Vasodilan

John Hunter Peel Alexander, MD

• Professor of Medicine
• Member in the Duke Clinical Research Institute

https://medicine.duke.edu/faculty/john-hunter-peel-alexander-md

With respect to mergers blood pressure medication vivid dreams buy 20 mg vasodilan visa, Israeli tax law allows for tax deferral in certain circumstances but makes the deferral contingent on the fulfillment of numerous conditions blood pressure 4060 order 20mg vasodilan with amex, including a holding period of two years from the date of the transaction during which sales and dispositions of shares of the participating companies are restricted arrhythmia education inc vasodilan 20 mg discount. Moreover hypertension table order cheap vasodilan online, with respect to certain share swap transactions arteria facialis linguae buy vasodilan 20 mg fast delivery, the tax deferral is limited in time pulse pressure neurogenic shock buy cheap vasodilan 20 mg on-line, and when such time expires, the tax becomes payable even if no actual disposition of the shares has occurred. Our business could be negatively impacted by unsolicited takeover proposals, by shareholder activism or by proxy contests relating to the election of directors or other matters. Our business could be negatively affected as a result of an unsolicited takeover proposal, by shareholder activism or a proxy contest. During 2019, an activist shareholder sought to make changes to our Board of Directors, among other matters, which ultimately resulted in us entering into a settlement agreement with the shareholder, and for which considerable costs were incurred and absorbed significant time and attention by management and the Board of Directors. A future proxy contest, unsolicited takeover proposal, or other shareholder activism relating to the election of directors or other matters would most likely require us to incur significant legal fees and proxy solicitation expenses and require significant time and attention by management and our Board of Directors. The potential of a proxy contest, unsolicited takeover proposal, or other shareholder activism could interfere with our ability to execute our strategic plan, give rise to perceived uncertainties as to our future direction, result in the loss of potential business opportunities or make it more difficult to attract and retain qualified personnel, any of which could materially and adversely affect our business and operating results. As of January 31, 2020, we had 142,931,223 ordinary shares issued and outstanding and we had no preferred shares outstanding. As of January 31, 2020, we also had warrants to purchase 75,205,306 ordinary shares and options to purchase 2,673,400 ordinary shares outstanding, of which options to purchase 1,278,090 ordinary shares are currently fully vested or vest within the next 60 days. In addition, immediately following consummation of this offering, any additional equity financing in order to fund our operations will require us to increase our authorized share capital prior to initiating any such financing transaction. In the event we fail to obtain the approval of our shareholders to such increase in our authorized share capital, our ability to raise sufficient funds, if at all, might be adversely effected. We have not declared or paid any cash dividends on our ordinary shares, nor do we expect to pay any cash dividends on our ordinary shares for the foreseeable future. We currently intend to retain any additional future earnings to finance our operations and growth and for future stock repurchases and, therefore, we have no plans to pay cash dividends on our ordinary shares at this time. Any future determination to pay cash dividends on our ordinary shares will be at the discretion of our Board of Directors and will be dependent on our earnings, financial condition, operating results, capital requirements, any contractual restrictions, and other factors that our Board of Directors deems relevant. Additionally, market prices for securities of biotechnology and pharmaceutical companies historically have been very volatile. The market for these securities has from time to time experienced significant price and volume fluctuations for reasons unrelated to the operating performance of any one company. In the past, following periods of market volatility, shareholders have often instituted securities class action litigation and we have been named in the past in a lawsuit requesting recognition as a class action, in which we ultimately prevailed. If we were involved in securities litigation, it could have a substantial cost and divert resources and attention of management from our business, even if we are successful. In the event of such delisting, our shareholders would likely find it significantly more difficult to dispose of, or to obtain accurate quotations as to the value of our securities, and our ability to raise future capital through the sale of our securities could be severely limited. Additional regulatory requirements apply to trading by broker-dealers of penny stocks that could result in the loss of an effective trading market for our securities. Israeli law and our Amended and Restated Articles of Association govern shareholder rights. Shareholders are entitled to our notices of general meetings and to attend and vote at our general meetings of shareholders. At a general meeting, every shareholder present (in person or by proxy, attorney or representative) and entitled to vote has one vote. This is subject to any other rights or restrictions which may be attached to any shares. However, you may not know about the meeting enough in advance to withdraw the shares. In addition, the Depositary and its agents are not responsible for failing to carry out voting instructions or for the matter of carrying out voting instructions. This means that you may not be able to exercise your right to vote and there may be nothing you can do if your shares are not voted as requested. Subject to any special rights or restrictions attached to a share, the directors may determine that a dividend will be payable on a share and fix the amount, the time for payment and the method for payment (although we have never declared or paid any cash dividends on our ordinary shares and we do not anticipate paying any cash dividends in the foreseeable future). Dividends and other distributions payable to our shareholders with respect to our ordinary shares generally will be payable directly to them. The trading prices of our securities on these two markets may differ due to these and other factors. Any decrease in the price of our securities on one of these markets could cause a decrease in the trading price of our securities on the other market. As a public company in the United States, we incur additional significant accounting, legal and other expenses that we did not incur before becoming a reporting company in the United States. These rules and regulations have increased our legal and financial compliance costs, introduced new costs such as investor relations, stock exchange listing fees and shareholder reporting, and made some activities more time consuming and costly. The implementation and testing of such processes and systems may require us to hire outside consultants and incur other significant costs. These laws, rules and regulations could make it more difficult or more costly for us to obtain certain types of insurance, including director and officer liability insurance, and we may be forced to accept reduced policy limits and coverage or incur substantially higher costs to obtain the same or similar coverage. The impact of these requirements could also make it more difficult for us to attract and retain qualified persons to serve on our Board of Directors, our Board committees or as executive officers. For instance, we may follow home country practice in Israel with regard to , among other things, composition and function of the audit committee and other committees of our Board of Directors and certain general corporate governance matters. Following our home country governance practices as opposed to the requirements that would otherwise apply to a U. In addition, as a foreign private issuer, we are exempt from the rules and regulations under the U. Securities Exchange Act of 1934, as amended, or the Exchange Act, related to the furnishing and content of proxy statements, and our officers, directors and principal shareholders are exempt from the reporting and short-swing profit recovery provisions contained in Section 16 of the Exchange Act. Because we became a reporting company under the Exchange Act by means of filing a Form 20-F, we may have difficulty attracting the attention of research analysts at major brokerage firms. Because we did not become a reporting company by conducting an underwritten initial public offering in the United States, we may have difficulty attracting the attention of security analysts at major brokerage firms in order for them to provide coverage of our company. If we are unable to satisfy the requirements of Section 404 of the Sarbanes-Oxley Act as they apply to a foreign private issuer that is listed on a U. Section 404 of the Sarbanes-Oxley Act requires companies subject to the reporting requirements of the U. To comply with this statute, we must document and test our internal control procedures and our management and issue a report concerning our internal control over financial reporting. In addition, as long as we do not become an accelerated or large accelerated filer, we are exempt from the auditor attestation requirements of Section 404(b) of the Sarbanes-Oxley Act. We will need to prepare for compliance with Section 404 by strengthening, assessing and testing our system of internal controls to provide the basis for our report. However, the continuous process of strengthening our internal controls and complying with Section 404 is complicated and time-consuming. Furthermore, as our business continues to grow both domestically and internationally, our internal controls will become more complex and will require significantly more resources and attention to ensure our internal controls remain effective overall. During the course of the testing, our management may identify material weaknesses or significant deficiencies, which may not be remedied in a timely manner to meet the deadline imposed by the Sarbanes-Oxley Act. If our management cannot favorably assess the effectiveness of our internal control over financial reporting, or our independent registered public accounting firm identifies material weaknesses in our internal controls, investor confidence in our financial results may weaken, and the market price of our securities may suffer. In addition, from time to time, we or our representatives have made or may make forward-looking statements, orally or in writing. Forward-looking statements relate to anticipated or expected events, activities, trends or results as of the date they are made. Because forward-looking statements relate to matters that have not yet occurred, these statements are inherently subject to risks and uncertainties that could cause our actual results to differ materially from any future results expressed or implied by the forward-looking statements. Many factors could cause our actual activities or results to differ materially from the activities and results anticipated in forward-looking statements, including, but not limited to , the factors summarized below. Given these uncertainties, readers are cautioned not to place undue reliance on such forward-looking statements. Factors that could cause our actual results to differ materially from those expressed or implied in such forward-looking statements include, but are not limited to: our history of losses and needs for additional capital to fund our operations and our inability to obtain additional capital on acceptable terms, or at all; uncertainties of cash flows and inability to meet working capital needs; the initiation, timing, progress and results of our preclinical studies, clinical trials and other product candidate development efforts; our ability to advance our product candidates into clinical trials or to successfully complete our preclinical studies or clinical trials; our receipt of regulatory approvals for our product candidates, and the timing of other regulatory filings and approvals; the clinical development, commercialization and market acceptance of our product candidates; our ability to establish and maintain strategic partnerships and other corporate collaborations; the implementation of our business model and strategic plans for our business and product candidates; the scope of protection we are able to establish and maintain for intellectual property rights covering our product candidates and our ability to operate our business without infringing the intellectual property rights of others; competitive companies, technologies and our industry; and statements as to the impact of the political and security situation in Israel on our business. All forward-looking statements attributable to us or persons acting on our behalf speak only as of the date of this prospectus and are expressly qualified in their entirety by the cautionary statements included in this prospectus. We undertake no obligations to update or revise forward-looking statements to reflect events or circumstances that arise after the date made or to reflect the occurrence of unanticipated events. In evaluating forward-looking statements, you should consider these risks and uncertainties. These estimates exclude the proceeds, if any, from the exercise of Warrants sold in this offering. A 100,000 increase (decrease) in the number of Units offered by us would increase (decrease) the net proceeds we receive from this offering by $0. We intend to use the net proceeds from the sale of our securities in this offering for working capital and general corporate purposes, including research and development, clinical trials and general and administrative expenses. However, we have no present binding commitments or agreements to enter into any acquisitions. The amounts and timing of our actual expenditures will depend upon numerous factors, including the progress of our development and commercialization efforts, whether or not we enter into strategic collaborations or partnerships, and our operating costs and expenditures. Accordingly, our management will have significant flexibility in applying the net proceeds of this offering. Pending application of the net proceeds for the purposes as described above, we expect to invest the net proceeds in short-term, interest-bearing securities, investment grade securities, certificates of deposit or direct or guaranteed obligations of the U. Any future determination relating to our dividend policy will be at the discretion of our Board of Directors and will depend on a number of factors, including future earnings, our financial condition, operating results, contractual restrictions, capital requirements, business prospects, applicable Israeli Companies Law and other factors our Board of Directors may deem relevant. The pro forma as adjusted information below is illustrative only and our capitalization following the completion of this offering is subject to various adjustments. The information in this table should be read in conjunction with and is qualified by reference to the financial statements and notes thereto and other financial information contained in this prospectus. A 100,000 Unit increase (decrease) in the number of Units offered by us would increase (decrease) our pro forma as adjusted cash and cash equivalents by approximately $0. Our net tangible book value as of September 30, 2019, was approximately $7 million, or approximately $1. After giving effect to the issuance and sale in this offering of 3,023,256 Units at an assumed public offering price of $2. This represents an immediate dilution in the pro-forma as adjusted net tangible book value of $0. The following table illustrates this dilution on a per share basis: Assumed public offering price per Unit $ 2. The above table is based on 119,655,993 ordinary shares outstanding as of September 30, 2019 and excludes the following as of such date: 2,173,400 ordinary shares issuable upon the exercise of stock options outstanding at a weighted-average exercise price of $1. Under the collaboration agreement, Univo will provide us with cannabis and cannabis components, as well as full access to its laboratories for both research and manufacturing. In addition, in connection therewith, we issued 996,690 ordinary shares to a consultant. Since inception, we have incurred significant losses in connection with our research and development. Such research and development activities are budgeted to expand over time and will require further resources if we are to be successful. As a result, we expect to incur operating losses, which may be substantial over the next several years, and we will need to obtain additional funds to further develop or research and development programs. We expect to continue to fund our operations over the next several years through our existing cash resources, potential future milestone payments that we expect to receive from our licensees, interest earned on our investments, if any, and additional capital to be raised through public or private equity offerings or debt financings. Under the Kwang Dong License Agreement, we are entitled to up-front and milestone payments of up to $1. In accordance with the Kwang Dong License Agreement, we received an up-front payment of $0. Under the terms of the Kwang Dong License Agreement, in addition to the payments mentioned above, we are entitled to certain additional payments based on the sale of raw materials, subject to the terms and conditions of the respective agreements. To date, we have received a total of $500,000 from Kwang Dong in an upfront payment. In addition, following regulatory approval, we shall be entitled to a royalty of 16. We are also entitled to a royalty payment for any authorized generic of Piclidenoson that Cipher distributes in Canada. In addition, we are entitled to a transfer price of the higher of (a) the manufacturing cost plus 10% or (b) 23% of net sales of Namodenoson following commercial launch in South Korea. Under the License, Collaboration and Distribution Agreement, we are entitled to $2,000,000 upon execution of the agreement plus milestone payments of up to $14,000,000 upon achieving certain regulatory milestones and payments of up to $58,500,000 upon achieving certain sales milestones.

However arrhythmia associates 20mg vasodilan with mastercard, although their specific hosts seem to be limited blood pressure medication good or bad buy vasodilan pills in toronto, infections have been found in many animals hypertension diagnosis code buy vasodilan canada. Except for a few epidemiological studies heart attack proof discount 20mg vasodilan with visa, human infection by pentastomids is infrequent: only eight cases had been reported in the United States up to 1991 (Guardia et al heart attack nightcore vasodilan 20mg free shipping. Etiology: Linguatula serrata is a linguiform parasite with discreet transverse segmentation blood pressure medication used for headaches purchase vasodilan 20 mg on-line. The development cycle of the parasite requires herbivorous intermediate hosts, mainly sheep, goats, and lagomorphs. Bovines, deer, equines, swine, and various other mammals can also serve as intermediate hosts. Linguatula lays its eggs in the upper respiratory passages of the host, and they are then expelled into the environment by sneezing or splitting, or if swallowed, with the feces. The eggs ingested by the intermediate host with food or water release the first-stage larvae in the intestine; they possess four clawed feet and an apparatus that enables them to perforate the intestinal wall. The larvae migrate through the blood to the internal organs and encyst in the lymph glands, the liver, spleen, lungs, and other organs, where they form small pentastomid nodules that are discovered during the veterinary inspection of meat. Between 250 and 300 days after infection and after some 12 molts within the cyst, the larva reaches the nymph, or infective stage. The nymph can break the cystic envelope, migrate through the peritoneal cavity, and penetrate different tissues. If a carnivore consumes the tissues or organs of an infected intermediate host, the infective nymph migrates through the stomach and esophagus to the nasopharynx, where after several molts it reaches maturity and begins oviposition. Most cases have been reported in several countries of North Africa, Europe, and the Middle East. From 1989 to mid-2001, only one ocular case, in Ecuador, was reported worldwide (Lazo et al. The highest rates are seen in areas where dogs are fed raw viscera from sheep and goats. Data on the frequency of nymphal infection in domestic herbivores are not available. A study conducted in eight southeastern states found that 2% of 260 Sylvilagus floridanus rabbits had nymphs of L. When the infection occurs from the ingestion of eggs, the larvae become encapsulated in various organs, where they can survive up to two years. The encysted nymphs do not produce clinical symptoms, and the infection is almost always discovered during surgery, radiological examination, or autopsy. Clinical cases of prostatitis, ocular infection (anterior chamber of the eye), and acute abdomen have been described; their origin is a parasitized, inflamed lymph node adhering to the intestinal wall. The symptoms appear a few minutes to a halfhour after the infective food is eaten. The variation in the incubation period probably depends on the place where the nymphs are released from their cysts, since the ones that are swallowed require more time to migrate to the tonsils and nasopharyngeal mucosa than the ones that become free in the mouth. Sometimes there is congestion and intense edema of the region, which may extend to the larynx, eustachian tube, conjunctiva, nose, and lips. At times, there is also dyspnea, dysphagia, vomiting, headaches, photophobia, and exophthalmia. The most serious symptomatology is believed to occur in persons sensitized by visceral infections with L. About half of the patients recover in less than one day; in others the illness may last one to two weeks. The Disease in Animals: the adult parasite causes a mucopurulent nasal catarrh, with sneezing, copious nasal discharge, and sometimes epistaxis in dogs. Larval infection in domestic herbivores and omnivores (intermediate hosts) is asymptomatic. Source of Infection and Mode of Transmission: the natural reservoirs are wild and domestic canids and, rarely, felids. Carnivores acquire the infection by ingesting viscera and tissues of infected intermediate hosts. In endemic areas, the cycles between dogs and goats and between dogs and sheep are of special interest. In the wild cycle, the infection circulates between wild herbivores and their carnivore predators. Herbivores become infected by ingesting pasture contaminated with feces or nasal secretions of the canids. Man contracts halzoun or marrara by consuming raw liver or lymph nodes from sheep, goats, or other infected domestic herbivores. Diagnosis: the visceral form (small pentastomid nodules) caused by nymphs is rarely diagnosed in living persons or domestic animals, except during surgery. Specific diagnosis is effected by identification of the nymph in a biopsy specimen. Histopathological examination reveals a granulomatous reaction with multiple eosinophilic abscesses, at the center of which degenerated nymphs are found. In very old cases, there may not be pathological findings around the calcified cysts. In dogs with suspicious nasal catarrh, diagnosis can be confirmed by detecting eggs in the nasal secretion or feces. Control: Visceral infection from ingestion of the eggs can be prevented by guarding against contamination of untreated water or raw food with carnivore depositions and washing hands carefully before eating. Halzoun and marrara or nasal infection with the adult parasite can be prevented by not consuming raw or undercooked viscera. Likewise, dogs must not be fed the raw viscera of goats, sheep, or other herbivores. In 1996, a local Chinese journal described the first human case of infection with larvae of A. The pre-adult stages are found in rodents, livestock, and many other animals, including man. The life cycle of Armillifer is similar to that of Linguatula,but the definitive hosts are snakes and the intermediate hosts are rodents and other wild mammals. The female of Armillifer deposits eggs in the respiratory cavities of snakes, and the eggs are expectorated or swallowed and then eliminated with the feces. In the cases that are known, the life cycle of the other species is similar (for example, Porocephalus crotali in the rattlesnake). Armilliferiasis occurs mainly in West Africa (Nigeria, Democratic Republic of Congo) and South and Southeast Asia; it seems to be infrequent in eastern and southern Africa, and no cases have been diagnosed in the Americas. The three cases of calcification in Nigeria were found during radiographic examination of 214 patients, thus revealing a prevalence of 1. The Disease in Man: Man is infected only with the larval forms; no cases of infection caused by the adult are known. The infection is similar to the visceral form of linguatuliasis and generally asymptomatic. Severe infections can give rise to serious illness, especially when the larvae lodge in vital organs where they can produce multifocal abscesses, tumors, or obstruction of ducts. In the case in China, high fever, abdominal pain, diarrhea, moderate anemia, eosinophilia, hepatosplenomegaly, and polyps in the colon were observed. In the ocular case, the patient complained of pain, conjunctivitis, and vision problems. The autopsy of the Nigerian in Canada, in which death was due to a longstanding infection, found nodules in the liver, lungs, pleura, and peritoneum, but there was no inflammatory or degenerative reaction around the nodules. In the case of an 18-year-old woman in Nigeria, the patient suffered from fever, dizziness, weakness, jaundice, hypotension, and a confused mental state. She died shortly after being admitted, and the autopsy revealed disseminated infection encompassing the thoracic and abdominal serous membranes and internal organs (Obafunwa et al. The diagnostic laparoscopy of a woman from Benin who had abdominal pain for 10 years found hundreds of calcified masses 1 to 2 cm in diameter in the abdominal cavity. Microscopy of the nodules revealed questionable remains of parasites, but the X-ray showed crescentor horseshoe-shaped calcifications that were attributed to Armillifer (Mulder, 1989). The Disease in Animals: Nonhuman primates are also accidental hosts of the infection. Source of Infection and Mode of Transmission: the reservoirs and definitive hosts of Armillifer spp. Man contracts the infection by consuming water or vegetables contaminated with eggs eliminated in the feces or saliva of infected snakes, by consuming raw or undercooked snake meat, or by placing hands to the mouth after handling contaminated snake meat. The other intermediate hosts also become infected by ingesting the parasite eggs. Diagnosis: Some cases can be diagnosed by radiographic examination, which reveals the calcified, half-moon-shaped larvae. In the overwhelming majority of cases, however, the encapsulated nymphs of the pentastomids are found during autopsies or laparotomies performed for other reasons. Jones and Riley (1991) identified a protein of Porocephalus crotali that combined with rat immune serum in the Western blot test; an enzyme-linked immunosorbent assay can thus presumably be designed for the diagnosis of pentastomiasis. Endoparasites of selected populations of cottontail rabbits (Sylvilagus floridanus) in the southeastern United States. Hepatic granuloma due to a nymph of Linguatula serrata in a woman from Michigan: A case report and review of the literature. Ocular linguatuliasis in Ecuador: Case report and morphometric study of the larva of Linguatula serrata. Man is not affected by specific ticks, but can occasionally be infested by ticks of other vertebrates that transmit various infections (Table 4). Ticks are divided into two groups: the family Argasidae, comprised of soft ticks whose bodies are covered by a coriaceous tegument, with the mouthparts located on the ventral surface, and the family Ixodidae, comprised of ticks which have an enlargement of the shield-shaped cuticle on their backs, and mouthparts on the anterior end. That shield covers the entire back in the males, but just the anterior half of the back in females, to permit their bodies to engorge while feeding. Ornithodoros, which transmit the relapsing fevers in man caused by strains of Borrelia recurrentis, and several species of Argas, in particular those of chickens, pigeons, and other birds that attack man when they cannot find their natural host. The species of Ornithodoros that infest man live hidden in the ground, in tools and equipment, and in the cracks of shack or cabin walls, and emerge at night to suck blood from people or chickens that take shelter there. The nymphs that go through four stages molt into adult males; those that go through five stages molt into adult females. Also, more than half of the females can survive between 9 and 56 months without feeding. Among the hard ticks, the species of the genera Amblyomma, Boophilus, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, and Rhipicephalus are important in human medicine. The life cycle of all these ticks is similar, with small variations among the genera. The female produces several thousand eggs at a time for a few days, and then dies. Hexapodal larvae emerge from the eggs; they measure about 1 mm in length, feed on blood for a few days, and molt into nymphs a few days thereafter. These differences are important in the spread of disease and the design of tick control plans. Geographic Distribution and Occurrence: the transmission areas of tick-borne infections are shown in Table 4. The distribution of the ticks themselves is diverse; those of the genus Amblyomma are mainly parasites of small and large mammals distributed throughout the tropical and subtropical areas of the Americas and subSaharan Africa. Ticks of the genus Boophilus are parasites of cattle, and, exceptionally, of other herbivores, and are distributed in tropical to temperate zones throughout the world. Ticks of the genus Dermacentor are parasites of rodents and large mammals ranging from the tropical zone of Latin America to Canada. Ticks of the genus Haemaphysalis are parasites of small mammals and birds and are found throughout the world. Those of the genus Hyalomma are mainly parasites of domestic animals found in the Old World below the 45th parallel North. Ticks of the genus Ixodes are parasites of birds as well as large and small mammals and are distributed worldwide. Rhipicephalus are ticks of a variety of African and Eurasian animals; only Rhipicephalus sanguineus is distributed worldwide. Humans can be infested by 12 species of Argasidae (Argas and Ornithodoros) and 22 species of Ixodidae (4 of the genus Amblyomma,7of Dermacentor,3of Haemaphysalis,2of Hyalomma, and 6 of Ixodes) (Estrada-Pena and Jongejan, 1999). The most common were Amblyomma americanum in the south and near the Atlantic Ocean; Dermacentor variabilis and Ixodes scapularis in the east; Dermacentor andersoni in the west; Ixodes pacificus near the Pacific; and Ornithodoros spp. North Carolina reported human infestations with Otobius megnini, Amblyomma maculatum, Haemaphysalis leporispalustris, Ixodes cookei, Ixodes dentatus, and R.

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At the plot or farm level hypertension over 55 generic 20 mg vasodilan with amex, yield loss is estimated experimentally by allowing some plots to be attacked while protecting others arteria carotida interna buy vasodilan on line amex, with the difference in yield being the loss due to the pest lennox pulse pressure test kit 20mg vasodilan free shipping. Using this approach on maize in Nicaragua blood pressure 20090 purchase 20mg vasodilan with mastercard, van Huis (1981) reported yield losses of 30% to 60% hypertensive crisis purchase vasodilan in united states online, and Hruska & Gladstone (1988) reported 45% loss when all plants were infested arteria carotis externa buy vasodilan 20 mg on line. While localised studies would be needed to precisely determine economic injury levels for particular crops in particular situations (Cruz et al. When feeding is on the lower canopy leaves, yield loss is minimal, but if the larvae feed on the flag leaves, they are more problematic. Of greater concern is when they move into rice during grain fill and move to the panicle to feed directly on the high moisture, filling grains. Sorghum is relatively tolerant of defoliation, so thresholds for treatment are generally higher than for maize, and pesticide application is much less frequently justifiable. Three approaches to monitoring are used in Latin America: scouting, pheromone traps and light traps. Scouting involves visual inspection of the crop to assess the level of damage and/or the presence/abundance of the pest. A commonly used scheme is to examine 20 consecutive plants from five different locations in the field. Thus, it is not clear how many small-scale farmers undertake scouting in Latin America, or at least undertake it accurately. Scouting can begin not long after germination, and should continue until the silks begin to dry. More frequent scouting allows earlier detection of infestations, though it takes more time. Some authors recommend scouting every two days, but once or twice a week should be adequate. More frequent scouting is appropriate in hotter areas where the pest develops more rapidly. If scouting aims to count larvae, then it should be undertaken in the early morning or late afternoon, when the larvae are more likely to be visible. The chemical composition of this has been determined, and synthetic pheromone can be used as a lure in a trap to monitor the moth population. However, not all the chemical components of the natural pheromone are required to make an effective lure, and different manufacturers market lures with different blends of usually two to four different chemicals. A kit containing synthetic pheromone plus a trap is marketed in various countries in South America, including Brazil. According to one manufacturer the trap should be placed in the centre of the planting area and used at a density of one trap for every five hectares of crop (BioControle). If the planted seed has not been treated, monitoring should start soon after emergence (Cruz et al. However, some farmers in Peru and Colombia make their own traps, which reduce the cost. However, in North America, the number of moths caught in a trap is a poor predictor of crop damage (Johnson, undated), although this does not necessarily mean that trap catches are giving a poor estimate of the adult population. They may have a role to play in monitoring in cases where they are also being used with the aim of reducing the moth population (see mass trapping). Some small-scale farmers in Latin America make their own light traps, but it is not clear how effective or practical these are. An intervention is economically justifiable if the value of the crop loss it reduces is more than the cost of the intervention. If one has information on the costs of control, the expected yield with and without the intervention, the relationship between the parameter monitored and expected yield loss, and the value of the crop, it is possible to define a threshold value of the monitored parameter at which an intervention should be made. For example, if a farmer expects a yield of 1 tonne/ha which fetches a price of $200, a pesticide application costing $10/ha would need to reduce yield loss by over 5% to be economically worthwhile. In commercial farms, where the damage relationship has been well researched, this approach is feasible, but in small-scale systems it may be less suitable due to the many factors affecting yield. Also, small-scale farmers may have other goals apart from profit maximisation: for example they might seek to reduce risk of low yield, or minimise the cost of inputs. Nevertheless, it is still appropriate to define action thresholds that can guide on-farm decision-making. Van Huis (1981) evaluated thresholds of 20% and 50% of maize whorls damaged and concluded that the 20% threshold generally performed better. This depended on the subsequent rate of increase in the number of injured whorls: as infestation is difficult to forecast, the 20% level was deemed most appropriate for small-scale farmers in Nicaragua. If pheromone traps are being used, the threshold will be in terms of number of moths caught. Cruz (2010) proposed a minimum of three moths per trap per hectare in Brazil, but, as with a threshold based on the percentage of plants damaged, this needs testing in Africa. Thus, spray applications are more likely to be effective if undertaken around dawn or dusk. Therefore, where possible, pesticide applications should be timed to coincide with the presence of the younger larvae. This could affect the extent to which populations build up in an area, and whether control strategies that have inter-seasonal, as well as intra-seasonal, impacts on the pest population are beneficial. For example, there would be little value in spending time and effort ploughing up pupae if the emerging moths would in any case migrate elsewhere. When adults emerge from pupae, if there are food plants available, they are likely to stay in the same area, mate and lay eggs, unless the population density is high, in which case migration to other areas is more likely (Regiane Bueno, pers. This contrasts with the African armyworm, Spodoptera exempta, which almost always migrates away from its emergence site, and is considered an obligate migrant (Rose et al. The patterns of population persistence, dispersal and migration in Africa have yet to be determined. In Brazil, the level of infestation in one season is said to be poorly correlated with the level in the previous season (Regiane Bueno, pers. In contrast, in Central America a high infestation in one season is likely to be followed by a high infestation the next season, unless control is effected (Patricia Castillo, Gregorio Varela, pers, comm. Thus, coordinated area-wide control efforts are worthwhile, including methods that limit survival from one season to the next. This could include synchronised planting, although this would be difficult to achieve over large areas with many smallholders. Infestation also tends to be spatially patchy rather than uniformly distributed in fields (Patricia Castillo, Luis Medina, Juan Jose Lagrava, pers. Farms where planting takes place later tend to show a more uniform distribution of the larvae (and higher levels of damage). A knapsack, hand-operated sprayer can be used to spray selected plants, whereas a tractor mounted boom sprayer is less targeted. Less frequently used approaches are to treat the seed with a pesticide before planting, and the use of dry pesticide applied to the plant funnel. As well as inorganic molecules, a number of products are based on products of microorganisms (such as spinosad), so are sometimes classified as biopesticides (see below). Several highly or extremely hazardous compounds are effective as seed treatments, but these should not be used. Another approach is to apply pesticide to the soil at planting, though this is likely to be less efficient than seed treatments. Pesticides applied to the growing crop are most effective when used at the right time and in the correct way. This includes spraying when the larvae are still young; spraying in the early morning, later afternoon or night when the larvae are more active; and directing the spray into the funnel (when using knapsack sprayers) of affected plants. Feeding stimulants or attractants mixed with pesticides can increase effectiveness at lower concentrations, although they are not widely used. The Peruvian Ministry of Environment recommends mixing dry formulations of trichlorfon with sand, and applying the mixture into the whorl with a plastic bottle. In trials in Nicaragua van Huis 65 (1981) found that a mixture of sawdust and chlorpyrifos reduced the amount of pesticide needed by 20%, without loss of control. Converting the cost of a bottle of pesticide to a cost per hectare treated requires assumptions to be made regarding the dilution and volume applied. However, assuming a fixed volume of application, some observations on costs can be made. Not surprisingly, small packets/bottles are more expensive than larger ones, which makes the effective cost higher for small-scale farmers. Neem-based products, the most widely available botanical, are generally more expensive. This price differential makes it very unlikely that resource poor farmers, if they can afford pesticides, will purchase anything other than the cheap inorganic chemicals. In Ghana, it was noted that cheaper products were made from generic formulations of the active ingredients, and that the binary products (containing more than one active ingredient) are more costly than those made from a single active ingredient. In Kenya, a retailer noted that a number of products recommended by the government are not stocked, due to low demand. This is either due to a perception that the product is ineffective, or to it being too expensive. Considerations for Africa: A key issue around pesticide use in Africa is the risk to human health. Resource-poor farmers are often unwilling or unable to buy the appropriate safety equipment and in some cases they use pesticides without appropriate application equipment. Farmers may also be disinclined to use safety equipment when hot weather can make this extremely uncomfortable. Recognising that farmers will still want to use pesticides, specific measures are needed to make lower risk pesticides more accessible. Many of the cheapest and most widely used pesticides in Africa fall into the mode-of-action classes, to which resistance has developed in the Americas. Pests develop resistance to pesticides through repeated exposure of successive generations to chemicals with the same mode of action, so the following strategies should be implemented. A widespread problem with pesticides (and other inputs) in Africa is adulteration or selling of fake products. As with chemical pesticides, application methods can play a major part in determining the effectiveness of microbial pesticides. They are often slower to act than chemical pesticides, 67 which can result in damage being done after application, even if the insects eventually die. This can reduce their attractiveness to farmers and can be interpreted as failure. Ultraviolet light and high temperatures can destroy the virus, so the formulation as well as application time affects their efficacy. It is possible that they will be less efficacious than chemical pesticides but still be a cost-effective component of an integrated approach. Products containing several different viruses to control the major pests can be produced. A critical determinant is the cost of production, so where efficient production systems can be established, the product can be marketed at competitive rates. Considerations for Africa: Having lower risk than chemical pesticides, microbial pesticides are suitable for Africa. However, they can be adversely affected by climatic conditions and suboptimal application procedures, both of which could occur in Africa. Their widespread use would need to be supported by effective awareness-raising/communication campaigns. There are a number of microbial pesticides registered for use in Africa, and some countries are recommending the use of Bt. There is no expectation that the high populations of the agent will persist and affect any control the following season. Trichogramma spp are egg parasitoids that can be reared relatively easily in very large numbers and have been used for controlling insect pests in crops such as corn, sugarcane, tomatoes, rice, cotton, sugar beet, apple, prune, vegetables, and forests (Parra et al. Around four releases might be required in a season, at weekly or shorter intervals. There are several methods for releasing the parasitoid: one is through the release of adult wasps that have already emerged; another is by placing cards containing parasitised hosts in the field, from which the adults then emerge.

We measured plasma histamine levels by radioimmunoassay in a severe case of solar urticaria (15) pulse pressure with age purchase vasodilan without prescription. The histamine level greatly increased after an exposure to visible light on a limited area of the forearm and reached more than 100 times the preexposure level in five minutes hypertension levels cheap vasodilan 20mg online. There is edema in the upper and mid-dermis resulting in separation of the connective tissue pulse pressure 50-60 generic 20mg vasodilan overnight delivery. A minimal to moderate perivascular infiltrate ulterior motive quotes order vasodilan in united states online, consisting of neutrophils arrhythmia after heart surgery generic 20 mg vasodilan free shipping, mononuclear cells blood pressure levels vary cheap 20mg vasodilan, and sometimes a few eosinophils, is found. They found a significant increase in neutrophil and eosinophil numbers in the upper dermis at five minutes and two hours, but not at 24 hours, in a dose-dependent manner. Eosinophil degranulation associated with deposition of eosinophil major basic protein has been reported in solar urticaria (35). Sequential ultrastructural analysis demonstrated margination and activation of platelets, formation of interendothelial clefts, and alteration of nerve fibers as primary events in solar urticaria, preceding mast cell degranulation. Mediators other than histamine are most probably involved in the early stage of solar urticaria. Once the wheal is formed, mast cell degranulation is evident by dissolution of granular matrix, fusion of perigranular membranes including labyrinth formation and opening to the extracellular space. Nerve fibers, which initially demonstrate partial swelling, then show edema of endoneurium (37). The patient developed a wheal immediately after the sunlight exposure, whereas edematous erythema with burning sensation, blisters, and scars, which are the typical manifestations of erythropoietic protoporphyria, were delayed. No additional case has been reported, and the authors have not seen such a patient. It is our opinion that this patient had erythropoietic protoporphyria with urticarial symptoms rather than solar urticaria sensu strictu. More recently, a patient with coexisting porphyria cutanea tarda and solar urticaria was reported (40). Although porphyrin is a phototoxic substance that is activated by visible light, solar urticaria is not observed in the vast majority of patients with porphyrias. Frain-Bell recorded two patients with solar urticaria that occurred in association with lymphocytoma (3). There are sporadic case reports of solar urticaria associated with other physical urticarias including cold urticaria (41), dermographism (14,41), heat urticaria (42), and pressure urticaria (43). In our series, patients with solar urticaria lacked atopic dermatitis, and their total IgE levels were normal. Frain-Bell also found both personal and family history of atopy only in a minority of patients and stated that solar urticaria was not associated with an atopic background (3). A study of 57 patients from Italy reported the occurance of atopic dermatitis in 21% of the patients, asthma or rhinitis in 26%, and elevated serum immunoglobulin in 33% (42). In the Japanese patients followed by one of the authors, the disease had lasted for 5 to 10 years before consultation in 7 of 42 patients and more than 10 years in five patients. Similarly, many of the patients studied by Ryckaert and Roelandts (6) had the disease for 4 to 11 years before consultation. Nearly half of the 57 patients reported from Italy were free of disease within five years of the onset of disease (42). On the basis of a study of 87 patients, the group in Scotland estimated that the probability of disease resolution is 15%, 24%, and 46% in 5, 10, and 15 years, respectively (38). For the treatment of urticaria, the prevention of its development is required, since the wheal, once appeared, spontaneously subsides in a short time. Photoprotection by the use of clothing, wide-brimmed hat, and gloves is an important measure to prevent wheal development. Oral histamine H1 receptor antagonists have a beneficial effect to some degree in reducing the whealing and itching in patients with solar urticaria. Terfenadine, at doses higher than the conventional dose (up to 360 mg per day), has been reported to be effective (45,46). However, high-dose terfenadine must be used with caution because of the risk of life-threatening cardiac arrhythmias. Other forms of antihistamines have also been widely used and reported to be at least partially effective (38,42). The new generation of histamine H1 receptor blocking agents, such as desloratadine and levocetiricine, are well tolerated and can be given in higher doses. Skin constantly exposed to the sunlight and an area in which urticaria has recently been produced are tolerant to subsequent irradiation. However, caution must be taken in not exposing too large an area and not to increase the dose too rapidly to avoid systemic side effects that may include sycope. The mechanism by which tolerance is induced is not clear, but may be partially due to the exhaustion of chemical mediators by repeated exposures (24). It is likely that the binding sites of IgE on mast cells remain occupied by the photoallergen during the state of tolerance and IgE-mediated histamine release from mast cells is blocked until new IgE is generated. Elimination of causative agent is very difficult in solar urticaria, because the photosensitizer is of endogenous origin in the majority of cases. Plasmapheresis has been used with a beneficial effect for the treatment of patients with solar urticaria in whom a photoallergen can be detected in the serum or plasma (58,59). More recently, extracorporeal photochemotherapy (photopheresis) has been reported to be successful in one patient (61). It should be emphasized that the use of a single treatment modality is not usually sufficient to obtain a complete prevention. Combination therapy is necessary depending upon the clinical response of the patients. However, more information about pathomechanisms are now available in solar urticaria; it is most probably a type I allergic reaction to an as yet to be defined photoallergen. Identification of this photoallergen is the most important issue remaining to be resolved in the future. Photoallergic urticaria induced by visible light: additional cases and further studies. The clinical and photobiological characteristics of solar urticaria in 40 patients. Benoxaprofen photosensitization of phospholipase activation in mammalian cells in culture. Solar urticaria: release of mast cell mediators in to the circulation after experimental challenge. Evidence for eosinophil degranulation with deposition of granule major basic protein in solar urticaria. Sequential ultrastructural analysis of solar urticaria: infiammatory cells, blood vessels, and nerve fibers. Characteristics and prognosis of idiopathic solar urticaria: a cohort of 87 cases. Erythropoietic protoporphyria: a new porphyria syndrome with solar urticaria due to protoporphyrinaemia. A case with increased skin mast cells and good therapeutic response to an antihistamine. B the diagnosis of drug or chemical-induced photosensitization offers the opportunity of cure through removal of the chromophore. B Topical agents produce photosensitization by a range of toxic and allergic mechanisms. B the commonest recent photoallergens are sunscreens and topical nonsteroidal anti-infiammatory agents. B Systemic photoactive drugs most commonly produce phototoxicity; five distinguishable clinical patterns are seen. B Susceptibility to photosensitivity can persist for several months after cessation of a photoactive drug. The W correct diagnosis offers the possibility of prevention by simply avoiding the agent. Systemic agents, either ingested or parenterally administered, are usually therapeutic chemicals with photosensitivity as an adverse effect (1). The clinical impact for the patient relates not only to the degree of sensitization, but also to the wavelength involved. A range of mechanisms exist to explain how a therapeutic drug enhances the photosensitivity of cellular skin components. It does appear that phototoxicity, a nonimmunological event due to combination of a drug or metabolite, with light of appropriate wavelength, is the most commonly encountered mechanism. Other significant, less common, routes exist, which includes drug-induced photosensitive lichen planus and lupus erythematous, pellagra, photoallergy, and erythema multiforme. Photosensitization, whether immune-based or not, can be reduced to the simple concept of absorption of radiant energy by a chromophore within the skin. Excitation of the electronic state from ground level with transfer of the radiant energy into a biologically active free radical species will induce cellular damage resulting in either direct toxicity, that is, phototoxicity, or via the immune system or other mechanisms. Topical photosensitizers, that is, those in contact with the skin, are often nontherapeutic agents. A wide variety of plant materials and other chemicals, including sunscreens, and topical drugs are recognized to be responsible (2). Some of these have the ability to absorb radiation from the sun or artificial sources. In all such reactions, both chemicals and radiation are necessary for the photochemistry necessary to produce biological changes and disease. Photopatch testing in such patients is contraindicated, since a positive response might be severe and since, as stated above, such a positive response would be expected to occur in the general population and would not aid in the diagnosis. Certain agents like tar absorb radiation and transfer that energy to membranes of skin cells inducing cell damage. Although the mechanism of production has been extensively studied for a number of photoallergens, the process is still poorly defined. The pathophysiological mechanisms involved in production of the skin lesions, however, routinely reveal that the immunological process involved in this reaction is analogous to the process occurring in plain allergic contact dermatitis to a nonphotosensitized antigen. Rarely, particularly sensitive patients may react to artificial light from indoor lighting sources. Review of large studies of patients being evaluated for photosensitivity reveals a fairly low incidence of this diagnosis (7). This may be because the diagnosis is made clinically, since phototesting and photopatch testing are not done in these patients. This necessitates a careful history for exposure to photosensitizers at home, in the work place, and in the recreational setting. The diagnosis is suggested by the classic morphology, erythema and edema, with bullae in severe cases. In fact, patients may present with only hyperpigmentation without a history of preceding infiammation. However, other clinical morphologies including psoriasiform dermatitis and even hypopigmentation after infiammation can occur. The patients experience burning and stinging almost immediately on exposure to the sun. Roofers with exposure to pitch and coal tar are most susceptible and direct skin contact is not necessary, since aerosolized contact is sufficient to produce the reaction. The sensitizers in coal tar include acridine, anthracene, benzopyrene, and fiuoranthene (11). Reactions to creosote in roof paper and creosote-soaked wood products including saw dust and boxes have also been reported in a large number of workers (12,13). Since tar-based products such as creams, soaks, and shampoos are routinely used to treat skin disease, patients treated with these agents should be reminded that sun exposure can cause skin lesions. Furocoumarins Furocoumarins are photosynthesizing chemicals that occur in nature in wild and cultivated plants. Such agents have been synthesized for many uses including fragrances and as therapeutic agents. The most common agents used therapeutically, 8-methoxypsoralen and Drug and Chemical Photosensitivity 203 5-methoxypsoralen, are also the ones most commonly present in plants that are potent photosensitizers. These reactions are relatively rare since most fragrance agents containing photosensitizers have been removed from products used in the United States and Western Europe. Many consumers, however, do continue to use containers of perfumes and colognes for many years or even decades.