Latency of mechanically stimulated escape responses in the Pacific spiny dogfish, Squalus suckleyi.

Fast escape responses to a predator threat are fundamental to the survival of mobile marine organisms. However, elasmobranchs are often underrepresented in such studies. Here, we measured the escape latency (time interval between the stimulus and first visible reaction) of mechanically induced escape responses in the Pacific spiny dogfish, Squalus suckleyi, and in two teleosts from the same region, the great sculpin, Myoxocephalus polyacanthocephalus, and the pile perch, Rhacochilus vacca We found that the dogfish had a longer minimum latency (66.7 ms) compared with that for the great sculpin (20.8 ms) and pile perch (16.7 ms). Furthermore, the dogfish had a longer latency than that of 48 different teleosts identified from 35 different studies. We suggest such long latencies in dogfish may be due to the absence of Mauthner cells, the giant neurons that control fast escape responses in fishes.

Pharmacokinetics of salmeterol and its main metabolite α-hydroxysalmeterol after acute and chronic dry powder inhalation in exercising endurance-trained men: Implications for doping control.

As of 2020, use of beta2 -agonist salmeterol is restricted by the World Anti-Doping Agency (WADA) and is only permitted by inhalation at therapeutic doses not exceeding 200 µg in 24 h. In contrast to beta2 -agonists salbutamol and formoterol, WADA has not established a urine threshold for salmeterol despite its muscle hypertrophic actions observed in animals. Herein, we investigated plasma (0-4 h) and urine (0-24 h) concentrations (by ultra-high-performance liquid chromatography-tandem mass spectrometry [UHPLC-MS/MS]) of salmeterol and α-hydroxysalmeterol after dry powder inhalation at supratherapeutic (400 µg) and high therapeutic (200 µg) doses, and after seven consecutive days of therapeutic inhalation (200 µg × day-1 ) in 11 healthy endurance-trained men. During each trial, participants inhaled salmeterol before 1½ h moderate-intensity cycling. Mean ± SD maximum urine concentrations of salmeterol unadjusted for specific gravity reached 4.0 ± 1.6, 2.1 ± 1.5, and 2.2 ± 1.1 ng × ml-1 for 400 µg, 200 µg, and seven consecutive days of 200 µg, respectively, with corresponding maximum urine concentrations of α-hydroxysalmeterol being 11.6 ± 6.1, 5.7 ± 4.6, and 6.5 ± 2.6 ng × ml-1 . Within the relevant window for doping control (first 6 h post-inhalation), the present data (119 samples), along with 64 biobank urine samples, showed that a combined salmeterol and α-hydroxysalmeterol urine threshold with equal cut-offs of 3.3 ng × ml-1 was superior to a salmeterol-only threshold to discriminate therapeutic (200 µg) from supratherapeutic use (400 µg) with a sensitivity of 24% with 0% false positives when applying the WADA technical document (TD2019DL.v2) method of specific gravity adjustment. Thus, a combination of urine salmeterol and α-hydroxysalmeterol concentrations may be suitable for discriminating between therapeutic and supratherapeutic prohibited inhalation of salmeterol.

A randomized, double-blind, placebo-controlled phase 1 trial of inhaled and intranasal niclosamide: A broad spectrum antiviral candidate for treatment of COVID-19.

BACKGROUND: Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed. METHODS: We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1-4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined. FINDINGS: The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a ß2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration. INTERPRETATION: UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials. FUNDING: The study was funded by Innovationsfonden Denmark and UNION therapeutics.

The Association of Appendectomy, Adhesions, Tubal Pathology, and Female Infertility.

BACKGROUND AND OBJECTIVES: The aim of the study was to investigate a potential association between previous childhood appendectomy, tube pathology, and female infertility. METHODS: We reviewed patients seeking care at the fertility clinic of our university medical center between 2006 and 2016. The history of previous appendectomy was extracted from hospital documentation and by telephone follow-up. Tubal patency was assessed by diagnostic laparoscopy and chromopertubation. RESULTS: In our study cohort (N = 237), 24.9% (n = 59) had a history of previous appendectomy. Previous appendectomy, therefore, was about 3-fold more prevalent in women seeking fertility treatment than in the general population. Patients with previous appendectomy had more intra-abdominal adhesions (P < .001) and patients with adhesions tended to have compromised tubal patency (P = .05). However, there was no direct correlation between a previous appendectomy and tube pathology (P = .727). CONCLUSION: Because previous appendectomy was associated with intra-abdominal adhesions, and these were in turn associated with tube pathology, but appendectomy was not directly associated with compromised tubal patency, previous appendectomy may indirectly affect female fertility through mechanisms other than direct tubal obstruction. This is one of the largest study analyzing laparoscopic chromopertubation in association with previous childhood appendectomy.

Fertility in males after childhood, adolescent, and adult inguinal operations.

BACKGROUND/PURPOSE: Inguinal hernia repair and orchidopexy are among the most common operations in boys. The impact on future fertility has not been conclusively defined. This study evaluates sperm quality after previous inguinal surgery. METHODS: Spermiograms of men with a desire to conceive children were analyzed. History of previous inguinal surgery (hernia repair, orchidopexy, varicocele ligation) was correlated with sperm quality. Other influential factors (age, BMI, chronic medication, tobacco use) were also tested. RESULTS: A total of 333 patients were included. Overall, 12.6% of the subjects had undergone previous inguinal surgery. Of these, 17 (43%) were inguinal hernia repairs, 8 (20%) orchidopexies, and 6 (15%) varicocele ligations, while 9 (22%) could not give an exact history. Abnormal spermiograms were found in 60% (n = 24) of those with previous inguinal surgery versus 48% in controls (p = 0.16). On multivariate analysis, pathologic spermiogram parameters were associated with previous inguinal surgery, orchidopexy, use of chronic medication, and smoking, but NOT with inguinal hernia or varicocele repair alone. CONCLUSIONS: Previous inguinal hernia or varicocele repair does not seem to impact negatively on quality of sperm later in life. Orchidopexy, smoking, and use of chronic medication, however, were all associated with pathologic sperm quality parameters. TYPE OF STUDY: Prospective comparative study. LEVEL OF EVIDENCE: Level II.