Inhibition of neurally-evoked transmitter release by calcium channel antagonists in rat parasympathetic ganglia.

1. Excitatory postsynaptic potentials (e.p.s.ps) were recorded from the submandibular parasympathetic ganglia of newborn rats (10-20 days old), by intracellular microelectrode recording and a suction electrode to deliver stimulus trains to the lingual nerve (15 stimuli at 0.1, 0.3, 1, 3, and 10 Hz, 22 degrees C). Only evoked responses without voltage-dependent action potentials were analyzed (observed at membrane potentials negative to -70 mV), and e.p.s.p. amplitudes were determined for the plateau responses during each train (5-15th response). 2. Cadmium, an inorganic calcium channel antagonist, reduced e.p.s.p. amplitudes in a dose-dependent manner (Kd 74 microM, P less than 0.01). Nickel (1-300 microM) did not attenuate the amplitude of evoked responses. 3. Verapamil (0.1-30 microM), a phenylamine, had no significant effects upon e.p.s.p. amplitudes at any frequency examined. Higher concentrations of verapamil (100 microM) blocked neurally evoked responses in a manner consistent with the antagonism of voltage-sensitive sodium currents. 4. Diltiazem, a benzothiazepine, reduced e.p.s.p. amplitudes in a dose-dependent manner, the depression being accentuated at high stimulation frequencies (80% block at 30 microM and 10 Hz). The pure (-)-cis enantiomer of diltiazem (10-30 microM) was without effect. 5. Amlodipine, a 1,4-dihydropyridine, did not antagonize synaptic transmission at any stimulus frequency examined (10-30 microM, 0.1-10 Hz, n = 3). 6. Amiloride, a potassium-sparing diuretic, depressed the amplitudes of evoked responses in a dose-dependent manner (one-site Kd 31 microM, P less than 0.005), although the extent of the block was alleviated with high stimulus frequencies. The effects of 30 microM amiloride were unlikely to be of post-synaptic origin as both the amplitudes of miniature e.p.s.ps, and the iontophoretic potentials induced by exogenous acetylcholine, were not attenuated by treatment with this compound. The amiloride derivative, 3',4'-dichlorobenzamil was ineffective in reducing the amplitude of e.p.s.ps (30-100 microM). 7. omega-Conotoxin GVIA, a marine neurotoxin, which depressed whole cell calcium currents recorded from cultured rat parasympathetic cardiac neurones (up to 90% block at 10 nM), was ineffective at blocking synaptic transmission in submandibular ganglia (0.1-1 microM). 8. The differential effects of these calcium channel antagonists upon synaptic transmission in rat parasympathetic ganglia, suggest that either more than one type of calcium channel may be involved in transmitter release, or that the presynaptic calcium channels possess pharmacological sensitivities different from those of channel types described in ne     

An outpatient anticoagulation protocol managed by a vascular nurse-clinician

Lifetime anticoagulation has become a therapeutic option for surgical patients with hypercoagulable states or prosthetic arterial bypass grafts. However, physicians may not achieve optimal anticoagulation or may attempt to limit the length of the therapy period because of the perceived morbidity from hemorrhagic complications of Coumadin therapy. A protocol for anticoagulant therapy monitored and regulated by a vascular nurse-clinician was reviewed. Coumadin was prescribed for 1,891 patient-months to 93 patients to maintain their prothrombin time 1.5 to 2 times control (range: 18 to 24 seconds). The mean (+/- SD) prothrombin time for the study population was 19.8 +/- 1.8 seconds. During follow-up, 472 (14%) of 3,479 prothrombin times measured were below the therapeutic range (n = 232) or prolonged (n = 240), prompting an adjustment in the Coumadin dose in 82 (88%) patients. Four patients developed recurrent vascular graft thrombosis while receiving anticoagulation. There were 6 major and 11 minor hemorrhagic complications. Patients with a chronic risk for arterial or venous thrombosis can have out-patient anticoagulant therapy administered at optimal intensity and regulated safely with a low incidence of hemorrhagic and thrombotic events.     

The distinction of bone and liver isoenzymes of alkaline phosphatase in serum using a monoclonal antibody

Out of 31 mouse monoclonal antibodies to human liver and bone ALP, one antibody coded BAP 1/9, showing a preference for binding the bone isoenzyme, and one antibody coded LAP 1/5, showing no preference, were selected to study binding of the serum forms of ALP. Using a plate capture assay format BAP 1/9 showed a 1.8-fold preference for binding purified bone versus liver ALP in the presence of 10% ALP-free serum compared with 2.1- to 2.25-fold preference in buffered salt solution. BAP 1/9 showed a preference for binding ALP from serum samples containing predominantly bone ALP compared to those containing predominantly liver ALP. Using predefined mixtures of serum forms of bone and liver ALP a linear relationship between ALP bound to BAP 1/9 and the fraction of bone ALP was obtained.     

Neurologic complications of reoperative and emergent abdominal aortic reconstruction

Patients undergoing emergent and reoperative abdominal aortic reconstructions are at increased risk for ischemic neurologic complications. Between 1986 and 1992 five patients sustained ischemic injuries to the spinal cord, nerve roots, or lumbosacral plexus. Four patients underwent reoperative aortic procedures including removal of an infected aortobifemoral graft and extra-anatomic bypass (n=3) and aortofemoral graft revision for primary graft failure (n=1). A fifth patient had a ruptured common iliac aneurysm repaired with an aortobifemoral graft. Three patients undergoing reoperative aortic procedures developed lower extremity paraparesis, patchy sensory deficits, and bowel and bladder dysfunction. Physical examination and electromyography localized the injury to the level of the cauda equina or lumbosacral plexus. The other patient in this group developed incomplete T12 paraplegia. Surgical reconstruction resulted in internal iliac exclusion in all four patients. The incidence of neurologic deficits during this study period was 18% (3/17) in patients requiring aortofemoral graft excision for infection. The patient undergoing aneurysm repair was noted to have paraplegia after surgery and died on the fourth postoperative day. Autopsy revealed evidence of multiple emboli to the kidneys, bowel, and spinal cord. Neurologic deficits after reoperative and emergent abdominal aortic reconstructions are uncommon but devastating complications. Of particular concern is the incidence of neurologic deficits after removal of aortofemoral grafts with disruption of collateral flow to the spinal cord and nerve roots. Consideration should be given to maintaining retrograde perfusion of at least one internal iliac artery via common femoral artery reconstruction in these patients.Presented at the Nineteenth Annual Meeting of the Peripheral Vascular Surgery Society, Seattle, Wash., June 5, 1994.     

The nitric oxide pathway in pre-eclampsia: pathophysiological implications

Pre-eclampsia, one of the most significant health problems inhuman pregnancy, complicates 6-7% of all gestations and is theleading cause of fetal growth retardation, infant morbidityand mortality, premature birth and maternal death. Recent researchimplicates free radicals in the pathophysiology of pre-eclampsia.This review covers the biochemistry of nitric oxide (NO) andpossible interactions with other free radicals. Studies in therat show that pregnancy is associated with enhanced productionand responsiveness to NO in both reproductive tissues and bloodvessels. Rats infused with N^G-nitro-L-arginine methyl ester(L-NAME, a NO synthase inhibitor) have been used as an animalmodel of pre-eclampsia, and the effects of steroid hormoneson blood pressure in this model have been tested. Results suggestthat pre-eclampsia may be a state of NO deficiency. However,in humans there seem to be contradictions regarding the involvementof NO in maternal adaptation to pregnancy. It is suggested thatNO may be one of several systems that act in concert to maintaina symbiotic relationship between mother and fetus. However,the input of each system may be genetically determined.     

Surgical sperm retrieval and intracytoplasmic sperm injection as treatment of obstructive azoospermia

Male genital tract obstructions may result from infections, previous inguinal and scrotal surgery (vasectomy) and congenital bilateral absence of the vas deferens (CBAVD). Microsurgery can sometimes be successful in treating the obstruction. In other cases and in cases of failed surgical intervention, the patient can be treated by microsurgical or percutaneous epididymal sperm aspiration (MESA, PESA) or testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). We present the results of 39 ICSI procedures for obstructive azoospermia in 24 couples. The aetiology of the obstruction was failed microsurgery in 11 patients, CBAVD in nine and genital infections in four. Sperm retrieval was accomplished via MESA in four cases, PESA in 18 cases and via TESE in 11 cases. TESE was only applied when PESA failed to produce enough spermatozoa for simultaneous ICSI. In six patients, the ICSI procedure was performed with cryopreserved spermatozoa after an initial PESA procedure. Fertilization occurred in 47% of the metaphase II oocytes; embryo transfer was performed in 92% of procedures and resulted in a clinical pregnancy in 13/39 procedures. Ongoing pregnancy was achieved in 10/39 procedures. One pregnancy was terminated early after prenatal investigation showed a cytogenetic abnormality (47,XX+18, Edwards syndrome). The other nine pregnancies resulted in the live birth of 10 children, without any congenital abnormalities. Epididymal and testicular retrieved spermatozoa were successfully used for ICSI to treat obstructive azoospermia, and resulted in an ongoing pregnancy in 10 of 24 couples (41.6%) after 39 ICSI procedures, a success rate of 25.6% per treatment cycle and of 27.7% per embryo transfer.      

Examining how changes in provincial policy on vape marketing impacted the distribution of vaping advertisements near secondary schools in London,Ontario

ObjectivesOn January 1, 2020, the Government of Ontario passed a regulation banning vaping advertisements by retailers, apart from specialty shops. A motivation for this ban was to limit youth exposure to vaping advertisements. The primary goal of this research was to evaluate the impact of this ban on the number and density of vaping advertisements surrounding secondary schools. Additionally, we examined whether the number of vaping advertisements varied by school socio-demographic characteristics.MethodsThis study used a pre-post design. Audits were conducted December 2019 (pre-ban) and again January to February 2020 (post-ban), to identify vaping advertisements within 800 m surrounding secondary schools (n = 18) in London, Ontario.ResultsPrior to the ban, there were 266 vaping advertisements within 800 m of secondary schools. After the ban, this was reduced to 58, a 78.2% reduction. The mean number of vaping advertisements surrounding schools significantly decreased from 18.1 before the ban to 3.6 after the ban (p < 0.001). A significant positive correlation was found, prior to the ban, between the number of vaping advertisements surrounding schools and school-level residential instability (r = 0.42, p = 0.02). After the ban, no significant correlations were found between the number of vaping advertisements and school socio-demographic characteristics.ConclusionThe provincial ban of vaping advertisements in select retail settings significantly reduced the number of vaping advertisements in the areas surrounding secondary schools in London, Ontario. The ban also reduced socio-demographic inequities in youths’ potential exposure to marketing of vaping products. Continued monitoring of the geographic accessibility and promotion of vaping products is warranted.     

Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein

Abnormal processing of amyloid precursor protein (APP), in particular the generation of beta-amyloid (Abeta) peptides, has been implicated in the pathogenesis of Alzheimer's disease. This study examined the consequences of deleting the APP gene on hippocampal synaptic plasticity, and upon the biophysical properties of morphologically identified neurones in APP-null mice. The hippocampus of APP-null mice had a characteristic increase in gliosis throughout the CA1 region and a disruption of staining for the dendritic marker MAP2 and the presynaptic marker synaptophysin. The disruption of MAP2 staining was associated with a significant reduction in overall dendritic length and projection depth of biocytin labeled CA1 neurones. In two groups of APP-null mice that were examined at 8-12 months, and 20-24 months of age, there was an impairment in the formation of long-term potentiation (LTP) in the CA1 region compared to isogenic age matched controls. This LTP deficit was not associated with an alteration in the amplitude of EPSPs at low stimulus frequencies (0.033 Hz) or facilitation during a 100 Hz stimulus train, but was associated with a reduction in post-tetanic potentiation. Paired-pulse depression of GABA-mediated inhibitory post-synaptic currents was also attenuated in APP-null mice. These data demonstrate that the impaired synaptic plasticity in APP deficient mice is associated with abnormal neuronal morphology and synaptic function within the hippocampus.