New Molecules of Diterpene Origin with Inhibitory Properties toward α-Glucosidase.

The incidence of diabetes mellitus (DM), one of the most common chronic metabolic disorders, has increased dramatically over the past decade and has resulted in higher rates of morbidity and mortality worldwide. The enzyme, α-Glucosidase (α-GLy), is considered a therapeutic target for the treatment of type 2 DM. Herein, we synthesized arylidene, heterocyclic, cyanoetoxy- and propargylated derivatives of quinopimaric acid (levopimaric acid diene adduct with p-benzoquinone) 1-50 and, first, evaluated their ability to inhibit α-GLy. Among the tested compounds, quinopimaric acid 1, 2,3-dihydroquinopimaric acid 8 and its amide and heterocyclic derivatives 9, 30, 33, 39, 44, with IC50 values of 35.57-65.98 µM, emerged as being good inhibitors of α-GLy. Arylidene 1ß-hydroxy and 1ß,13α-epoxy methyl dihydroquinopimarate derivatives 6, 7, 26-29, thiadiazole 32, 1a,4a-dehydroquinopimaric acid 40 and its indole, nitrile and propargyl hybrids 35-38, 42, 45, 48, and 50 showed excellent inhibitory activities. The most active compounds 38, 45, 48, and 50 displayed IC50 values of 0.15 to 0.68 µM, being 1206 to 266 more active than acarbose (IC50 of 181.02 µM). Kinetic analysis revealed the most active diterpene indole with an alkyne substituent 45 as a competitive inhibitor with Ki of 50.45 µM. Molecular modeling supported this finding and suggested that the indole core plays a key role in the binding. Compound 45 also has favorable pharmacokinetic and safety properties, according to the computational ADMET profiling. The results suggested that quinopimaric acid derivatives should be considered as potential candidates for novel alternative therapies in the treatment of type 2 diabetes.

Evolution of a melanoma in situ to a sarcomatoid dedifferentiated melanoma.

Sarcomatoid dedifferentiated melanoma (SDDM) is a recently recognized subtype of melanoma that stains diffusely for CD10 and lacks the expression of the usual melanocytic markers including S100, SOX10, MITF, and Melan A. Advances in next-generation DNA sequencing technology have facilitated the increased recognition of this rare, aggressive spindle cell melanoma. Herein, a case of relatively early lesion of SDDM arising in association with melanoma in situ is highlighted. A 72-year-old man with a history of previously treated melanoma in situ on the face five years prior presented with a new rapidly growing lesion within the scar of the treated site. A shave biopsy of the lesion revealed a centrally located 1.8-mm deep, poorly differentiated spindle cell neoplasm in association with an adjacent recurrent melanoma in situ. The spindle cell component stained diffusely for CD10, but failed to stain for S100, SOX10, and Melan-A while the melanoma in situ expressed all three melanocytic markers. Next-generation DNA sequencing assay revealed mutations in NF1, CDKN2A, TP53, and TSC1. A diagnosis of stage 2B SDDM arising in association with melanoma in situ was established based on the clinical context and genomic assay results.

Acute generalized exanthematous pustulosis due to terbinafine.

Acute generalized exanthematous pustulosis is a rare adverse cutaneous reaction characterized by the rapid appearance of numerous pustules arising on edematous, erythematous skin. It is commonly accompanied by fever and leukocytosis and usually resolves with discontinuation of the offending agent. Herein, acute generalized exanthematous pustulosis induced by terbinafine is described, followed by a brief review of the literature.

Generalized basaloid follicular hamartoma syndrome versus Gorlin syndrome: A diagnostic challenge.

Basaloid follicular hamartoma is a relatively rare benign neoplasm of follicular origin that can be mistaken histologically for basal cell carcinoma, but hereditary forms of basaloid follicular hamartoma are associated with nevoid basal cell carcinoma syndrome, or Gorlin syndrome. The pathophysiology of basaloid follicular hamartoma development involves mutations in the patched gene, which is also causative in nevoid basal cell carcinoma syndrome. We present a mother and daughter with basaloid follicular hamartomas, with genetic testing confirming patched gene mutation in the daughter.

Leser-Trélat Sign in Tumor-Stage Mycosis Fungoides.

A 71-year-old man presented with numerous pruritic seborrheic keratoses, with an eruptive onset over the course of 3 months. At presentation, he was also found to have hypopigmented tumors diffusely scattered throughout his body that were found to be mycosis fungoides on histologic examination. A theory regarding the pathophysiology of the development of eruptive seborrheic keratoses in the presence of mycosis fungoides is briefly discussed and 10 previous case reports of the Leser-Trélat sign in the setting of mycosis fungoides are reviewed.

Antimicrobial Activity of Citrate-Coated Cerium Oxide Nanoparticles.

The purpose of this study was to investigate the antimicrobial activity of citrate-stabilized sols of cerium oxide nanoparticles at different concentrations via different microbiological methods and to compare the effect with the peroxidase activity of nanoceria for the subsequent development of a regeneration-stimulating medical and/or veterinary wound-healing product providing new types of antimicrobial action. The object of this study was cerium oxide nanoparticles synthesized from aqueous solutions of cerium (III) nitrate hexahydrate and citric acid (the size of the nanoparticles was 3-5 nm, and their aggregates were 60-130 nm). Nanoceria oxide sols with a wide range of concentrations (10-1-10-6 M) as well as powder (the dry substance) were used. Both bacterial and fungal strains (Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris, Candida albicans, Aspergillus brasielensis) were used for the microbiological studies. The antimicrobial activity of nanoceria was investigated across a wide range of concentrations using three methods sequentially; the antimicrobial activity was studied by examining diffusion into agar, the serial dilution method was used to detect the minimum inhibitory and bactericidal concentrations, and, finally, gas chromatography with mass-selective detection was performed to study the inhibition of E. coli's growth. To study the redox activity of different concentrations of nanocerium, we studied the intensity of chemiluminescence in the oxidation reaction of luminol in the presence of hydrogen peroxide. As a result of this study's use of the agar diffusion and serial dilution methods followed by sowing, no significant evidence of antimicrobial activity was found. At the same time, in the current study of antimicrobial activity against E. coli strains using gas chromatography with mass spectrometry, the ability of nanoceria to significantly inhibit the growth and reproduction of microorganisms after 24 h and, in particular, after 48 h of incubation at a wide range of concentrations, 10-2-10-5 M (48-95% reduction in the number of microbes with a significant dose-dependent effect) was determined as the optimum concentration. A reliable redox activity of nanoceria coated with citrate was established, increasing in proportion to the concentration, confirming the oxidative mechanism of the action of nanoceria. Thus, nanoceria have a dose-dependent bacteriostatic effect, which is most pronounced at concentrations of 10-2-10-3 M. Unlike the effects of classical antiseptics, the effect was manifested from 2 days and increased during the observation. To study the antimicrobial activity of nanomaterials, it is advisable not to use classical qualitative and semi-quantitative methods; rather, the employment of more accurate quantitative methods is advised, in particular, gas chromatography-mass spectrometry, during several days of incubation.

Disparities in Cutaneous T-Cell Lymphoma Incidence by Race/Ethnicity and Area-Based Socioeconomic Status.

Cutaneous T-cell lymphoma (CTCL) is a rare type of extranodal non-Hodgkin lymphoma (NHL). This study uses population-based data from the New Jersey (NJ) State Cancer Registry to examine geographic variation in CTCL incidence and evaluates whether CTCL risk varies by race/ethnicity and census tract socioeconomic status (SES). The study included 1163 cases diagnosed in NJ between 2006 and 2014. Geographic variation and possible clustering of high CTCL rates were assessed using Bayesian geo-additive models. The associations between CTCL risk and race/ethnicity and census tract SES, measured as median household income, were examined using Poisson regression. CTCL incidence varied across NJ, but there were no statistically significant geographic clusters. After adjustment for age, sex, and race/ethnicity, the relative risk (RR) of CTCL was significantly higher (RR = 1.47, 95% confidence interval: 1.22-1.78) in the highest income quartile than in the lowest. The interactions between race/ethnicity and SES indicated that the income gradients by RR were evident in all groups. Compared to non-Hispanic White individuals in low-income tracts, CTCL risk was higher among non-Hispanic White individuals in high-income tracts and among non-Hispanic Black individuals in tracts of all income levels. Our findings suggest racial disparities and a strong socioeconomic gradient with higher CTCL risk among cases living in census tracts with higher income compared to those living in lower-income tracts.

Combining thermal, tri-stereo optical and bi-static InSAR satellite imagery for lava volume estimates: the 2021 Cumbre Vieja eruption, La Palma.

Determining outline, volume and effusion rate during an effusive volcanic eruption is crucial as it is a major controlling factor of the lava flow lengths, the prospective duration and hence the associated hazards. We present for the first time a multi-sensor thermal-and-topographic satellite data analysis for estimating lava effusion rates and volume. At the 2021 lava field of Cumbre Vieja, La Palma, we combine VIIRS + MODIS thermal data-based effusion rate estimates with DSMs analysis derived from optical tri-stereo Pléiades and TanDEM-X bi-static SAR-data. This multi-sensor-approach allows to overcome limitations of single-methodology-studies and to achieve both, high-frequent observation of the relative short-term effusion rate trends and precise total volume estimates. We find a final subaerial-lava volume of [Formula: see text] with a MOR of 28.8 ± 1.4 m3/s. We identify an initially sharp eruption-rate-peak, followed by a gradually decreasing trend, interrupted by two short-lived-peaks in mid/end November. High eruption rate accompanied by weak seismicity was observed during the early stages of the eruption, while during later stage the lava effusion trend coincides with seismicity. This article demonstrates the geophysical monitoring of eruption rate fluctuations, that allows to speculate about changes of an underlying pathway during the 2021 Cumbre Vieja eruption.

Dupilumab Failure in Treating Dermatomyositis-Associated Pruritus.

Dermatomyositis (DM) is a multisystem inflammatory condition with diverse cutaneous and systemic symptoms. Both muscle and skin involvement are common and can occur simultaneously or sequentially, or individuals can have muscle- or skin-limited disease. Skin involvement in DM can be extensive, and pruritus is one of the most problematic symptoms for the patient. Its pathophysiology is poorly understood, making management challenging for clinicians. A limited number of therapeutic agents target pruritus in DM, adding another challenge for clinicians. Previous case reports suggest dupilumab as a treatment for pruritus in DM. However, our patient experienced no relief. Our patient's failure of dupilumab suggests that its targets, interleukin (IL)-4 and IL-13, do not play a significant role in the pruritus of DM. It is possible that targeting other small molecules in inflammatory pathways could greatly alleviate pruritus for individuals with DM. Further studies need to be conducted to extrapolate the mechanism of pruritus in DM so that individuals with DM can find more significant relief.

Thermal remote sensing reveals communication between volcanoes of the Klyuchevskoy Volcanic Group.

Volcanoes are traditionally considered isolated with an activity that is mostly independent of the surrounding, with few eruptions only (< 2%) associated with a tectonic earthquake trigger. Evidence is now increasing that volcanoes forming clusters of eruptive centers may simultaneously erupt, show unrest, or even shut-down activity. Using infrared satellite data, we detail 20 years of eruptive activity (2000-2020) at Klyuchevskoy, Bezymianny, and Tolbachik, the three active volcanoes of the Klyuchevskoy Volcanic Group (KVG), Kamchatka. We show that the neighboring volcanoes exhibit multiple and reciprocal interactions on different timescales that unravel the magmatic system's complexity below the KVG. Klyuchevskoy and Bezymianny volcanoes show correlated activity with time-predictable and quasiperiodic behaviors, respectively. This is consistent with magma accumulation and discharge dynamics at both volcanoes, typical of steady-state volcanism. However, Tolbachik volcano can interrupt this steady-state regime and modify the magma output rate of its neighbors for several years. We suggest that below the KVG the transfer of magma at crustal level is modulated by the presence of three distinct but hydraulically connected plumbing systems. Similar complex interactions may occur at other volcanic groups and must be considered to evaluate the hazard of grouped volcanoes.

Causes, pathophysiology, and treatment of pruritus in the mature patient.

Chronic itch is a common and debilitating health condition in the elderly. There are several common causes of itch in the mature population, such as skin xerosis, immunosenescence, and neuropathic changes. In addition, skin diseases, such as seborrheic dermatitis and stasis dermatitis, systemic conditions (end-stage renal disease and diabetes), or psychogenic derailments, such as depression, anxiety, and dementia, can all serve as triggers of pruritus. Polypharmacy, a common occurrence among the elderly population, may also serve as a cause of itch that may or may not be accompanied by dermatitis. Such medications as µ opioids and calcium channel blockers have been found to have a connection with pruritus in the advanced aging population. Determining the exact trigger for pruritus in the elderly may be especially challenging, because itch can be idiopathic in many cases. The role of treatments should not only take into account elimination of various underlying cutaneous, systemic, or psychogenic conditions associated with itch but also focus on the skin changes that are characteristic of the aging process. Development of such treatment options can be guided by elucidation of the mechanisms underlying the pathophysiology of itch in the geriatric population.

Suppression of scratching-induced pleasurable sensation by compression nerve blocking and its association with itch relief.

Itch can be suppressed by scratching. At the same time, scratching evokes a pleasurable sensation. In the present study, we investigated the peripheral mechanism of scratching-induced pleasurability and its association with itch relief using compression nerve block. We found that myelinated nerve fibers (Aß-fibers and possibly Aδ-fibers), are involved in transmission of scratching-induced pleasurability. We observed that itch relief effect was the same regardless of whether the pleasurable sensation was evoked by scratching an itch, indicating that pleasure is not a necessary component to induce itch relief. This is the first study to investigate the peripheral mechanism of scratching-induced pleasurability and itch relief.

The prevalence and characteristics of chronic ocular itch: a cross-sectional survey.

INTRODUCTION: In this cross-sectional study, we aimed to determine the prevalence and characteristics of chronic ocular itch in an outpatient ophthalmology and optometry clinic. METHODS: Four hundred patients from an outpatient ophthalmology and optometry clinic were enrolled. The presence and characteristics of chronic ocular itch were assessed by a questionnaire. Data regarding ophthalmologic, dermatologic, and systemic conditions as well as current medications were extracted from medical records. RESULTS: Chronic ocular itch was present in 118 (29.5%) of 400 participants. Chronic ocular pruritus was significantly more prevalent in females [P=0.015; odds ratio (OR)=1.8; 95% confidence interval (CI), 1.1-2.8] and was significantly associated with the presence of allergic conjunctivitis [51.8% (n=45); P<0.001; OR=5.0; 95% CI, 3.0-8.3], dry eye syndrome [40.1% (75); P<0.001; OR=2.6; 95% CI, 1.7-4.1], blepharitis [43.8% (n=21); P=0.021; OR=2.0; 95% CI, 1.1-3.8], and atopic dermatitis [50.0% (n=10); P=0.023; OR=2.6; 95% CI, 1.1-5.8]. Chronic ocular itch was not significantly associated with systemic conditions, or the use of prescribed ophthalmologic medications. DISCUSSION: Chronic ocular itch is common and may be related to ophthalmologic or dermatologic pathologies. The present findings highlight the importance of identifying and managing this uncomfortable symptom that may negatively impact the quality of life and sleep of affected patients.