to minimize renal toxicity. METHODS: Pharmacokinetic data were retrospectively collected on 218 Danish children with acute lymphoblastic leukemia treated with HD-MTX 5 or 8 g/m2 on the NOPHO2000 protocol. Moderately delayed MTX elimination was defined as 42-hour plasma MTX ≥ 4.0-9.9 µM, and severely delayed elimination was defined as 42-hour plasma MTX ≥ 10 µM. RESULTS: Median 42-hour plasma MTX was 0.61 µM (interquartile range, 0.4-1.06 µM). Of 1295 MTX infusions with 5 g/m2 (n = 140 patients) or 8 g/m2 (n = 78 patients), 5.1% were severely (1.5%) or moderately (3.6%) delayed. The risk of having delayed elimination was highest in the first of eight infusions with MTX 5 g/m² (7.4% vs 0.0 to 4.1% for subsequent MTX infusions) (P < 0.02). A 25 µM increase or a 1.5-fold increase in plasma creatinine within 36 hours from start of the MTX infusion had a sensitivity of 92% (95% CI, 82%-97%) and a specificity of 85% (95% CI, 83%-87%) for predicting 42-hour MTX ≥4.0 µM. CONCLUSIONS: A 25 µM increase or a 1.5-fold in plasma creatinine within 36 hours after start of an HD-MTX infusion can predict delayed MTX elimination, thus allowing intensification of hydration and alkalization to avoid further renal toxicity and promote the elimination of MTX.

Pain relief in a neuropathy patient by lacosamide: Proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors.

BACKGROUND: Small fiber neuropathy (SFN) is a severe and disabling chronic pain syndrome with no causal and limited symptomatic treatment options. Mechanistically based individual treatment is not available. We report an in-vitro predicted individualized treatment success in one therapy-refractory Caucasian patient suffering from SFN for over ten years. METHODS: Intrinsic excitability of human induced pluripotent stem cell (iPSC) derived nociceptors from this patient and respective controls were recorded on multi-electrode (MEA) arrays, in the presence and absence of lacosamide. The patient's pain ratings were assessed by a visual analogue scale (10: worst pain, 0: no pain) and treatment effect was objectified by microneurography recordings of the patient's single nerve C-fibers. FINDINGS: We identified patient-specific changes in iPSC-derived nociceptor excitability in MEA recordings, which were reverted by the FDA-approved compound lacosamide in vitro. Using this drug for individualized treatment of this patient, the patient's pain ratings decreased from 7.5 to 1.5. Consistent with the pain relief reported by the patient, microneurography recordings of the patient's single nerve fibers mirrored a reduced spontaneous nociceptor (C-fiber) activity in the patient during lacosamide treatment. Microneurography recordings yielded an objective measurement of altered peripheral nociceptor activity following treatment. INTERPRETATION: Thus, we are here presenting one example of successful patient specific precision medicine using iPSC technology and individualized therapeutic treatment based on patient-derived sensory neurons.

ECG with alternating electric axis in relation to left-sided tension pneumothorax: a case report and review of the literature.

The incidence of spontaneous pneumothorax has been estimated to 7.4-18.0/100,000 for men and 1.2-6.0/100,000 for women. The most common symptoms are sudden chest pain and dyspnoea. Due to chest pain many patients have an electrocardiogram (ECG) done in the acute setting. We present a case of unusual findings of electric alternans in the electrocardiogram (ECG) in a patient with a left-sided spontaneous pneumothorax. Reviewing the literature we found five former cases of pneumothoraxes with electric alternans in the ECG, all occurring in relation to left-sided pneumothorax.

Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists.

Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.

Conversion of Human Fibroblasts to Stably Self-Renewing Neural Stem Cells with a Single Zinc-Finger Transcription Factor.

Direct conversion of somatic cells into neural stem cells (NSCs) by defined factors holds great promise for mechanistic studies, drug screening, and potential cell therapies for different neurodegenerative diseases. Here, we report that a single zinc-finger transcription factor, Zfp521, is sufficient for direct conversion of human fibroblasts into long-term self-renewable and multipotent NSCs. In vitro, Zfp521-induced NSCs maintained their characteristics in the absence of exogenous factor expression and exhibited morphological, molecular, developmental, and functional properties that were similar to control NSCs. In addition, the single-seeded induced NSCs were able to form NSC colonies with efficiency comparable with control NSCs and expressed NSC markers. The converted cells were capable of surviving, migrating, and attaining neural phenotypes after transplantation into neonatal mouse and adult rat brains, without forming tumors. Moreover, the Zfp521-induced NSCs predominantly expressed rostral genes. Our results suggest a facilitated approach for establishing human NSCs through Zfp521-driven conversion of fibroblasts.

Pattern of Functional TTX-Resistant Sodium Channels Reveals a Developmental Stage of Human iPSC- and ESC-Derived Nociceptors.

Human pluripotent stem cells (hPSCs) offer the opportunity to generate neuronal cells, including nociceptors. Using a chemical-based approach, we generated nociceptive sensory neurons from HUES6 embryonic stem cells and retrovirally reprogrammed induced hPSCs derived from fibroblasts. The nociceptive neurons expressed respective markers and showed tetrodotoxin-sensitive (TTXs) and -resistant (TTXr) voltage-gated sodium currents in patch-clamp experiments. In contrast to their counterparts from rodent dorsal root ganglia, TTXr currents of hPSC-derived nociceptors unexpectedly displayed a significantly more hyperpolarized voltage dependence of activation and fast inactivation. This apparent discrepancy is most likely due to a substantial expression of the developmentally important sodium channel NAV1.5. In view of the obstacles to recapitulate neuropathic pain in animal models, our data advance hPSC-derived nociceptors as a better model to study developmental and pathogenetic processes in human nociceptive neurons and to develop more specific small molecules to attenuate pain.