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IntroductionCritical care in low-income and low-middle income countries (LLMICs) is an underdeveloped component of the healthcare system. Given the increasing growth in demand for critical care services in LLMICs, understanding the current capacity to provide critical care is imperative to inform policy on service expansion. Thus, our aim is to describe the provision of critical care in LLMICs with respect to patients, providers, location of care and services and interventions delivered.Methods and analysisWe will search PubMed/MEDLINE, Web of Science and EMBASE for full-text original research articles available in English describing critical care services that specify the location of service delivery and describe patients and interventions. We will restrict our review to populations from LLMICs (using 2016 World Bank classifications) and published from 1 January 2008 to 1 January 2020. Two-reviewer agreement will be required for both title/abstract and full text review stages, and rate of agreement will be calculated for each stage. We will extract data regarding the location of critical care service delivery, the training of the healthcare professionals providing services, and the illnesses treated according to classification by the WHO Universal Health Coverage Compendium.Ethics and disseminationReviewed and exempted by the Stanford University Office for Human Subjects Research and IRB on 20 May 2020. The results of this review will be disseminated through scholarly publication and presentation at regional and international conferences. This review is designed to inform broader WHO, International Federation for Emergency Medicine and partner efforts to strengthen critical care globally.PROSPERO registration numberCRD42019146802.

In the recent design and testing of the upgraded detonator used in the Titan IVB explosive bolt for jettison of expended strap-on solid rocket motors, it was determined that the 25-kV, 500 pF, pin-to-case electrostatic discharge test without the traditional 5-kΩ series resistor is a destructive test. After this test, pin-to-case insulation resistance in the detonator measured under the traditional 500 V could fail the 2-MΩ minimum requirement. An extensive investigation established a relationship between three phenomena: the electrostatic discharge, the insulation resistance, and the pin-to-case breakdown voltage. Several screening techniques were developed and verified. Parameters and designs for eliminating or reducing the failure were identified for future design of electroexplosive devices.

Background Livedoid vasculopathy, also known as atrophie blanche, is a recurrent painful vasculopathy appearing mostly on the lower limbs. Treatment is challenging and relapses are frequent. Objectives To analyse the long-term effect and safety of hyperbaric oxygen (HBO) therapy in treating livedoid vasculopathy. Methods Twelve patients with active livedoid vasculopathy were included in this study. All patients underwent HBO therapy five times a week. Each week photographs were taken and the total dose of analgesics was recorded. Side-effects were documented and assessed. Recurrence was defined as the presence of skin ulceration. Results Of the eight patients who completed the treatment, resumption of ambulation and reduction of analgesics were achieved at an average of 4.9 HBO therapy sessions. Leg ulcers in all eight patients healed completely at a mean of 3.4 weeks (range 2-5 weeks). Six patients suffered relapses of ulceration and responded to additional HBO therapy. No significant side-effects were found. Conclusions HBO is a relatively safe, fast and effective method to treat patients with livedoid vasculopathy.

The objective of this study was to determine the cytocompatibility of three different extracts of gingival retraction cords and to compare the cytotoxic effect of these materials on human gingival fibroblasts. Gingival retraction cords impregnated with aluminium sulphate (Gingi-Aid), dl-adrenaline HCl (Gingi-Pak) and non-drug-impregnated cord (Gingi-Plain) were eluted with culture medium for 10 min and 24 h. Cytotoxicity was judged using a tetrazolium bromide reduction assay. Our data demonstrated that gingival retraction cords applied alone almost completely inhibited cell viability (P0.05). In addition, the results also showed that the eluates from aluminium sulphate-impregnated cord, dl-adrenaline HCl-impregnated cord and non-drug-impregnated cord were cytotoxic to primary human gingival fibroblast cultures (P0.05). The cell viability of incubation of gingival fibroblasts containing 10-min eluates of aluminium sulphate, dl-adrenaline HCl and non-drug-impregnated cord was 61, 21 and 70%, respectively. The cell viability of incubation of gingival fibroblasts containing 24 h eluates of aluminium sulphate, dl-adrenaline HCl and non-drug-impregnated cord was 68, 58 and 72%, respectively. It was found that dl-adrenaline HCl-impregnated gingival retraction cord was the most toxic gingival retraction cord among the materials tested in all cultures (P0.05). The cytotoxicity decreased in an order of dl-adrenaline HCl-impregnated cordaluminium sulphate-impregnated cordnon-drug-impregnated cord. The extent or degree of the cytotoxicity depended on the materials tested. Gingival retraction cords have significant potential for gingival toxicity. Careful management of gingiva retraction cords would lower the risk of potential gingival tissue damage during clinical application procedure and thus increase the success of prosthodontic procedures.

Ordnance subsystems and components are critical elements in intercontinental ballistic missile systems. Ord- nance is required for stage ignition, stage separation, thrust vector control system actuation, �uid isolation valve actuation, battery actuation, thrust termination, and release of reentry vehicles. In addition, an ordnance destruct subsystem is mandatory for eachight test. The similarity between missile systems enabled the development and evolution of ordnance designs; for example, the isolation valves, linear-shaped charges for destruct subsystems, linear explosives for stage separation rings, and conned detonating cords for explosive train interconnections were used on allve missile systems developed by the U.S. Air Force since the early 1960s. The approach did not prevent the adoption of new technologies to improve performance. High-temperature resistant hexanitrostilbene explosive was adopted and the through-bulkhead initiator and exploding bridgewire initiator replaced the hot bridgewire-based squibs and detonators. A laser/�ber-optics-based ordnancering system was developed for a mobile missile system. Hermetic seal technologies were adopted for achieving a longer service life for explosive devices. Better methods were adopted for ordnance testing, for example, the thermal transient pulse test and the builtin reectometry. These approaches dramatically improved reliability, safety, weight efciency, service life, and cost effectiveness.

Injury to the peripheral nervous system can lead to spontaneous pain, hyperalgesia and allodynia. Previous studies have shown sprouting of Abeta-fibres into lamina II of the spinal cord dorsal horn after nerve injury and the formation of new synapses by these sprouts. Synaptophysin is a presynaptic vesicle protein, useful in the identification of synaptogenesis. Here we investigated whether synaptogenesis as measured by the expression of synaptophysin protein correlates with symptoms of neuropathic pain in rats with a chronic constriction injury (CCI) of the sciatic nerve. We used immunohistochemistry, Western immunoblotting and densitometry to study the distribution of synaptophysin and to quantify relative protein. Synaptophysin was increased in the ipsilateral dorsal horn with a peak level on day 14 and returned to baseline on day 21 post-CCI. Synaptophysin levels temporally correlated with thermal hyperalgesia but not with tactile allodynia. Our results indicate that thermal hyperalgesia in CCI significantly correlates with synaptogenesis within the superficial layers of the dorsal horn.

Background: Pain on injection is still a major problem with propofol. We performed this study to compare different doses of intravenous (i.v.) ketorolac with and without venous occlusion and its effect on the incidence and the severity of the pain after propofol injection. Methods: We conducted a prospective, randomized and double-blind study of 180 patients (20–60 years of age.) scheduled to undergo elective surgery. Six groups of patients were generated: group A received normal saline (NS) 2 ml i.v.; groups B, C, D received ketorolac 10 mg in 2 ml NS with venous occlusion (VO) and a subsequent propofol injection at either 30, 60 or 120 s; groups E and F received ketorolac 15 mg and 30 mg in 2 ml NS and propofol was injected after 60 s. The pain perception was assessed during injection of propofol in all patients. Result: The incidence of propofol-associated injection pain was for A: 46.7%; B: 43.4%; C: 23.3%; D:16.7%; E: 20%, and F: 10%. The incidence of pain following propofol injection was reduced by i.v. ketorolac 10 mg with venous occlusion for 120 s. Furthermore, i.v. ketorolac 15 mg and 30 mg but not 10 mg following propofol injection after 60 s without venous occlusion revealed significant pain reduction when compared to saline group. There was no difference in venous sequelae at 7 days postoperatively between the groups. Conclusion: Our results suggested that pretreatment with i.v. 15 and 30 mg ketorolac reduces pain following propofol injection. Moreover, pretreatment with i.v. ketorolac 10 mg with venous occlusion for 120 s achieves the same pain relief effect.

Intrathecal (IT) lamotrigine, a sodium channel blocker which suppresses neuronal release of glutamate, has been shown to produce a long-lasting antihyperalgesic effect in the neuropathic pain models. In the present study, we examined the anti-hyperalgesic effects of pre- versus post-treatment of IT lamotrigine in an animal inflammatory pain model, the inflamed knee joint model of the rat. Thermal and mechanical antinociception was assessed in rats using a modified Hargreaves box and von Frey hairs. Induction of tonic persistent inflammatory pain was induced by intra-articular injection (i.a.) of a carrageenan-kaolin mixture (CK) into the right knee-joint. Rats were randomly assigned to the groups receiving IT lamotrigine in distinct doses of 5, 50 or 100 ug either pre- (10 min before CK injection) or post-inflammation induction (4 h or 23 h). We observed that CK injection resulted in a significant thermal and mechanical hyperalgesia throughout a 24-h observation period. Pre-treatment with IT lamotrigine revealed a time and dose-dependent suppression of thermal and mechanical hyperalgesia, whereas the post-treatment with IT lamotrigine only showed an effect for mechanical nociception. Conclusion: IT Lamotrigine is antihyperalgesic at a dose larger than 50 ug in the early phase of inflammatory pain model. It reverses tactile allodynia but not thermal hyperalgesia when given after the inflammation induction.

Background: Deep vein thrombosis (DVT) remains a leading cause of postoperative morbidity and mortality in patients who undergo total knee arthroplasty (TKA). Although patients with previous thrombotic episodes are inherently at a higher risk for subsequent episodes of DVT, it remains difficult to predict such an occurrence and to make a diagnosis in early stages. One potentially useful assay that can be used in the determination of changes of coagulation among patients who undergo arthroplasty is platelet activation. The goal of this study was to establish a predictive value for DVT with measurement of P-selectin levels that could help in planning appropriate perioperative management strategies for patients at high risk for DVT. Methods: A total of 52 patients who underwent TKA with general anesthesia underwent contrast venography on the 5th postoperative day. Platelet activation before and after operation was measured with platelet surface expression of P-selectin with flow cytometry in these two groups of patients for TKA. None of the patients underwent any anticoagulation therapy. Results: Nineteen of the 52 patients for TKA showed radiologic evidence of DVT, whereas 33 patients for TKA had no radiologic signs of DVT. There was no difference in platelet activation at baseline, which was 1 hour before induction of anesthesia, between the two groups (P >.05) as measured with P-selectin assays. Differences were noted between the two groups on the 5th day after operation, wherein P-selectin was expressed in only 2.72% ± 0.9% (mean ± standard deviation) of platelets in patients for TKA with healthy venogram results. This differed significantly from platelets in patients for TKA with DVT, who had P-selectin expression of 6.56% ± 3.1% (mean ± standard deviation; P

UNLABELLED The release of excitatory amino acids (EAAs), nitric oxide, and prostaglandins plays a critical role in the development of peripheral tactile and thermal hypersensitivity after the induction of knee joint inflammation. In this study, we used a model of chronic spinal microdialysis to examine the effect of complete Freund's adjuvant (CFA)-induced inflammation on the spinal release of EAAs and also assessed the antinociceptive effect of a new alpha(2)-adrenergic agonist, apraclonidine, by using this model. Male Sprague-Dawley rats were implanted with microdialysis catheters. CFA was injected into the plantar surface of the left hindpaw to induce inflammation. Concentrations of amino acids in dialysate and thermal and tactile withdrawal latency were evaluated for 1 wk. Intraplantar injection of CFA evoked a significant release of glutamate, aspartate, and citrulline for 6 days. Three milligrams of intraperitoneal apraclonidine significantly suppressed the release of EAAs and citrulline. Apraclonidine was given intraperitoneally 2--3 days after CFA injection. Prominent thermal and tactile allodynia was observed for 6 days. Our results show that the significant modulatory effect of the alpha(2)-adrenergic agonist apraclonidine on the release of EAAs may account for its antinociceptive properties in adjuvant-induced inflammation. IMPLICATIONS This study showed a novel finding that the hypersensitivity state seems to be dependent on increased release of spinal excitatory amino acids (EAAs), and the significant modulatory effect of the alpha(2)-adrenergic agonist apraclonidine on the release of spinal EAAs accounts for its analgesic properties in adjuvant-induced inflammation.

A long-lasting antihyperalgesic effect has been demonstrated for intrathecal (IT) clonidine, an alpha2-adrenergic agonist. In the present study, the mechanism and antihyperalgesic effects of IT clonidine were examined post-treatment in a rat model of Complete Freund's Adjuvant (CFA)-induced inflammatory hyperalgesia. Using a chronic model of spinal cord dialysis, we examined the effect of the adjuvant-induced inflammation on spinal release of nitric oxide (NO) and the development of chronic pain and assessed the antinociceptive effects and mechanisms of the alpha2-adrenergic agonist, clonidine (IT). Chronic, persistent inflammatory pain was induced by left hind paw injection of 0.3 ml CFA prepared in a mixture with Mycobacterium butyricum. Rats were randomly assigned to groups receiving IT clonidine in discrete doses of 1, 10 or 50 μg, 3 or 24 hr post-inflammation. Measurement of total NO x (NO + $${\text{NO}}_{2 - } + {\text{NO}}_{3 - } $$ ) was used to determine NO release into the cerebrospinal fluid. Rat thermal antinociception was assessed using a radiant heat thermal hyperalgesia model. CFA injection resulted in significant thermal hyperalgesia throughout the four days of observation. A dose-dependent suppression of thermal hyperalgesia and spinal NO release was observed after IT clonidine treatment. Evidence from this CFA-induced inflammatory pain model suggests that clonidine's spinal antihyperalgesic mechanisms act through inhibition of spinal NO release.

Neurotoxicity is the dose-limiting side-effect of vincristine in cancer therapy. Using the nerve growth factor (NGF)-dependent neurite outgrowth and cell proliferation of the PC12 pheochromocytoma cell line as an in vitro assay, the protective effect of different intravenous anesthetics was assessed. Vincristine (1 nmol/L) significantly decreased the percentage of neurite-forming cells from 68% +/- 9% to 27% +/- 7% within a 3-day incubation period. The longer neurites (> 2 x cell body) in particular proved to be extremely sensitive to vincristine (from 17% +/- 4% to 0% of total neurite-expressing cells). Flow cytometry results revealed an S-phase percentage of 15.85% +/- 3.25% after NGF induction, with vincristine reducing this percentage to 0.68% +/- 0.38%. Reversal of the inhibitory effect of vincristine was noted in the cells treated with thiopental or propofol but not etomidate. Bicuculline partially antagonized the protective effect of thiopental and propofol in both studies. We conclude that thiopental and propofol, but not etomidate, have a protective effect in vincristine-induced neurotoxicity. The protective effect produced by thiopental and propofol is probably secondary to activation of GABAA receptors.

We utilize the Zn-diffusion technique to fabricate a single-mode high-speed 850-nm vertical-cavity surface-emitting laser. With this technique, we are able to minimize the thermal effect without greatly scaling down the diameter of the oxide-confined aperture. The demonstrated device has a 9-mum active diameter with which we can attain a bandwidth of 8 GHz, a small differential resistance (~47 Omega), and a maximum output power of 3 mW. The single-mode characteristics can be sustained under dynamic operation for the whole bias current range. The dynamic measurement results indicate that with this single-mode device the damping-limited bandwidth of our multimode control can be eliminated without a Zn-diffusion aperture. A larger intrinsic bandwidth (32 versus 21 GHz) is also obtained due to the minimization of damping. The narrower divergence angle (8deg versus 20deg) means that the device exhibits a larger alignment tolerance and much lower coupling loss (9 dB) when used with the standard multimode fiber than those of the control sample.

Preclinical studies suggest that systemic lidocaine acts at the level of the spinal dorsal horn to inhibit hyperalgesia resulting from nerve injury, yet no clinical data are available to support this view.Therefore, we sought to characterize the time course of lidocaine in the plasma and cerebrospinal fluid (CSF) after an IV bolus injection of lidocaine 2 mg/kg in patients scheduled for surgery involving spinal anesthesia. Sixty-five patients were randomly allocated to one of five study groups (n = 13 per group) receiving IV lidocaine before CSF/plasma sampling at 5, 10, 15, 30, or 60 min. Gas chromatographic analysis of these samples revealed a fast but transient peak (5-15 min) in lidocaine plasma levels (1.7 +/- 0.16 [micro sign]g/mL), which declined rapidly thereafter. Only small concentrations of IV lidocaine were found in the CSF (6%-8% of plasma concentration), but this fraction remained stable from 15 min until termination of the experiment. No statistical correlation was observed between plasma and CSF lidocaine levels. These data suggest that because of the prolonged availability of lidocaine at the spinal dorsal horn level, systemic administration of lidocaine suppresses central sensitization within the spinal cord after nerve injury in humans. Implications: Cerebrospinal fluid concentrations of lidocaine after its systemic bolus delivery in humans indicate that the spinal cord may be the major site of antinociceptive action by this route of drug administration. (Anesth Analg 1998;87:601-4)

This prospective study was undertaken to evaluate the prognostic value of uterine perfusion on the day of human chorionic gonadotropin administration in patients who were undergoing intrauterine insemination. Uterine perfusion was evaluated by measuring the pulsatility index of the ascending branch of the uterine arteries on the day of administration of human chorionic gonadotropin. No pregnancy occurred when the pulsatility index of the ascending branch of the uterine arteries was more than 3. The fecundity rate was 18% when the pulsatility index was less than 2 and was 19.8% when the pulsatility index was between 2 and 3 (not significant). The continuing pregnancy rate was 18% when the pulsatility index was less than 2, compared with 12.1% when the pulsatility index was between 2 and 3 (P < 0.05). Our data suggest that the measurement of uterine perfusion on the day of human chorionic gonadotropin administration may have predictive value regarding fecundity and the continuation of pregnancy in intrauterine insemination.

The neural and nonneural factors contributing to maintain the hemodynamic status in 14 to 16 weeks old stroke prone spontaneously hypertensive rats (SHRSP) and spontaneously hypertensive rats (SHR) were compared with those of the age matched normotensive Wistar Kyoto (WKY) rats under chloralose-urethane anesthesia. The ascending aortic blood flow, arterial blood pressure and heart rate were measured under resting condition, ganglionic blockade by hexamethonium, 5 mg/kg i.v. and maximum vasodilation by hexamethonium and 0.07 mg/kg nitroprusside. The neural component (hexamethonium blockable component) was the major factor in the maintenance of resting blood pressure and total peripheral resistance index (TPRI) in the above three strains of rats. In contrast, the residual component after hexamethonium and nitroprusside administrations was the most important controlling factor for cardiac index (CI). In SHRSPs, the neural component of TPRI and residual component of CI were both significantly higher than those of WKYs by 75% and 47%, respectively. In SHRs, the residual component of CI was 52% higher than that of WKYs. These results suggest that both the increased neural component of TPRI and nonneural component of CI are important contributing factors for the blood pressure increase in the early stage of established hypertension in SHRSPs. On the other hand, in the age matched SHRs, the most important contributing factor for hypertension is the increased nonneural component of CI. Considering the differences between these two strains of hypertensive rats, the neural component of TPRI is the major factor responsible for the different levels of hypertension in SHRSPs and SHRs.

Background Obesity has been found to be associated with an increased risk of psoriasis in general population. However, studies addressing the relationship between obesity and clinical severity of psoriasis are still scarce, especially in Asian people. Objectives In this study, we investigated the relationship between levels of obesity and the clinical severity of psoriasis in Taiwanese psoriasis patients. Methods This was a hospital-based cross-sectional study. A total of 399 patients with chronic plaque psoriasis were recruited. Their body mass index (BMI) was calculated as weight in kilograms divided by height in metres squared and was categorized into four groups (BMI

N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazolone-4-propionic acid (AMPA), and kainate (KA) receptors are members of the ionotropic glutamate receptor (iGluR) family and are increased in inflamed rat skin. These receptors contribute to inflammatory pain. In this study, we have examined whether there is a similar increase in iGluRs in inflamed human skin in the presence of inflammatory pain.Normal and inflamed-skin biopsies were obtained from eight patients undergoing elective wound-debridement surgery. Real-time-polymerase chain reaction (PCR) and western blot analysis were used for quantitation of iGluR mRNA and protein in normal and inflamed human skin.A significant increase in mRNA and protein for NMDA, AMPA, and KA receptor subunits was detected in inflamed compared with normal skin. The amounts of NMDA (NR1 subunit), AMPA (GluR2 subunit), and KA (GluR6 subunit) mRNA in inflamed skin were mean 6 (SD 1.6-fold), 2.5 (0.6-fold), and 3.8 (0.9-fold) (P0.05), respectively, greater than that measured in normal skin. The ratio of NR1, GluR2, and GluR6 protein in inflamed compared with normal skin was 5.7 (1.2), 2.4 (0.5), and 3.6 (0.9) (P0.05), respectively.These results, in human tissue, demonstrate that iGluR mRNA and protein expression are increased during persistent inflammation and that this increased activity may be involved in mediating clinical inflammatory pain in human skin.

Background: Morphine consumption after a given surgical procedure can vary considerably. Studies show that single nucleotide polymorphism involving the nucleotide position 118 at exon 1 of the μ-opioid receptor gene (OPRM1) may play a role in mediating the effects of opioids. This study was performed to correlate the A118G polymorphism at OPRM1 with morphine consumption in patients undergoing total knee arthroplasty. Methods: Post-operative pain was relieved by patient-controlled analgesia (PCA). The analgesic effect was evaluated using a visual analogue scale. Side-effects, such as sedation, nausea and vomiting, and pruritus, were recorded systematically. The genotypes were determined by sequencing polymerase chain reaction-amplified DNA. The differences in demographics and consumed morphine from the PCA device between the different genotypes were tested using one-way analysis of variance. The prevalence of side-effects from morphine and sex distribution were compared using the Kruskal–Wallis test. Results: One hundred and forty-seven patients were included in the study. Twenty-seven patients who required rescue analgesia were excluded; these patients did not differ demographically or genetically from the 120 who completed the study. Of the latter, 74 were A118 homozygous (AA), 33 were heterozygous (AG) and 13 were G118 homozygous (GG). Group GG consumed significantly more morphine (40.4 ± 22.0 mg) than group AA (25.3 ± 15.5 mg) and group AG (25.6 ± 11.7 mg) during the first 48 h post-operatively. The groups did not differ with respect to reported pain, age, sex, weight and adverse effects. Conclusions: G118 homozygotes have a poorer response to morphine for post-operative pain control than A118 homozygotes or heterozygotes. The genotype may thus influence the post-operative response to pain and cause differences in the amounts of analgesic consumed by patients after total knee arthroplasty.

Within the last 30 years, a number of methods have been proposed such as boundary-based shape optimization, homogenization-based method, evolutionary structural optimization etc [1]. Design optimization is used to produce a design that possesses some optimal character, such as minimum weight. However, these optimization capabilities are basically used to improve the design of structures or parts in the detailed design process. In the beginning of conceptual design process, another method of optimization what is called topology optimization is necessary. Based on the homogenization method, which is introduced by Bendsoe and Kikuchi [2] in 1998, topology optimization has become an important and well-recognized sub-area of structure optimization. This theory has been extended and applied to several of kinds of problems such as static problems and mode problems [3].

Background: The larger size of the first sacral nerve root has been reported to be an unfavorable factor leading to sacral sparing in epidural anesthesia. Previous studies have shown that an adequate analgesic effect of the epidural block was achieved with the catheter placement in the caudal direction. In this study, the anesthetic effect of epidural anesthesia with catheter placement of a cephalic or caudad direction was compared in ankle and hemorrhoid surgery. Methods: Twenty-one ASA physical status I or II patients undergoing surgery for ankle fractures with epidural anesthesia were enrolled and randomized into two groups. The epidural catheter was placed either to a cephalad (AU group) or caudal (AD group) direction. Another 21 patients undergoing hemorrhoidectomy were also randomized into two groups to receive epidural anesthesia in a similar way (HU and HD groups). The onset for, duration of, and recovery time from epidural anesthesia and the incidence of analgesic request were recorded. Results: No significant differences were demonstrated when age, height, weight or sex were compared between the four study groups. The onset time of the block and the incidence of intrasurgical analgesic request were lower in the caudal subgroup when the ankle surgery patients were compared. Otherwise, there were no significant differences in the duration of anesthesia and time to recovery or level of anesthesia. Conclusion: Injection of local anesthetic solution through a caudally oriented epidural catheter produces faster onset and superior quality of anesthesia in comparison with the injection through the cephaladly oriented catheter in ankle surgery, but not hemorrhoidectomy.

Interstitial cystitis is a bladder hypersensitivity disease associated with bladder pain that has been a major challenge to understand and treat. We hypothesized that targeted and localized expression of endogenous opioid peptide in the bladder could be useful for the treatment of bladder pain. Pro-opiomelanocortin (POMC) is one of such precursor molecules. In this study we developed a gene gun method for the transfer of POMC cDNA in vivo and investigated its therapeutic effect on acetic acid induced bladder hyperactivity in rats.Human POMC cDNA was cloned into a modified pCMV plasmid and delivered into the bladder wall of adult female rats by direct injection or the gene gun. Three days after gene therapy continuous cystometrograms were performed using urethane anesthesia by filling the bladder (0.08 ml per minute) with saline, followed by 0.3% acetic acid. Bladder immunohistochemical testing was used to detect endorphin after POMC cDNA transfer.The intercontraction interval was decreased after intravesical instillation of acetic acid (73.1% or 68.1% decrease) in 2 control groups treated with saline or the gene gun without POMC cDNA, respectively. However, rats that received POMC cDNA via the gene gun showed a significantly decreased response (intercontraction interval 35% decreased) to acetic acid instillation, whereas this antinociceptive effect was not detected in the plasmid POMC cDNA direct injection group. This effect induced by POMC gene gun treatment was reversed by intramuscular naloxone (1 mg/kg), an opioid antagonist. Increased endorphin immunoreactivity with anti-endorphin antibodies was observed in the bladder of gene gun treated animals.The POMC gene can be transferred in the bladder using the gene gun and increased bladder expression of endorphin can suppress nociceptive responses induced by bladder irritation. Thus, POMC gene gun delivery may be useful for the treatment of interstitial cystitis and other types of visceral pain.

We describe a new method for treating livedoid vasculopathy. The typical presentation of livedoid vasculopathy includes chronic, recurrent painful ulcers, satellite scar-like atrophy and telangiectasia involving the lower extremities. Histologically, these lesions show areas of ulceration and dermal vessel occlusion without frank inflammatory cell infiltration. There is currently no satisfactory therapy available for this disease. Hyperbaric oxygen (HBO) has recently established itself as one of the most effective methods of treating ischaemic wounds, including diabetic ulcers. We used this therapy in two patients whose lesions were resistant to multiple therapeutic modalities. Not only did their ulcers respond rapidly to the HBO therapy, but the disturbing wound pain also resolved at the same time. To our knowledge, this is the first successful trial of HBO therapy in livedoid vasculopathy. We believe this to be a very promising new therapy for livedoid vasculopathy and to be worth further investigation.

Opioids remain the most efficacious pharmacological agents for various clinical pain syndromes. Recently, various engineered cells capable of secreting opioidergic peptides have been applied to relieve pain in animal models. In vivo gene delivery by viruses encoding endogenous opioids has also been used with success. In this study, we attempted non-viral intrathecal in vivo gene delivery by electroporation to induce analgesia. Thirty Sprague-Dawley rats were used in this study, six in each of five groups. Rats were treated as follows: vehicle without electroporation (group A), vehicle with electroporation (group B), 100 microg of pCMV-hPOMC plasmid without electroporation (group C), or 100 microg of pCMV-hPOMC plasmid with electroporation (group D). Group E was treated with both pCMV-hPOMC plasmid and electroporation, and given naloxone (1mg/kg) 1h before the formalin test. The tail flick, paw withdrawal latency from radiant heat, and formalin test results for each groups were compared. Radioimmunoassay (RIA) and reverse transcription-polymerase chain reaction (RT-PCR) were used to determine the levels of expression of beta-endorphin in the spinal cord. beta-Endorphin expression was localized by immunohistochemistry. A significant decrease in the number of flinches in phase 2 of the formalin test was observed in the group treated with both plasmid and electroporation (group D), whereas the other measures of pain did not differ between groups. RIA and RT-PCR both showed increased expression of beta-endorphin in group D. The expression of beta-endorphin was highest in laminae I and II of the dorsal horn of the spinal cord. We conclude that electroporation successfully delivered intrathecally administered pCMV-hPOMC into the dorsal horn cells of the spinal cord, and induced analgesia in phase 2 of the formalin test in rats.

UNLABELLED We tested whether intrathecal electric stimulation would reduce the tolerance to chronic morphine use and the severity of precipitated morphine withdrawal. Rats received intrathecal electrode catheter implantation and a continuous intrathecal infusion of morphine (2 nmol/h) or saline for 7 days. Intrathecal electric stimulations (0, 20, or 200 V) were performed once daily during the same period. Daily tail-flick and intrathecal morphine challenge tests were performed to assess the effect of intrathecal electric stimulation on antinociception and tolerance to morphine. Naloxone withdrawal (2 mg/kg) was performed to assess morphine dependence, and changes in spinal neurotransmitters were monitored by microdialysis. The antinociceptive effect of intrathecal morphine was increased by 200 V of electric stimulation. The magnitude of tolerance was decreased in the rats receiving the 2 nmol/h infusion with 200 V of intrathecal electric stimulation compared with the control group (morphine 2 nmol/h alone) (AD(50), 13.6 vs 124.7 nmol). The severity of naloxone-induced withdrawal was less in the rats receiving 200 V of stimulation. Intrathecal stimulation thus enhances analgesia and attenuates naloxone-induced withdrawal symptoms in rats receiving chronic intrathecal morphine infusion. Increases in spinal glycine release may be the underlying mechanism. This method may merit further investigation in the context of the long-term use of intrathecal opioids for controlling chronic pain. IMPLICATIONS Control of chronic pain is a major health problem. We show here that direct electrical stimulation of the spinal cord in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. This may warrant further investigation in the context of long-term use of intrathecal opioids for controlling chronic pain.

Recent solar cell fabrication results based on a scalable hybrid sputtering and evaporation deposition process are described. A method for controlling adhesion problems, which are a major cause of poor device performance is presented based on a two-phase back contact substrate metallization; and results of transmission electron microscopy analyses of epitaxial CuInSe/sub 2/ are described. Polycrystalline CuInSe/sub 2/ was deposited on Mo or Cu-Mo coated glass. Single crystal CuInSe/sub 2/ was grown on GaAs substrates. The use of Cu-Mo two phase back contacts significantly improved adhesion of our CuInSe/sub 2/ films to the substrates. The best heterojunction solar cell produced to date on Cu-Mo has an efficiency of 10.0%. Cell performance uniformity was also improved relative to results on pure Mo. Single crystal CuInSe/sub 2/ grown on GaAs (111)A substrates showed very rough surface morphologies. Films on GaAs (111)B were smooth with occasional triangular pyramidal islands. The most stable faces of CuInSe/sub 2/ are concluded to be the Se-terminated (112) planes. >

We examined the effect of different combinations of esmolol and nicardipine upon the circulatory response to tracheal intubation. One hundred patients were randomly allocated into five groups of twenty to receive pretreatments of saline or different combinations of esmolol (0.5 or 1.0 mg x kg(-1)) and nicardipine (15 or 30 microg x kg(-1)). Significant tachycardia persisted over a 5-min period after intubation in all five groups compared with baseline levels (p < 0.05). Patients receiving esmolol 1.0 mg x kg(-1) and nicardipine 30 g x kg(-1) showed no significant change in systolic blood pressure after tracheal intubation compared with baseline and significant lower peak systolic blood pressure than those receiving saline (p = 0.023).

The relatively low expression levels achieved from transferred genes have limited the application of nonviral vectors for gene transfer into the spinal cord in vivo. Thus, the aim of this study was to evaluate the efficacy of electroporation-mediated pro-opiomelanocortin (POMC) gene therapy for neuropathic pain using an animal model of chronic constrictive injury (CCI). Firstly, the optimal pulse characteristics (voltage, pulse duration, number of shocks) were investigated for in vivo electroporation-mediated gene transfer into the spinal cord. The electroporation process makes use of plasmid DNA, which expresses the POMC gene. Expression levels were evaluated in this study by Western blot. We conclude that the optimal conditions for electroporation are a pulse voltage of 200 V, 75-ms duration, 925-ms interval, for five iterations. Secondly, electroporation treatment for neuropathic pain was attempted on CCI rats using plasmid DNA that expresses the POMC gene. Intrathecal administrations of the POMC vector elevated spinal beta-endorphin levels, as manifested in a significantly elevated pain threshold for the CCI limbs. This result suggests that gene therapy for neuropathic pain using this novel technique is very efficacious, and thus shows promise for further clinical trials.

Endogenous opioid peptides play an essential role in the intrinsic modulation and control of inflammatory pain, and could be therapeutically useful. These opioid peptides are synthesized as parts of larger precursor molecules. One such precursor molecule is pro-opiomelanocortin (POMC). In this study, we developed a gene-gun method for the transfer of POMC cDNA in vivo, and investigated its therapeutic effect on inflammatory pain in a rat model of formalin-induced pain. Human POMC cDNA was cloned into a modified pCMV plasmid and delivered to the skin of rats by gene gun. Three days after gene-gun injection, 1% formalin was injected. Endorphin levels were measured in the serum and skin after the formalin test, and skin histology was used to detect endorphin after green fluorescent protein (GFP; control) or POMC cDNA transfer. There was no significant difference in the results of acute nociceptive tests between the experimental and control groups. There was also no difference in response between the groups to phase 1 of the formalin test. However, rats which received POMC cDNA via gene-gun injection showed a significantly reduced response in phase 2 of the formalin test. Endorphin immunoreactivity in the skin increased approximately three- to four-fold in experimental animals compared with GFP-treated controls at day 3 after injection. The phase 2 response in animals treated with formalin and naloxone did not differ significantly from the control, implying that the analgesic effects of POMC cDNA particle injection in phase 2 of the formalin test are reversed by naloxone. There are two major findings from this study. First, in vivo DNA delivery by gene gun to the skin is feasible. Second, the production of beta-endorphin is insufficient to block phasic pain, but is effective against sensitization of the afferent neurons during phase 2 of the formalin test.

Background: Neuronal damage is a possible complication of cardiac surgery. To reduce the potential risk of postoperative neurological deficit, the functional state of affectedcentral nervous system pathways is monitored intraoperatively by recording evoked potentials (EPs). Apart from animal research, there is little clinical evidence of EPs recordingduring cardiac arrest and cardio-pulmonary resuscitation (CPR). Methods: Both scalp (SCEPs) and spinal (SSEPs) short-latency somatosensory EPs were recorded as the response to theelectrical stimulation of the right median nerve during mitral valve replacement surgery. Evoked potentials were recorded before, during, and after sudden ventricular fibrillationfollowed by CPR. Results: Preoperative control recordings of both SCEPs and SSEPs were in the normal ranges. During the first 4 min of cardiac arrest and resuscitation, all SCEPs waves disappeared, while the spinal component of the SSEPs was still recognizable. After CPR, all waves of both EPs recordings recovered completely. The patient woke from anesthesia without neurological deficits. Conclusions: As expected, scalp-recorded EPs are more sensitive to the cardiac arrest than spinal EPs. Rapid and almost complete recovery of postoperative EPs, namely SCEPs, correlated well with normal neurological recovery.

Metal-semiconductor-metal ultraviolet photodetectors were fabricated by using the sputtered Ga-doped ZnO (GZO) thin films on sapphire substrate as an active layer. Current-voltage (I-V) and opto-electrical characteristics of the devices were investigated. It is found that the peak optical responsivity of the devices can be significantly improved by selecting appropriate thermal annealing temperature, i.e., from 12.0 A/W (annealed at 500 °C) and 54.0 A/W (700 °C). Furthermore, dark current of the devices drops by two orders of magnitude after annealing process. The significant improvement in performance of the device is ascribed to the removal of massive defect centers of the GZO thin films and increase of Schottky barrier height between the GZO and metal electrodes after thermal annealing at appropriate temperatures.

Postoperative vomiting causes patients distress and delays discharge after outpatient surgery. Although P6 electroacupuncture is recognized as having an antiemetic effect, its inconvenient instrumentation may limit its clinical applicability. The purpose of this study was to explore a simple and effective alternative method for control of postoperative vomiting in outpatient surgery. We prospectively compared the effect of P6 acupoint injection with 0.2 ml 50% glucose in water (G/W) and intravenous injection of 20 micrograms/kg droperidol for prevention of vomiting in 120 consecutive outpatients undergoing gynecological laparoscopy with general anesthesia. Patients were randomly allocated to receive P6 acupoint injection, i.v. droperidol, or nothing as control group. Both P6 acupoint injection and i.v. droperidol 20 micrograms/kg were found to have a significant antiemetic effect when compared with the control group. We conclude that P6 acupoint injection with 50% G/W is a simple and effective method for reducing the incidence of postoperative emesis in outpatient surgery.

Indium tin oxide (ITO) thin films have been proposed as diffusion barriers for ultralarge scale integrated microelectronic devices. High-resolution transmission electron microscopy and electron diffraction showed that in the Cu/ITO/Si film, the 10 nm thick nanocrystalline ITO film layer works effectively as a barrier. Transmission electron microscopy, scanning electron microscopy, sheet resistance measurement, X-ray diffraction, and energy dispersive spectroscopy analyses revealed that ITO was found to be a good diffusion barrier against Cu at least up to 650°C. The failure temperature of ITO films diffusion barrier (10 nm) was 700°C. Our results show that ITO film can be considered as diffusion barriers for Cu metallization.

Investigation results on stress waves generated by Q-switched ruby laser irradiated thin metal films under confinement, studied over a wide range of film materials and film thicknesses, are reviewed. The results indicate that the dependence on these parameters is much weaker than is predicted by heat transfer estimations commonly used to describe the interaction of laser irradiation with unconfined bulk-solid surfaces.

The test results of 320 units of a laser initiated microdetonator are summarized. The commercially fabricated units used a lead styphnate/lead azide/HMX (1 mg/13.5 mg) explosive train design contained in a miniature aluminum can that was capped with a glass-metal seal window. The test parameters were the laser energy, temperature, laser pulse duration, laser wavelength and nuclear radiation (5,000,000 rad of 1 MeV gamma rays). The performance parameters were the laser energy for ignition and the actuation response time.

Immediate longitudinal detonations have been observed in confined small-diameter columns of PETN, RDX, and tetryl by using a focused Q-switched ruby laser. The energy ranged from 0.8 to 4.0 J in a pulse width of 25 nsec. A 1000-A-thick aluminum film deposited on a glass window was used to generate a shock wave at the window-explosive interface when irradiated by the laser. In some cases, steady-state detonations were reached in less than .5 microsec with less than 10% variation in the detonation velocity.