Mesothelioom Research US

Mesothelioma is a form of cancer that is almost always caused by previous exposure to asbestos. In this disease, malignant cells develop in the mesothelium, a protective lining that covers most of the body's internal organs. Its most common site is the pleura (outer lining of the lungs and chest cavity), but it may also occur in the peritoneum (the lining of the abdominal cavity) or the pericardium (a sac that surrounds the heart).

Most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles, or have been exposed to asbestos dust and fibre in other ways, such as by washing the clothes of a family member who worked with asbestos, or by home renovation using asbestos cement products. Unlike lung cancer, there is no association between mesothelioma and smoking.

Signs and symptoms
Symptoms of mesothelioma may not appear until 20 to 50 years after exposure to asbestos. Shortness of breath, cough, and pain in the chest due to an accumulation of fluid in the pleural space are often symptoms of pleural mesothelioma.

Symptoms of peritoneal mesothelioma include weight loss and cachexia, abdominal swelling and pain due to ascites (a buildup of fluid in the abdominal cavity). Other symptoms of peritoneal mesothelioma may include bowel obstruction, blood clotting abnormalities, anemia, and fever. If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face.

These symptoms may be caused by mesothelioma or by other, less serious conditions.

Mesothelioma that affects the pleura can cause these signs and symptoms:

chest wall pain
pleural effusion, or fluid surrounding the lung
shortness of breath
fatigue or anemia
wheezing, hoarseness, or cough
blood in the sputum (fluid) coughed up
In severe cases, the person may have many tumor masses. The individual may develop a pneumothorax, or collapse of the lung. The disease may metastasize, or spread, to other parts of the body.

Tumors that affect the abdominal cavity often do not cause symptoms until they are at a late stage. Symptoms include:

abdominal pain
ascites, or an abnormal buildup of fluid in the abdomen
a mass in the abdomen
problems with bowel function
weight loss
In severe cases of the disease, the following signs and symptoms may be present:

blood clots in the veins, which may cause thrombophlebitis
disseminated intravascular coagulation, a disorder causing severe bleeding in many body organs
jaundice, or yellowing of the eyes and skin
low blood sugar level
pleural effusion
pulmonary emboli, or blood clots in the arteries of the lungs
severe ascites
A mesothelioma does not usually spread to the bone, brain, or adrenal glands. Pleural tumors are usually found only on one side of the lungs.

Diagnosis
Diagnosing mesothelioma is often difficult, because the symptoms are similar to those of a number of other conditions. Diagnosis begins with a review of the patient's medical history. A history of exposure to asbestos may increase clinical suspicion for mesothelioma. A physical examination is performed, followed by chest X-ray and often lung function tests. The X-ray may reveal pleural thickening commonly seen after asbestos exposure and increases suspicion of mesothelioma. A CT (or CAT) scan or an MRI is usually performed. If a large amount of fluid is present, abnormal cells may be detected by cytology if this fluid is aspirated with a syringe. For pleural fluid this is done by a pleural tap or chest drain, in ascites with an paracentesis or ascitic drain and in a pericardial effusion with pericardiocentesis. While absence of malignant cells on cytology does not completely exclude mesothelioma, it makes it much more unlikely, especially if an alternative diagnosis can be made (e.g. tuberculosis, heart failure).

If cytology is positive or a plaque is regarded as suspicious, a biopsy is needed to confirm a diagnosis of mesothelioma. A doctor removes a sample of tissue for examination under a microscope by a pathologist. A biopsy may be done in different ways, depending on where the abnormal area is located. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples.

If the cancer is in the abdomen, the doctor may perform a laparoscopy. To obtain tissue for examination, the doctor makes a small opening in the abdomen and inserts a special instrument into the abdominal cavity. If these procedures do not yield enough tissue, more extensive diagnostic surgery may be necessary.

Typical immunohistochemistry results Positive Negative
EMA (epithelial membrane antigen) in a membranous distribution CEA (carcinoembryonic antigen)
WT1 (Wilms' tumour 1) B72.3
Calretinin MOC-3 1
Mesothelin-1 CD15
Cytokeratin 5/6 Ber-EP4
HBME-1 (human mesothelial cell 1) TTF-1 (thyroid transcription factor-1)

Screening
There is no universally agreed protocol for screening people who have been exposed to asbestos. However some research indicates that the serum osteopontin level might be useful in screening asbestos-exposed people for mesothelioma. The level of soluble mesothelin-related protein is elevated in the serum of about 75% of patients at diagnosis and it has been suggested that it may be useful for screening.

Staging
Mesothelioma is described as localized if the cancer is found only on the membrane surface where it originated. It is classified as advanced if it has spread beyond the original membrane surface to other parts of the body, such as the lymph nodes, lungs, chest wall, or abdominal organs.

Pathophysiology
The mesothelium consists of a single layer of flattened to cuboidal cells forming the epithelial lining of the serous cavities of the body including the peritoneal, pericardial and pleural cavities. Deposition of asbestos fibres in the parenchyma of the lung may result in the penetration of the visceral pleura from where the fibre can then be carried to the pleural surface, thus leading to the development of malignant mesothelial plaques. The processes leading to the development of peritoneal mesothelioma remain unresolved, although it has been proposed that asbestos fibres from the lung are transported to the abdomen and associated organs via the lymphatic system. Additionally, asbestos fibres may be deposited in the gut after ingestion of sputum contaminated with asbestos fibres.

Pleural contamination with asbestos or other mineral fibres has been shown to cause cancer. Long thin asbestos fibers (blue asbestos, amphibole fibers) are more potent carcinogens than "feathery fibers" (chrysotile or white asbestos fibers). However, there is now evidence that smaller particles may be more dangerous than the larger fibers. They remain suspended in the air where they can be inhaled, and may penetrate more easily and deeper into the lungs. "We probably will find out a lot more about the health aspects of asbestos from [the World Trade Center attack], unfortunately," said Dr. Alan Fein, chief of pulmonary and critical-care medicine at North Shore-Long Island Jewish Health System. Dr. Fein has treated several patients for "World Trade Center syndrome" or respiratory ailments from brief exposures of only a day or two near the collapsed buildings.

Mesothelioma development in rats has been demonstrated following intra-pleural inoculation of phosphorylated chrysotile fibres. It has been suggested that in humans, transport of fibres to the pleura is critical to the pathogenesis of mesothelioma. This is supported by the observed recruitment of significant numbers of macrophages and other cells of the immune system to localised lesions of accumulated asbestos fibres in the pleural and peritoneal cavities of rats. These lesions continued to attract and accumulate macrophages as the disease progressed, and cellular changes within the lesion culminated in a morphologically malignant tumour.

Experimental evidence suggests that asbestos acts as a complete carcinogen with the development of mesothelioma occurring in sequential stages of initiation and promotion. The molecular mechanisms underlying the malignant transformation of normal mesothelial cells by asbestos fibres remain unclear despite the demonstration of its oncogenic capabilities. However, complete in vitro transformation of normal human mesothelial cells to malignant phenotype following exposure to asbestos fibres has not yet been achieved. In general, asbestos fibres are thought to act through direct physical interactions with the cells of the mesothelium in conjunction with indirect effects following interaction with inflammatory cells such as macrophages.

Analysis of the interactions between asbestos fibres and DNA has shown that phagocytosed fibres are able to make contact with chromosomes, often adhering to the chromatin fibres or becoming entangled within the chromosome. This contact between the asbestos fibre and the chromosomes or structural proteins of the spindle apparatus can induce complex abnormalities. The most common abnormality is monosomy of chromosome 22. Other frequent abnormalities include structural rearrangement of 1p, 3p, 9p and 6q chromosome arms.

Common gene abnormalities in mesothelioma cell lines include deletion of the tumor suppressor genes:

Neurofibromatosis type 2 at 22q12
P16INK4A
P14ARF
Asbestos has also been shown to mediate the entry of foreign DNA into target cells. Incorporation of this foreign DNA may lead to mutations and oncogenesis by several possible mechanisms:

Inactivation of tumor suppressor genes
Activation of oncogenes
Activation of proto-oncogenes due to incorporation of foreign DNA containing a promoter region
Activation of DNA repair enzymes, which may be prone to error
Activation of telomerase
Prevention of apoptosis
Asbestos fibres have been shown to alter the function and secretory properties of macrophages, ultimately creating conditions which favour the development of mesothelioma. Following asbestos phagocytosis, macrophages generate increased amounts of hydroxyl radicals, which are normal by-products of cellular anaerobic metabolism. However, these free radicals are also known clastogenic and membrane-active agents thought to promote asbestos carcinogenicity. These oxidants can participate in the oncogenic process by directly and indirectly interacting with DNA, modifying membrane-associated cellular events, including oncogene activation and perturbation of cellular antioxidant defences.

Asbestos also may possess immunosuppressive properties. For example, chrysotile fibres have been shown to depress the in vitro proliferation of phytohemagglutinin-stimulated peripheral blood lymphocytes, suppress natural killer cell lysis and significantly reduce lymphokine-activated killer cell viability and recovery. Furthermore, genetic alterations in asbestos-activated macrophages may result in the release of potent mesothelial cell mitogens such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) which in turn, may induce the chronic stimulation and proliferation of mesothelial cells after injury by asbestos fibres.

Mesothelioom Research US

Huntington Diease

Huntington's disease (HD), also known as Huntington disease and previously as Huntington's chorea and chorea maior, is a rare inherited neurological disorder affecting up to almost 8 people per 100,000. It affects 1 out of 20,000 people of Western European descent and 1 out of one million in people of Asian and African descent. It takes its name from the New York physician George Huntington who described it precisely in 1872 in his first medical paper. HD has been heavily researched in the last few decades and it was one of the first inherited genetic disorders for which an accurate test could be performed. Huntington's disease is caused by a trinucleotide repeat expansion in the Huntingtin (Htt) gene and is one of several polyglutamine (or PolyQ) diseases. This expansion produces an altered form of the Htt protein, mutant Huntingtin (mHtt), which results in neuronal cell death in select areas of the brain. Huntington's disease is a terminal illness.

Huntington's disease's most obvious symptoms are abnormal body movements called chorea and a lack of coordination, but it also affects a number of mental abilities and some aspects of personality. These physical symptoms commonly become noticeable in a person's forties[citation needed], but can occur at any age. If the age of onset is below 20 years then it is known as Juvenile HD. As there is currently no proven cure, symptoms are managed with various medications and care methods.

Symptomatology and pathology
Although there is no sudden loss of abilities or exhibition of symptoms, there is a progressive decline. Physical signs are usually the first noticed, but it is unknown how long before the cognitive and psychiatric deficits manifest. Physical symptoms are almost always visible, cognitive symptoms are exhibited differently from person to person, and psychiatric problems may not be evident.

Degeneration of neuronal cells, especially in the frontal lobes, the basal ganglia, and caudate nucleus (the striatum) occurs. There is also astrogliosis and loss of medium spiny neurons. This results in the selective degeneration of the indirect (inhibitory) pathway of the basal ganglia, via the lateral pallidum and the subthalamic nucleus coupled pacemaker system.

Physical
Most people with HD eventually exhibit jerky, random, uncontrollable movements called chorea, although some exhibit very slow movement and stiffness (bradykinesia, dystonia). These abnormal movements are initially exhibited as general lack of coordination and an unsteady gait and gradually increase as the disease progresses. This eventually causes problems with loss of facial expression (called "masks in movement") or exaggerated facial gestures, ability to sit or stand stably, speech, chewing and swallowing (which can lead to weight loss if diet and eating methods are not adjusted accordingly), and loss of determination. In the later stages of the disease, speaking is impaired with slurred words and uncontrollable movements of the mouth, eating and mobility are extremely difficult if not impossible, and full-time care is required.

Cognitive
Selective cognitive abilities are progressively impaired, whereas others remain intact. Abilities affected are executive function (planning; cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions, and inhibiting inappropriate actions), psychomotor function (slowing of thought processes to control muscles), speech like slurring of the words and some uncontrollable movement of the lips, perceptual and spatial skills of self and surrounding environment, selection of correct methods of remembering information (but not actual memory itself), and ability to learn new skills, depending on the affected parts of the brain.

Psychopathological
Psychopathological symptoms vary more than cognitive and physical symptoms, and may include anxiety, depression, a reduced display of emotions called blunting, egocentrism, aggressive behavior, compulsivity which can cause addictions such as alcoholism and gambling, or hypersexuality.

Many patients are unable to recognize expressions of disgust in others and also don't show reactions of disgust to foul odors or tastes. The inability to recognize disgust in others appears in carriers of the Huntington gene before symptoms are manifest. A number of related studies have been published.

Inheritance

HD is inherited in an autosomal dominant fashion.Huntington's disease is autosomal dominant, needing only one affected allele from either parent to inherit the disease. Although this generally means there is a one in two chance of inheriting the disorder from an affected parent, the inheritance of HD and other trinucleotide repeat disorders is more complex.

When the gene has more than 36 copies of the repeated trinucleotide sequence, the DNA replication process becomes unstable and the number of repeats can change in successive generations. If the gene is inherited from the mother, the count is usually similar. Paternal inheritance tends to increase the number of repeats. Because of the progressive increase in length of the repeats, the disease tends to increase in severity and have an earlier onset in successive generations. This is known as anticipation.

De novo mutations are rare.

Homozygous individuals generally do not show an earlier onset of disease, but may have an increased rate of decline.

Causes
The gene involved in Huntington's disease, called the HD gene or Interesting Transcript 15 (IT15), is located on the short arm of chromosome 4 (4p16.3). The end of the HD gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), that is repeated multiple times (i.e. ...CAGCAGCAG...); this is called a trinucleotide repeat. CAG is the codon for the amino acid glutamine, thus a CAG repeat may be termed a polyglutamine (polyQ) expansion. A sequence of fewer than 36 glutamine amino acid residues is the normal form, producing a 348 kDa cytoplasmic protein called huntingtin (Htt). A sequence of 40 or more CAG repeats produces a mutated form of Htt, mHtt. The greater the number of CAG repeats, the earlier the onset of symptoms. In genetically altered "knockin" mice, the mutant CAG repeat portion of the gene (which codes for the N-terminal end of mHtt) is all that is needed to cause disease. Aggregates of mHtt are present in the brains of both HD patients and HD mice, specifically in striatal neurons. These aggregates consist mainly of the amino terminal end of mHtt (CAG repeat), and are found in both the cytoplasm and nucleus of neurons. The presence of these aggregates however does not correlate with cell death. Thus mHtt acts in the nucleus but does not cause apoptosis through aggregation.

Mechanism
The exact mechanism by which mHtt causes or contributes towards neuronal cell death and HD symptoms remains unclear. Research exploring the actions of Htt and mHtt have shed light on the subject.

Like all proteins Htt is translated, then performs an action, and then is degraded. Both Htt and mHtt are cleaved (the first step in degradation) by Caspase-3, which removes the (amino end) N-terminal. Caspase-2 then further breaks down the amino terminal fragment of Htt, but cannot act upon mHtt. The mHtt amino fragments are thus able to affect gene expression in polyQ dependent transcription. Specifically, mHtt binds with TAFII130, a coactivator to CREB dependent transcription. The mHtt N-fragments also interact with SP1, thereby preventing it from binding to DNA. Thus mHtt alters the normal functioning of these proteins. Mutant Huntingtin also downregulates brain-derived neurotropic factor (BDNF) which protects striatal neurons. This loss of BDNF may contribute to striatal cell death, which does not follow apoptotic pathways as the neurons appear to die of starvation. Huntingtin appears to be involved in vesicle trafficking as it interacts with HIT1, a clathrin binding protein, to mediate endocytosis.

In the June 16, 2006 issue of Cell, scientists at the University of British Columbia (UBC) and Merck Labs presented findings that the neurodegeneration caused by mHtt is related to the caspase-6 enzyme cleaving the Htt protein. Transgenic mice that have caspase-6 resistant Htt did not show effects of HD. The researchers found "substantial support for the hypothesis that cleavage at the caspase-6 site in mHtt represents a crucial rate-limiting event in the pathogenesis of HD.... Our study highlights the importance of preventing cleavage of Htt at this site and also reinforces the importance of modulating excitotoxicity as a potential therapeutic approach for HD." In essence, scientists have managed to prevent the appearance of HD in genetically modified mice. Dr. Marian DiFiglia, a world-renowned HD researcher and neurobiologist at Harvard University, called this find "very important" and "extremely intriguing".

Diagnosis
To determine whether initial symptoms are evident, a physical and/or psychological examination is required. The uncontrollable movements are often the symptoms which cause initial alarm and lead to diagnosis; however, the disease may begin with cognitive or emotional symptoms, which are not always recognized. Every child of a person with HD has a fifty percent chance of inheriting the faulty copy of the gene and therefore the disease. Pre-symptomatic testing is possible by means of a blood test which counts the number of repetitions in the gene. A negative blood test means that the individual does not carry the expanded copy of the gene, will never develop symptoms, and cannot pass it on to children. A positive blood test means that the individual does carry the expanded copy of the gene, will develop the disease, and has a 50% chance of passing it on to children. A pre-symptomatic positive blood test is not considered a diagnosis, because it may be decades before onset. Because of the ramifications on the life of an at-risk individual, with no cure for the disease and no proven way of slowing it, several counseling sessions are usually required before the blood test. Unless a child shows significant symptoms of the juvenile form or is sexually active or considered to be Gillick competent, children under eighteen will not be tested. The members of the Huntington's Disease Society of America strongly encourage these restrictions in their testing protocol. A pre-symptomatic test is a life-changing event and a very personal decision. For those living in America, there is a list of testing centers available on the HDSA homepage[26] and embryonic genetic screening is also possible, giving mutation-positive or at-risk individuals the option of making sure their children will not inherit the disease. Expense and the ethical considerations of abortion are potential drawbacks to these procedures. The full pathological diagnosis is established by a neurological examination's findings and/or demonstration of cell loss, especially in the caudate nucleus, supported by a cranial CT or MRI scan findings.

Management
There is no treatment to fully arrest the progression of the disease, but symptoms can be reduced or alleviated through the use of medication and care methods. Huntington mice models exposed to better husbandry techniques, better access to water especially, lived much longer than mice who were not well cared for.

Medication
There are treatments available to help control the chorea, although these may have the side effect of aggravating bradykinesia or dystonia.

Other standard treatments to alleviate emotional symptoms include the use of antidepressants and sedatives, with antipsychotics (in low doses) for psychotic symptoms. Care needs to be taken with antipsychotic usage as people suffering psychotic symptoms of organic origin are often more sensitive to the side effects of these drugs.

Nutrition
Nutrition is an important part of treatment; most HD sufferers need two to three times the calories than the average person to maintain body weight, so a nutritionist's advice is needed (the normal population's average daily intake is approximately 2000 calories for women and 2500 for children and men).

Speech therapy can help by improving speech and swallowing methods. This advice should be sought early on, as the ability to learn is reduced as the disease progresses.

To aid swallowing, thickener can be added to drinks. The option of using a stomach PEG is available when eating becomes too hazardous or uncomfortable, this will reduce the chances of pneumonia due to aspiration of food and increase the amount of nutrients and calories that can be ingested.

EPA, an Omega-III fatty acid, slows and possibly reverses the progression of the disease. It is currently in FDA clinical trial, as Miraxion© (LAX-101), for prescription use. Clinical trials utilize 2 grams per day of EPA. In the United States, it is available over the counter in lower concentrations in Omega-III and fish oil supplements.

A calorie restrictive diet delays the onset of symptoms in HD mice.

Potential treatments
Trials and research are conducted on Drosophila fruit flies and mice that have been genetically modified to exhibit HD, before moving on to human trials.

Research is reviewed on various websites for HD sufferers and their families, including the Huntington's Disease Lighthouse, Hereditary Disease Foundation, and Stanford HOPES websites. Primary research can be found by searching the National Library of Medicine's PubMed. Clinical trials of various treatments are ongoing, or yet to be initiated. For example, the US registrar of trials has nine that are currently recruiting volunteers.

Intrabody Therapy
Engineered intracellular antibody fragments (intrabodies) have shown efficacy in vivo as therapeutic agents against pathogenic mutant huntingtin protein in fly models of HD. An intracellularly expressed single-chain Fv against the amino-terminal end of mutant huntingtin (mHtt) has been shown to reduce mHtt aggregate formation and increase turnover of the mHtt fragments in tissue culture models of HD. In a drosophila HD model, the expression of this anti-HD intrabody rescued fly survival through the larval and pupal stages to adult emergence. Additionally, the intrabody delayed neurodegeneration in the fly model, and significantly increased the mean adult lifespan. The engineered antibody approach shows promise as a tool for drug discovery and as a potential novel therapeutic for other neurodegenerative disorders resulting from protein misfolding or abnormal protein interactions, including Parkinson’s, Alzheimer’s and prion diseases.

Gene silencing
The most hopeful prospective treatment currently studied is based on gene silencing. Since HD is caused by expression of a single gene, silencing of the gene could theoretically halt the progression of the disease. One study with a mouse model of HD treated with siRNA therapy achieved 60% knockdown in expression of the defective gene. Progression of the disease halted. Full recovery of motor function is observed in late stage Tet/HD94 mice after addition of doxycycline.

Others
Other agents and measures that have shown promise in initial experiments include dopamine receptor blockers, creatine, CoQ10, the antibiotic Minocycline, exercise, antioxidant-containing foods and nutrients, antidepressants (notably, but not exclusively, selective serotonin reuptake inhibitors SSRIs, such as sertraline, fluoxetine, and paroxetine) and select Dopamine antagonists, such as Tetrabenazine.

Pig cell implants in HD trial: Living Cell Technologies in New Zealand has attempted trials with positive results in primates, but has yet to conduct a human trial.

Prognosis
Onset of HD seems to be correlated to the number of CAG repeats a person has in their HD gene. Generally, the higher the number of repeats the sooner is the onset. The number of repeats may change slightly with each successive generation, so that the age of onset may vary as well. Symptoms of Huntington’s disease usually become noticeable in the mid 30s to mid 40s.

Juvenile HD has an age of onset anywhere between infancy and 20 years of age. The symptoms of juvenile HD are different from those of adult-onset HD in that they generally progress faster and are more likely to exhibit rigidity and bradykinesia (very slow movement) instead of chorea.

Mortality is due to infection (mostly pneumonia), fall-related injuries, other complications resulting from HD, or suicide (The suicide rate for HD sufferers is much greater than the national average.), rather than the disease itself. Life expectancy is generally between 10 and 25 years after the onset of obvious symptoms.


Epidemiology
The prevalence is 5 to 8 per 100,000, varying geographically.

About 10 percent of HD cases occur in people under the age of 20 years. This is referred to as Juvenile HD, "akinetic-rigid", or "Westphal variant" HD.

Ethical aspects
Whether or not to have the test for HD Genetic counseling may provide perspective for those at risk of the disease. Some choose not to undergo HD testing due to numerous concerns (for example, insurability). Testing of a descendant of a person 'at-risk', has serious ethical implications, as a positive result in a child's test automatically diagnoses the parent.

Parents and grandparents have to decide when and how to tell their children and grandchildren. The issue of disclosure also comes up when siblings are diagnosed with the disease, and especially in the case of identical twins. It is not unusual for entire segments of a family to become alienated as a result of such information or the withholding of it.

For those at risk, or known to have the disease, consideration is necessary prior to having children due to the genetically dominant nature of the disease. In vitro and embryonic genetic screening now make it possible (with 99% certainty) to have an HD-free child; however, the cost of this process can easily reach tens of thousands of dollars. Financial institutions are also faced with the question of whether to use genetic testing results when assessing an individual, e.g. for life insurance. Some countries organisations have already agreed not to use this information.

Cultural references
HD has been depicted in books, in films and in television programmes, including an episode of the BBC drama Waterloo Road, Arlo Guthrie's film Alice's Restaurant, Pål Johan Karlsen's 2002 Norwegian novel Daimler (main character Daniel Grimsgaard is afflicted), Nancy Werlin's Double Helix, (Ava Samuels, Kayla Matheson and others), Kurt Vonnegut's novel Galapagos, Valley of the Dolls by Jacqueline Susann (night club singer Tony Polar has HD), Gene Roddenberry's Earth: Final Conflict (Season 3 episode #8 and in season 4 episode #3), and the book Saving Jasey by Diane Tulson (Trist, Jasey and their Grandfather). Ian McEwan, in his 2005 novel Saturday, has the character of Baxter suffering from HD, which the protagonist Dr Henry Perowne diagnoses correctly. However, in a comment published by the Lancet, Nancy Wexler and Michael Rowlins deplore that "Mc Ewan sadly reinforces the stigma and stereotypes from which families with Huntington's disease suffer, and which make them hide both their inheritance and their destiny". Woody Guthrie suffered with this disease and finally died from it. In the TV series Everwood, Hannah's father has HD, and she undergoes testing to see if she has the inherent gene. At first she is afraid to learn the results, but is relieved when the test is negative. Steven T. Seagle's autobiographical graphic-novel It's a Bird features the author coming to grips with the presence of HD in his family.

Huntington Diease

Benefits of Gallbladder Surgery

The gallbladder (or cholecyst, sometimes gall bladder) is a pear-shaped organ that stores about 50 ml of bile (or "gall") until the body needs it for digestion.

Anatomy
The gallbladder is about 10-12 cm long in humans and appears dark green because of its contents (bile), rather than its tissue. It is connected to the liver and the duodenum by the biliary tract.

The cystic duct connects the gallbladder to the common hepatic duct to form the common bile duct.
The common bile duct then joins the pancreatic duct, and enters through the hepatopancreatic ampulla at the major duodenal papilla.

Microscopic anatomy
The different layers of the gallbladder are as follows:

The gallbladder has a simple columnar epithelial lining characterized by recesses called Aschoff's recesses, which are pouches inside the lining.
Under the epithelium there is a layer of connective tissue (lamina propria).
Beneath the connective tissue is a wall of smooth muscle (muscularis muscosa) that contracts in response to cholecystokinin, a peptide hormone secreted by the duodenum.
There is essentially no submucosa separating the connective tissue from serosa and adventitia.

Stained section of a gall bladder showing the highly convoluted mucosal foldsSection References

Function
The gallbladder stores about 50ml of bile (1.7 US fluid ounces / 1.8 Imperial fluid ounces), which is released when food containing fat enters the digestive tract, stimulating the secretion of cholecystokinin (CCK). The bile, produced in the liver, emulsifies fats and neutralizes acids in partly digested food.

After being stored in the gallbladder, the bile becomes more concentrated than when it left the liver, increasing its potency and intensifying its effect on fats. Most digestion occurs in the duodenum.

Role in disease
Cholestasis is the blockage in the supply of bile into the digestive tract. It can be "intrahepatic" (the obstruction is in the liver) or "extrahepatic" (outside the liver). It can lead to jaundice, and is identified by the presence of elevated bilirubin level that is mainly conjugated.

Biliary colic is when a gallstone blocks either the common bile duct or the duct leading into it from the gallbladder.

Up to 25% of all people have gallstones (cholelithiasis), composed of lecithin and bile acids. These can cause abdominal pain, usually in relation with a meal, as the gallbladder contracts and gallstones pass through the bile duct.

Acute or chronic inflammation of the gallbladder (cholecystitis) causes abdominal pain. 90% of cases of acute cholecystitis are caused by the presence of gallstones. The actual inflammation is due to secondary infection with bacteria of an obstructed gallbladder, with the obstruction caused by the gallstone.

When gallstones obstruct the common bile duct (choledocholithiasis), the patient develops jaundice and liver cell damage. It is a medical emergency, requiring endoscopic or surgical treatment such as a cholecystectomy.

A rare clinical entity is ileus (bowel) obstruction by a large gallstone, or gallstone ileus. This condition develops in patients with longstanding gallstone disease, in which the gallbladder forms a fistula with the digestive tract. Large stones pass into the bowel, and generally block the gut at the level of Treitz' ligament or the ileocecal valve, two narrow points in the digestive tract. The treatment is surgical.
Cancer of the gallbladder is a rare but highly fatal disease. It has been associated with gallstone disease, estrogens, cigarette smoking, alcohol consumption and obesity. Despite aggressive modern surgical approaches, advanced imaging techniques, and endoscopy, nearly 90% of patients die from advanced stages of the disease and experience pain, jaundice, weight loss, and ascites.

Polyps (growths) are sometimes detected during diagnostic tests for gallbladder disease. Small gallbladder polyps (up to 10 mm) pose little or no risk, but large ones (greater than 15 mm) pose some risk for cancer, so the gallbladder should be removed. Patients with polyps 10 mm to 15 mm have a lower risk but they should still discuss removal of their gallbladder with their physician. Of special note is a condition called primary sclerosing cholangitis, which causes inflammation and scarring in the bile duct. It is associated with a lifetime risk of 7% to 12% for gallbladder cancer. The cause is unknown, although primary sclerosing cholangitis tends to strike younger men who have ulcerative colitis. Polyps are often detected in this condition and have a very high likelihood of malignancy.

Benefits of Gallbladder Surgery

Diverticulosus

Diverticulosis, otherwise known as "diverticular disease", is the condition of having diverticula in the colon which are outpocketings of the colonic mucosa and submucosa through weaknesses of muscle layers in the colon wall. These are more common in the sigmoid colon, which is a common place for increased pressure. This is uncommon before the age of 40 and increases in incidence after that age.

Causes
Diverticula are thought to be caused by increased pressure within the lumen of the colon. Increased intra-colonic pressure secondary to constipation may lead to weaknesses in the colon walls giving way to diverticula. Other causes may include a colonic spasm which increases pressure, which may be due to dehydration or low-fiber diets (merck manual online 2005); although this may also be due to constipation. Fiber causes stools to retain more water and become easier to pass (either soluble or insoluble fiber will do this). A diet without sufficient fiber makes the stools small, requiring the bowel to squeeze harder to remove the smaller stool. Summarizing the risk factors from this and the introduction: low-fiber/high-fat diet, increasing age, constipating conditions, and connective tissue disorders which may cause weakness in the colon wall (ex. Marfan syndrome).

Epidemiology
About 10% of the US population over the age of 40 and half over the age of 60 has diverticulosis. This disease is common in the US, England, Australia, Canada, and is uncommon in Asia and Africa. It is the most common cause for rectal bleeding in US adults over the age of 40 years.

Large mouth diverticula are associated with scleroderma.

Symptoms
Often this disorder has no symptoms. The most common is bleeding (variable amounts), bloating, abdominal pain/cramping after meals or otherwise often in the left lower abdomen, and changes in bowel movements (diarrhea or constipation). Sometimes, symptoms include unspecific chronic discomfort in the lower left abdomen, with occasional acute episodes of sharper pain. The discomfort is sometimes described as a general feeling of pressure in the region, or pulling sensation. A tickling sensation may be felt as the small pockets fill and unfill; a feeling like gas may be moving in areas outside the colon. First-time bleeding from the rectum should be followed up with a physician, especially if over age 40 because of the possibility of colon cancer. Symptoms of anemia may present: fatigue, light-headedness, or shortness of breath.

Testing
Colonoscopy is the most used test for diagnosis. This is important for treatment and investigation of other diseases. Other tests include abdominal X-ray, barium enema, CT, or MRI.

Complications
Infection of a diverticulum can result in diverticulitis. This occurs in 10-25% of persons with diverticulosis (NIDDK website). Tears in the colon leading to bleeding or perforations may occur, intestinal obstruction may occur (constipation or diarrhea does not rule this possibility out), peritonitis, abscess formation, retroperitoneal fibrosis, sepsis, and fistula formation.

Infection of a diverticulum often occurs as a result of stool collecting in a diverticulum.

Treatment
Often no treatment is needed. Increases in hydration, increasing fiber content in the diet (the American Dietetic Association recommends 20-35 grams each day), or removing factors resulting in constipation help decrease the incidence of new diverticula or possibly keep them from bursting or becoming inflamed (ADA website). Fiber supplements may aid if diet is inadequate. If the diverticula are unusually large (greater than 1 inch), often infected (see diverticulitis), or exhibit uncontrollable bleeding, surgery can be performed to decrease relapse or other complications. The NIDDK says foods such as nuts, popcorn hulls, sunflower seeds, pumpkin seeds, caraway seeds, and sesame seeds have traditionally been labeled as problem foods for people with this condition; however, no scientific data exists to prove this hypothesis. The seeds in tomatoes, zucchini, cucumbers, strawberries, raspberries, and poppy seeds, are not considered harmful by the NIDDK. Treatments, like some colon cleansers, that cause hard stools, constipation, and straining, are not recommended.

Diverticulosus

Culposcopy

Colposcopy or colcoscopy is a medical diagnostic procedure to examine an illuminated, magnified view of the cervix and the tissues of the vagina and vulva. Many premalignant lesions and malignant lesions in these areas have discernible characteristics which can be detected thorough the examination. It is done using a colposcope, which provides an enlarged view of the areas, allowing the colposcopist to visually distinguish normal from abnormal appearing tissue and take directed biopsies for further pathological examination. The main goal of calposcopy is to prevent cervical cancer by detecting precancerous lesions early and treating them. The procedure was developed in 1925 by the German physician Hans Hinselmann.

Indications for colposcopy
Most women undergo a colposcopic examination to further investigate a cytological abnormality on their pap smears. Other indications for a woman to have a colposcopy include:

assessment of diethylstilbestrol (DES) exposure in utero,
immunosuppression such as HIV infection, or
an abnormal appearance of the cervix as noted by a physician.
Many physicians base their current evaluation and treatment decisions on the report "Guidelines for the Management of Cytological Abnormalities and Cervical Cancer Precursors", created by the American Society for Colposcopy and Cervical Pathology, during a September 2001 conference. (See ASCCP Consensus Guidelines.)

The procedure

ColposcopeDuring the initial evaluation, a medical history is obtained, including gravidity (number of prior pregnancies), parity (number of prior deliveries), last menstrual period, contraception use, prior abnormal pap smear results, allergies, significant past medical history, other medications, prior cervical procedures, and smoking history. In some cases, a pregnancy test may be performed before the procedure. The procedure is fully described to the patient, questions are asked and answered, and she then signs a consent form.

A colposcope is used to identify visible clues suggestive of abnormal tissue. It functions as a lighted binocular microscope to magnify the view of the cervix, vagina, and vulvar surface. Low power (2× to 6×) may be used to obtain a general impression of the surface architecture. Medium (8× to 15×) and high (15× to 25×) powers are utilized to evaluate the vagina and cervix. The higher powers are often necessary to identify certain vascular patterns that may indicate the presence of more advanced precancerous or cancerous lesions. Various light filters are available to highlight different aspects of the surface of the cervix. Acetic acid solution and iodine solution (Lugol's or Schiller's) are applied to the surface to improve visualization of abnormal areas.

Colposcopy is performed with the woman on her back, legs in stirrups, and buttocks close to the lower edge of the table (a position known as the dorsal lithotomy position). A speculum is placed in the vagina after the vulva is examined for any suspicious lesions.

Three percent acetic acid is applied to the cervix using cotton swabs. The transformation zone is a critical area on the cervix where many precancerous and cancerous lesions most often arise. The ability to see the transformation zone and the entire extent of any lesion visualized determines whether an adequate colposcopic examination is attainable.

Areas of the cervix which turn white after the application of acetic acid or have an abnormal vascular pattern are often considered for biopsy. If no lesions are visible, an iodine solution may be applied to the cervix to help highlight areas of abnormality.

After a complete examination, the colposcopist determines the areas with the highest degree of visible abnormality and obtains biopsies from these areas using a long biopsy instrument. Some doctors consider anesthesia unnecessary, however, many colposcopists now recommend and use a topical anesthetic such as lidocaine or a cervical block to diminish patient discomfort, particularly if many biopsy samples are taken.

Following any biopsies, an endocervical curettage (ECC) is often done. The ECC utilizes a long straight curette to scrape the inside of the cervical canal. The ECC should never be done on a pregnant woman. Monsel's solution is applied with large cotton swabs to the surface of the cervix to control bleeding. This solution looks like mustard and becomes black in color when exposed to blood. After the procedure this material will be expelled naturally: women can expect to have a thin coffee-ground like discharge for up to several days after the procedure.

Complications
Significant complications from a colposcopy are not common, but may include bleeding, infection at the biopsy site or endometrium, and failure to identify the lesion. Monsel's solution and silver nitrate interfere with interpretation of biopsy specimen, so these substances should not be applied until all biopsies have been taken. Most patients experience some degree of pain during the curettage, and almost all experience pain during the biopsy.

Follow up
Adequate follow-up is critical to the success of this procedure. Human Papilloma Virus (HPV) is a common infection and the underlying cause for most cervical dysplasia.

A new vaccination against HPV (Gardasil) was approved June 8, 2006 by the US Food and Drug Administration after being tested for five years on 20,541 girls from age 16 to 26. The vaccine is indicated for prevention of cervical cancer, precancerous and dysplastic lesions and genital warts caused by HPV types 6, 11, 16 and 18. Adequate widespread vaccination may reduce the need for colposcopic examinations in the future.

Smoking predisposes women to developing cervical abnormalities. A smoking cessation program should be part of the treatment plan for women who smoke.

Without proper treatment, minor abnormalities may develop into cancerous lesions. Various treatments exist for significant lesions, most commonly cryotherapy, loop electrical excision procedure (LEEP), and laser ablation.

Future technologies
Colposcopy is the "gold standard" tool in the United States for diagnosing cervical abnormalities after an abnormal pap smear. The procedure requires many resources and can be expensive to perform, making it a less-than-ideal screening tool.

Newer visualization techniques on the horizon utilize broad-band light (e.g., direct visualization, speculoscopy, cervicography, and colposcopy) and electronic detection methods (e.g., Polarprobe and in-vivo Spectroscopy). These techniques are less expensive and can be performed with significantly less training. At this point, these newer techniques have not been validated by large-scale trials and are not in general use.

Culposcopy

Human HIV AIDS Reserch

Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS or Aids) is a collection of symptoms and infections resulting from the specific damage to the immune system caused by the human immunodeficiency virus (HIV) in humans, and similar viruses in other species (SIV, FIV, etc.). The late stage of the condition leaves individuals prone to opportunistic infections and tumors. Although treatments for AIDS and HIV exist to slow the virus' progression, there is no known cure. HIV, et al., are transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk. This transmission can come in the form of anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, or breastfeeding, or other exposure to one of the above bodily fluids.

Most researchers believe that HIV originated in sub-Saharan Africa during the twentieth century; it is now a pandemic, with an estimated 38.6 million people now living with the disease worldwide. As of January 2006, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate that AIDS has killed more than 25 million people since it was first recognized on June 5, 1981, making it one of the most destructive epidemics in recorded history. In 2005 alone, AIDS claimed an estimated 2.4–3.3 million lives, of which more than 570,000 were children. A third of these deaths are occurring in sub-Saharan Africa, retarding economic growth and destroying human capital. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries. HIV/AIDS stigma is more severe than that associated with other life-threatening conditions and extends beyond the disease itself to providers and even volunteers involved with the care of people living with HIV.

Infection by HIV

Scanning electron micrograph of HIV-1 budding from cultured lymphocyte.AIDS is the most severe acceleration of infection with HIV. HIV is a retrovirus that primarily infects vital organs of the human immune system such as CD4+ T cells (a subset of T cells), macrophages and dendritic cells. It directly and indirectly destroys CD4+ T cells. CD4+ T cells are required for the proper functioning of the immune system. When HIV kills CD4+ T cells so that there are fewer than 200 CD4+ T cells per microliter (µL) of blood, cellular immunity is lost, leading to the condition known as AIDS. Acute HIV infection progresses over time to clinical latent HIV infection and then to early symptomatic HIV infection and later to AIDS, which is identified on the basis of the amount of CD4+ T cells in the blood and the presence of certain infections.

In the absence of antiretroviral therapy, the median time of progression from HIV infection to AIDS is nine to ten years, and the median survival time after developing AIDS is only 9.2 months. However, the rate of clinical disease progression varies widely between individuals, from two weeks up to 20 years. Many factors affect the rate of progression. These include factors that influence the body's ability to defend against HIV such as the infected person's general immune function. Older people have weaker immune systems, and therefore have a greater risk of rapid disease progression than younger people. Poor access to health care and the existence of coexisting infections such as tuberculosis also may predispose people to faster disease progression. The infected person's genetic inheritance plays an important role and some people are resistant to certain strains of HIV. An example of this is people with the CCR5-Δ32 mutation are resistant to infection with certain strains of HIV. HIV is genetically variable and exists as different strains, which cause different rates of clinical disease progression. The use of highly active antiretroviral therapy prolongs both the median time of progression to AIDS and the median survival time.

Diagnosis
Since June 5, 1981, many definitions have been developed for epidemiological surveillance such as the Bangui definition and the 1994 expanded World Health Organization AIDS case definition. However, clinical staging of patients was not an intended use for these systems as they are neither sensitive, nor specific. In developing countries, the World Health Organization staging system for HIV infection and disease, using clinical and laboratory data, is used and in developed countries, the Centers for Disease Control (CDC) Classification System is used.

WHO disease staging system for HIV infection and disease
Main article: WHO Disease Staging System for HIV Infection and Disease
In 1990, the World Health Organization (WHO) grouped these infections and conditions together by introducing a staging system for patients infected with HIV-1. An update took place in September 2005. Most of these conditions are opportunistic infections that are easily treatable in healthy people.

Stage I: HIV infection is asymptomatic and not categorized as AIDS
Stage II: includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections
Stage III: includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis
Stage IV: includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma; these diseases are indicators of AIDS.

CDC classification system for HIV infection
Main article: CDC Classification System for HIV Infection
In the beginning, the Centers for Disease Control and Prevention (CDC) did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus. They also used Kaposi's Sarcoma and Opportunistic Infections, the name by which a task force had been set up in 1981. In the general press, the term GRID, which stood for Gay-Related Immune Deficiency, had been coined. However, after determining that AIDS was not isolated to the homosexual community, the term GRID became redundant and AIDS was introduced at a meeting in July 1982. By September 1982 the CDC started using the name AIDS, and properly defined the illness. In 1993, the CDC expanded their definition of AIDS to include all HIV positive people with a CD4+ T cell count below 200 per µL of blood or 14% of all lymphocytes. The majority of new AIDS cases in developed countries use either this definition or the pre-1993 CDC definition. The AIDS diagnosis still stands even if, after treatment, the CD4+ T cell count rises to above 200 per µL of blood or other AIDS-defining illnesses are cured.

HIV test
Main article: HIV test
Many people are unaware that they are infected with HIV. Less than 1% of the sexually active urban population in Africa has been tested, and this proportion is even lower in rural populations. Furthermore, only 0.5% of pregnant women attending urban health facilities are counseled, tested or receive their test results. Again, this proportion is even lower in rural health facilities. Therefore, donor blood and blood products used in medicine and medical research are screened for HIV. Typical HIV tests, including the HIV enzyme immunoassay and the Western blot assay, detect HIV antibodies in serum, plasma, oral fluid, dried blood spot or urine of patients. However, the window period (the time between initial infection and the development of detectable antibodies against the infection) can vary. This is why it can take 3–6 months to seroconvert and test positive. Commercially available tests to detect other HIV antigens, HIV-RNA, and HIV-DNA in order to detect HIV infection prior to the development of detectable antibodies are available. For the diagnosis of HIV infection these assays are not specifically approved, but are nonetheless routinely used in developed countries.

Symptoms and complications

A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably. CD4+ T Lymphocyte count (cells/mm³)
HIV RNA copies per mL of plasma
The symptoms of AIDS are primarily the result of conditions that do not normally develop in individuals with healthy immune systems. Most of these conditions are infections caused by bacteria, viruses, fungi and parasites that are normally controlled by the elements of the immune system that HIV damages. Opportunistic infections are common in people with AIDS. HIV affects nearly every organ system. People with AIDS also have an increased risk of developing various cancers such as Kaposi's sarcoma, cervical cancer and cancers of the immune system known as lymphomas.

Additionally, people with AIDS often have systemic symptoms of infection like fevers, sweats (particularly at night), swollen glands, chills, weakness, and weight loss. After the diagnosis of AIDS is made, the current average survival time with antiretroviral therapy (as of 2005) is estimated to be more than 5 years, but because new treatments continue to be developed and because HIV continues to evolve resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year. Most patients die from opportunistic infections or malignancies associated with the progressive failure of the immune system.

The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility and immune function health care and co-infections, as well as factors relating to the viral strain. The specific opportunistic infections that AIDS patients develop depend in part on the prevalence of these infections in the geographic area in which the patient lives.

Major pulmonary illnesses

X-ray of Pneumocystis jirovecii caused pneumonia. There is increased white (opacity) in the lower lungs on both sides, characteristic of Pneumocystis pneumoniaPneumocystis pneumonia (originally known as Pneumocystis carinii pneumonia, and still abbreviated as PCP, which now stands for Pneumocystis pneumonia) is relatively rare in healthy, immunocompetent people, but common among HIV-infected individuals. It is caused by Pneumocystis jirovecii. Before the advent of effective diagnosis, treatment and routine prophylaxis in Western countries, it was a common immediate cause of death. In developing countries, it is still one of the first indications of AIDS in untested individuals, although it does not generally occur unless the CD4 count is less than 200 per µL.

Tuberculosis (TB) is unique among infections associated with HIV because it is transmissible to immunocompetent people via the respiratory route, is easily treatable once identified, may occur in early-stage HIV disease, and is preventable with drug therapy. However, multidrug resistance is a potentially serious problem. Even though its incidence has declined because of the use of directly observed therapy and other improved practices in Western countries, this is not the case in developing countries where HIV is most prevalent. In early-stage HIV infection (CD4 count >300 cells per µL), TB typically presents as a pulmonary disease. In advanced HIV infection, TB often presents atypically with extrapulmonary (systemic) disease a common feature. Symptoms are usually constitutional and are not localized to one particular site, often affecting bone marrow, bone, urinary and gastrointestinal tracts, liver, regional lymph nodes, and the central nervous system. Alternatively, symptoms may relate more to the site of extrapulmonary involvement.

Major gastro-intestinal illnesses
Esophagitis is an inflammation of the lining of the lower end of the esophagus (gullet or swallowing tube leading to the stomach). In HIV infected individuals, this is normally due to fungal (candidiasis) or viral (herpes simplex-1 or cytomegalovirus) infections. In rare cases, it could be due to mycobacteria.
Unexplained chronic diarrhea in HIV infection is due to many possible causes, including common bacterial (Salmonella, Shigella, Listeria, Campylobacter, or Escherichia coli) and parasitic infections; and uncommon opportunistic infections such as cryptosporidiosis, microsporidiosis, Mycobacterium avium complex (MAC) and cytomegalovirus (CMV) colitis. In some cases, diarrhea may be a side effect of several drugs used to treat HIV, or it may simply accompany HIV infection, particularly during primary HIV infection. It may also be a side effect of antibiotics used to treat bacterial causes of diarrhea (common for Clostridium difficile). In the later stages of HIV infection, diarrhea is thought to be a reflection of changes in the way the intestinal tract absorbs nutrients, and may be an important component of HIV-related wasting.

Major neurological illnesses
Toxoplasmosis is a disease caused by the single-celled parasite called Toxoplasma gondii; it usually infects the brain causing toxoplasma encephalitis but it can infect and cause disease in the eyes and lungs.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease, in which the gradual destruction of the myelin sheath covering the axons of nerve cells impairs the transmission of nerve impulses. It is caused by a virus called JC virus which occurs in 70% of the population in latent form, causing disease only when the immune system has been severely weakened, as is the case for AIDS patients. It progresses rapidly, usually causing death within months of diagnosis.
AIDS dementia complex (ADC) is a metabolic encephalopathy induced by HIV infection and fueled by immune activation of HIV infected brain macrophages and microglia which secrete neurotoxins of both host and viral origin. Specific neurological impairments are manifested by cognitive, behavioral, and motor abnormalities that occur after years of HIV infection and is associated with low CD4+ T cell levels and high plasma viral loads. Prevalence is 10–20% in Western countries but only 1–2% of HIV infections in India. This difference is possibly due to the HIV subtype in India.
Cryptococcal meningitis is an infection of the meninx (the membrane covering the brain and spinal cord) by the fungus Cryptococcus neoformans. It can cause fevers, headache, fatigue, nausea, and vomiting. Patients may also develop seizures and confusion; left untreated, it can be lethal.

Major HIV-associated malignancies

Kaposi's sarcomaPatients with HIV infection have substantially increased incidence of several malignant cancers. This is primarily due to co-infection with an oncogenic DNA virus, especially Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human papillomavirus (HPV). The following confer a diagnosis of AIDS when they occur in an HIV-infected person.

Kaposi's sarcoma (KS) is the most common tumor in HIV-infected patients. The appearance of this tumor in young homosexual men in 1981 was one of the first signals of the AIDS epidemic. Caused by a gammaherpes virus called Kaposi's sarcoma-associated herpes virus (KSHV), it often appears as purplish nodules on the skin, but can affect other organs, especially the mouth, gastrointestinal tract, and lungs.
High-grade B cell lymphomas such as Burkitt's lymphoma, Burkitt's-like lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary central nervous system lymphoma present more often in HIV-infected patients. These particular cancers often foreshadow a poor prognosis. In some cases these lymphomas are AIDS-defining. Epstein-Barr virus (EBV) or KSHV cause many of these lymphomas.
Cervical cancer in HIV-infected women is considered AIDS-defining. It is caused by human papillomavirus (HPV).
In addition to the AIDS-defining tumors listed above, HIV-infected patients are at increased risk of certain other tumors, such as Hodgkin's disease and anal and rectal carcinomas. However, the incidence of many common tumors, such as breast cancer or colon cancer, does not increase in HIV-infected patients. In areas where HAART is extensively used to treat AIDS, the incidence of many AIDS-related malignancies has decreased, but at the same time malignant cancers overall have become the most common cause of death of HIV-infected patients.

Other opportunistic infections
AIDS patients often develop opportunistic infections that present with non-specific symptoms, especially low-grade fevers and weight loss. These include infection with Mycobacterium avium-intracellulare and cytomegalovirus (CMV). CMV can cause colitis, as described above, and CMV retinitis can cause blindness. Penicilliosis due to Penicillium marneffei is now the third most common opportunistic infection (after extrapulmonary tuberculosis and cryptococcosis) in HIV-positive individuals within the endemic area of Southeast Asia.

Human HIV AIDS Reserch

Cures For Mad Cow

Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is a fatal, neurodegenerative disease of cattle, which infects by a mechanism that surprised biologists upon its discovery in the late 20th century. In the UK, the country worst affected, 179,000 cattle were infected and 4.4 million killed as a precaution.

The disease can be transmitted to human beings who eat or inhale material from infected carcasses. In humans, it is known as new variant Creutzfeldt-Jakob disease (vCJD or nvCJD), and by June 2007, it had killed 165 people in Britain, and six elsewhere with the number expected to rise because of the disease's long incubation period. Between 460,000 and 482,000 BSE-infected animals had entered the human food chain before controls on high-risk offal were introduced in 1989.

A British inquiry into BSE concluded that the epidemic was caused by feeding cattle, who are normally herbivores, the remains of other cattle in the form of meat and bone meal (MBM), which caused the infectious agent to spread. The origin of the disease itself remains unknown. The current scientific view is that infectious proteins called prions developed through spontaneous mutation, probably in the 1970s, and there is a possibility that the use of organophosphorus pesticides increased the susceptibility of cattle to the disease. The infectious agent is distinctive for the high temperatures it is able to survive; this contributed to the spread of the disease in Britain, which had reduced the temperatures used during its rendering process.[4] Another contributory factor was the feeding of infected protein supplements to very young calves.

Infectious agent

Microscopic "holes" of tissue sections are examined in the lab. Source: APHISThe infectious agent in BSE is believed to be a specific type of misfolded protein called prion. Misfolded prion proteins carry the disease between individuals and cause deterioration of the brain. BSE is a type of transmissible spongiform encephalopathy (TSE). TSEs can arise in animals that carry an allele which causes normal prions to contort by themselves from an alpha helical arrangement to a beta pleated sheet, which is the disease-causing shape. Transmission can occur when healthy animals come in contact with tainted tissues from others with the disease. In the brain these proteins cause native cellular prion protein to deform into the infectious state, which then goes on to deform further prion protein in an exponential cascade. This results in protein aggregates, which then form dense plaque fibers, leading to the microscopic appearance of "holes" in the brain, degeneration of physical and mental abilities, and ultimately death.

Different theories exist for the origin of prion proteins in cattle. Two leading theories suggest that it may have jumped species from the disease scrapie in sheep, or that it evolved from a spontaneous form of "mad cow disease" which has been seen occasionally in cattle for many centuries. Publius Flavius Vegetius Renatus records cases of a disease with similar characteristics in the 4th and 5th Century AD. The British Government enquiry took the view the cause was not scrapie as had originally been postulated, and was some event in the 1970s which was not possible to identify.

The BSE epidemic in British cattle
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Cattle, like most other food animals, are normally herbivores. In nature, cattle eat grass or grains. In modern industrial cattle-farming, various commercial feeds are used, which may contain ingredients including antibiotics, hormones, pesticides, fertilizers, and protein supplements. The use of meat and bone meal, produced from the ground and cooked left-overs of the slaughtering process as well as from the cadavers of sick and injured animals such as cattle, sheep, or chickens, as a protein supplement in cattle feed was widespread in Europe prior to about 1987. Worldwide, soya bean meal is the primary plant-based protein supplement fed to cattle. However, soya beans do not grow well in Europe, so cattle raisers throughout Europe turned to the less expensive animal by-product feeds as an alternative. A change to the rendering process in the early 1980s may have resulted in a large increase of the infectious agents in the cattle feed. A contributing factor was suggested to have been a change in British laws that allowed a lower temperature sterilization of the protein meal. While other European countries like Germany required said animal byproducts to undergo a high temperature steam boiling process, this requirement had been eased in Britain as a measure to keep prices competitive. Later the British Inquiry dismissed this theory saying "changes in process could not have been solely responsible for the emergence of BSE, and changes in regulation were not a factor at all."

Following an epizootic of BSE in Britain, 165 people (up until 2007) acquired and died of a disease with similar neurological symptoms subsequently called vCJD, or (new) variant Creutzfeldt-Jakob disease. This is a separate disease from 'classical' Creutzfeldt-Jakob disease, which is not related to BSE and has been known about since the early 1900s. Three cases of vCJD occurred in people who had lived in or visited Britain — one each in Ireland, Canada and the United States. There is also some concern about those who work with (and therefore inhale) cattle meat and bone meal, such as horticulturists, who use it as fertilizer. Up to date statistics on all types of CJD are published by the UK CJD Surveillance Centre in Edinburgh.

For many of the vCJD patients, direct evidence exists that they had consumed tainted beef, and this is assumed to be the mechanism by which all affected individuals contracted it. Disease incidence also appears to correlate with slaughtering practices that led to the mixture of nervous system tissue with hamburger and other beef. It is estimated that 400,000 cattle infected with BSE entered the human food chain in the 1980s. Although the BSE epizootic was eventually brought under control by culling all suspect cattle populations, people are still being diagnosed with vCJD each year (though the number of new cases currently has dropped to less than 5 per year). This is attributed to the long incubation period for prion diseases, which are typically measured in years or decades. As a result the full extent of the human vCJD outbreak is still not fully known.

The scientific consensus is that infectious BSE prion material is not destroyed through normal cooking procedures, meaning that contaminated beef foodstuffs prepared "well done" may remain infectious.

In 2004 researchers reported evidence of a second contorted shape of prions in a rare minority of diseased cattle. In other words, this implies a second strain of BSE prion. Very little is known about the shape of disease-causing prions, because their insolubility and tendency to clump thwarts application of the detailed measurement techniques of structural biology. But cruder measures yield a "biochemical signature" by which the newly discovered cattle strain appears different from the familiar one, but similar to the clumped prions in humans with traditional CJD Creutzfeldt-Jakob Disease .The finding of a second strain of BSE prion raises the possibility that transmission of BSE to humans has been underestimated, because some of the individuals diagnosed with spontaneous or "sporadic" CJD may have actually contracted the disease from tainted beef. So far nothing is known about the relative transmissibility of the two disease strains of BSE prion.

In 2005 a controversial paper in The Lancet introduced a theory that BSE might have originated in British cattle when they ate imported animal feed that included infected human remains from Hindu funeral ceremonies in India. This paper is merely a conjecture, however, and the authors suggest only that further investigation should occur.

UK epizootic and UK licensed medicines
During the course of the investigation into the BSE epizootic, an enquiry was also made into the activities of the Department of Health and its Medicines Control Agency. On May 7, 1999, in his written statement number 476 to the BSE Inquiry, David Osborne Hagger reported on behalf of the Medicines Control Agency that in a previous enquiry the Agency had been asked to:

"... identify relevant manufacturers and obtain information about the bovine material contained in children’s vaccines, the stocks of these vaccines and how long it would take to switch to other products." It was further reported that the: "... use of bovine insulin in a small group of mainly elderly patients was noted and it was recognised that alternative products for this group were not considered satisfactory." A medicines licensing committee report that same year recommended that: "... no licensing action is required at present in regard to products produced from bovine material or using prepared bovine brain in nutrient media and sourced from outside the United Kingdom, the Channel Isles and the Republic of Ireland provided that the country of origin is known to be free of BSE, has competent veterinary advisers and is known to practise good animal husbandry." In 1990 the British Diabetic Association became concerned regarding the safety of bovine insulin and the government licensing agency assured them that: "... there was no insulin sourced from cattle in the UK or Ireland and that the situation in other countries was being monitored." In 1991 a European Community Commission: "... expressed concerns about the possible transmission of the BSE/scrapie agent to man through use of certain cosmetic treatments." Sources in France reported to the British Medicines Control Agency: "... that there were some licensed surgical sutures derived from French bovine material." Concerns were also raised: "... regarding a possible risk of transmission of the BSE agent in gelatin products."

Husbandry practices in the United States relating to BSE
Soybean meal is cheap and plentiful in the United States. As a result, the use of animal byproduct feeds was never common, as it was in Europe. However, U.S. regulations only partially prohibit the use of animal byproducts in feed. In 1997, regulations prohibited the feeding of mammalian byproducts to ruminants such as cows and goats. However, the byproducts of ruminants can still be legally fed to pets or other livestock such as pigs and poultry such as chickens. In addition, it is legal for ruminants to be fed byproducts from some of these animals. A proposal to end the use of cow blood, restaurant scraps, and poultry litter (fecal matter, feathers) in January 2004 has yet to be implemented, despite the efforts of some advocates of such a policy, who cite the fact that cows are herbivores, and that blood and fecal matter could potentially carry BSE.

In February 2001, the USGAO reported that the FDA, which is responsible for regulating feed, had not adequately policed the various bans. Compliance with the regulations was shown to be extremely poor before the discovery of the Washington cow, but industry representatives report that compliance is now 100%. Even so, critics call the partial prohibitions insufficient. Indeed, US meat producer Creekstone Farms alleges that the USDA is preventing BSE testing from being conducted.

Japan was the top importer of U.S. beef, buying 240,000 tons valued at $1.4 billion in 2003. After the discovery of the first case of BSE in the U.S. on December 23, 2003, Japan stopped U.S. beef imports in December 2003. In December 2005, Japan once again allowed imports of U.S. beef, but reinstated its ban in mid-January 2006 after a technical violation of the U.S.-Japan beef import agreement: a vertebral column, which should have been removed prior to shipment, was included in a shipment of veal.

Tokyo yielded to U.S. pressure to resume imports, ignoring consumer worries about the safety of U.S. beef, said Japanese consumer groups. Michiko Kamiyama from Food Safety Citizen Watch said about this: "The government has put priority on the political schedule between the two countries, not on food safety or human health."

Possibly due to pressure from large agribusiness, the United States has drastically cut back on the number of cows inspected for BSE.

Sixty-five nations have full or partial restrictions on importing U.S. beef products because of concerns that U.S. testing lacks sufficient rigor. As a result, exports of U.S. beef declined from $3.8 billion in 2003, before the first mad cow was detected in the US, to $1.4 billion in 2005.

On December 31, 2006, Hematech, a biotechnology company based in Sioux Falls, South Dakota, announced that it had used genetic engineering and cloning technology to produce cattle that lacked a necessary gene for prion production - thus theoretically making them immune to BSE.

Cures For Mad Cow