Use of Janus kinase inhibitors in atopic dermatitis - an update.

Atopic dermatitis is among the cutaneous inflammatory disorders whose pathophysiology is thought to be influenced by the JAK-STAT intracellular signalling system. The effectiveness of systemic and topical Janus kinase (JAK) inhibitors in the treatment of atopic dermatitis has been shown in clinical trials and case studies. At present, oral abrocitinib (Cibinqo), oral upadacitinib (Rinvoq), oral baricitinib (Olumiant) and topical ruxolitinib (Opzelura) have approval from the US-FDA for their use in the treatment of atopic dermatitis. The efficacy and safety of oral and topical Janus kinase inhibitors for the treatment of atopic dermatitis have been reviewed in this article.

Identification and characterization of a novel outer membrane protein receptor required for hemin utilization in Vibrio vulnificus.

Vibrio vulnificus, the cause of septicemia and serious wound infection in humans and fishes, require iron for its pathogenesis. Hemin uptake through the outer membrane receptor, HupA, is one of its many mechanisms by which it acquires iron. We report here the identification of an additional TonB-dependent hemin receptor HvtA, that is needed in conjunction with the HupA protein for optimal hemin utilization. The HvtA protein is significantly homologous to other outer membrane hemin receptors and its expression in trans restored the uptake of hemin and hemoglobin, the latter to a weaker extent, in a mutant strain that was defective in both receptors. Quantitative RT-PCR suggested that transcription of the hvtA gene was iron regulated. The operon containing the hvtA gene is homologous to the operon in V. cholerae containing the hemin receptor gene hutR suggesting a vertical transmission of the hvtA cluster from V. cholerae to V. vulnificus.

Rapidly progressive growth of Renal Clear Cell Carcinoma and Gastrointestinal Stromal Tumor during the 3rd trimester of pregnancy: A clinical and diagnostic dilemma.

The incidence of cancer among pregnancy, albeit rare, presents as a significant diagnostic challenge for clinicians especially with considerations for materno-fetal well-being. The double-edged sword of Renal Clear Cell Carcinoma and Gastrointestinal Stromal Tumor in near-term pregnant woman was encountered in our case and skillfully maneuvered via combination of advanced diagnostic techniques involving CT, MRI and endoscopy. A discussion board comprising of experts was set up and after extended consultation involving patient's relatives, elective cesarean was performed at 34 weeks after which surgical excision resulted in successful extraction of both the tumors, ensuring the survival of both mother and child.

Coronavirus disease 2019 on routine testing in eclampsia: a case report.

BACKGROUND: Coronavirus disease 2019 has been associated with adverse pregnancy outcomes, including preeclampsia. Coronavirus disease 2019 and preeclampsia have overlapping clinical features and are therefore challenging to differentiate. Since pregnant women are not routinely tested for coronavirus disease 2019, it is prudent to test for it among patients presenting with preeclampsia or eclampsia. CASE PRESENTATION: A 23-year-old female, a Munda, gravida 1 para 0, at 36 weeks and 5 days of amenorrhea presented to Mal Super Specialty Hospital as a referral in a semiconscious state after a severe attack of tonic-clonic seizures. Detailed history from the husband was insignificant except for a persistent cough for the last 7 days. She had denied any visual changes, headaches, or vaginal discharge. Physical examination revealed tachycardia (150 beats per minute), elevated blood pressure (187/111 mmHg), tachypnea (36 breaths per minute), and oxygen saturation of 94% on room air. Routine coronavirus disease 2019 rapid test was positive, and urine dipstick was +3. Additional tests revealed leukocytosis and elevated liver enzymes. Chest radiograph revealed prominent interstitial markings, and a bedside transabdominal ultrasonography showed a live single intrauterine fetus in cephalic presentation with normal cardiac activity and movements. A diagnosis of a prime gravida with eclampsia and coronavirus disease 2019 was made. She was managed with intravenous labetalol; she had already received a loading dose of intravenous magnesium sulfate, and we administered two maintenance doses during monitoring. Within an hour of admission, she had a spontaneous rupture of the amniotic membranes, with meconium-stained liquor (grade 2), and the fetal heart rate (148 beats per minute) was reassuring. She had an uncomplicated vaginal delivery of a live male newborn. Shortly after delivery, she developed slight respiratory distress and significant fluid overload that was managed with furosemide. Coronavirus disease 2019 reverse-transcription polymerase chain reaction test came back negative for the neonate and positive for the mother. She was shifted to the coronavirus disease 2019 treatment unit, and her contact with the child was limited. She was kept on a course of tablets ivermectin, zinc, vitamin C, montelukast, azithromycin, metronidazole, and injectable pantoprazole. The mother and child were discharged on day 15 after recovery with negative COVID nasopharyngeal swab. CONCLUSION: A diagnosis of preeclampsia or eclampsia should prompt testing for coronavirus disease 2019.

Calcified chronic subdural hematoma: illustrative case.

BACKGROUND: Calcified chronic subdural hematomas (CCSDHs) are rare variants of chronic subdural hematomas (CSDHs) accounting to only 0.3-2.7% of CSDHs. Although the majority of the patients with CSDHs recover from surgery, there still is some doubt about its being applied to CCSDHs. OBSERVATIONS: In this case report, the authors present a case of a 75-year-old male presenting with deterioration of motor function in his left limbs over the course of 18 months and acute neurological deterioration in the form of altered sensorium for 7 days. The patient experienced an episode of aspiration in the preoperative period that led to deterioration of pulmonary function in the postoperative period. A chest radiograph showed diffuse patches suggesting pulmonary compromise. Computed tomography and magnetic resonance imaging (MRI) documented a large subdural collection at the right frontal and parietal hemisphere with calcification, which was successfully and completely removed by surgery. LESSONS: The chances of a subdural hematoma progressing to calcification is extremely rare. The presentation of this case was such that surgical intervention was the only option left for the patient. The presence of lacunar infarcts in the thalamus on MRI can also be attributed to the calcified hematoma.

Severe Postpartum Hemorrhage in an Asymptomatic COVID-19 Patient: A Call to Be on Guard.

Postpartum hemorrhage (PPH), the loss of more than 500 mL of blood following childbirth, is a leading cause of maternal mortality worldwide. The current coronavirus disease 2019 (COVID-19) pandemic has strained health-care systems globally. Pregnant women are a vulnerable group at a high risk of severe infection with COVID-19 due to the physiological changes in their immune state. Although the infection can be asymptomatic, severe COVID-19 infection is associated with respiratory distress, fever and coagulopathies that can complicate an already hypercoagulable pregnancy state. There is a dearth of existing literature regarding the complications of COVID-19 infection during pregnancy, and much is yet to be known about this rapidly evolving pandemic. In our case report, we received a 23-year-old gravida 2 para 1 woman who was COVID-19 positive but asymptomatic; she presented to the obstetric department with labor pains which progressed to severe postpartum hemorrhage and development of mild respiratory distress.

Functional profiling of p53-binding sites in Hdm2 and Hdmx using a genetic selection system.

Upregulation of structurally homologous oncoproteins Hdm2 and Hdmx has been linked to the depletion or inactivation of their common regulation target the tumor suppressor p53 protein leading to the progression of cancer. The restoration of the p53 function, rendered suppressed or dormant by these negative regulators, establishes, therefore, a unique opportunity for a targeted induction of apoptosis in cancers that retain wild-type p53. While several small molecules have been reported to rescue the tumor suppressor by antagonizing the Hdm2-p53 interaction, these agents displayed limited application scope by being ineffective in tumors enriched with active Hdmx. Here, we describe the use of a genetic selection system and encoded library of conformationally pre-organized peptides to perform functional profiling of each regulator revealing specific recognition features that guide the antagonism of Hdm2-p53 and Hdmx-p53 interactions. Structure-activity relationship analysis of the most effective leads identified functional and structural elements mediating selective recognition of the two structurally related regulators, while providing convenient starting points for further activity optimization.

Characterization of temperature-dependent hemin uptake receptors HupA and HvtA in Vibrio vulnificus.

The Gram-negative pathogen Vibrio vulnificus produces several iron-sequestration systems including a hemin uptake system in response to iron limitation as a means to acquire this essential element. Strains of this organism are capable of causing serious septicemia in humans and eels, where hemin is abundant and an advantageous source of iron. Vibrio vulnificus hemin uptake systems consist of HupA, a well studied outer membrane protein, and a recently identified HvtA protein receptor. In this study, we confirmed that the expression of the hvtA gene is iron-regulated in a fur-dependent manner. When analyzed for virulence in a hemin-overloaded murine model system, the hupA gene was more important for establishing infection than the hvtA gene. Transcriptional profiling of these genes using strains of two different biotypes, biotype 1 (human pathogen) and biotype 2 (eel pathogen), showed that the expression of the two receptors was also regulated in response to temperature. The expression of hupA was highly induced in elevated temperatures in the human pathogenic strain when tested in iron-depleted conditions. Conversely, hvtA expression was induced significantly in the eel pathogenic strain at a lower temperature, a condition where the hupA locus was relatively repressed. Our results indicate that although both hupA and hvtA are involved for optimal hemin uptake in V. vulnificus, their expression is dually regulated by the environmental cues of iron concentration and temperature. Together, these data suggest that the virulence genes hupA and hvtA are tightly regulated and strictly induced during iron limitation combined with the physiological temperature of the host organism.

Long-term Characterization of Retinal Degeneration in Royal College of Surgeons Rats Using Spectral-Domain Optical Coherence Tomography.

Purpose: Prospective treatments for age-related macular degeneration and inherited retinal degenerations are commonly evaluated in the Royal College of Surgeons (RCS) rat before translation into clinical application. Historically, retinal thickness obtained through postmortem anatomic assessments has been a key outcome measure; however, utility of this measurement is limited because it precludes the ability to perform longitudinal studies. To overcome this limitation, the present study was designed to provide a baseline longitudinal quantification of retinal thickness in the RCS rat by using spectral-domain optical coherence tomography (SD-OCT). Methods: Horizontal and vertical linear SD-OCT scans centered on the optic nerve were captured from Long-Evans control rats at P30, P60, P90 and from RCS rats between P17 and P90. Total retina (TR), outer nuclear layer+ (ONL+), inner nuclear layer (INL), and retinal pigment epithelium (RPE) thicknesses were quantified. Histologic sections of RCS retina obtained from P21 to P60 were compared to SD-OCT images. Results: In RCS rats, TR and ONL+ thickness decreased significantly as compared to Long-Evans controls. Changes in INL and RPE thickness were not significantly different between control and RCS retinas. From P30 to P90 a subretinal hyperreflective layer (HRL) was observed and quantified in RCS rats. After correlation with histology, the HRL was identified as disorganized outer segments and the location of accumulated debris. Conclusions: Retinal layer thickness can be quantified longitudinally throughout the course of retinal degeneration in the RCS rat by using SD-OCT. Thickness measurements obtained with SD-OCT were consistent with previous anatomic thickness assessments. This study provides baseline data for future longitudinal assessment of therapeutic agents in the RCS rat.

Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist.

PURPOSE: To assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model. METHODS: Albino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections. RESULTS: A five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice. CONCLUSIONS: Intraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation.

Sarpogrelate, a 5-HT2A Receptor Antagonist, Protects the Retina From Light-Induced Retinopathy.

PURPOSE: To determine if sarpogrelate, a selective 5-HT2A receptor antagonist, is protective against light-induced retinopathy in BALB/c mice. METHODS: BALB/c mice were dosed intraperitoneally with 5, 15, 30, 40, or 50 mg/kg sarpogrelate 48, 24, and 0 hours prior to bright light exposure (10,000 lux) as well as 24 and 48 hours after exposure. Additionally, a single injection regimen was evaluated by injecting mice with 50 mg/kg sarpogrelate once immediately prior to light exposure. To investigate the potential for additive effects of serotonin receptor agents, a combination therapy consisting of sarpogrelate (15 mg/kg) and 8-OH-DPAT (1 mg/kg) was evaluated with the 5-day treatment regimen. Neuroprotection was characterized by the preservation of retinal thickness and function, measured by spectral-domain optical coherence tomography (SD-OCT) and electroretinography (ERG), respectively. RESULTS: Mice that were light damaged and injected with saline had significantly reduced outer retinal thickness, total retinal thickness, and ERG amplitudes compared with naïve mice. A 5-day administration of 15, 30, or 40 mg/kg of sarpogrelate was able to partially protect retinal morphology and full protection of retinal morphology was achieved with a 50 mg/kg dose. Both 15 and 30 mg/kg doses of sarpogrelate partially preserved retinal function measured by ERG, whereas 40 and 50 mg/kg doses fully preserved retinal function. Additionally, a single administration of 50 mg/kg sarpogrelate was able to fully preserve both retinal morphology and function. Administration of 15 mg/kg of sarpogrelate and 1 mg/kg of 8-OH-DPAT together demonstrated an additive effect and fully preserved retinal morphology. CONCLUSIONS: A 5- or 1-day treatment with 50 mg/kg sarpogrelate can completely protect the retina of BALB/c mice from light-induced retinopathy. Partial protection can be achieved with lower doses starting at 15 mg/kg and protection increases in a dose-dependent manner. Treatment with low doses of sarpogrelate and 8-OH-DPAT elicits an additive effect that results in full protection of retinal morphology.