Effects of starvation on the pharmacokinetics and optimal dosages of florfenicol and associated serum biochemistry in Asian seabass (Lates calcarifer).

Starvation has influence on physiology and pharmacokinetic (PK) characteristics of many drugs in land animals. However, similar PK information in fish is lacking. The current study examined the effects of starvation on fish PK, taking florfenicol (FF) in Asian seabass as an example. FF was orally administered at a single dose of 10 mg/kg into 35-day starved fish reared at 25 and 30°C and the serum FF concentration was analyzed by HPLC-FLD. At 30°C, the absorption and elimination half-lives of the starved fish were increased by 30% (from 0.44 to 0.57 h) and 55% (from 7.2 to 11.18 h), respectively. The volume of distribution, clearance, and area under the curve were changed from 1.25 to 0.71 L/kg, 0.120 to 0.044 L/kg/h, and 88 to 228 h·µg/ml, respectively. Similar starvation-induced PK changes were also observed at 25°C. The serum biochemical parameters, mainly the alanine aminotransferase, aspartate aminotransferase, and glucose levels, were significantly reduced in the starvation group. Overall, FF absorption, distribution, and elimination rates were reduced by starvation, resulting in four to five times lower optimal dosage than the non-starved fish. Drug treatment in starved fish should be treated with caution as overdosing and/or tissue residues could perceivably occur.

Diffusion-weighted imaging as a follow-up modality for evaluation of major salivary gland function in nasopharyngeal carcinoma patients: a preliminary study.

PURPOSE: To investigate the value of diffusion-weighted imaging (DWI) in assessing dynamic changes of major salivary gland function during follow-up post radiotherapy (RT) in nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: 31 consecutive patients with pathologically confirmed NPC scheduled for RT underwent six routine follow-up MRI examinations including DWI sequence prior to (pre-RT) and 1, 3, 6, 9, and 12 months post RT. Mean apparent diffusion coefficient (ADC) values of bilateral parotid glands (PGs) and submandibular glands (SMGs) were measured. Objective measurement of salivary flow rate (SFR) under unstimulated (uSFR) and stimulated conditions (sSFR) as well as subjective xerostomia assessment according to a patient-rated questionnaire were conducted before each MRI. Variance analysis was used to evaluate dynamic changes of ADC, SFR and xerostomia questionnaire summary scores (XQ-sum) at different timepoints and the correlation between ADC and XQ-sum. Pearson's correlation test was used to evaluate the correlations between pre- and post-RT changes of ADC (ΔADC) and SFR (ΔSFR) or mean RT dose. RESULTS: At each timepoint, ADCs of PGs were significantly lower than of SMGs, uSFR was significantly lower than sSFR. For both PGs and SMGs, ADCpost-RT were all higher than ADCpre-RT, with significant differences. ADC1m-post-RT initially increased and changed little to ADC3m-post-RT, ADC6m-post-RT, ADC9m-post-RT, and ADC12m-post-RT, then gradually declined over time. The dynamic change trends of SFR were negatively paralleled to those of ADC, while that of XQ-sum was similar. Dose-response relationships were detected between salivary gland mean RT dose and ΔADC. In PGs, negative correlations between ΔsSFR9m-post-RT and ΔADC9m-post-RT, and ΔsSFR12m-post-RT and ΔADC12m-post-RT were detected. In SMGs, negative correlations between ΔsSFR12m-post-RT and ΔADC12m-post-RT, and ΔuSFR12m-post-RT and ΔADC12m-post-RT were also detected. The ADCs of patients with severe subjective xerostomia were significantly higher, while patients with moderate subjective xerostomia presented a tendency toward higher ADCs compared to those with mild xerostomia from 6 to 12 months post RT. CONCLUSION: As part of routine follow-up MRI in NPC patients, DWI might be a promising modality for follow-up assessing the dynamic changes of major salivary gland function and might be more powerful in the late post-RT period.

Characterization of the monoclonal antibody specific to the ORF72 protein of koi herpesvirus and cellular distribution analysis of the viral protein.

Koi herpesvirus (KHV) is an emerging pathogen of koi and common carp that causes a severe disease and mass mortality of infected fish. The KHV ORF72 protein is an important capsid protein that has been suggested to be a candidate for the development of diagnostic reagents and KHV vaccines. The purpose of this study was to clone and express the KHV ORF72 gene for further preparation of a specific monoclonal antibody (mAb) and to analyse cellular distribution of the viral protein. The mAb 3E1 could specifically recognize the expressed ORF72 protein of transfected cells by indirect immunofluorescence, and the antigenic site recognized by the mAb 3E1 was mapped to the region of N-terminal 124 residues of KHV ORF72. This mAb was further demonstrated to specifically detect the KHV-infected fish tissue by immunohistochemistry, thereby suggesting its high diagnostic potential. In addition, the cellular distribution analysis of the KHV ORF72 protein revealed that the region of amino acid residues 125-247 was related to mitochondrial localization and proliferation. Furthermore, a putative nuclear export signal (NES) of ORF72 at the residues 201-212 was confirmed on the basis of its function associated with NES activity.

[Darolutamide: A new drug for non-metastatic castration-resistant prostate cancer].

Prostate cancer (PCa) is one of the most common tumors in male. Castration-resistant PCa (CRPC) refers to the prostate malignancy with a PSA increase or imaging progression after androgen-deprivation therapy (ADT), which is divided into metastatic CRPC (mCRPC) and non-metastatic CRPC (nmCRPC) based on the presence or absence of imaging metastasis. Two second-generation antiandrogens, enzuramide and abiraterone, were approved for the treatment of nmCRPC in 2018. A recently completed three-stage large-scale clinical ARAMIS trial shows that the new drug, darolutamide, compared with the placebo, could prolong the metastasis-free survival (MFS) of nmCRPC patients. Darolutamide is now an anti-androgen drug available for patients with nmCRPC. This review focuses on the clinical trial of darolutamide and comparison of its therapeutic effect with that of another two second-generation antiandrogens.

MR imaging features of spinal pilocytic astrocytoma.

BACKGROUND: The purpose of this retrospective review is to determine the MR imaging features of pilocytic astrocytoma (PA) in the spinal cord to help neuroradiologists preoperatively differentiate PA from other intramedullary tumors. METHODS: Neuro-oncology database review revealed 13 consecutive patients with a pathological spinal PA diagnosis and availability of preoperative MR imaging. Three patients had preoperative diffusion-weighted MR imaging. Demographics and conventional and diffusion MR imaging records were retrospectively evaluated. RESULTS: Among 13 cases of spinal PA, six PAs were located in the cervical region, 4 in the cervical-thoracic region, and 3 in the thoracic region. The average length of vertebral segments involved for the tumors were 4.7 ± 4.6 segments. Six tumors had associated syringomyelia. Eight PAs were located eccentrically in the spinal cord, and eleven had well-defined margins. Eight tumors (61.5%) were intermixed cystic and solid. All were contrast-enhanced, and 53.8% of all PAs showed focal nodule enhancement of the solid components. Two PAs showed intratumoral hemorrhages, and only one demonstrated cap sign. The ADC values (n = 3) of the tumors were 1.40 ± 0.28 × 10- 3 mm2/s (min-max: 1.17-1.71 × 10- 3 mm2/s). CONCLUSIONS: PA should be considered in the differential diagnosis of intramedullary tumors that occur in the cervical and thoracic regions. Eccentric growth pattern, well-defined margin, intermixed cystic and solid appearance, focal nodular enhancement of solid components and syringomyelia are relatively frequent features. Relatively high ADC values compared with normal-appearing spinal cord parenchyma are common in spinal PA.

Protective effect of bone marrow mesenchymal stem cells modified with klotho on renal ischemia-reperfusion injury.

OBJECTIVE: To detect the combination protective effect of bone marrow mesenchymal stem cells (BMSCs) and Klotho gene on the renal ischemia-reperfusion injury (RIRI). METHODS: BMSCs isolated from rats were transfected with Klotho gene to form BMSCKl. We injected BMSCKl to allogenic rat RIRI model. After 24 h and 72 h, we detected the serum creatinine (SCr), malondialdehyde (MDA), and superoxide dismutase (SOD) in renal tissue, Hematoxylin-eosin (HE) staining, and TUNEL of renal pathology. The expression of FoxO1 and p-FoxO1 in post-hypoxia tubular epithelial cells of normal rat kidney (NRK-52E) were detected by Western blot after cocultured with BMSCKl. RESULTS: Comparing with BMSCCon group, Rats in BMSCKl group had lower SCr and MDA but higher SOD. Both HE and TUNEL score of renal tissue in BMSCKl group were lower than that of BMSCCon group. Western blot indicated that FoxO1 was upregulated, while p-FoxO1 was downregulated in post-hypoxia NRK-52E cells. CONCLUSIONS: BMSCs transfected with Klotho gene can further ameliorate RIRI. The possible mechanism may be attributed to the upregulation of SOD in NRK-52E caused by Klotho-FoxO1 axis.

Short-term efficacy and safety of low-intensity extracorporeal shock wave therapy in erectile dysfunction: a systematic review and meta-analysis.

AIM: The role of low-intensity extracorporeal shock wave therapy (LI-ESWT) in erectile dysfunction (ED) is not clearly determined. The purpose of this study is to investigate the short-term efficacy and safety of LI-ESWT for ED patients. MATERIALS AND METHODS: Relevant studies were searched in Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG and VIP databases. Effective rate in terms of International Index of Erectile Function-Erectile Function Domain (IIEF-EF) and Erectile Hardness Score (EHS) at about 1month after LI-ESWT was extracted from eligible studies for meta-analysis to calculate risk ratio (RR) of effective treatment in ED patients treated by LI-ESWT compared to those receiving sham-treatment. RESULTS: Overall fifteen studies were included in the review, of which four randomized controlled trials (RCTs) were for meta-analysis. Effective treatment was 8.31 [95% confidence interval (CI): 3.88-17.78] times more effective in the LI-ESWT group (n=176) than in the sham-treatment group (n=101) at about 1 month after the intervention in terms of EHS, while it was 2.50 (95% CI: 0.74-8.45) times more in the treatment group (n=121) than in the control group (n=89) in terms of IIEF-EF. Nine-week protocol with energy density of 0.09mJ/mm2 and 1500 pluses seemed to have better therapeutic effect than five-week protocol. No significant adverse event was reported. CONCLUSION: LI-ESWT, as a noninvasive treatment, has potential short-term therapeutic effect on patients with organic ED irrespective of sensitivity to PDE5is. Owing to the limited number and quality of the studies, more large-scale, well-designed and long-term follow-up time studies are needed to confirm our analysis.

[Minimally invasive techniques in the treatment of benign prostatic hyperplasia: An update].

Lower urinary tract symptoms (LUTS) resulting from benign prostatic hyperplasia (BPH) obviously impair the quality of life of middle-aged and elderly men. Current management of BPH includes wait-and-watch, medical therapy, and conventional surgery. As a new approach, minimally invasive surgery has been playing an increasingly important role in the management of BPH, with potential advantages of less operative trauma, quicker recovery, lower risk of postoperative complications and higher quality of life. This review mainly discusses prostatic urethral lift (Urolift® System), transurethral water vapor therapy (Rezum® System) and robot-guided high-energy water ablation (PROCEPT Aquablation™ System).

[Low-intensity extracorporeal shockwave therapy for erectile dysfunction: An update].

Low-intensity extracorporeal shockwave therapy (LI-ESWT) is a novel treatment for erectile dysfunction (ED). With the property of angiogenesis, LI-ESWT acts on vasculogenic ED by improving penile hemodynamics and endothelial function. LI-ESWT is proved to be safe and effective in the treatment of vasculogenic ED in various prospective clinical studies, including randomized, double-blind, and sham-controlled trails. With more multi-centered larger-sample randomized controlled trials, LI-ESWT will play a valuable role in the treatment of ED.

[Prostatic urethral lift: A novel minimally invasive treatment for benign prostatic hyperplasia].

Benign prostatic hyperplasia (BPH) and BPH-induced lower urinary tract symptoms (LUTS) are common factors influencing the quality of life (QOL) of elderly males. In case of undesirable or adverse effects of medication, many BPH patients seek surgical treatment. Transurethral resection of the prostate (TURP), though evidently effective for BPH, fails to preserve the sexual function and therefore reduces the QOL of the patients. Moreover, some elderly patients with comorbidities may be unfit for TURP. Prostatic urethral lift (PUL) is a newly developed surgical procedure for the treatment of LUTS secondary to BPH. With the advantages of minimal invasiveness, low rate of peri- and post-operative complications, and maximal preservation of patients' erectile and ejaculatory functions, PUL is winning more and more attention from the clinicians and patients.

[Pro-prostate-specific antigen and its related indexes in the diagnosis of prostate cancer].

Pro-prostate-specific antigen (proPSA) is the precursor of PSA and a form of free PSA (fPSA). In recent years, a lot of studies have been done on proPSA, the roles of its related indexes in the diagnosis of prostate cancer, and the value of its clinical application. The correlated indexes of proPSA include proPSA, % pPSA, p2PSA, % p2PSA and prostate health index (PHI). They are more effective than total PSA (tPSA) and fPSA in the diagnosis of prostate cancer, especially % p2PSA and PHI, which may significantly increase our ability to detect and identify PCa and lower the rate of unnecessary biopsies. This article presents an overview on the advances in the studies of proPSA and the application of its related indexes in the diagnosis of prostate cancer.

[Application of traction therapy for Peyronie's disease: present and prospect].

Peyronie's disease is an acquired connective tissue disorder affecting the tunica albuginea of the corpus cavernosum, causing penile plaque formation and persistent scar. It typically affects males between the ages of 45 and 60 years. The exact cause of Peyronie's disease is not clear and its pathological and physiological performance is the local deposition of fibrin and collagen. Men afflicted by this disorder may present with erectile pain, penile deformity (such as penile curvature or penile shortening), psychological disorder and/or erectile dysfunction. Though many medical and surgical options have been developed for the treatment of Peyronie's disease and each has its own indications, advantages and disadvantages, none of them produces very desirable effect. The studies of traction therapy for Peyronie's disease have been gradually increased in recent years. Traction therapy can be employed as a solo therapy or a part of combination therapy, preoperative or postoperative therapy for Peyronie's disease. Recent researches show that traction therapy can prevent the progression of scar, restore the length and diameter of a short penis, reduce the curvature of the penis and improve sexual function. However, large sample, multi-center, randomized controlled studies are needed to confirm its validity for Peyronie's disease. In addition, more endeavors should be exerted at its pathogenesis in order to achieve effective prevention and cure of the disease.

Aldehyde dehydrogenase 2 family member repression promotes colorectal cancer progression by JNK/p38 MAPK pathways-mediated apoptosis and DNA damage.

BACKGROUND: Aldehyde (ALDH2) dysfunction has been verified to contribute to human cancers. AIM: To investigate the molecular mechanism and biological function of ALDH2 in colorectal cancer (CRC) progression. METHODS: Human CRC cells with high expression of ALDH2 were screened. After shRNA ALDH2 (sh-ALDH2) transfection, phenotypes [proliferation, apoptosis, acetaldehyde (ACE) accumulation, DNA damage] of CRC cells were verified using cell counting kit-8, flow cytometry, ACE assay, and comet assays. Western blotting was used for evaluation of the apoptosis proteins (Bax and Bcl-2) and JNK/p38 MAPK pathway-associated proteins. We subjected CVT-10216 (a selective ALDH2 inhibitor) to nude mice for establishment of SK-CO-1 mouse xenograft model and observed the occurrence of CRC. RESULTS: The inhibition of ALDH2 could promote the malignant structures of CRC cells, including apoptosis, ACE level, and DNA damage, and cell proliferation was decreased in the sh-ALDH2 group, whereas ALDH2 agonist Alda-1 reversed features. ALDH2 repression can cause ACE accumulation, whereas ACE enhanced CRC cell features related to increased DNA damage. Additionally, ALDH2 repression led to JNK/P38 MAPK activation, and apoptosis, ACE accumulation, and DNA damage were inhibited after p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125 addition. ACE accumulation and raised DNA damage were recognized in CVT-10216 treated-mouse tumor tissues in vivo. CONCLUSION: The repression of ALDH2 led to ACE accumulation, inducing cell apoptosis and DNA damage by the JNK/p38 MAPK signaling pathway activation in CRC.

Pharmacokinetics, optimal dosages and withdrawal time of amoxicillin in Nile tilapia (Oreochromis niloticus) reared at 25 and 30 °C.

Knowledge of amoxicillin (AMX) pharmacokinetics (PK) and tissue residues in fish, which is necessary for prudent drug use, remains limited. The study aimed to explore the PK characteristics of AMX in Nile tilapia (Oreochromis niloticus) reared at 25 and 30 °C as well as to determine optimal dosages and drug withdrawal time (WDT). In the PK investigation, the fish received a single dose of 40 mg/kg AMX via oral gavage, and the optimal dosage was determined by the pharmacokinetic-pharmacodynamic approach. In the tissue residue study, the fish were orally gavaged with 40 mg/kg/day AMX once daily for 5 days and the WDT was established by the linear regression analysis. The results revealed the temperature-dependent drug elimination; the clearance relative to bioavailability (CL/F) and elimination half-life at 30 °C (0.180 L/kg/h and 6.06 h, respectively) were about twice those at 25 °C (0.090 L/kg/h and 10.49 h, respectively). The optimal dosages at the minimum inhibitory concentration (MIC) of 2 µg/mL were 10.97 (25 °C) and 41.03 (30 °C) mg/kg/day, respectively. Finally, following the multiple oral administration, the muscle/skin residue of AMX on day 1 after the last dosing at 25 and 30 °C were 548 and 264 ng/g, respectively. The average tissue residues were depleted below the maximum residue limits (MRL) of 50 µg/kg on day 5 (25 °C) and 3 (30 °C), respectively, and the WDT were 6 and 4 days when rearing at 25 and 30 °C, respectively. This knowledge serves as a practical guideline for responsible use of AMX in treating bacterial diseases in Nile tilapia aquaculture.

The Use of Tricaine Methanesulfonate (MS-222) in Asian Seabass (Lates calcarifer) at Different Temperatures: Study of Optimal Doses, Minimum Effective Concentration, Blood Biochemistry, Immersion Pharmacokinetics, and Tissue Distributions.

This study was conducted to determine the optimal doses and minimum effective concentrations (MECs) of tricaine methanesulfonate (MS-222) in marketable-size Asian seabass reared at two temperatures (22 and 28 °C). Serum biochemical parameters, pharmacokinetics, and tissue distributions of MS-222 following immersion at the determined optimal doses were also evaluated in order to delineate possible mechanisms dictating the temperature difference. The definition of optimal dose is set as the dose when fish attain stage III anesthesia within 5 min, sustain this stage for 3 min, and re-attain equilibrium within 5 min. The MEC is the fish serum MS-222 concentration when stage III anesthesia is reached. The results showed that water temperature exerted no or minimal impact on the designated parameters. The optimal doses at 22 and 28 °C were 140 and 150 µg/mL, while the MECs were 70.48 and 78.27 µg/mL, respectively. Fish exposed to the optimal doses of MS-222 had significantly elevated blood concentrations of lactate, glucose, calcium, magnesium, and sodium, while the blood pH was significantly decreased. The fish eliminated MS-222 faster at 28 °C than at 22 °C, with serum half-lives of 18.43 and 37.01 h, respectively. Tissue-specific distribution patterns were evident. Irrespective of water temperature, MS-222 peaked at 5 min for the brain and gill but peaked slightly later at 10-20 min for the liver and kidney. Most tissues exhibit a gradual decline of drug concentration except for the gill, which was maintained at a steady level. Muscle is the least perfused tissue with the lowest drug concentration throughout the 90 min period. This study provided physiological and pharmacokinetic evidence contributing to a better understanding of the actions of MS-222 in Asian seabass at different temperatures.

Effects of temperature on the pharmacokinetics, optimal dosage, tissue residue, and withdrawal time of florfenicol in asian seabass (lates calcarifer).

Drug behavior in the bodies of fish is largely influenced by the water temperature. Antimicrobial drugs are needed for the control of bacterial outbreaks in farmed fish including Asian seabass (Lates calcarifer). However, little is known about the temperature effect on appropriate drug uses in this species. The purpose of this study was to investigate the differences in pharmacokinetics (PK), optimal dosages, tissue depletion, and withdrawal time (WDT) of florfenicol (FF) in Asian seabass reared at 25 and 30 °C. In the PK study, the fish were administered with a single oral dose of 10 mg/kg FF. The optimal dosing regimen was determined by the pharmacokinetic-pharmacodynamic (PK-PD) approach. In the tissue depletion and WDT study, FF was administered at the optimal dosages once daily for 5 days and the WDT was determined by linear regression analysis based on the sum of FF and its metabolite florfenicol amine (FFA) in the muscle/skin. When the temperature was increased from 25 to 30 °C, the elimination half-life of FF was significantly decreased from 11.0 to 7.2 h. While the other PK parameters were not changed significantly, the calculated optimal dosages for the target minimum inhibitory concentration (MIC) of 2 µg/mL were 10.9 and 22.0 mg/kg/day, respectively for 25 and 30 °C. The sum of FF + FFA is a preferable marker residue for WDT determination because differential FF metabolism was observed at different temperatures. The depletion half-life of the muscle/skin was shortened from 41.1 to 32.4 h by the 5 °C temperature increase. Despite different absolute amounts of FF given between the two temperature levels, the WDTs were very similar at 6-7 days. Thus, it appears that a single temperature-independent WDT can potentially be assigned when the drug was applied at the optimal dosage.

[Application of extracorporeal shockwave therapy in andrology].

Extracorporeal shockwave therapy (ESWT) has been widely used in various fields ever since it was first introduced for the treatment of urinary stones in 1983. Recent years see a growing application of ESWT to andrology. Studies show that ESWT can relieve pain in 83% of the patients with Peyronie's disease, and has won favorable comments from 66% of the patients. ESWT can significantly improve the sexual life quality of the patients with organic erectile dysfunction, yields good effect in the treatment of chronic nonbacterial prostatitis, especially in pain relief. ESWT has offered new ideas and options for the treatment of andrological diseases. However, its mechanisms have yet to be clarified by more in-depth basic studies and multi-centered, large-sample randomized controlled trials.

[Study on the correlation of the 5-HTTLPR polymorphism with premature ejaculation in Han Chinese population].

OBJECTIVE: To investigate the relationship between 5-HT transporter gene-linked polymorphism (5-HTTPLR) and the clinical characters of premature ejaculation in Han Chinese population. METHODS: By case-control study approach, we set primary premature ejaculation (PPE) group (119 cases), secondary premature ejaculation (SPE) group (60 cases) with IELT < 1 min in more than 90% coitus and normal control group (90 cases) with IELT ≥ 3 min. The gene polymorphism of the 5-HTT was detected by polymerase chain reaction analysis in all the cases, and the gene frequency differences among the three groups were evaluated. RESULTS: The frequency of the genotype S/S was higher in PPE group than in normal control group(51.3% vs. 37.8%,P<0.01), and the frequency of genetype L/S was lower in PPE group than in normal vontrol group(28.6% vs. 34.4%,P<0.05).The S allele was higher in PPE group than in control group (P<0.05), but there was no difference between the SPE group and the normal control group. CONCLUSION: The 5-HTTLPR polymorphism is associated with PPE, which shows that genetics may play an important role in the occurrence of PPE but not of SPE. The etiology of PPE and SPE is different.