Successful Treatment of Severe Psoriasis in an Adolescent with Ustekinumab

Psoriasis is a chronic, inflammatory, immune‐mediated disease. Approximately 30% of patients have disease onset before age 18 years. Psoriasis in children and adolescents may be difficult to control, with subsequent poor quality of life and psychosocial consequences. We describe the case of a 12‐year‐old boy with severe, refractory, chronic plaque psoriasis for 6 years. Various therapeutic regimens including different topical corticosteroids, topical vitamin D analogs, phototherapy, photochemotherapy, systemic therapy with methotrexate, cyclosporin, and combination therapies showed only partial or transient responses with frequent relapses. Because anti‐interleukin‐12/23 agents have been successfully used in adults with psoriasis, ustekinumab was initiated and our patient showed a rapid, excellent, sustained response. No recurrence or flares have been observed after 33 months of follow‐up. This case illustrates that ustekinumab may be an effective and safe therapeutic option in adolescents with psoriasis.     

Cardinal points and image–object magnification with an accommodative lens implant (1 CU)

A simple mathematical method for the determination of the cardinal points of pseudophakic eyes after implantation of an accommodative intraocular lens [posterior chamber intraocular lenses (PCIOL)] is presented. The purpose of this study was to explore the changes during pseudophakic accommodation (PAC) in (1). the positions of the cardinal points, (2). the distance of the object conjugate with the retina, and (3). the image-object magnification. These theoretical accommodation data are compared with clinical measurements. METHODS AND PATIENTS: Using biometrical measurements of the axial length, equivalent power of the cornea and the anterior chamber depth (ACD) in the non-accommodated state we used linear geometric optics for determination of the cardinal points and object distance as well as lateral magnification (the ratio of image to object size). With the measurement of ACD decrease (following pharmacological stimulation of the ciliary muscle with 2% pilocarpine eye drops) we determined the changes of the cardinal points and magnification to assess PAC amplitude from the shortening of the object distance. Calculated values of PAC amplitude were compared with the respective measured values derived from amplitude measures by accommodometer, defocusing and streak retinoscopy. We analysed the results of a prospective study on 35 eyes of 28 patients after cataract surgery (target refraction: -0.2 D) and accommodative PCIOL implantation (1 CU, Human Optics AG, Erlangen, Germany) 3 months after surgery. RESULTS: After pilocarpine eye drops, ACD (mean +/- S.D., range; median) decreased by 0.88 +/- 0.48 mm (0.51-1.91; 0.66). Distance of the in-focus object decreased from the non-accommodated state (-5.62 +/- 1.83 m, -25 to -1.1; -4.83 m) to the accommodated state (ACD decrease) (-0.81 +/- 0.21, -2.11 to -0.65; -0.79 m). For a theoretical ACD decrease of 1.0 mm (the intrinsic limitation of the PCIOL design) it was -0.59 +/- 0.28, -1.31 to -0.51; -0.63 m and resulted in an objective accommodative response of 1.49 +/- 0.16, 1.21-1.81; 1.46 D, depending on the actual geometry of the individual eye. On average, magnification as induced by PAC in contrast to that induced by adequate spectacle addition differed by only about 1%. Accommodation measured with defocusing and the accommodometer correlated significantly with the theoretical value based on IOLMaster measurement of ACD decrease (r = 0.752, p = 0.005 and r = 0.676, p = 0.02). Likewise, accommodation measured with streak retinoscopy correlated weakly with the theoretical value based on IOLMaster ACD decrease (r = 0.465, p = 0.05). CONCLUSIONS: Using geometrical optics, PAC can be derived from the biometric data of the eye and the measured ACD decrease. This approach may be an additional indicator for the accommodative response in pseudophakic patients and may allow a subdivision of the measured accommodation into true PAC and pseudoaccommodation, for example, because of increased depth of focus induced by pupillary constriction.     

A density functional theory study on silver and bis-silver complexes with lighter tetrylene: are silver and bis-silver carbenes candidates for SARS-CoV-2 inhibition? Insight from molecular docking simulation

Ribavirin and remdesivir have been preclinically reported as potential drugs for the treatment of SARS-CoV-2 infection, while light silver tetrylene complexes (NHE_Ph–AgCl and (NHE_Ph–AgCl)₂ with E = C, Si, and Ge) have gained significant interest due to their promising applicability on the cytological scale. Firstly, the structures and bonding states of silver–tetrylene complexes (NHE–Ag) and bis-silver–tetrylene complexes (NHE–Ag-bis) were investigated using density functional theory (DFT) at the BP86 level with the def2-SVP and def2-TZVPP basis sets. Secondly, the inhibitory capabilities of the carbene complexes (NHC–Ag and NHC–Ag-bis) and the two potential drugs (ribavirin and remdesivir) on human-protein ACE2 and SARS-CoV-2 protease PDB6LU7 were evaluated using molecular docking simulation. The carbene ligand NHC bonds in a head-on configuration with AgCl and (AgCl)₂, whereas, the other NHE (E = Si and Ge) tetrylene ligands bond in a side-on mode to the metal fragments. The bond dissociation energy (BDE) of the NHE–Ag bond in the complex families follows the order of NHC–Ag > NHSi–Ag > NHGe–Ag and NHSi–Ag-bis > NHGe–Ag-bis > NHC–Ag-bis. The natural bond orbital analysis implies that the [NHE_Ph→AgCl] and [(NHE_Ph)₂→(AgCl)₂] donations are derived mainly from the σ- and π-contributions of the ligands. The docking results indicate that both the ACE2 and PDB6LU7 proteins are strongly inhibited by silver–carbene NHC–Ag, bis-silver–carbene NHC–Ag-bis, ribavirin, and remdesivir with the docking score energy values varying from −17.5 to −16.5 kcal mol⁻¹ and −16.9 to −16.6 kcal mol⁻¹, respectively. The root-mean-square deviation values were recorded to be less than 2 Å in all the calculated systems. Thus, the present study suggests that silver–carbene NHC–Ag and bis-silver–carbene NHC–Ag-bis complexes are potential candidates to inhibit ACE2 and PDB6LU7, and thus potentially conducive to prevent infection caused by the SARS-CoV-2 virus.

Simultaneous inhibition of silver–carbene complexes to ACE2 and PDB6LU7 is conducive for the prevention of SARS-CoV-2 infection: a virtual prediction.     

Rapid and specific identification of 5 human pathogenic Vibrio species by multiplex polymerase chain reaction targeted to dnaJ gene

A multiplex polymerase chain reaction (PCR) method, specifically designed for application in routine diagnostic laboratories, was developed for identifying 5 human pathogen Vibrio species: Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Vibrio mimicus, and Vibrio alginolyticus. This assay directed toward the dnaJ gene was tested on a total of 355 strains representing 13 Vibrio species and 17 non-Vibrio species. Specific PCR fragments were produced in isolates belonging to the 5 target species and were absent from all strains other than these 5 species and non-Vibrio strains, indicating a high specificity of this multiplex PCR. The multiplex PCR for the detection of Vibrio pathogens in clinical specimens was experimentally applied to spiked stool samples. Only 1 specific amplicon was observed, corresponding to the pathogen spiked into the stool sample. The detection limitation was 10(5) to 10(6) cells per milliliter stool. Our data showed that this method represented a robust tool for the specific and rapid detection of the 5 major pathogenic Vibrio species.     

Platelet adhesion and thrombus formation on subendothelium in platelets deficient in glycoproteins IIb-IIIa, Ib, and storage granules

Patients whose platelets are deficient in glycoprotein (GP) Ib, IIb- IIIa (thrombasthenia), or granule substances (storage pool deficiency, SPD) were studied to define further the properties of platelets that mediate platelet adhesion and thrombus formation on subendothelium. Both nonanticoagulated and citrated blood were exposed to everted, de- endothelialized rabbit vessel segments under controlled flow conditions and shear rates varying from 650 to 3,300 sec-1. Morphometry was used to measure platelet thrombus dimensions and the percentage of the subendothelial surface covered with contact (C) or spread (S) platelets. Adhesion was defined as C + S. The results in SPD demonstrated (1) reduced thrombus dimensions in delta-SPD (pure dense granule deficiency) in proportion to the magnitude of the dense granule defect; (2) an even greater reduction in thrombus dimensions in patients with combined deficiencies of alpha and dense granules (alpha delta-SPD); and (3) impaired platelet adhesion at several conditions in alpha delta-SPD and, in delta-SPD, a hematocrit-dependent impairment of adhesion in citrated blood at 2,600 sec-1. In thrombasthenia, platelets were present as a monolayer on the subendothelial surface in both nonanticoagulated and citrated blood, indicating an absolute requirement for GPIIb-IIIa in promoting platelet-platelet interaction at all shear rates and perfusion times. Two types of abnormalities in platelet-vessel wall interactions were observed. In nonanticoagulated blood, the percentage of platelets in the C phase was consistently increased at all shear rates, but C + S values were normal. These observations indicate that platelets deficient in GPIIb-IIIa do not spread normally on the subendothelial surface exposed to nonanticoagulated blood. With citrated blood, the C + S value in thrombasthenia was reduced at both 800 and 2,600 sec-1, as in von Willebrand's disease, and a similar degree of reduction (about 50%) was observed in normal blood treated with a monoclonal antibody to GPIIb- IIIa. The findings, together with theoretical considerations, are consistent with an hypothesis that GPIIb-IIIa mediates the spreading of platelets on subendothelium following the initial attachment through GPIb and that GPIIb-IIIa may be considered an adhesion site on the platelet membrane. Abnormalities of GPIIb-IIIa may, depending on the conditions of study, result in either increased values of C platelets or decreased values of C + S. The results of the study further suggest that a complex interaction of platelet granule factors and membrane GP mediate platelet adhesion and thrombus formation.     

Gold nanoclusters as prospective carriers and detectors of pramipexole

Pramipexole (PPX) is known in the treatment of Parkinson''s disease and restless legs syndrome. We carried out a theoretical investigation on pramipexole–Au cluster interactions for the applications of drug delivery and detection. Three Au_N clusters with sizes N = 6, 8 and 20 were used as reactant models to simulate the metallic nanostructured surfaces. Quantum chemical computations were performed in both gas phase and aqueous environments using density functional theory (DFT) with the PBE functional and the cc-pVDZ-PP/cc-pVTZ basis set. The PPX drug is mainly adsorbed on gold clusters via its nitrogen atom of the thiazole ring with binding energies of ca. −22 to −28 kcal mol⁻¹ in vacuum and ca. −18 to −24 kcal mol⁻¹ in aqueous solution. In addition to such Au–N covalent bonding, the metal–drug interactions are further stabilized by electrostatic effects, namely hydrogen-bond NH⋯Au contributions. Surface-enhanced Raman scattering (SERS) of PPX adsorbed on the Au surfaces and its desorption process were also examined. In comparison to Au₈, both Au₆ and Au₂₀ clusters undergo a shorter recovery time and a larger change of energy gap, being possibly conducive to electrical conversion, thus signaling for detection of the drug. A chemical enhancement mechanism for SERS procedure was again established in view of the formation of nonconventional hydrogen interactions Au⋯H–N. The binding of PPX to a gold cluster is expected to be reversible and triggered by the presence of cysteine residues in protein matrices or lower-shifted alteration of environment pH. These findings would encourage either further theoretical probes to reach more accurate views on the efficiency of pramipexole–Au interactions, or experimental attempts to build appropriate gold nanostructures for practical trials, harnessing their potentiality for applications.

Gold clusters as prospective carriers and detectors of pramipexole.     

Antioxidant and UV-radiation absorption activity of aaptamine derivatives – potential application for natural organic sunscreens

Antioxidant and UV absorption activities of three aaptamine derivatives including piperidine[3,2-b]demethyl(oxy)aaptamine (C1), 9-amino-2-ethoxy-8-methoxy-3H-benzo[de][1,6]naphthyridine-3-one (C2), and 2-(sec-butyl)-7,8-dimethoxybenzo[de]imidazo[4,5,1-ij][1,6]-naphthyridin-10(9H)-one (C3) were theoretically studied by density functional theory (DFT). Direct antioxidant activities of C1–C3 were firstly evaluated via their intrinsic thermochemical properties and the radical scavenging activity of the potential antioxidants with the HOO˙/HO˙ radicals via four mechanisms, including: hydrogen atom transfer (HAT), single electron transfer (SET), proton loss (PL) and radical adduct formation (RAF). Kinetic calculation reveals that HOO˙ scavenging in water occurs via HAT mechanism with C1 (k_app, 7.13 × 10⁶ M⁻¹ s⁻¹) while RAF is more dominant with C2 (k_app, 1.40 × 10⁵ M⁻¹ s⁻¹) and C3 (k_app, 2.90 × 10⁵ M⁻¹ s⁻¹). Antioxidant activity of aaptamine derivatives can be classified as C1 > C3 > C2. Indirect antioxidant properties based on Cu(i) and Cu(ii) ions chelating activity were also investigated in aqueous phase. All three studied compounds show spontaneous and favorable Cu(i) ion chelating activity with ΔG⁰ being −15.4, −13.7, and −15.7 kcal mol⁻¹, whereas ΔG⁰ for Cu(ii) chelation are −10.4, −10.8, and −2.2 kcal mol⁻¹ for C1, C2 and C3, respectively. In addition, all compounds show UVA and UVB absorption; in which the excitations are determined mostly as π–π* transition. Overall, the results suggest the potential applications of the aaptamines in pharmaceutics and cosmetics, i.e. as a sunscreen and antioxidant ingredient.

Antioxidant and UV absorption activities of three aaptamine derivatives were theoretically studied by density functional theory (DFT) and time-dependent density functional theory (TD-DFT).     

Enhancing the chloramphenicol sensing performance of Cu–MoS2 nanocomposite-based electrochemical nanosensors: roles of phase composition and copper loading amount

The rational design of nanomaterials for electrochemical nanosensors from the perspective of structure–property–performance relationships is a key factor in improving the analytical performance toward residual antibiotics in food. We have investigated the effects of the crystalline phase and copper loading amount on the detection performance of Cu–MoS₂ nanocomposite-based electrochemical sensors for the antibiotic chloramphenicol (CAP). The phase composition and copper loading amount on the MoS₂ nanosheets can be controlled using a facile electrochemical method. Cu and Cu₂O nanoparticle-based electrochemical sensors showed a higher CAP electrochemical sensing performance as compared to CuO nanoparticles due to their higher electrocatalytic activity and conductivity. Moreover, the design of Cu–MoS₂ nanocomposites with appropriate copper loading amounts could significantly improve their electrochemical responses for CAP. Under optimized conditions, Cu–MoS₂ nanocomposite-based electrochemical nanosensor showed a remarkable sensing performance for CAP with an electrochemical sensitivity of 1.74 μA μM⁻¹ cm⁻² and a detection limit of 0.19 μM in the detection range from 0.5–50 μM. These findings provide deeper insight into the effects of nanoelectrode designs on the analytical performance of electrochemical nanosensors.

In this work, we clarify the roles of phase composition and copper loading amount on the CAP sensing performance of Cu–MoS₂ nanocomposite-based electrochemical nanosensors.     

New insights into the competition between antioxidant activities and pro-oxidant risks of rosmarinic acid

Direct and indirect antioxidant activities of rosmarinic acid (RA) based on HOO˙/CH₃OO˙ radical scavenging and Fe(iii)/Fe(ii) ion chelation were theoretically studied using density functional theory at the M05-2X/6-311++G(2df,2p) level of theory. First, four antioxidant mechanisms including hydrogen atom transfer (HAT), radical adduct formation (RAF), proton loss (PL) and single electron transfer (SET) were investigated in water and pentyl ethanoate (PEA) phases. Regarding the free radical scavenging mechanism, HAT plays a decisive role with overall rate coefficients of 1.84 × 10³ M⁻¹ s⁻¹ (HOO˙) and 4.49 × 10³ M⁻¹ s⁻¹ (CH₃OO˙) in water. In contrast to PL, RAF and especially SET processes, the HAT reaction in PEA is slightly more favorable than that in water. Second, the [Fe(iii)(H₂O)₆]³⁺ and [Fe(ii)(H₂O)₆]²⁺ ion chelating processes in an aqueous phase are both favorable and spontaneous especially at the O5, site-1, and site-2 positions with large negative Δ_rG⁰ values and great formation constant K_f. Finally, the pro-oxidant risk of RA⁻ was also considered via the Fe(iii)-to-Fe(ii) complex reduction process, which may initiate Fenton-like reactions forming reactive HO˙ radicals. As a result, RA⁻ does not enhance the reduction process when ascorbate anions are present as reducing agents, whereas the pro-oxidant risk becomes remarkable when superoxide anions are found. The results encourage further attempts to verify the speculation using more powerful research implementations of the antioxidant activities of rosmarinic acid in relationship with its possible pro-oxidant risks.

Direct and indirect antioxidant activities of rosmarinic acid (RA) based on HOO˙/CH₃OO˙ radical scavenging and Fe(iii)/Fe(ii) ion chelation were theoretically studied using density functional theory at the M05-2X/6-311++G(2df,2p) level of theory.