Buergers disease: Smokers beware Buerger's disease, also known as thromboangiitis obliterans, is a rare disease of the small arteries

and veins in the arms and legs. The disease is characterized by narrowing/blockage of the blood vessels, mainly in the hands and feet, leading to blockage of the blood vessel. This eventually leads to gangrene of the fingers or toes. Buerger's disease is rare in the United States, but is very common in the Middle East and Far East. Buerger's disease most commonly affects men between ages 20 and 40, though it's becoming more common in women. With the recent wave of immigrants, the disorder is now becoming more prominent in North America. The majority of individuals diagnosed with buergers disease smoke cigarettes or use chewing tobacco. Quitting all forms of tobacco is the only way to stop Buerger's disease. For those who don't quit, amputation of all or part of a limb may ultimately be necessary. The first reported case of thromboangiitis obliterans was described in Germany in 1879. A little more than a quarter of a century later, in Brooklyn, NY, Leo Buerger published a detailed description of the disease in which he referred to the clinical presentation of thromboangiitis obliterans as "presenile spontaneous gangrene." The paper discussed the pathological findings in 11 limbs amputated from Jewish patients with the disease. It was then discovered that the disorder was intimately associated with smoking and affected the small blood vessels in the hands and the feet. The disorder typically involves the distal vessels with proximal progression and is most often seen in middle aged men between the ages of 20-40, who have a history of smoking. Even though usually seen in men, cases have been reported in women. While more common in Middle and Far Eastern races, the disease is seen universally in all races. While the exact cause of this disorder remains unknown, all patients with TAO are smokers. It is believed that TAO is an autoimmune disorder (your own immune system starts to attack your body), most likely triggered by the use of tobacco. Pathophysiology Buergers disease generally affects the small and medium sized vessels in the body. It may involve the blood vessels in the arms, hands legs and feet. In addition the blood vessels to the kidney, bowels and event the brain may be involved. When the blood vessels are affected, the vessel becomes narrower and eventually closes offresulting in no blood supply. There are numerous reports that the small blood vessels supplying the penis are also blocked and the majority of these individuals also complain of impotence (erectile failure). While the etiology of Buerger disease is unknown, exposure to tobacco is essential for both initiation and progression of the disease. The idea that the condition is linked to tobacco exposure is supported by the fact that the disease is more common in countries with heavy use of tobacco. In the Middle East, Asia and the Pacific where tobacco use is endemic, the condition is extremely common. While the majority of the cases are seen in smokers, a few cases have also been reported in non smokers and this has been attributed to either the use of chewing tobacco or second hand smoke. Pathophysiology Buerger's disease is a vasculitis affecting crural and brachial arteries. Advanced disease may include subclavian and axillary artery involvement. It has been known to affect cerebral, coronary, renal, gonadal, and mesenteric vessels to a much lesser degree. In the acute pathological phase, active inflammation of all 3 vessel layers is seen. In the chronic pathological phase, the thrombus is organised with revascularisation of the medial and adventitial layers. A hypercellular thrombus rich in lymphocytes, fibroblasts, and giant cells fills the vessel lumen. The internal elastic lamina remains intact, with no vessel wall necrosis, calcification, or atheromatous plaques. The vasculitis may be triggered by a hypersensitivity to tobacco constituents. Impaired endothelium-dependent vasodilation has been identified in patients with thromboangiitis obliterans, which may encourage thrombus formation. [14] A cell-mediated immune response to artery collagen components has been suggested. The histocompatibility leukocyte antigen (HLA)-DRA was more frequently found and HLA-DRW6 less frequently found in patients with Buerger's disease compared with smokers without Buerger's disease and non-smokers. [15] Plasma levels of kallikreins and kininase II (componenets of the kinin system of blood proteins) are higher in patients with Buerger's disease who are active smokers compared with non-Buerger's disease patients, whether or not they smoke. These protein levels were significantly greater in patients with Buerger's disease who were active smokers than in those who were ex-smokers. This may indicate that vasodilatation occurs in response to the vascular changes taking place, supporting a theory of immune complex deposition due to nicotine stimulation.[16] PATHOPHYSIOLOGY OF MULTIPLE SCLEROSIS Multiple Sclerosis is classified amongst the autoimmune conditions, which are diseases deriving from a malfunction of the immune system that attacks substances and tissues normally present in the body as it wrongly

recognises them as foreign agents to the body system. In the case of Multiple Sclerosis the immune system attacks the nervous system. MS Lesions The name Multiple Sclerosis refers to lesions (also called plaques or scars) that generate in the nervous system. The majority of MS lesions are located in the white area near the cerebellum, the spinal cord, the brain stem and the optical nerve. When MS lesions are present neurons cannot transmit impulses efficiently. In fact the disease destroys the layer (myelin) which covers the nervous systems fibres and facilitates the neurons transmitting signals to the body. This results in the diminishing or complete disappearance of myelin. A partial restorative process - called remyelination occurs at the early stages of the disease. However, as the cells myelin cover cannot completely be rebuilt; repeated attacks lead to fewer successful remyelinations and thus to the formation of lesions in the irreversibly damaged areas. Inflammation Multiple Sclerosis also generates an inflammatory process. This inflammation is caused by the T-cells which are cells that play a crucial role in the bodys defences. In MS T-cells manage to infiltrate into the brain via the blood-brain barrier, which is both a physical barrier and system of cellular transport. This barrier is not normally accessible to T-cells, unless it is affected by a virus, which reduces the strength of the junctions forming the barrier. T-cells remain then locked inside the brain, wrongly perceiving myelin as an alien agent and attack it as if it were a virus. This generates inflammatory processes and further damaging effects such as swelling and activation of other immune cells and antibodies. PATHOPHYSIOLOGY OF MS Blood-brain barrier breakdown The bloodbrain barrier is a capillary system that should prevent entrance of T cells into the nervous system.[4] The bloodbrain barrier is normally not permeable to these types of cells, unless triggered by infection or a virus, which decreases the integrity of the tight junctionsforming the barrier.[4] When the bloodbrain barrier regains its integrity, usually after infection or virus has cleared, the T cells are trapped inside the brain.[4] Autoimmunology MS is currently believed to be an immune-mediated disorder mediated by a complex interaction of the individual's genetics and as yet unidentified environmental insults.[4]Damage is believed to be caused by the patient's own immune system. The immune system attacks the nervous system, possibly as a result of exposure to a molecule with a similar structure to one of its own.[4] Lesions The name multiple sclerosis refers to the scars (scleroses better known as plaques or lesions) that form in the nervous system. MS lesions most commonly involve white matter areas close to the ventricles of the cerebellum, brain stem, basal ganglia and spinal cord; and the optic nerve. The function of white matter cells is to carry signals between grey matter areas, where the processing is done, and the rest of the body. The peripheral nervous system is rarely involved.[4] More specifically, MS destroys oligodendrocytes, the cells responsible for creating and maintaining a fatty layer known as the myelinsheathwhich helps the neurons carry electrical signals.[4] MS results in a thinning or complete loss of myelin and, as the disease advances, the cutting (transection) of the neuron's extensions or axons. When the myelin is lost, a neuron can no longer effectively conduct electrical signals.[4] A repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes cannot completely rebuild the cell's myelin sheath.[29] Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons.[29] Different lesion patterns have been described.[30] Inflammation Apart from demyelination, the other pathologic hallmark of the disease is inflammation. According to a strictly immunological explanation of MS, the inflammatory process is caused by T cells, a kind of lymphocyte. Lymphocytes are cells that play an important role in the body's defenses. [4] In MS, T cells gain entry into the brain via the previously described bloodbrain barrier. Evidence from animal models also point to a role of B cells in addition to T cells in development of the disease.[31]

The T cells recognize myelin as foreign and attack it as if it were an invading virus. This triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. Leaks form in the bloodbrain barrier, which in turn cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins.[4] Pathophysiology Myelin comprises lipids and protein, serving to insulate and aid in nerve fiber conduction. In multiple sclerosis (MS), plaques (scleroses) form on the myelin coating of nerve fibers in the central nervous system (CNS). When myelin is damaged by plaque formation, nerve fiber conduction is reduced or absent. This phenomenon, demyelination, causes a disruption in the nerve signals sent from the brain. Some nerve fibers, or axons, never recover from the effects of demyelination and become impaired, leading to permanent axonal damage. This demyelination and axonal damage can affect multiple systems and result in symptomatic problems. Huntington's Disease Pathophysiology HD is associated with progressive degeneration of neurons in certain regions of the brain and the presence of astrocytes that accumulate due to destruction of nearby neurons (gliosis). These neurodegenerative changes primarily occur within the caudate nuclei and the putamen, substructures of the basal ganglia that are collectively known as the striatum. (The basal ganglia consist of specialized nerve cell clusters deep within the brain that organize motor behavior. Major substructures of the basal ganglia include the caudate nuclei, the putamen, and the globus pallidus as well as other cell groups.) HD is also characterized by associated neuronal degeneration within the temporal and frontal lobes of the cerebral cortex. This part of the brain is responsible for integrating higher mental functioning, movements, and sensations. The degenerative changes in HD primarily affect certain nerve cells of the striatum known as medium-sized "spiny" neurons, which are named for their size and appearance and project into the globus pallidus and substantia nigra. These highly specialized "spiny" neurons secrete gamma-aminobutyric acid (GABA), a neurotransmitter that inhibits the release of neurotransmitters from other nerve cells. One theory suggests that selective loss of these specialized cells results in decreased inhibition (i.e., increased activity) of the thalamus. Therefore the thalamus increases its output to certain regions of the brain's cerebral cortex. This may lead to the disorganized, excessive (hyperkinetic) movement patterns of chorea. Some studies demonstrate reduced uptake of the neurotransmitter dopamine within the striatum, potentially playing a role in causing the choreic movements associated with HD. Several investigations indicate that impaired energy metabolism (mitochondrial dysfunction) may result in excessive or prolonged activation (excitotoxicity) by neurotransmitters, such as glutamate or Nmethyl-D-aspartate (NMDA). This may cause damage to and loss of nerve cells (apoptosis). (For more on apoptosis, see "Mutant huntingtin protein and intracellular abnormalities.") Evidence suggests that the formation of toxic compounds known as oxygen-free radicals may contribute to striatal cell injury. An imbalance between free radical production and elimination results in an increasing accumulation of these toxins in certain tissues. Eventually, this causes damage and impaired functioning of affected cells. Many researchers theorize that free radicals may play some role in the loss of neurons associated with many neurodegenerative diseases. In patients with HD, positron emission tomography (PET) scanning has shown decreased glucose and oxygen metabolism within the caudate nuclei early in the course of the disease. These findings occur in patients with other neurodegenerative diseases associated with chorea. This lends support to the theory that disturbances in the metabolism of certain neurotransmitters and heightened sensitivity of particular neuroreceptors may contribute to the symptoms associated with HD. Pathophysiology The expanded CAG repeat generates an elongated polyglutamine tail on the huntingtin protein, which leads to cleavage and the generation of toxic fragments of this abnormal protein. [10]The polyglutamine composition of the toxic fragments predisposes them to cross-link, forming aggregates that resist degradation and interfere with a variety of normal cellular functions, particularly mitochondrial energy metabolism. [11] [12] However, these aggregates also interfere with the regulation of transcription, axonal and vesicular transport, apoptosis, proteasome function, and cell-cell interactions. [1] Haploinsufficiency, the reduction in levels of wild-type huntingtin, does not cause disease. [1] However, it may contribute to the adverse effects of aggregates. Therapeutic interventions designed to improve mitochondrial function, block huntingtin cleavage at sites that generate toxic fragments, prevent expression of mutant huntingtin, improve cell-cell interactions, enhance autophagic consumption of mutant proteins, and retard apoptosis are under active investigation. [13] [14] [15]

Huntington's disease primarily affects the striatum, and most clinical features are directly attributable to damage in this area, including cognitive impairment, behavioural changes, and loss of coordination. [4] [16] However, pathological changes occur in multiple cortical and sub-cortical structures as well. [17] Chorea, the most striking feature of Huntington's disease, results from striatal dysfunction.