Characterization of cardiovascular reflexes evoked by airway stimulation with allylisothiocyanate, capsaicin, and ATP in Sprague-Dawley rats.

Acute inhalation of airborne pollutants alters cardiovascular function and evidence suggests that pollutant-induced activation of airway sensory nerves via the gating of ion channels is critical to these systemic responses. Here, we have investigated the effect of capsaicin [transient receptor potential (TRP) vanilloid 1 (TRPV1) agonist], AITC [TRP ankyrin 1 (TRPA1) agonist], and ATP (P2X2/3 agonist) on bronchopulmonary sensory activity and cardiovascular responses of conscious Sprague-Dawley (SD) rats. Single fiber recordings show that allyl isothiocyanate (AITC) and capsaicin selectively activate C fibers, whereas subpopulations of both A and C fibers are activated by stimulation of P2X2/3 receptors. Inhalation of the agonists by conscious rats caused significant bradycardia, atrioventricular (AV) block, and prolonged PR intervals, although ATP-induced responses were lesser than those evoked by AITC or capsaicin. Responses to AITC were inhibited by the TRP channel blocker ruthenium red and the muscarinic antagonist atropine. AITC inhalation also caused a biphasic blood pressure response: a brief hypertensive phase followed by a hypotensive phase. Atropine accentuated the hypertensive phase, while preventing the hypotension. AITC-evoked bradycardia was not abolished by terazosin, the α1-adrenoceptor inhibitor, which prevented the hypertensive response. Anesthetics had profound effects on AITC-evoked bradycardia and AV block, which was abolished by urethane, ketamine, and isoflurane. Nevertheless, AITC inhalation caused bradycardia and AV block in paralyzed and ventilated rats following precollicular decerebration. In conclusion, we provide evidence that activation of ion channels expressed on nociceptive airway sensory nerves causes significant cardiovascular effects in conscious SD rats via reflex modulation of the autonomic nervous system.

Mechanical contribution of lamellar and interlamellar elastin along the mouse aorta.

The mechanical properties of aortic elastin vary regionally, but the microstructural basis for this variation is unknown. This study was designed to identify the relative contributions of lamellar and interlamellar elastin to circumferential load bearing in the mouse thoracic and abdominal aortas. Forces developed in uniaxial tests of samples of fresh and autoclaved aorta were correlated with elastin content and morphology obtained from histology and multiphoton laser scanning microscopy. Autoclaving should render much of the interlamellar elastin mechanically incompetent. In autoclaved tissue force per unit sample width correlated with lamellar elastin content (P≪0.001) but not total elastin content. In fresh tissue at low strain where elastin dominates the mechanical response, forces were higher than in the autoclaved tissue, but force did not correlate with total elastin content. Therefore although interlamellar elastin likely contributed to the stiffness in the fresh aorta, its contribution appeared not in proportion to its quantity. In both fresh and autoclaved tissue, elastin stiffness consistently decreased along the abdominal aorta, a key area for aneurysm development, and this difference could not be fully accounted for on the basis of either lamellar or total elastin content. These findings are relevant to the development of mathematical models of arterial mechanics, particularly for mouse models of arterial diseases involving elastic tissue. In microstructural based models the quantity of each mural constituent determines its contribution to the total response. This study shows elastin's mechanical response cannot necessarily be accounted for on the basis of fibre quantity, orientation, and modulus.

Growth of magneto-optically active (Zn,Mn)Se nanowires.

We describe the growth of Zn(1-x)Mn(x)Se nanowires in ultrahigh vacuum seeded by Au nanodroplets. Electron microscopy reveals the formation of single-crystal c-axis wurtzite nanowires (typically 1-3 microm long) with Mn concentrations up to x approximately 0.6, accompanied by a dense horizontal undergrowth of shorter, crooked nanowires. Magnetophotoluminescence measurements show evidence for sp-d exchange effects in a reduced symmetry environment. We find that the optical emission is surprisingly dominated by the undergrowth of crooked nanowires.

Leukotriene D4 increases the excitability of capsaicin-sensitive nasal sensory nerves to electrical and chemical stimuli.

BACKGROUND AND PURPOSE: Clinical studies have demonstrated significant reductions in allergen-induced nasal symptoms of atopic rhinitis subjects by CysLT1 antagonists, including neuronally mediated symptoms such as sneeze, itch and reflex hypersecretion. Here, we test the hypothesis that cysteinyl leukotrienes activate and/or alter the activity of nasal nociceptive (capsaicin-sensitive) sensory neurones. EXPERIMENTAL APPROACH: Using retrograde tracer (DiI), we labelled guinea-pig trigeminal sensory neurones that projected fibres to the nasal mucosa. Single-neurone reverse transcriptase (RT)-PCR was used to evaluate CysLT receptor gene expression. The effect of cysteinyl leukotrienes on individual nasal sensory nerve activity was assessed in Ca2+ assays and whole-cell gramicidin-perforated patch-clamp studies. KEY RESULTS: Nasal C-fibre neurones express CysLT1 but not CysLT2 mRNA. LTD4 and LTC4 increased intracellular [Ca2+]free in a population of capsaicin-sensitive trigeminal nerves, an effect blocked by the CysLT1 antagonist ICI198615. In current clamp mode, LTD4 had no effect on resting membrane potential. However, LTD4 significantly increased electrical excitability (action potential discharge during current pulses) threefold in capsaicin-sensitive nasal neurones, which was inhibited by CysLT1 antagonists ICI198615 and montelukast. LTD4 had no effect on electrical excitability in capsaicin-insensitive neurones. Finally, LTD4 significantly augmented histamine-induced responses in capsaicin-sensitive neurones as measured by increased action potential discharge, peak frequency and membrane depolarization. CONCLUSIONS AND IMPLICATIONS: LTD4, likely through CysLT1 receptors, directly increases the excitability of capsaicin-sensitive guinea-pig nasal trigeminal neurones, demonstrating a novel mechanism for the actions of cysteinyl leukotrienes and potentially explains the effectiveness of CysLT1 antagonists in treating nasal allergen-induced neuronal symptoms.

Relative contributions of TRPA1 and TRPV1 channels in the activation of vagal bronchopulmonary C-fibres by the endogenous autacoid 4-oxononenal.

Transient receptor potential (TRP) A1 channels are cation channels found preferentially on nociceptive sensory neurones, including capsaicin-sensitive TRPV1-expressing vagal bronchopulmonary C-fibres, and are activated by electrophilic compounds such as mustard oil and cinnamaldehyde. Oxidative stress, a pathological feature of many respiratory diseases, causes the endogenous formation of a number of reactive electrophilic alkenals via lipid peroxidation. One such alkenal, 4-hydroxynonenal (4HNE), activates TRPA1 in cultured sensory neurones. However, our data demonstrate that 100 microm 4HNE was unable to evoke significant action potential discharge or tachykinin release from bronchopulmonary C-fibre terminals. Instead, another endogenously produced alkenal, 4-oxononenal (4ONE, 10 microm), which is far more electrophilic than 4HNE, caused substantial action potential discharge and tachykinin release from bronchopulmonary C-fibre terminals. The activation of mouse bronchopulmonary C-fibre terminals by 4ONE (10-100 microm) was mediated entirely by TRPA1 channels, based on the absence of responses in C-fibre terminals from TRPA1 knockout mice. Interestingly, although the robust increases in calcium caused by 4ONE (0.1-10 microm) in dissociated vagal neurones were essentially abolished in TRPA1 knockout mice, at 100 microm 4ONE caused a large TRPV1-dependent response. Furthermore, 4ONE (100 microm) was shown to activate TRPV1 channel-expressing HEK cells. In conclusion, the data support the hypothesis that 4-ONE is a relevant endogenous activator of vagal C-fibres via an interaction with TRPA1, and at less relevant concentrations, it may activate nerves via TRPV1.

Thalomid (Thalidomide) capsules: a review of the first 18 months of spontaneous postmarketing adverse event surveillance, including off-label prescribing.

The sedative/hypnotic thalidomide was withdrawn from the worldwide market nearly 40 years ago, because of its teratogenic and neurotoxic effects. Thalidomide was later found to very effectively suppress erythema nodosum leprosum (ENL). The US Food and Drug Administration (FDA) has approved Thalomid (thalidomide) capsules for the acute treatment of the cutaneous manifestations of moderate to severe ENL. Thalidomide is currently under investigation for the treatment of a wide variety of diseases, including conditions thought to have an inflammatory or immune basis, malignancies and complications of infection with HIV. Interest in the potential anti-inflammatory, immunomodulatory and anti- angiogenic effects of thalidomide has resulted in off-label use of prescription thalidomide. During the first 18 months of spontaneous postmarketing adverse event surveillance for Thalomid, 1210 spontaneous postmarketing adverse event reports were received for patients treated with prescription thalidomide for all therapeutic indications, including off-label use. The most common adverse events spontaneously reported would have been expected on the basis of the current Thalomid labelling/product information. The current labelling/product information reflects what was known about the risks associated with thalidomide therapy in limited patient populations at the time of the approval of Thalomid. With the postmarketing use of thalidomide in populations other than patients with ENL, it becomes increasingly important to identify patient groups that may be particularly susceptible to specific adverse drug effects and to identify conditions under which specific adverse events may be more likely to occur. Oncology patients may represent a patient population with increased susceptibility to thalidomide-associated adverse effects, including thromboembolic events. Consideration of the spontaneous postmarketing safety surveillance data may help to identify and characterise factors associated with increased risk in this and other patient groups. Serious unexpected adverse events reported with sufficient frequency to signal previously undetected product-event associations for which there may potentially be plausible evidence to suggest a causal relationship have included seizures and Stevens-Johnson syndrome. The potential effects of thalidomide on wound healing are also being closely monitored. Premarketing human clinical trials of drug products are inherently limited in their ability to detect adverse events. Broader postmarketing experience with thalidomide in more varied patient populations and more experience in the setting of long term thalidomide use will increase our ability to detect rare adverse events and to identify signals that may need to be evaluated in more controlled settings.

A randomized trial of emotion-focused therapy for couples in a training clinic.

Forty married couples participated in a randomized trial comparing 8 weekly sessions of emotion-focused therapy (EFT) for couples to a group of couples who were placed on an 8-week waiting list. A composite marital satisfaction score was created from scores on the Dyadic Adjustment Scale, Positive Feelings Questionnaire, and Personal Assessment of Intimacy in Relationships scale. Controlling for pretest scores, participants in the treatment group had significantly higher levels of marital satisfaction after 8 weeks than wait-list participants. Supplementary analyses identified variables associated with gains in therapy and with dropping out of the study.

Schistosomiasis and the use of indigenous plant molluscicides: a rural South African perspective.

In the last decade plant molluscicides have received considerable attention in the search for cheaper alternatives to chemotherapy and synthetic molluscicides in schistosomiasis control. The attraction of a locally grown molluscicidal plant is based on the development of a philosophy of self-reliance and community involvement. This approach is dependent on community recognition of the infection as a public health problem and their acceptance of proposed control measures. The objectives of this study were: (i) firstly, to assess the knowledge of schistosomiasis in a rural community and their attitude to the use of indigenous plant molluscicides; (ii) secondly, to assess the prevalence and intensity of infection in relation to its severity as perceived within the community. Study sites were located at Mtwalume (KwaZulu-Natal, South Africa). Sixty-nine community members were interviewed during six focus-group interviews and two depth interviews. Urine and stool samples (354 and 306, respectively) from children and young adults (2-25 years old) were analysed for Helminth and Protozoal infections. Results indicate that despite a poor understanding of schistosomiasis, it is a primary health concern for those dependent on river-water for their water requirements. Concern for schistosomiasis is indeed matched by a prevalence of 75.14% for Schistosoma haematobium. Oral antischistosomal drugs are inaccessible primarily due to the cost of transport and secondarily, due to the cost of treatment. The concept of molluscicidal control, as an alternative, was enthusiastically received by all respondents.

A semi-quantitative approach to the selection of appropriate candidate plant molluscicides--a South African application.

The high cost of synthetic molluscicides, used in the control of the intermediate snail hosts of schistosomiasis (bilharzia), has resulted in renewed interest in plant molluscicides. The history of the use of plant molluscicides is reviewed. Although screening programmes have been conducted in other African countries, no efforts have been made to identify South African plants which would be suitable for use locally, using appropriate technology. The prohibitive costs (time and financial) of random surveys for activity necessitated the development of an objective selection procedure. A simple scoring system derived for this purpose is described. Of 600 plant species with potential, or recorded activity, 150 occurred in South Africa. Twenty-six taxa were active according to standards set by WHO. A further 37 species, although untested, warrant further investigation. Species were ranked on cumulative scores for: (a) coincidence of the endemic areas of the plant, snail host and disease; (b) ethnomedicinal value which would provide greater incentive for cultivation; (c) molluscicidal activity (if known, a minimum LD90 of < or = 100 ppm). Two lists resulted, those with recorded and those with potential activity. Both are important in prioritizing research on molluscicidal plants in South Africa. Problems inherent to the scoring system and to the development of plant molluscicides are discussed.

The molluscicidal activity of Apodytes dimidiata E. Meyer ex Arn (Icacinaceae), Gardenia thunbergia L.f. (Rubiaceae) and Warburgia salutaris (Bertol. F.) Chiov. (Cannelaceae), three South African plants.

Mollusciciding is still considered the most important means of control of schistosomiasis where the volume of water per caput is small. In rural communities the cost of synthetic molluscicides and/or chemotherapy prohibits their use. Plant molluscicides, applied as crude aqueous suspensions are the source of cheap, effective and environmentally acceptable alternatives. Further, infected communities are likely to accept the use of local indigenous plants, particularly if they have more than one local application, since they are familiar with their properties and growth characteristics. In this study the activity of crude aqueous suspensions of six South African plants were assessed. Suspensions of leaf material were bioassayed for activity using Bulinus africanus. Probit analysis was used to calculate LD50 and LD90 values. Three species would receive priority for further investigations of extract stability and toxicology, i.e. comprehensive evaluation. For this purpose species were ranked on toxicity as aqueous suspensions, the highest toxicity level previously recorded in the literature, and on their cultivation potential. Ranks for each plant were summed and Gardenia thunbergia, Apodytes dimidiata, and Warburgia salutaris had the lowest cumulative rankings (i.e. the highest molluscicidal activity and greatest cultivation potential).

Energy dependence of the response of lithium fluoride TLD rods in high energy electron fields.

The energy dependence of lithium fluoride dosemeters is a complicated function of energy as well as of cavity size. In the application of TLD to charged particle dosimetry, a cavity perturbation effect may exist even though the ratios of the mass stopping powers are constant over the energies encountered. This effect was investigated for lithium fluoride rods in electron fields ranging in energy from 2-5 to 20 MeV. A 13% change of TL response per unit of absorbed dose was measured over that energy range. A semi-empirical theory was developed to account for the cavity effect, using Burlin cavity theory as a starting point. The agreement between theory and measurement is satisfactory.