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W. Cyrus, M.A., M.D., M.P.H.

Program Director, New York Institute of Technology College of Osteopathic Medicine

The acetylation status of histones, the core proteins of nucleosomes, can regulate gene expression by altering chromatin coiling. Methylation-induced transcriptional silencing begins early during the process of genetic instability and can affect many genes that are important in tumour progression. Given that methylation is a potentially reversible state, this creates a target for novel cancer therapeutic strategies involving gene reactivation. Oncogenes and tumour suppressor genes There is substantial evidence that multiple genes must be mutated or deregulated in a single cell to cause malignant transformation and cancer growth. Most cells that harbour even a single mutation are either targeted for repair or are cleared from the organism by protective mechanisms including immune surveillance or activation of cellular suicide programs (apoptosis). Not all mutations contribute to tumour development: the genetic material in each of our cells is estimated to encode approximately 30,000 genes, 67 and mutations in less than 10 percent of these genes contribute to the carcinogenic process. Genes that may contribute to tumourigenesis play key roles in regulating critical cellular processes such as cell division, lifespan, differentiation, angiogenesis, invasion, and death. Specific mutation of one allele converts the normal "protooncogene" to the activated, transforming oncogene that can contribute to the carcinogenic process. The oncogene is dominant over the protooncogene and generally results in a protein product that is deregulated and/or constitutively active. Oncogenic conversion is a gain to loss or inactivation of both alleles is required for transformation. Tumour suppressors are also known as recessive oncogenes or anti-oncogenes and their inactivation represents a loss-of-function mutation. Both oncogene activation and tumour suppressor inactivation collaborate in the stepwise progression to tumourigenesis. Here we will focus on these cancer genes and outline how they have been identified, the genetic abnormalities associated with deregulation, the nature of the specific gene products, their mechanisms of action, and recent advances to counteract these tumour-promoting lesions with novel anticancer therapeutics. Tumour suppressor genes Approximately 1 percent of all human cancers arise in individuals with a hereditary cancer syndrome. Even though such conditions are relatively rare, investigations of the affected individuals and of mutations of genes associated with their disease have proven invaluable in understanding the genetics and etiology of cancer. Most inherited cancer syndromes are a consequence of germline transmission of inactivating, loss-of-function mutations in tumour suppressor genes. Unlike oncogenes, whose mutations are associated with sporadic tumours and act in a dominant manner, mutations of tumour suppressor genes are recessive at the somatic level, and the remaining wild-type allele is inactivated during cancer development. Studies by Knudson investigating the epidemiology of familial retinoblastoma, an autosomal dominant hereditary form of retinal cancer led to the two hit hypothesis (Knudson, 2001), highlighting the importance of recessive mutations in tumourigenesis. In contrast to sporadic cases of retinoblastoma (Rb), patients with familial disease were likely to develop a more severe, bilateral or multifocal disease at an earlier age of onset. Based on these observations, Knudson proposed that two mutations, or two hits, were required for retinoblastoma to appear in both sporadic and familial cases. In familial retinoblastoma, the first mutation (in one of the alleles of the Rb gene) is transmitted through the germline and is present in all cells, whereas the second mutation needs to occur somatically. Thus a second hit (in the other allele of the Rb gene) in only one retinal cell is sufficient for the tumour to arise, in agreement with the dominant inheritance of familial retinoblastoma. In sporadic (noninherited) retinoblastoma, both mutations and hits have to occur within the same somatic cell, statistically a far less likely event. Genetic defects of tumour suppressor genes also occur frequently in sporadic cancer, both during tumour initiation and progression. Cytogenetic studies in lymphocytes of patients with familial cancers provided important information about the chromosomal location of tumour suppressor genes. For instance, 5 percent of retinoblastoma patients had interstitial deletions on chromosome 13q14, whereas Wilms tumour patients frequently had deletions on chromosome 11p13, pointing to the 68 chromosomal position of tumour suppressor genes associated with these diseases. Recent studies have indicated that small deletions and point mutations are more commonly found than large deletions in tumours. Information relating to genetic alterations in cancer can be accessed through an interactive, database cgap.

Disbudding a kid Disbudded kid Scurs Scurs are small portions of horn which grow back after incomplete disbudding. If she has adequate energy and protein in her feed, plenty of clean, fresh water, proper health care and exercise she can provide milk for up to 300 days a year. If given rice bran, wheat bran, cottonseed cake or other protein supplements, a dairy goat will give more milk. Her udder will become hard, but gradually the milk will stop and she will not produce any more. It is important to dry off the doe (meaning to stop milking) during the last two months of pregnancy because the kids are growing fast inside the doe and need the sustenance her body provides. The family wanted to improve their livelihood, but without the necessary skills and startup capital, this was difficult. He was very excited hearing how Heifer China helped other needy communities move out of poverty and closer to self-reliance. The project staff approved his application and after training, in June he received 10 Lezhi Black goats. Farmers favor the Lezhi Black Goat because it is an improved meat breed and has high productivity. Wu and his family actively participated in all project activities and strictly followed the goat management requirements introduced by the Lezhi Promotion Association for Rural Development. The goat operation has also generated bio-gas for cooking and light, saving firewood and Continue on page 48 Wu Yuantian feedin g his goats. Before they participated in the project, during the slow season, Wu went fishing or simply hung around in town, leaving his wife, Wen Yongqing, home to do the housework. Now, because the whole family is dedicated to raising goats, Wu and his wife share responsibilities. They have agreed that Wen keeps the income gained from selling goats, and whenever a family member needs money, they discuss it together. If I keep working hard, I will complete passing on the gift later this year and renovate my house in three years. Check with farmer about what equipment and supplies will be needed as per the above list. Practice Proper Milking Procedure Demonstrate proper milking procedure including checking milk in strip cup for abnormal signs, using teat dip and recording production on a daily milk record. With the proper milking equipment and procedures, milk, cheese and other dairy products can be produced not only for personal consumption, but also for sale, generating an additional source of income. Avoid plastic as it is difficult to sanitize A bucket of cold water to cool milk Teat dip** Soap Water Clean cloths A soft brush to loosen dirt and hair from udder (if needed) Be sure all of the milking equipment is kept clean. If only plastic is available, be sure to wash and rinse the pail well and sterilize with boiling water. Although some people milk only once a day, the highest milk production can be obtained through two daily milkings. Record time of milking and milk production for each doe, using the chart in the record section of this manual. Put her on the milking stand (if available) or tie her so she can eat from the bucket. If the udder is dirty, brush away loose dirt and if necessary wash the udder with soap and water. This will become routine with practice and is not as time consuming as it may seem. This first squirt clears bacteria in the teat canal and allows for careful examination of the milk. If color and consistency are normal, discard milk in the cup, place the pail or other container under the goat and continue milking. Grasp the teat at the top with thumb and index finger together to trap the milk in the teat. Gently, but firmly, bring pressure on the teat with the index finger forcing the milk down to the sphincter. Let the doe remain in the milking area until the teats are dry and then return the doe to the pen.

It was there in the past, long before Europeans came, and it 221 affected many-perhaps all of us. A few people who have acquired material wealth are very scared of sliding back into poverty. So they acquire more land, marry more wives, and take all the young men to work for them on their farms and factories distilling gin. Youth are most affected; they see no real chance for participation in the development of the country. In spite of their education and energy they are helpless, frustrated, and dangerous. Economic Difficulties this is not the desert of sand, but the desert of unemployment. If he has two chickens and gets two eggs a day, this gives him the salary of a professor. In Eastern Europe, Central Asia, and the former Soviet Union, the decline is linked to dramatic shifts away from occupations that once provided a living wage. While some of the elites have been able to take advantage of 222 new trading and business openings, the poor have been excluded from those same opportunities. The perceived unfairness of unequal access to opportunities results in frustration and disorder, further exacerbating economic difficulties. In Armenia the dramatic drop in the value of salaries has forced professionals and the intellectual elite to abandon their jobs, because they are no longer able to live on their salaries. In their ownl communities the poor feel ashamed and constantly humiliated in their encounters with former neighbors and friends who have prospered. Although poor people extensively rely on each other, at the same time frequent mutual suspicions and animosity, as well as fear of those in authority, often prevent people from cooperating on a community scale to help each other more effectively and improve community conditions. Unfortunately, economichardship touches the household as well, and people report that the unending problems of poverty create stress, arguments, and even violencewithin families. A woman in Latvia says that endless arguments have made her sons "aggressive, ready to fight and defend themselves" (Latvia 1997). In Ukraine the collapse of public sector employment has resulted in the poor trying to learn the new ways of trading. For the poor in developing countries unemployment seems to have become a fact of life. Cambodia has been shattered by war, yet migrant workers, despite their hardships, are sometimes viewed as the lucky ones, whereas those left in the rural areas are seen as the losers. New mechanized boats have arrived to do fishing on a large scale" (Cambodia 1998). In Pakistan the poor say that new opportunities are beyond their reach (Pakistan 1993). They have some knowledge and skill but they are not getting a chance to use it" (Nepal 1999). In Kenya and South Africa the poor not only speak extensively about lack of wage opportunities, but explicitly link it to increasing violence (South Africa 1998). In Ethiopia the poor say that because of unemployment, the unemployed "are exposed to durayenet, behaviors and acts which are morally unacceptable and disapproved by the family and community at large" (Ethiopia 1998). Family members left behind for long stretches of time have less time and fewer resources to contribute to and sustain community relations. In Ecuador communities feel that "communal organization has seriously slipped recently, partly reflecting that many male members have migrated to the urban centers on the coast" (Ecuador 1996a). Similarly in India the institutional framework of caste panchayats (traditional caste-based councils) across the district was found to be under constant erosion. Caste elders attributed this mainly to migration in search of employment, which greatly reduced the opportunities for community gatherings, and changes in the attitude of the younger generation toward caste norms (India 1998d). In Ethiopia, for example, prostitution increases as women in the urban areas losetheir jobs as maids and are joined by more female migrants 224 who arrive from rural areas seeking work, all of whom find no other options (Ethiopia 1998).

The cause of the psychiatric symptoms is usually not clearly defined in such cases. In some patients, however, symptoms have improved when antiretroviral therapy was initiated. Efavirenz, in particular, has been associated with several adverse psychiatric side effects. Many patients who initiate efavirenz develop neuropsychiatric side effects, including depressed mood, sleep disturbances, anxiety, psychosis, impaired concentration, vivid dreams, and nightmares. Warning patients and family members that these side effects may occur is important. The problems usually resolve after a few weeks or months on efavirenz and discontinuation is usually not necessary. Psychiatric problems also lead to increased stigmatization and present significant challenges to medication adherence. In low-resource settings, specialized medical professionals are usually not available to perform comprehensive psychiatric evaluations. Dosing may have to be altered, however, because of the presence of interactions between certain psychotropic and antiretroviral medications. Effect of perinatally acquired human immunodeficiency virus infection on neurodevelopment in children during the first two years of life. Psychiatric diagnoses in adolescents seropositive for the human immunodeficiency virus. Early cognitive and motor development among infants born to women infected with human immunodeficiency virus. Identify the appropriate rehydration plan for use with patients experiencing dehydration. Others include vomiting, wasting, hepatitis, esophagitis, malabsorption, jaundice, and failure to thrive. Nausea and Vomiting Nausea and vomiting are common physical complaints with many causes. Many medications can also cause nausea and vomiting, including antiretroviral agents, drugs used to treat or prevent opportunistic infections, and antineoplastic (anticancer) drugs. Patients with diarrhea and/or vomiting should be monitored for signs and symptoms of dehydration. Assessment the assessment of a patient with nausea and vomiting should include both subjective and objective data. Some danger signs include bilious (dark green) emesis, hematemesis (vomit with blood), jaundice, severe headache, altered mental status, focal neurologic signs, and severe flank or abdominal tenderness on exam. Patients should be instructed to drink fluids frequently, small volumes at a time; eat five to six small meals a day; avoid greasy, highfat foods; and eat food at room temperature. In addition to restoring and maintaining adequate hydration, treatment should be directed at the underlying cause of nausea and vomiting if appropriate. Antiemetic medications can be sedating and may be harmful in the pediatric setting and are not recommended for children. Diarrhea Overview Diarrhea remains one of the most common causes of death worldwide among children younger than 5 years. Diarrhea is an excessive loss of fluid and electrolytes in the stool resulting in three or more loose stools in a 24-h period. The consistency of the stools is the most important factor, and frequent passage of soft or well-formed stools should not be considered diarrhea. Infections, toxins, medications, anatomic abnormalities such as tumors, and dietary intolerance can cause diarrhea. Infections can be classified as causing predominantly watery, large-volume diarrhea due to a small-bowel infection or bloody, small-volume dysentery due to a predominant colonic infection. Agents such as rotavirus, Norwalk virus, adenoviruses, enteroviruses, Vibrio cholerae, enterotoxigenic Escherichia coli, Giardia, and Cryptosporidium commonly cause watery diarrhea. The patient and family should be educated about the signs of dehydration and the importance of maintaining adequate fluid intake. Food- or waterborne pathogens may cause diarrheal infections in immunocompromised hosts at a smaller inoculum than that needed to infect healthy hosts; they may also cause opportunistic infections. Staphylococcus aureus, Bacillus cereus, and Clostridium perfringens can cause food poisoning.

Naturally, the curvature that is obtainable with the standard 19-mm- (nominal 1-in. Tapered Straight Members Glulam beams are often tapered to meet architectural requirements, provide pitched roofs, facilitate drainage, and lower wall height requirements at the end supports. The taper is achieved by sawing the member across one or more laminations at the desired slope. It is recommended that the taper cut be made only on the compression side of the glulam member, because violating the continuity of the tension-side laminations would decrease the overall strength of the member. Erected in 1934 at the Forest Products Laboratory in Madison, Wisconsin, this building is one of the first constructed with glued-laminated timbers arched, designed, and built using engineering principles. To optimize the bending stiffness of this type of glulam member, equal amounts of high-quality laminations on the outside faces should be included to produce a "balanced" combination. To optimize bending strength, the combination can be "unbalanced" with more high-quality laminations placed on the tension side of the member compared with the quality used on the compression side. For high-quality lumber placed on the tension side of the glulam combination, stringent requirements are placed on knot size, slope of grain, and lumber stiffness. For compression-side laminations, knot size and slope-ofgrain requirements are less stringent and only lumber stiffness is given high priority. In the case where the glulam member is used over continuous supports, the combination would need to be designed as a balanced member for strength and stiffness because of the exposure of both the top and bottom of the beam to tensile stresses. The knot and slope-of-grain requirements for this type of combination are generally applied equally to both the top and bottom laminations. Axial Members Glulam axial combinations were developed to provide the most efficient and economical section for resisting axial forces and flexural loads applied parallel to the wide faces of the laminations. Members having loads applied parallel to the wide faces of the laminations are commonly referred to as vertically laminated members. Unlike the practice for bending combinations, the same grade of lamination is used throughout the axial combination. Properties considered include bending, tension, compression parallel to grain, modulus of elasticity, horizontal shear, radial tension, and compression perpendicular to grain. Grading standards published by the regional lumber grading associations describe the characteristics that are permitted in various grades of lumber. The rules for visually graded lumber are based entirely upon the characteristics that are readily apparent. The lumber grade description consists of limiting characteristics for knot sizes, slope of grain, wane, and several other characteristics. Manufacturers generally purchase graded lumber and verify the grades through visual inspection of each piece and, if Erated, testing of a sample. To qualify the material for some of the higher design stresses for glulam timber, manufacturers must also conduct additional grading for material to be used in the tension zone of certain beams. Another option is to purchase lumber manufactured under a quality assurance system that meets the required tensile strength. End Jointing To manufacture glulam timber in lengths beyond those commonly available for lumber, laminations must be made by end jointing lumber to the proper length. Other configurations are also acceptable, provided they meet specific strength and durability requirements. The advantages of fingerjoints are that they require only a short length of lumber to manufacture (thus reducing waste) and continuous production equipment is readily available. Careful control at each stage of the process-determining lumber quality, cutting the joint, applying the adhesive, mating, applying end pressure, and curing-is necessary to produce consistent high strength joints. Face Bonding the assembly of laminations into full-depth members is another critical stage in manufacture. To obtain clear, parallel, and gluable surfaces, laminations must be planed to strict tolerances. The best procedure is to plane the two wide faces of the laminations just prior to the gluing process. This ensures that the final assembly will be rectangular and that the pressure will be applied evenly. Adhesives that have been pre-qualified are then spread, usually with a glue extruder. Phenol resorcinol is the most commonly used adhesive for face gluing, but other adhesives that have been adequately evaluated and proven to meet performance and durability requirements may also be used.