A Marine Natural Product, Harzianopyridone, as an Anti-ZIKV Agent by Targeting RNA-Dependent RNA Polymerase.

The Zika virus (ZIKV) is a mosquito-borne virus that already poses a danger to worldwide human health. Patients infected with ZIKV generally have mild symptoms like a low-grade fever and joint pain. However, severe symptoms can also occur, such as Guillain-Barré syndrome, neuropathy, and myelitis. Pregnant women infected with ZIKV may also cause microcephaly in newborns. To date, we still lack conventional antiviral drugs to treat ZIKV infections. Marine natural products have novel structures and diverse biological activities. They have been discovered to have antibacterial, antiviral, anticancer, and other therapeutic effects. Therefore, marine products are important resources for compounds for innovative medicines. In this study, we identified a marine natural product, harzianopyridone (HAR), that could inhibit ZIKV replication with EC50 values from 0.46 to 2.63 µM while not showing obvious cytotoxicity in multiple cellular models (CC50 > 45 µM). Further, it also reduced the expression of viral proteins and protected cells from viral infection. More importantly, we found that HAR directly bound to the ZIKV RNA-dependent RNA polymerase (RdRp) and suppressed its polymerase activity. Collectively, our findings provide HAR as an option for the development of anti-ZIKV drugs.

LC-MS metabolomics reveal skin metabolic signature of psoriasis vulgaris.

Recent metabolic studies have indicated that several metabolites in blood and urine of psoriasis functionally involved in the pathogenesis of psoriasis, but the skin metabonomics research of psoriasis is limited. We aimed to investigate the metabolic profiling of lesional and nonlesional skin and screen out potential biomarkers for psoriasis. We performed liquid chromatography-mass spectrometry (LC-MS)-based nontargeted metabolomic analysis to compare metabolic profile between lesional and nonlesional skin from 12 patients with psoriasis vulgaris. A total of 3463 metabolites were detected, of which 769 (346 named and 423 unnamed) in positive ion mode and 179 (80 named and 99 unnamed) in negative ion mode were significantly different between lesional and nonlesional skin. These different metabolites were mainly derived from amino acid, lipid and nucleotide metabolism, and involved in cell proliferation and apoptosis regulation. Fourteen metabolites (10 upregulated and 4 downregulated) were identified as the most potentially significant biomarkers. Interestingly, seven of them were positively (l-gamma-glutamyl-l-leucine, 2-methylcitric acid, l-palmitoylcarnitine, inosine, eicosapentaenoic acid and 13-hydroxy-octadecaenoic acid) or negatively (l-serine) correlated with disease severity. Significant differences of metabolic characteristics were found between lesional and nonlesional skin, which may contribute to assess the severity of psoriasis and therapeutic responses.

Sanguinarine, similar to the MICs of spectinomycin, exhibits good anti-Neisseria gonorrhoeae activity in vitro.

The increasing antibiotic resistance of Neisseria gonorrhoeae (NG) is an urgent need to explore new and effective drugs. The antibacterial activities of spectinomycin and sanguinarine against 117 clinical NG isolates and time-kill curve of sanguinarine were evaluated. Almost all isolates were resistant to penicillin (91.5%) and ciprofloxacin (96.5%), 8.5% showed resistance to azithromycin, 10.3% and 10.3% had decreased susceptibility/resistance to ceftriaxone and cefixime, respectively, whereas 100% were susceptible to spectinomycin. The minimum inhibitory concentration (MIC) ranges, MIC50, MIC90 and MICmean values of sanguinarine were 2-64 µg/ml, 16 µg/ml, 32 µg/ml and 16.9 µg/ml, respectively, and time-kill curve showed killing of bacteria in a dose-dependent manner during the assay time of 6h, very similar to spectinomycin. Sanguinarine has great potential as an effective and novel anti-NG agent.

Review of secukinumab-induced adverse events of special interest and its potential pathogenesis.

Although secukinumab has demonstrated high efficacy and favorable safety in moderate-to-severe psoriasis and psoriatic arthritis, patients developing adverse events of special interest (AESI) were reported increasingly in real-world practice. A systematic literature search of the PubMed database was conducted to identify clinical studies or case reports on secukinumab-induced AESI. More than 1077 patients (aged 18-74 years) from 55 studies were reported to have 24 AESI 3 days to 96 weeks after secukinumab treatment. The four most common AESI was inflammatory bowel disease (n > 1000), eczematous drug eruption (n > 30), drug-associated vasculitis (n = 8), and drug-induced lupus erythematosus (n = 4). Most of these AESI were only mild to moderately severe and resolved after secukinumab discontinuation without or with symptomatic treatment. Secukinumab has the potential to develop a number of AESI by probably dysregulating the different expression of polar T-cell axes (Th1, Th2, Th17, Th22, and/or Treg) and driving various cytokines in some patients. Physicians should be aware of these AESI for timely diagnosis and proper treatment.

Secukinumab-induced multiple lentigines in areas of resolved psoriatic plaques: A case report and literature review.

Psoriasis is a systemic inflammatory disease commonly associated with postinflammatory hyper- and hypo-pigmentation. Psoriasis-related cytokines such as IL-17 and TNF can contribute to these pigmentation changes by regulating both the growth and pigment production of melanocytes. Here, we present the first reported the case of a patient with a 10-year history of severe psoriasis vulgaris, who developed multiple lentigines in areas of resolved psoriatic plaques during anti-IL-17A antibody secukinumab.

Secukinumab monotherapy successfully treated severe refractory type V (atypical juvenile) pityriasis rubra pilaris: A case report and literature review.

Pityriasis rubra pilaris (PRP) is a rare heterogeneous group of papulosquamous inflammatory disorders with unknown etiology. PRP is often resistant to many conventional therapies which has made more challenging on treatment. More recently, several studies have shown encouraging clinical results of secukinumab in the treatment of PRP in adult, but no studies have explored its effects in children. We herein report a 7-year-old boy with severe type V PRP responded rapidly to secukinumab monotherapy (150 mg once weekly) when conventional therapies have failed. The patient showed rapid and dramatic improvement of erythema, palmoplantar hyperkeratosis, scaling, and itching within only 5 weeks, with no adverse effects. Secukinumab could be considered as a treatment option for refractory PRP in children, as recently reported in adult.

Successful clearance of extensive/recalcitrant cutaneous warts by acitretin monotherapy: A case series study.

Most available options for the treatment of warts are limited by the potential for scarring, pain, lack of response, or recurrences, and the patients are often unable to tolerate and accept those experiences. The aim of this study was to evaluate the clinical efficacy and safety of oral systemic acitretin monotherapy in patients with extensive/recalcitrant cutaneous warts. The patients were given a dose of acitretin of 0.8 mg kg-1 day-1 , and the clinical efficacy and safety of acitretin was assessed every 2 weeks for 2 months. A total of 14 patients (12 males and 2 females) were included, with an age of 14-60 years (mean 33 ± 14.7 years) and a course of 4-48 months (mean 21.6 ± 13.4 months). After 2 months of acitretin treatment, 42.9% (6/14) of patients (including warts of the feet, legs, and hands) exhibited complete response, 28.6% (4/14) excellent response, and 28.6% (4/14) good response. All patients demonstrated significant improvement, and the drug was well tolerated, with no patients discontinuing therapy due to side effects. Common mild side effects included dry skin and cheilitis. There were no recurrences during a follow-up period of 6 months. Acitretin monotherapy is an effective, safe, and well-tolerated treatment for patients with extensive/recalcitrant cutaneous warts who are unsuitable for or unwilling to accept traditional treatment methods.

Successful treatment of facial localized discoid lupus erythematosus with intralesional betamethasone: A report of three cases.

Discoid lupus erythematosus (DLE) is a chronic autoimmune skin disease that usually causes disfiguring scarring, dyspigmentation, and atrophy. Despite a range of available topical and systemic therapies, the treatment of DLE remains a therapeutic challenge, especially in some refractory cases. Here, we reported three male patients with long-term chronic lesions of unilateral facial localized DLE, who failed to have their disease controlled with many previous topical/systemic treatments, showed rapid and well response to intralesional injections of betamethasone (2 mg/mL, 0.2 mL/site) monotherapy once every 2 weeks for two, two, and four times of treatment, respectively. Intralesional betamethasone may provide a safe and effective alternative in the management of refractory localized DLE skin lesions.

Azithromycin-resistant Neisseria gonorrhoeae isolates in Guangzhou, China (2009-2013): coevolution with decreased susceptibilities to ceftriaxone and genetic characteristics.

BACKGROUND: The recent emergence of azithromycin-resistant (AZM-R) N. gonorrhoeae isolates that have coevolved decreased susceptibility to extended-spectrum cephalosporins has caused great concern. Here we investigated the prevalence of decreased susceptibility to ceftriaxone (CRO(D)) in AZM-R isolates and genetically characterized AZM-R isolates in Guangzhou, China from 2009 to 2013. METHODS: The minimum inhibitory concentration (MIC) of AZM and ceftriaxone was determined using an agar-dilution method. All AZM-R isolates were screened for mutations in 23S rRNA, mtrR and penA genes and genotyped using N. gonorrhoeae multi-antigen sequence typing (NG-MAST). RESULTS: Of the 485 identified N. gonorrhoeae isolates, 445 (91.8%) were isolated from male urethritis subjects, and 77 (15.9%) were AZM-R (MIC ≥ 1 mg/L), including 33 (6.8%) with AZM low-level resistant (AZM-LLR, MIC = 1 mg/L) and 44 (9.1%) with AZM middle-level resistant (AZM-MLR, MIC ≥ 2 mg/L). Significantly more CRO(D) (MIC ≥ 0.125 mg/L) showed in AZM-MLR isolates (43.2%, 19/44) as compared with that in AZM-LLR isolates (18.2%, 6/33) (p < 0.05). For the 23S rRNA, mtrR, penA or combined 23S rRNA/MtrR/penA mutations, no significant difference was found between AZM-LLR isolates and AZM-MLR isolates (P > 0.05); similar results were detected between combined AZM-LLR/CRO(D) isolates and combined AZM-MLR/CRO(D) isolates (P > 0.05). No mutation A2059G or AZM high-level resistant (AZM-HLR, MIC ≥ 256 mg/L) isolate was detected. Among 77 AZM-R isolates, 67 sequence types (STs) were identified by NG-MAST, of which 30 were novel. Most STs were represented by a single isolate. CONCLUSIONS: The AZM-R together CRO(D) isolates are now present in Guangzhou, China, which deserve continuous surveillance and the mechanism of concurrent resistance needs further study.

Trends in antimicrobial resistance in Neisseria gonorrhoeae isolated from Guangzhou, China, 2000 to 2005 and 2008 to 2013.

A total of 1224 Neisseria gonorrhoeae isolates from Guangzhou in 2 periods (2000-2005 and 2008-2013) were subjected to antimicrobial susceptibility testing. The percentage of penicillin- and ciprofloxacin-resistant isolates increased from 71.1% (473/665) to 90.9% (508/559) and 88.9% (591/665) to 98.0% (548/559), respectively. All isolates remain susceptible to spectinomycin and ceftriaxone, with increasing minimum inhibitory concentrations.

Complete hydatidiform mole and a coexistent fetus following ovulation induction in a patient with Sheehan's syndrome: a first case report and review of literature.

Pregnancy in Sheehan's syndrome (SS) is extremely rare. We present the first reported case of twin pregnancy with complete hydatiform mole (CHM) and a coexistent fetus (CHCF) in a patient with SS. A 29-year-old Chinese patient with SS became pregnant following one cycle of ovulation induction with human menopausal gonadotropin after secondary infertility. A normal live fetus and a low echogenic mass suspected hydatidiform mole (HM) were detected by ultrasound examinations at gestational week 8. The couple highly desired to continue the pregnancy because it is very hard to get pregnant for the patients with SS. However, the pregnancy was terminated for the size of the HM component increased rapidly at gestational week 15. Histological examinations confirmed CHCF. Genetic studies showed that the CHM genome was derived from paternal diploidy, and the normal fetus was from biparental genomes. Furthermore, a literature review on these topics is included. This case highlighted that even in a patient with SS, twin pregnancy with CHCF can still occur after ovulation induction.

Assessing the relationship between psoriasis and thyroid dysfunction through two sample MR analysis.

BACKGROUND: The association between psoriasis and hyperthyroidism/hypothyroidism remains inconclusive, with conflicting findings in prior studies. OBJECTIVES: This study employs Mendelian randomization methods to assess the potential relationship. METHODS: Given the inability to accurately observe the link between psoriasis and thyroid dysfunction, we prioritized utilizing known genetic variants to investigate the potential impacts of the disease.We analyzed data from genome-wide association studies (GWASs), FinnGen, and UK Biobank to extract information on psoriasis, hyperthyroidism, and hypothyroidism. Three MR approaches (MR Egger, weighted median, and inverse variance weighted) were used to scrutinize the causal link. RESULTS: Our analysis revealed no correlation between psoriasis and hyperthyroidism/hypothyroidism. However,  vulgar psoriasis and guttate psoriasis were associated with hypothyroidism/myxedema (IVW odds ratio (OR) = 1.00, 95% confidence interval (CI) = 1.00-1.00, P = 2.53E-03), and Graves' disease (IVW OR = 0.86, 95% CI = 0.72-1.01, P = 4.75E-02).In a subsequent analysis, we observed that hypothyroidism with mucinous edema showed no correlation with Graves' disease in the opposite(P = 9.33E-01). CONCLUSION: This MR analysis suggests no association between psoriasis and thyroid dysfunction, but highlights associations of vulgar/guttate psoriasis with hypothyroidism/myxedema and Graves' disease. In clinical practice, diagnosing guttate psoriasis requires vigilance for associated risks from hypothyroidism and Graves' disease. For patients with both vulgar psoriasis and hypothyroidism, careful monitoring for mucinous edema is crucial, as it may signal a hypothyroid crisis.

Oral abrocitinib in the treatment of granuloma annulare: a case report.

Aim: To evaluate the therapeutic efficacy and safety of JAK inhibitor abrocitinib in patients with localized granuloma annulare (GA) and to review the available cases documented in English.Methods: We presented a patient who had a persistent, localized granuloma anulare (GA) for one year and did not respond to traditional therapies. This patient was treated with oral abrocitinib at a dosage of 150 mg daily.Results: After 6 weeks of treatment with abrocitinib, the patient exhibited notable symptom improvement with no new lesions. No adverse events or recurrences were reported during the 5-month follow-up period.Conclusions: Abrocitinib may be a promising and safe treatment option for patients with localized GA who do not respond to traditional therapies.

Abrocitinib as a Novel Treatment for Multiple Skin Disorders: 3 Case Reports and a Scoping Review.

Janus kinase (JAK) inhibitors are increasingly being used in dermatology due to their broad potential in managing both local and systemic inflammation. More recently, abrocitinib, an oral JAK 1 inhibitor, has shown promising clinical efficacy in the treatment of various skin disorders beyond moderate to severe atopic dermatitis (AD). We firstly presented three cases, each with diagnosis of pyoderma gangrenosum (PG), livedoid vasculopathy (LV), or hidradenitis suppurativa (HS), and conducted a comprehensive scoping review of the available literature on the use of abrocitinib in the treatment of diverse skin disorders. We summarized a total of 16 skin disorders, including our cases. The results indicated that abrocitinib, whether used as monotherapy or in combination with other treatments, was effective and well-tolerated in these disorders. These findings expanded the range of diseases for which abrocitinib may serve as an alternative therapeutic choice.

Effect of amitriptyline on tetrodotoxin-resistant Nav1.9 currents in nociceptive trigeminal neurons.

BACKGROUND: Amitriptyline (AMI) is tricyclic antidepressant that has been widely used to manage various chronic pains such as migraines. Its efficacy is attributed to its blockade of voltage-gated sodium channels (VGSCs). However, the effects of AMI on the tetrodotoxin-resistant (TTX-r) sodium channel Nav1.9 currents have been unclear to present. RESULTS: Using a whole-cell patch clamp technique, this study showed that AMI efficiently inhibited Nav1.9 currents in a concentration-dependent manner and had an IC50 of 15.16 µM in acute isolated trigeminal ganglion (TG) neurons of the rats. 10 µM AMI significantly shifted the steady-state inactivation of Nav1.9 channels in the hyperpolarizing direction without affecting voltage-dependent activation. Surprisingly, neither 10 nor 50 µM AMI caused a use-dependent blockade of Nav1.9 currents elicited by 60 pulses at 1 Hz. CONCLUSION: These data suggest that AMI is a state-selective blocker of Nav1.9 channels in rat nociceptive trigeminal neurons, which likely contributes to the efficacy of AMI in treating various pains, including migraines.

Nummular headache: peripheral or central? One case with reappearance of nummular headache after focal scalp was removed, and literature review.

BACKGROUND: Nummular headache, or coin-shaped cephalagia, is defined as a mild to moderate, pressure-like pain that is felt exclusively in a circumscribed area. More than 200 cases of nummular headache have been reported since it was defined in 2002, but the pathogenesis remains unclear. METHODS: A patient with nummular headache who had the symptomatic area of his scalp removed but suffered headache reappearance was reported. All published cases of nummular headache in the English literature were reviewed and analyzed for demographic and clinical features, image and laboratory findings, and response to treatment. RESULTS: The patient with nummular headache had the symptomatic area of the scalp removed but suffered reappearance of headache in another area that overlapped with the former one. The literature review showed that nummular headache was a chronic, mild to severe, pressure-like pain with a circular or elliptical shape of 1-10 cm in diameter. The parietal region was the most affected region. Exacerbations and sensory disturbances in the affected area were reported in 43% and 56% of cases, respectively. Observational data suggested botulinum toxin type A (BoNTA) and gabapentin may be beneficial. DISCUSSION: Our case and evidence from the literature review support the peripheral mechanism of nummular headache. Nummular headache might be a local pain disorder stemming from terminal branches of a sensory nerve and could induce peripheral sensitization in one or several primary sensory neurons.

Clinical profile of cluster headaches in China - a clinic-based study.

BACKGROUND: The clinical profile of cluster headache in Chinese patients have not been fully studied. METHODS: The classification and clinical features of 120 consecutive patients with cluster headache (105 males, 15 females; mean age, 34.9 ± 10.5 years) visiting at International Headache Center from May 2010 to August 2012 were analyzed. RESULTS: Patients came from 16 different regions of China. Mean age at onset of cluster headache was 26.7 ± 10.9 years. Only 13 patients (10.8%) had previously been diagnosed with cluster headache. Mean time to diagnosis from first symptoms was 8.2 ± 7.1 years (range, 0-35 years). Chronic cluster headache was observed in only 9 patients (7.5%). The most commonly reported location of cluster headache was temporal region (75.0%), followed by retro-orbital region (68.3%), forehead (32.5%), vertex (32.5%) and occipital (22.5%). Lacrimation was the most consistently reported autonomic feature (72.5%). During acute attacks, 60.0% of patients experienced nausea, and 41.7% experienced photophobia and 40.8% experienced phonophobia. In addition, 38.3% reported restless behavior and 45.8% reported that physical activity exacerbated the pain. None of patients experienced visual or other kinds of aura symptoms before cluster attacks. We found that 38.3% of patients had <1 cluster period and 35.8% for 1-2 cluster periods per year with these periods occurring less frequently during the summer than during other seasons. Cluster duration was 1-2 months in 32.5% of patients. During cluster periods, 73.3% of patients had 1-2 attacks per day, and 39.2% experienced cluster attacks ranging in duration from 1 h to less than 2 h. The duration of attacks were 1.5 (1-2.25) hours for males and 1.5 (1-3) for females respectively. The World Health Organization quality of life-8 questionnaire showed that cluster headache reduced life quality. CONCLUSIONS: Compared to Western patients, Chinese patients showed a relatively low prevalence of chronic cluster headaches, pain sites mainly focused on areas distributed by the first division of the trigeminal nerve, a low frequency of restlessness and absent aura. These clinical features may be more common in Eastern populations, including mainland Chinese, Japanese and Taiwanese patients, than in Western patients.