The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern ...underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells.
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•New pyrrolidine-based pharmacological chaperones for Fabry disease are developed.•Compound 8 is a potent and selective pharmacological chaperone for Fabry disease.•It is a durable and non-substrate competitive pharmacological chaperone.
Heart rate variability (HRV) has been linked to mortality in maintenance hemodialysis (HD) patients, but it is less clear whether HRV is associated with major adverse cardiovascular events (MACEs) ...and hospitalization.
This study enrolled 179 maintenance HD patients. HRV was measured to assess its prognostic significance in relation to MACEs and hospitalization.
During the follow-up period of 33.3 ± 6.7 months, 36 (20.1%) patients had a MACE, and 98 (54.7%) experienced hospitalization. In multivariate adjusted Cox regression analysis, low very low frequency (VLF) power (hazard ratio HR, 0.727; 95% confidence interval CI, 0.624-0.848; p < 0.001), a history of coronary artery disease, high ultrafiltration rate, the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and the use of beta-blockers were all significantly associated with MACEs. Low VLF power (HR, 0.873; 95% CI, 0.785-0.971; p = 0.012), low serum albumin, low serum creatinine, low Kt/V levels, and high serum calcium-phosphorus product levels significantly predicted hospitalization in maintenance HD patients.
Reduced VLF power is linked to an increased risk of MACEs and hospitalization in maintenance HD patients. Assessing cardiac autonomic function through HRV is of pivotal prognostic significance for this patient population.
Overhead line ice-shedding causes line breakage and results in electrical faults occurring between transmission lines, which seriously affects the safe operation of the power grid. In this paper, a ...risk assessment method for ice-shedding on 500 kV compact overhead lines is proposed. Two ratios were used to assess the discharge risk and mechanical failure risk of a line. A 500 kV compact overhead line in southern China was taken as an example, the proposed risk assessment method was used to carry out a risk assessment of the ice-shedding line with an ice thickness of 15 mm, and the suppression effects of different spacer arrangement schemes on the ice-shedding line were analyzed. The results showed that the impact coefficient of the conductor reached 1.88, the maximum jump height of the lower phase conductor reached 22.596 m, and the interphase clearance of the conductor decreased sharply when the lower phase conductor of 500 kV case line underwent full-span ice-shedding synchronously. The ice-shedding line displayed both a discharge risk and a mechanical failure risk. When interphase spacers were installed at L/3 from both ends of the span for the upper-left phase and the lower phase, the upper-right phase, and the lower phase, the impact coefficient of the line became 1.76, which was lower than the recommended value of 1.8; there was no mechanical failure risk; and the maximum jump height became 10.266 m. This study verified the effectiveness of this spacer arrangement scheme.
Plaque-type psoriasis is a common skin disorder. Tirbanibulin (KX01) is a new Src kinase inhibitor with potent antiproliferative activity against keratinocytes and has been approved for treatment of ...actinic keratosis. This Phase I study investigates the safety and activity of KX01 ointment in patients with plaque-type psoriasis. We recruited 28 patients from two medical centers in Taiwan. This study was performed in four stages. Double-blind treatments were randomized in stages I (KX01 0.01% + placebo, two rounds of two-week treatment) and II (KX01 0.1% + placebo, four weeks) and open-labelled in stages III (KX01 1%, five days) and IV (KX01 1%, five days weekly for four weeks). The safety, tolerability, KX01 concentration, target area score, physician global assessment, and disease relapse were determined. Most treatment-emergent adverse events were mild-to-moderate application site reactions. Three (50.0%) subjects from the stage IV group showed ≥50% reduction in the target area score (TAS50), while two subjects (33.3%) showed a clinically meaningful improvement in the physician global assessment score. KX01 0.01%, 0.1%, and 1% were safe and well-tolerated. KX01 1% at four weeks showed a promising activity for the treatment of plaque-type psoriasis.
This work proposes a feed-forward PWM-intermodulated-distortion reduction (FFPIDR) technique for closed-loop class-D audio amplifiers. The proposed FFPIDR technique overcomes the trade-off between ...out-of-band loop attenuation and in-band loop gain to reduce the PWM-intermodulated distortion while maintaining a high in-band distortion suppression capability without increasing the switching frequency. This results in a high-fidelity and low-quiescent-current audio amplifier suitable for mobile devices. This work is implemented in a 0.5 μm CMOS technology, and the measurement result with a 4.2 V supply voltage shows that the proposed FFPIDR technique improves the TiD + N by 12 dB when an output power of 340 mW is delivered to an 8-Ω load. Compared with other state of the arts, the proposed class-D amplifier achieves 0.0037% TiD + N with a quiescent current of 2.4 mA and the smallest chip area of 0.86 mm 2 , and the measured peak efficiency reaches 92%.
Drug-related problems (DRPs) are common in recipients of solid organ transplants. Pharmacist-led medication therapy management (MTM) has cost benefits in kidney and liver transplants; however, ...whether MTM is also beneficial in heart transplants remains unclear. This study explored the cost benefits of involving pharmacists in the heart transplant clinic.
This retrospective study evaluated DRPs for 1 year after implementation of pharmacist-led MTM in a heart transplant clinic. The DRPs were compared between patients receiving transplantation for <1 and >1 year. The risk matrix method was used to assess each DRP in terms of the estimated probability and severity of consequent adverse drug events (ADEs). For cost analysis, both estimated cost savings and avoidance were calculated.
During the 1-year MTM, 372 DRPs were identified by the pharmacist, among which 169 (45%) and 203 (55%) were from patients at <1-year and ≥1-year post-transplant periods, respectively. The 2 post-transplant periods (<1 year and ≥1 year) exhibited significant differences in the distribution of the dosage or frequency problems (30% vs 18%, P = .005) and the suggestion of more appropriate medication (4% vs 10%, P = .024). In all, 92 (29%) DRPs had an ADE probability of >10%; and 63 (17%) DRPs were estimated to cause ADEs with moderate severity or higher. The estimated cost savings and cost avoidance were US $4902 and US $4519, which equaled a cost–benefit ratio of 2.39.
Integration of pharmacists into heart transplant clinics could help address DRPs and may have cost benefits.
To determine and compare the treatment efficacy of subacromial steroid injections and dextrose prolotherapy (DPT) for chronic subacromial bursitis patients.
54 patients with chronic subacromial ...bursitis were enrolled in this double-blind randomized controlled trial. Shoulder pain and disability index (SPADI) and visual analog scale (VAS) were the primary outcomes.
The steroid group (n = 26) exhibited significant VAS score improvements comparing to baseline at weeks 2, 6, and 12; the DPT group (n = 28) exhibited VAS score improvements at weeks 6, and 12. The steroid group displayed significant SPADI score improvements compared to baseline at weeks 2, 6, and 12, the DPT group exhibited significant score decreases at weeks 2, and 6. Compared with the DPT group, the steroid group demonstrated significantly greater decreases in VAS scores at weeks 2, and 6; the steroid group showed significantly greater decreases in SPADI scores at weeks 2, 6, and 12.
Both hypertonic DPT and steroid injections can provide short-term improvements of pain and disability among chronic subacromial bursitis patients. Moreover, steroid injections showed better effectiveness than hypertonic DPT in ameliorating pain and improving function.
This study focused on the assessment of wave energy resources around the Taiwan sea area. The forecasted wave data of TaiCOMS, offered by Harbor and Marine Technology Center of Taiwan, records wave ...buoys deployed by the Central Weather Bureau of Taiwan, and information on typhoons were used to analyze the temporal and spatial characteristics of wave power density in Taiwan's coastal area. In addition, the effects of monsoon and typhoon that contributed to the wave energy resource were investigated, and the average annual wave power around Taiwan was also estimated. The northeastern coastal area is the potential area for wave energy usage in Taiwan. The peak density of wave power occurs in autumn and winter for most of Taiwan's sea area, except for the southwestern coast, in which peak seasons occur in spring and summer. These results imply that the wave power in Taiwan's sea area is dominated by monsoons. However, because a typhoon usually generates substantial power, the annual wave energy may be affected by the quantity, path, and scale of a typhoon that hits Taiwan. In particular, the effects of typhoons on to the annual wave energy are crucial for the southwestern coastal area. Finally, for resources assessment, the average annual wave energy of coastal area surrounding Taiwan Island was estimated to an amount of approximately 16.9 TWh per year.
► This study focused on the assessment of wave energy around the Taiwan sea area. ► The wave data of TaiCOMS, wave buoys, and typhoon information were used to analyze. ► The annual wave energy was estimated to an amount of approximately 16.9 TWh per year.
In this study, we screened compounds with skin whitening properties and favorable safety profiles from a series of marine related natural products, which were isolated from Formosan soft coral ...Cladiella australis. Our results indicated that 4-(phenylsulfanyl)butan-2-one could successfully inhibit pigment generation processes in mushroom tyrosinase platform assay, probably through the suppression of tyrosinase activity to be a non-competitive inhibitor of tyrosinase. In cell-based viability examinations, it demonstrated low cytotoxicity on melanoma cells and other normal human cells. It exhibited stronger inhibitions of melanin production and tyrosinase activity than arbutin or 1-phenyl-2-thiourea (PTU). Also, we discovered that 4-(phenylsulfanyl)butan-2-one reduces the protein expressions of melanin synthesis-related proteins, including the microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1 (Trp-1), dopachrome tautomerase (DCT, Trp-2), and glycoprotein 100 (GP100). In an in vivo zebrafish model, it presented a remarkable suppression in melanogenesis after 48 h. In summary, our in vitro and in vivo biological assays showed that 4-(phenylsulfanyl)butan-2-one possesses anti-melanogenic properties that are significant in medical cosmetology.
Few reports have investigated genetic alterations between patients with early and late recurrence following curative surgery for colorectal cancer (CRC).
A total of 1227 stage I-III CRC patients who ...underwent curative resection were included retrospectively. Among them, 236 patients had tumor recurrence: 139 had early (<2 years after surgery) and 97 had late (≥2 years after surgery) recurrence. Clinicopathological features and genetic alterations were compared between the two groups.
Compared to those with late recurrence, patients with early recurrence were more likely to have advanced pathological node (N) categories; tumor, node, metastasis (TNM) stages; adjuvant chemotherapy treatment; liver metastases;
mutations; and worse five-year overall survival rates. Patients with right-sided colon cancer were more likely to develop early recurrence than were those with left-sided colon cancer or rectal cancer. Regarding rectal cancer, patients with early recurrence were more likely to be at advanced pathological N categories and TNM stages than those with late recurrence. Multivariate analysis revealed old age, early recurrence, multiple-site recurrence, and
and
mutations to be independent prognostic factors.
CRC patients with early recurrence have a worse OS rate and more
mutations than those with late recurrence.
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