The naturally occurring and synthetic butylinenephthalide (Bdph) has two geometric isomers. Z- and E-Bdph were reported to have geometric stereoselectivity for voltage-dependent calcium channels ...(VDCCs) in guinea-pig ileum. The aim of this study was to investigate whether the binding of Z- and E-Bdph on prejunctional VDCCs of rat vas deferens (RVD) is stereoselective. The twitch responses to electrical field stimulation (EFS, supramaximal voltage, 1 ms, 0.2Hz) were recorded on a polygraph. Z- and E-Bdph concentration-dependently inhibited the twitch responses to EFS in full tissue, prostatic portion and epididymal portion of RVD. The pIC50 value of Z-Bdph was greater than that of E-Bdph in the electrically stimulated prostatic portion of RVD, suggesting that the binding of Bdph on the non-adrenergic prejunctional VDCCs of cell membrane is stereoselective. In the prostatic portion, exogenous Ca(2+) only partially reversed the twitch inhibition by Z-Bdph, but effectively reversed those by Ca(2+) channel blockers, such as verapamil, diltiazem and aspaminol, suggesting that the action mechanisms may be different from those of Ca(2+) channel blockers. K(+) channel blockers, such as tetraethylammonium (TEA) and 4-aminopyridine (4-AP), may prolong duration of action potential to allow greater Ca(2+) entry and induced more release of transmitters. Therefore both blockers via their prejunctional actions reversed the twitch inhibition induced by Z-Bdph in all preparations of RVD by a non-specific antagonism.
The presence of predominant pain in the arm vs the neck as a predictor of postoperative outcomes after anterior cervical discectomy and fusion (ACDF) has been seldom reported; therefore, the purpose ...of this study was to determine whether patients with predominant neck pain improve after surgery compared to patients with predominant arm pain or those with mixed symptoms in patients undergoing ACDF for radiculopathy.
A retrospective cohort study was conducted on patients who underwent ACDF at a single center from 2016 to 2018. Patients were split into groups based on preoperative neck and arm pain scores: neck (N) pain dominant group (visual analog scale VAS neck ≥ VAS arm by 1.0 point); neutral group (VAS neck < VAS arm by 1.0 point); or arm (A) pain dominant group (VAS arm ≥ VAS neck by 1.0 point), using a threshold difference of 1.0 point. Subsequently, individuals were substratified into 2 groups based on the arm to neck pain ratio (ANR): non-arm pain dominant defined as ANR ≤1.0 and arm pain dominant (APD) defined as ANR >1.0. Patient-reported outcome measurements including Neck Disability Index (NDI), Physical Component Score-12, and Mental Component Score (MCS-12) were compared between groups.
No significant differences between groups when stratifying patients using a threshold difference of 1.0 point. When stratifying patients using the ANR, those in the APD group had significantly higher postoperative MCS-12 (
= 0.008) and NDI (
= 0.011) scores. In addition, the APD group showed a greater magnitude of improvement for MCS-12 and NDI scores (
= 0.043 and
= 0.038, respectively). Multiple linear regression showed that the A and the APD groups were both independent predictors of improvement in NDI.
Patients with dominant arm pain showed significantly greater improvement in terms of MCS-12 and NDI scores compared to patients with dominant neck pain.
To compare the impact of ACDF on arm and neck pain in the context of cervical radiculopathy using patient-reported outcome measures as an objective measurement.
Background and purpose:
α
1
‐Adrenoceptor antagonists are extensively used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia. Among the ...side effects, ejaculatory dysfunction occurs more frequently with drugs that are relatively selective for
α
1A
‐adrenoceptors compared with other drugs of this class. This suggests that
α
1A
‐adrenoceptors may contribute to ejaculation. However, this has not been studied at the molecular level.
Experimental approach:
The physiological contribution of each
α
1
‐adrenoceptor subtype was characterized using
α
1
‐adrenoceptor subtype‐selective knockout (KO) mice (
α
1A
‐,
α
1B
‐ and
α
1D
‐AR KO mice) since the subtype‐specific drugs available are only moderately selective. We analysed the role of
α
1
‐adrenoceptors in the blood pressure and vascular response as well as ejaculation by determining these variables in
α
1
‐adrenoceptor subtype‐selective KO mice and in mice with all their
α
1
‐adrenoceptor subtypes deleted (
α
1
‐AR triple‐KO mice).
Key results:
The pregnancy rate was reduced by 50% in
α
1A
‐adrenoceptor KO mice, and this reduction was dramatically enhanced in
α
1
‐adrenoceptor triple‐KO mice. Contractile tension of the vas deferens in response to noradrenaline was markedly decreased in
α
1A
‐adrenoceptor KO mice, and this contraction was completely abolished in
α
1
‐adrenoceptor triple‐KO mice. This attenuation of contractility was also observed in the electrically stimulated vas deferens.
Conclusions and implications:
These results demonstrate that
α
1
‐adrenoceptors, particularly
α
1A
‐adrenoceptors, are required for normal contractility of the vas deferens and consequent sperm ejaculation as well as having a function in fertility.
British Journal of Pharmacology
(2007)
152
, 332–340; doi:
10.1038/sj.bjp.0707366
; published online 2 July 2007
Congenital absence of the vas deferens (CAVD) may have various clinical presentations depending on whether it is bilateral (CBAVD) or unilateral (CUAVD), complete or partial, and associated or not ...with other abnormalities of the male urogenital tract. CBAVD is usually discovered in adult men either during the systematic assessment of cystic fibrosis or other
CFTR
-related conditions, or during the exploration of isolated infertility with obstructive azoospermia. The prevalence of CAVDs in men is reported to be approximately 0.1%. However, this figure is probably underestimated, because unilateral forms of CAVD in asymptomatic fertile men are not usually diagnosed. The diagnosis of CAVDs is based on clinical, ultrasound, and sperm examinations. The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants
CFTR
testing and in case of a positive result, genetic counseling prior to conception. Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the
ADGRG2
gene that may cause a familial form of X-linked infertility. However, despite this recent finding, 10–20% of CBAVDs and 60–70% of CUAVDs remain without a genetic diagnosis. An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an early organogenesis disorder (Wolffian duct), unlike CAVDs related to
CFTR
or
ADGRG2
mutations, which might be the result of progressive degeneration that begins later in fetal life and probably continues after birth. How the dysfunction of
CFTR
,
ADGRG2,
or other genes such as
SLC29A3
leads to this involution is the subject of various pathophysiological hypotheses that are discussed in this review.
Vasectomy damage is a common complication of open nonmesh hernia repair. This study was a retrospective analysis of the characteristics and possible causes of vas deferens injuries in patients ...exhibiting unilateral or bilateral vasal obstruction caused by open nonmesh inguinal herniorrhaphy. The site of the obstructed vas deferens was intraoperatively confirmed. Data, surgical methods, and patient outcomes were examined. The Anderson-Darling test was applied to test for Gaussian distribution of data. Fisher's exact test or Mann-Whitney U test and unpaired t-test were used for statistical analyses. The mean age at operation was 7.23 (standard deviation s.d.: 2.09) years and the mean obstructive interval was 17.72 (s.d.: 2.73) years. Crossed (n = 1) and inguinal (n = 42) vasovasostomies were performed. The overall patency rate was 85.3% (29/34). Among the 43 enrolled patients (mean age: 24.95 s.d.: 2.20 years), 73 sides of their inguinal regions were explored. The disconnected end of the vas deferens was found in the internal ring on 54 sides (74.0%), was found in the inguinal canal on 16 sides (21.9%), and was found in the pelvic cavity on 3 sides (4.1%). Location of the vas deferens injury did not significantly differ according to age at the time of hernia surgery (≥12 years or <12 years) or obstructive interval (≥15 years or <15 years). These results underscore that high ligation of the hernial sac warrants extra caution by surgeons during open nonmesh inguinal herniorrhaphy.
Purpose
Congenital aplasia of vas deferens (CAVD) is an atypical form of cystic fibrosis (CF) and causes obstructive azoospermia and male infertility. Compound heterozygous variants of
CFTR
are the ...main cause of CAVD. However, most evidence comes from genetic screening of sporadic cases and little is from pedigree analysis. In this study, we performed analysis in a Chinese pedigree with two CAVD patients in order to determine the genetic cause of this familial disorder.
Methods
In the present study, we performed whole-exome sequencing and co-segregation analysis in a Chinese pedigree involving two patients diagnosed with CAVD.
Results
We identified a rare frameshift variant (NM_000492.3: c.50dupT;p.S18Qfs*27) and a frequent CBAVD-causing variant (IVS9-TG13-5T) in both patients. The frameshift variant introduced a premature termination codon and was not found in any public databases or reported in the literature. Co-segregation analysis confirmed these two variants were in compound heterozygous state. The other male members, who harbored the frameshift variant and benign IVS9-7T allele, did not have any typical clinical manifestations of CF or CAVD.
Conclusion
Our findings may broaden the mutation spectrum of
CFTR
in CAVD patients and provide more familial evidence that the combination of a mild variant and a severe variant in
trans
of
CFTR
can cause vas deferens malformation.
In 80% of infertile men with obstructive azoospermia caused by a congenital bilateral absence of the vas deferens (CBAVD), mutations are identified in the cystic fibrosis transmembrane conductance ...regulator gene (CFTR). For the remaining 20%, the origin of the CBAVD is unknown. A large cohort of azoospermic men with CBAVD was retrospectively reassessed with more stringent selection criteria based on consistent clinical data, complete description of semen and reproductive excurrent ducts, extensive CFTR testing, and kidney ultrasound examination. To maximize the phenotypic prioritization, men with CBAVD and with unilateral renal agenesis were considered ineligible for the present study. We performed whole-exome sequencing on 12 CFTR-negative men with CBAVD and targeted sequencing on 14 additional individuals. We identified three protein-truncating hemizygous mutations, c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21), in ADGRG2, encoding the epididymal- and efferent-ducts-specific adhesion G protein-coupled receptor G2, in four subjects, including two related individuals with X-linked transmission of their infertility. Previous studies have demonstrated that Adgrg2-knockout male mice develop obstructive infertility. Our study confirms the crucial role of ADGRG2 in human male fertility and brings new insight into congenital obstructive azoospermia pathogenesis. In men with CBAVD who are CFTR-negative, ADGRG2 testing could allow for appropriate genetic counseling with regard to the X-linked transmission of the molecular defect.
Precise regulation of vas deferens fluid pH is essential for sperm. However, the mechanisms underlying effect of testosterone on vas deferens fluid pH have never been identified, which could involve ...changes in expression and functional activity of vacoular (V)-ATPase.
Orchidectomized, adult male Sprague-Dawley rats were treated subcutaneously with 125 μg/kg/day and 250 μg/kg/day testosterone with or without flutamide (androgen receptor blocker) and finasteride (5α-reductase inhibitor) for seven (7) days. Following treatment completion, in vivo perfusion of vas deferens lumen was performed and changes in fluid secretion rate, pH and HCO3− content were measured with and without bafilomycin, a V-ATPase inhibitor. Rats were then sacrificed and vas deferens were harvested and subjected for V-ATPase A1 and B1/2 protein expression and distribution analysis by western blotting and immunohistochemistry, respectively.
In sham-operated and testosterone-treated orchidectomized rats, higher fluid secretion rate, which was not antagonized by bafilomycin but lower HCO3− content and pH which were antagonized by bafilomycin were observed when compared to orchidectomized-only and orchidectomized, testosterone-treated rats receiving flutamide or finasteride, respectively. Bafilomycin had no effect on fluid secretion rate, HCO3− content and pH in orchidectomized and testosterone-treated orchidectomized rats receiving flutamide and finasteride. V-ATPase A1 and B1/2 proteins were expressed at high levels in vas deferens and were highly distributed at the apical membrane of luminal epithelium and in muscle layer of this organ, mainly in sham and testosterone-treated orchidectomized rats.
V-ATPase is involved in acidification of vas deferens fluid under testosterone influence.
•Testosterone causes increased vas deferens fluid secretion.•Testosterone causes increased HCO3− content but decreased the pH of vas deferens fluid.•Low vas deferens fluid pH in sham and testosterone-treated orchidectomized rats were antagonized by bafilomycin, a V-ATPase inhibitor.•V-ATPase A and B1/2 proteins were distributed in vas deferens epithelium in sham-operated and testosterone-treated orchidectomized rats.•Flutamide and finasteride antagonized testosterone effects on above parameters.
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