Differential regulation of calcium signalling pathways by components of Piper methysticum ('Awa).

Kava is a soporific, anxiolytic and relaxant in widespread ritual and recreational use throughout the Pacific. Traditional uses of kava by indigenous Pacific Island peoples reflect a complex pharmacopeia, centered on GABA-ergic effects of the well-characterized kavalactones. However, peripheral effects of kava suggest active components other than the CNS-targeted kavalactones. We have previously shown that immunocytes exhibit calcium mobilization in response to traditionally prepared kava extracts, and that the kavalactones do not induce these calcium responses. Here, we characterize the complex calcium-mobilizing activity of traditionally prepared and partially HPLC-purified kava extracts, noting induction of both calcium entry and store release pathways. Kava components activate intracellular store depletion of thapsigargin-sensitive and -insensitive stores that are coupled to the calcium release activated (CRAC) current, and cause calcium entry through non-store-operated pathways. Together with the pepper-like potency reported by kava users, these studies lead us to hypothesize that kava extracts contain one or more ligands for the transient receptor potential (TRP) family of ion channels. Indeed, TRP-like conductances are observed in kava-treated cells under patch clamp. Thus TRP-mediated cellular effects may be responsible for some of the reported pharmacology of kava.

The psychological wellbeing of patients following excision of a pilonidal sinus.

OBJECTIVE: To explore the effects of a pilonidal sinus wound on patients' psychological wellbeing. METHOD: An interpretive descriptive approach, using the Model of Living conceptual framework, guided data collection and analysis. The Model of Living was chosen to elicit information on how a pilonidal sinus wound affected activities of living. Participants were recruited from a database of a community nursing service, using purposive sampling, until data saturation was evident. Semi-structured interviews were used to collect the data. Data were examined for frequent patterns, which were organised into themes. RESULTS: Seven males and four females with ages ranging 17-39 years were selected through purposive sampling. Five participants reported that their wound affected their psychological wellbeing. Three themes and eight sub themes were identified from the data: adaption, perception and control. Depression and stress were associated with pain, physical inactivity, body weight changes and delayed wound healing. CONCLUSION: A pilonidal sinus wound can affect the psychological wellbeing of patients through pain,physical inactivity, changed body weight and delayed wound healing. Pre-existing conditions could also be exacerbated by the wound.

Medicine in motion: Opportunities, challenges and data analytics-based solutions for traditional medicine integration into western medical practice.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional pharmacopeias have been developed by multiple cultures and evaluated for efficacy and safety through both historical/empirical iteration and more recently through controlled studies using Western scientific paradigms and an increasing emphasis on data science methodologies for network pharmacology. Traditional medicines represent likely sources of relatively inexpensive drugs for symptomatic management as well as potential libraries of new therapeutic approaches. Leveraging this potential requires hard evidence for efficacy that separates science from pseudoscience. MATERIALS AND METHODS: We performed a review of non-Western medical systems and developed case studies that illustrate the epistemological and practical translative barriers that hamper their transition to integration with Western approaches. We developed a new data analytics approach, in silico convergence analysis, to deconvolve modes of action, and potentially predict desirable components of TM-derived formulations based on computational consensus analysis across cultures and medical systems. RESULTS: Abstraction, simplification and altered dose and delivery modalities were identified as factors that influence actual and perceived efficacy once a medicine is moved from a non-Western to Western setting. Case studies on these factors highlighted issues with translation between non-Western and Western epistemologies, including those where epistemological and medicinal systems drive markets that can be epicenters for zoonoses such as the novel Coronavirus. The proposed novel data science approach demonstrated the ability to identify and predict desirable medicinal components for a test indication, pain. CONCLUSIONS: Relegation of traditional therapies to the relatively unregulated nutraceutical industry may lead healthcare providers and patients to underestimate the therapeutic potential of these medicines. We suggest three areas of emphasis for this field: First, vertical integration and embedding of traditional medicines into healthcare systems would subject them to appropriate regulation and evidence-based practice, as viable integrative implementation mode. Second, we offer a new Bradford-Hill-like framework for setting research priorities and evaluating efficacy, with the goal of rescuing potentially valuable therapies from the nutraceutical market and discrediting those that are pseudoscience. Third, data analytics pipelines offer new capacity to generate new types of TMS-inspired medicines that are rationally-designed based on integrated knowledge across cultures, and also provide an evaluative framework against which to test claims of fidelity and efficacy to TMS made for nutraceuticals.

Myrcene and terpene regulation of TRPV1.

Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization. Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terpenes found in Cannabis for activity at TRPV1. We used inducible expression of TRPV1 to examine TRPV1-dependency of terpene-induced calcium flux responses. Terpenes contribute differentially to calcium fluxes via TRPV1 induced by Cannabis-mimetic cannabinoid/terpenoid mixtures. Myrcene dominates the TRPV1-mediated calcium responses seen with terpenoid mixtures. Myrcene-induced calcium influx is inhibited by the TRPV1 inhibitor capsazepine and Myrcene elicits TRPV1 currents in the whole-cell patch-clamp configuration. TRPV1 currents are highly sensitive to internal calcium. When Myrcene currents are evoked, they are distinct from capsaicin responses on the basis of Imax and their lack of shift to a pore-dilated state. Myrcene pre-application and residency at TRPV1 appears to negatively impact subsequent responses to TRPV1 ligands such as Cannabidiol, indicating allosteric modulation and possible competition by Myrcene. Molecular docking studies suggest a non-covalent interaction site for Myrcene in TRPV1 and identifies key residues that form partially overlapping Myrcene and Cannabidiol binding sites. We identify several non-Cannabis plant-derived sources of Myrcene and other compounds targeting nociceptive TRPs using a data mining approach focused on analgesics suggested by non-Western Traditional Medical Systems. These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.

Disruption of a behavioral sequence by targeted death of peptidergic neurons in Drosophila.

The neuropeptide eclosion hormone (EH) is a key regulator of insect ecdysis. We tested the role of the two EH-producing neurons in Drosophila by using an EH cell-specific enhancer to activate cell death genes reaper and head involution defective to ablate the EH cells. In the EH cell knockout flies, larval and adult ecdyses were disrupted, yet a third of the knockouts emerged as adults, demonstrating that EH has a significant but nonessential role in ecdysis. The EH cell knockouts had discrete behavioral deficits, including slow, uncoordinated eclosion and an insensitivity to ecdysis-triggering hormone. The knockouts lacked the lights-on eclosion response despite having a normal circadian eclosion rhythm. This study represents a novel approach to the dissection of neuropeptide regulation of a complex behavioral program.

Agreement between grating acuity at age 1 year and Snellen acuity at age 5.5 years in the preterm child. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

PURPOSE: To examine the relation between grating acuity at age 1 year and Snellen acuity and grating acuity at 5.5 years, in preterm children with birth weights less than 1251 g. METHODS: Subjects were participants in the multicenter study of Cryotherapy for Retinopathy of Prematurity. The Teller acuity card (TAC; Vistech Consultants, Dayton, OH) procedure was used to measure monocular grating acuity in children at ages 1 and 5.5 years. Early-treatment diabetic retinopathy study (ETDRS) charts were used to measure the childrens' monocular recognition (Snellen) acuity at age 5.5 years. Data are presented for 575 eyes with measurable TAC grating acuity at 1 year and 111 eyes that had no measurable acuity at 1 year. RESULTS: Among eyes with normal acuity at 1 year, 86.8% showed normal Snellen acuity, and 94.3% showed normal grating acuity at 5.5 years. Among eyes that were blind (i.e., had no measurable TAC grating acuity) at 1 year, 96.8% showed no quantifiable Snellen acuity, and 89.2% showed no quantifiable grating acuity at 5.5 years. Only 2.4% of eyes had acuity in the range between normal and blind at 1 year (i.e., measurable grating acuity <1.6 cyc/deg); thus, the predictive value of acuity scores in this range could not be determined. Correlation analysis indicated that the relative position within the normal range of an eye's grating acuity score at 1 year was not predictive of the relative position within the normal range of that eye's acuity score at 5.5 years. CONCLUSIONS: Among a large population of low-birth-weight infants, eyes with normal grating acuity at age 1 year generally showed normal Snellen and grating acuity at age 5.5 years, and eyes that had no quantifiable acuity at 1 year remained blind at 5.5 years. Relative position of an eye's acuity score within the normal range was not predictive of the relative position of that eye's later acuity score.

A rational approach to anaesthetic premedication.

Rational use of premedication for anaesthesia must always be modified and updated to keep pace with the evolving fields of anaesthesiology and surgery, as well as to meet changing patient needs and preferences. It is no longer axiomatic that all patients require, and therefore should receive, premedication. Unfortunately, a variety of traditional reasons have been proposed to justify routine premedication in many institutions. Smoothing induction, decreasing reflexes and arrhythmias, decreasing nausea and vomiting, decreasing pain, decreasing secretions, and producing sedation and amnesia have all been claimed historically as beneficial results of premedication. Modern anaesthetic agents and techniques have come a long way towards eliminating the routine need for premedication. In the preoperative period, the goal of an anxiety-free patient who is physiologically uncompromised requires an individualised approach based on experience and an adequate knowledge of current pharmacology. As our knowledge of potential problems associated with anaesthesia has expanded, we have added other classes of drugs such as the H2-histamine receptor blockers and antacids to our premedicant armamentarium. Outpatient and short-stay patients have further challenged our preoperative goal of an anxiety-free patient by requiring individuals to be 'street ready' within a brief period of time after surgery. Even for in-house elective procedures, not every patient is a candidate for routine premedication. A frank preoperative discussion is all that is necessary to effectively allay anxiety in many persons. In these and other special situations, this article will hopefully guide the reader toward a more rational approach to premedicating patients.

Monofixational intermittent exotropia.

The surgical correction of intermittent exotropia occasionally results in a monofixational sensory pattern. Stereopsis as a measure of bifixation was studied preoperatively and postoperatively in 39 cases of intermittent exotropia. Of 26 patients with bifixation, 25 remained so after surgery. Of 13 patients with monofixation, 11 remained unchanged by surgery, one improved, and one lost all binocularity. The presence of preoperative monofixational intermittent exotropia, to explain a monofixation result from intermittent exotropia surgery, is proposed.

Pediatric intraocular knife.

An intraocular knife was developed that is of fine sharpness and small size to permit easy use in the eyes of young children.

Adenoid cystic carcinoma of the lacrimal gland in a child.

An unusual case of adenoid cystic carcinoma of the lacrimal gland occurred in an 11-year-old child. Clinical, echographic, and histopathologic characteristics, as well as the management of this usually fatal disease, are discussed. The subtle signs and symptoms of this tumor were noted at the age of 9 years. A review of the literature reveals this to be the youngest patient in whom this tumor has been reported.

Strabismus in premature infants in the first year of life. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

OBJECTIVES: To present the 3- and 12-month strabismus data from 3030 premature infants with birth weights less than 1251 g enrolled in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. DESIGN: Data from the 3- and 12-month examinations conducted at 23 regional study centers were tabulated for all infants. The main outcome measure, ocular motility, was compared with baseline demographic variables and retinopathy of prematurity severity for the worse eye. Findings at 3 months were compared with the incidence of strabismus at 12 months. RESULTS: At 3 months, 200 (6.6%) of the 3030 infants were strabismic. In the 2449 infants examined at both time points, 289 (11.8%) were found to have strabismus at 12 months. Retinopathy of prematurity was significant for strabismus at both 3 and 12 months (P<.001). The presence of strabismus at 3 months was found to be a highly significant predictor of strabismus at 12 months. Anisometropia, abnormal fixation, and unfavorable retinal structure also were significant predictors of strabismus at 1 year. The total prevalence of strabismus in the first year of life was 14.7%. CONCLUSION: The presence of acute-phase retinopathy of prematurity places the premature infant at increased risk for strabismus.

The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning.

Five groups of rats were given Pavlovian fear conditioning. Four groups were then given extinction training. Prior to extinction these groups received an injection of either the noncompetitive NMDA antagonist MK-801 (0.025, 0.05, or 0.1 mg/kg) or saline. The 5th group received saline but no extinction. During testing, the extinction groups given saline or 0.025 mg/kg of MK-801 showed reduced fear, but the groups that had received the higher doses exhibited as much conditioned fear as the saline group, which had not received extinction. This study showed that MK-801 blocked extinction in a dose-dependent manner. The design of the study ruled out the possibility that the effect was due to state-dependency or to MK-801 interfering with the processing of the conditioned stimulus.

Effects of D2 dopamine receptor blockade with raclopride on intracranial self-stimulation and food-reinforced operant behaviour.

To examine the involvement of D2 dopamine receptors in the neural mechanism of reinforcement, raclopride tartrate, a D2 specific dopamine antagonist with a relatively fast central action, was injected into 32 rats. The D2 antagonist reduced bar-pressing responses reinforced with electrical stimulation of the ventral tegmental area (ED50 = 0.079 mumol/kg) and those reinforced with food (ED50 = 0.58 mumol/kg) in 18-30 min after IP injection. The reduction in response rates could not be attributed to an interference with motor functions. An increase in the frequency of brain-stimulation pulses and a change in the schedule of food reinforcement, which respectively increased the baseline rate of responding, did not alter the effectiveness of raclopride. SCH 23,390, a D1-specific dopamine antagonist, was sensitive to similar manipulation of reinforcement. These results seem to suggest that D1 and D2 antagonists may be acting at different locations in the neural mechanism underlying the reinforcement of operant behaviour.

Variability of Doppler ankle pressures with arterial occlusive disease: an evaluation of ankle index and brachial-ankle pressure gradient.

The variability of Doppler ankle pressures was studied in 35 men with clinically stable claudication. An average of 6.8 measurements was obtained from each man. The mean range of ankle index was 0.18 with a mean standard deviation of 0.07. The brachial-ankle pressure gradient had a wider spread, with a mean range of 38 mm Hg and a standard deviation of 13.9. The amount of variation in a given patient was unrelated to mean blood pressure or mean ankle index. The results of this study show that the ankle index must change at least 0.15 before it can be considered significant. Based on the variability found, we recommend that multiple baseline determinations be obtained on patients who are to be followed longitudinally.

Vertebral artery aneurysm: case report and review of the literature.

A nontender, nonpulsatile large anterior neck mass was found at operation to be an atherosclerotic aneurysm of the vertebral artery, an extremely rare condition. Proximal control and distal control were obtained and the aneurysm was excised. Aneurysms of the vertebral artery are infrequent but well-defined complications in connective tissue disorders such as the Ehlers-Danlos syndrome, and they can develop subsequent to penetrating neck trauma. However, no cases of atherosclertic vertebral artery aneurysms have been reported recently in the English-language literature. The case presented illustrates that this rare condition should be considered in all patients who have neck masses of undetermined etiology.

Pathogenesis of aortoduodenal fistula: experimental and clinical correlates.

An aortoduodenal fistula (ADF) is believed to stem from erosion of a rigid prosthesis into the fixed retroperitoneal duodenum. Experimental and clinical data do not support a mechanical etiology, but indicate that the pathogenesis is an unrecognized graft infection with pseudoaneurysm formation. A 5 cm segment of Dacron was interposed in the infrarenal aortas of 24 dogs that were divided into four groups of six animals each. In group 1 (control) the duodenum was fixed by sutures to the proximal anastomosis of the Dacron graft. At 6 weeks' follow-up, no ADFs or deaths had occurred among this group. In group 2 the duodenum was fixed to the aortoprosthetic anastomosis and the dogs received an intravenous infusion of 10(8) S. aureus; two of these dogs developed ADF (P less than 0.01). In group 3 the duodenum was incorporated as a patch on the anterior aspect of the aortoprosthetic suture line, creating a false aneurysm; three of these animals died as a result of ADF. A false aneurysm was created in group 4 dogs, as in group 3, but in addition, 10(8) S. aureus was administered intravenously; here five to six animals developed ADF. Clinical and bacteriological evidence of graft infection was present in seven of 11 patients with ADF who were seen over an 18 year period. Five had pseudoaneurysm formation at the proximal anastomosis. Operation was performed in eight patients; three had closure of the aortic leak and repair of the duodenum with omentum interposition. All resulted in recurrent fistula and delayed hemorrhage. Simple graft excision in two patients without reconstitution of peripheral circulation resulted in lower extremity gangrene. The three survivors had graft excision and axillofemoral bypass. These data suggest that the etiology of ADF is primary low-grade infection. Successful operation necessitates excision of the graft, duodenal closure, and an extraanatomical axillofemoral bypass graft.

An evaluation of electroencephalographic monitoring for carotid study.

Continuous electroencephalogram (EEG) monitoring was used during 213 carotid endarterectomies in 157 patients to identify cerebral ischemia. General anesthesia was used for all patients. An intraluminal shunt was not used routinely, but was inserted in 23 operations when EEG abnormalities associated with ischemia appeared. EEG changes occurred in 31 operations (14.5 percent). Four patterns of abnormal recordings were identified and are discussed. Six patients developed ischemic EEG changes in association with hypotension during endarterectomy. In two of these patients changes appeared with a blood pressure drop of only 20 mm. Hg below preoperative levels. Four patients with internal carotid artery back pressures of 75 to 100 mm. Hg developed EEG abnormalities which disappeared after shunt insertion. Our experience emphasizes the value of continuous EEG monitoring in detecting inadequate cerebral perfusion.

Poststress Doppler ankle pressures: a comparison of treadmill exercise with two other methods of induced hyperemia.

Postocclusion reactive hyperemia and isolated leg exercise were evaluated as techniques for functional evaluation of lower extremity arterial insufficiency by comparing them with treadmill exercise. Sixty patients with claudication and six normal subjects were evaluated. Changes in Doppler ankle pressures were measured after each form of stress. With substantial occlusive disease, there is a drop in pressure with gradual recovery. Postocclusion reactive hyperemia and isolated leg exercise are abnormal if the pressure does not return to resting levels within two minutes. There was good correlation between the three methods. Postocclusion reactive hyperemia avoids the problems of patient cooperation inherent in the other two methods. Postocclusion reactive hyperemia should probably replace treadmill exercise as the first method of stress testing lower extremities.

Incidence and mechanism of post-carotid endarterectomy hypertension.

Hypertension following carotid endarterectomy occurs frequently but is poorly understood. Its occurrence has been correlated with an increased incidence of neurologic complication. We identified those factors that correlate with an increased incidence of post-carotid endarterectomy hypertension. The records of 100 patients who underwent carotid endarterectomy at UCLA Medical Center from November 1981 to September 1983 were examined. One hundred fifty variables were surveyed to determine those factors associated with this problem. Fifty-eight percent of the study patients developed post-carotid endarterectomy hypertension (an increase in systolic blood pressure greater than 35 mm Hg over baseline, and/or blood pressure requiring treatment with sodium nitroprusside). Of patients who developed this problem, 93% had diabetes mellitus, 75% received isoflurane anesthesia, 71% had peripheral vascular occlusive disease, 71% underwent ipsilateral transient ischemic attacks, and 65% had high-grade ipsilateral carotid stenosis. These variables have in common the loss of or interference with cerebral autoregulation. Central dysautoregulation may set the stage for a positive feedback mechanism that results in increased blood pressure. Anesthetic agents that do not interfere with cerebral autoregulation may reduce the incidence of this complication, and an aggressive treatment program may prevent neurologic complications.

Cost of treating advanced leg ischemia. Bypass graft vs primary amputation.

We compared the hospital costs of 94 patients undergoing femoropopliteal bypass grafts with those of 53 patients undergoing primary amputation. The total cost of uncomplicated bypass surgery averaged +20,300, compared with +14,000 for uncomplicated below-knee amputation. However, including the cost of prosthesis and rehabilitation, the total cost of primary amputation was +20,400, equivalent to that of the bypass operation. Complications requiring revision of a bypass graft increased hospitalization by 4.5 days with the total cost rising to +28,700; complications that ended with major amputation added 15 hospitalization days and had an average cost of +42,200. In contrast, complicated below-knee amputation cost +40,600 and added 12.5 hospitalization days. There is therefore no cost-benefit in primary amputation when compared with arterial reconstruction, and cost should not be used to deny a patient the opportunity for limb salvage.