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In a motor behavior such as reaching for a glass of water birth control pills mononessa buy mircette 15mcg otc, neurons in premotor areas birth control 999 order generic mircette on-line, as well as corticospinal tract neurons in primary motor cortex, are thought to be excited by the actions of the direct path. The indirect path has the opposite effect on the thalamus and cerebral cortex as the direct path. Because the output ofthe external segment ofthe globus pallidus is inhibitory, indirect path neurons of the putamen disinhibit the subthalamic nucleus, resulting in a burst of action potentials. This period of disinhibition will, in turn, excite the internal segment of the globus pallidus and substantia nigra pars reticulata (which are both inhibitory) and thereby increase the strength of the inhibitory output signal directed to the thalamus. Increased striatal dopamine enhances the excitatory effects of the direct path on cortical motor areas and diminishes the inhibitory effects of the indirect path. Because of these different actions on striatal neurons, the combined effect of dopamine on both paths is to reduce the inhibitory output of the basal ganglia, thereby reducing inhibition of the thalamus. The power of this model is that it helps to explain the mechanisms of some hypokinetic and hyperkinetic signs seen in basal ganglia disease. Together these effects would drastically reduce the thalamic signals to the cortex. For the premotor and motor cortical areas, this would reduce cortical outflow along the corticospinal and corticobulbar tracts and reduce production of motor behaviors ie, hypokinesia). This reduces basal ganglia inhibitory outflow and triggers greater thalamic outflow to the cortex. This nucleus normally exerts an excitatory action on the internal segment of the globus pallidus. When the subthalamic nucleus becomes lesioned, the internal segment of the globus pallidus would be expected to inhibit the thalamus less (thin dashed line), thereby increasing outflow to the cerebral cortex. The model does not predict the pattern of the complex hyperkinetic responses; like why there are flailing ballistic movements with hemiballism or chorea in Huntington disease. In addition, patients exhibit a resting tremor, and when an examiner moves their limbs, a characteristic stiffness or rigidity can be noted. This name derives from the presence ofthe black pigment neoromelanin, a polymer of the catecholamine precursor dihydroxy-phenylalanine (or dopa), which is contained in the neurons of the pars compacta. Not surprisingly, neuromelanin is not present in the substantia nigra pars compacta of people who die from the effects of Parkinson disease. Dopaminergic neurons in other parts of the central nervous system are also destroyed in Parkinson disease. Dopamine loss in the basal ganglia, however, apparently produces the most debilitating neurological sjgns. Riied neuronal cell bodies and terminals Indicate Inhibitory actions, and open cell bodies Indicate excitatory actions. Neural activity for each circuit can be followed, beginning with a phasic excitatory input from the cortex and the rei;ulting phasic chilnge in the thalamus. The thickness of the llnes lndlartes relatlve changes In the number of neurons and strength of connections brought about as a consequence of disease. Thicker means stronger connections and mere activity; thinner means fewer and weaker connections. These paths follow only tonic dlanges in neural actiViltion, because phasic changes are not well dlaracterized. The diffuse tan areas highlight the anatomical components located within the basal ganglia. They discovered that a certain kind of synthetic heroin produces a permanent clinical syndrome in humans that is remarkably similar to Parkinson disease. Involuntary distal limb movements, such as writhing of the hand, or athetolia, may also occur. This mutation, which is present in all cells of the body but apparently affecting primarily medium spiny neuron function, making them particularly vulnerable to cell death. This mutation also leads to the dysfunction and death of neurons in other brain regions, including the cortex.

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Low B12 concentrations in patients without anemia: the effect of folic acid fortification of grain birth control pill 5 minutes late cheap mircette 15mcg with amex. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption birth control pills good for skin order genuine mircette online. Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis. Vitamin B supplementation, homocysteine levels and the risk of cerebrovascular disease. Reconciling the evidence on serum homocysteine and ischaemic heart disease: a meta-analysis. Effects of folic acid supplementation on overall and site - specific cancer incidence during randomized trials: meta-analysis of data on 50,000 individuals. Elevated homocysteine level and folate deficiency associated with an increased overall risk of carcinogenesis: meta-analysis of 83 case control studies involving 35,758 individuals. Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus-associated birth defects. Maternal vitamin B 12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. Further studies of erythrocyte thiamin transport and phosphorylation in seven patients with thiamin-responsive megaloblastic anaemia. Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts. Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the Framingham heart study. Serum homocysteine and dementia: metaanalysis of eight cohort studies involving 8669 participants. They cause significant morbidity and mortality in those individuals who are severely affected and place a major burden on health services in some places, in particular the Mediterranean region, sub-Saharan Africa, and South-East Asia, when economic conditions improve and infant and childhood death rates fall. Migrations of populations from high-incidence areas for the haemoglobin disorders, together with the general ease of international travel, means that patients with these conditions are now seen in all regions of the world. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China. The most important disorders are the genetic conditions thalassaemia and sickle cell disease. Thalassaemias A heterogeneous group of genetic disorders, all resulting from a reduced rate of production of one or more of the globin chains of haemoglobin and inherited in a simple Mendelian fashion. They are clinically classified according to their severity into major (a severe transfusion-dependent disorder), intermediate (characterized by anaemia and splenomegaly), and minor (a symptomless carrier state) forms. The thalassaemias, which occur in patients with ethnic origin from a broad belt ranging from the Mediterranean and parts of North and West Africa through the Middle East and Indian subcontinent to South-East Asia, are the most important types of thalassaemia because they are very common and produce severe anaemia in their homozygous and compound heterozygous states. Most countries in which the disease is common are putting a major effort into programmes for its prevention (population screening and prenatal diagnosis). Symptomatic management of severe disease requires regular blood transfusion, judicious use of splenectomy if hypersplenism develops, and chelating agents to reduce iron overload. There has therefore been intense selection for these mutations in countries where malaria is common. As economic conditions improve in these countries, and infant and childhood death rates fall, the genetic disorders of haemoglobin place a major burden on health services. As a result of migration of populations from high-incidence areas for the haemoglobin disorders, these conditions are now seen with increasing frequency in all parts of the world. Some of them, particularly sickle cell anaemia and the more severe forms of thalassaemia, can produce life-threatening medical emergencies. It is important for all clinicians to have a working knowledge of their clinical features, management, and prevention. Haemoglobin disorders are also of particular interest because they were the first group of diseases to be analysed genetically. More is known about their molecular pathology than any other genetic disorders and their study has given us insight into the wide repertoire of mutations that underlie inherited diseases in humans. Before describing the haemoglobin disorders, it is necessary to discuss briefly the structure, function, and synthesis of haemoglobin and the way that it is genetically determined.

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Monocytosis may arise from primary malignancies of the marrow or in the setting of marrow infiltration with solid tumours birth control for depression generic 15mcg mircette with mastercard. Primary marrow disorders causing monocytosis include acute monocytic leukaemia birth control meme effective mircette 15mcg, chronic myeloid leukaemia and other myeloproliferative disorders, and chronic myelomonocytic leukaemia, which has features of both myelodysplastic and myeloproliferative disorders. Juvenile chronic myeloid leukaemia is a rare disorder occurring in children less than 4years of age. Monocytopenia is sometimes seen following steroid administration, endotoxaemia, or in marrow failure syndromes such as aplastic anaemia. Granules contain high concentrations of eosinophil major basic protein, histaminase, eosinophil cationic protein, hydrolases, and peroxidase. Eosinophils are capable of phagocytic function but more commonly release their granule contents to the environment. Eosinophils are also capable of producing reactive oxygen species, and produce prostaglandins, thromboxane A2, and leukotriene C4. Clinical features, diagnosis, and classification Most patients present with features of chronic anaemia or manifestations related to thrombocytopenia or infection. The diagnosis may be suggested by the presence of normocytic or macrocytic anaemia, with the peripheral blood smear showing dysplastic changes in red blood cells or neutrophils. Bone marrow aspirate and biopsy permits detailed cytogenetic study, which is critical for diagnostic classification and prognosis. Increasingly, molecular genetic assays (nextgeneration sequencing panels) aid in diagnosis and prognosis. They are structurally similar to mast cells but the exact relationship between these cell types is not clear. Hypereosinophilic syndrome: approach to treatment in the era of precision medicine. Some patients with lower-risk disease may show a response to immunosuppression with antithymocyte globulin and ciclosporin. Patients with isolated chromosome 5q deletions and lower-risk disease may respond dramatically to lenalidomide, an immunomodulatory drug. Prognosis varies widely (median survival <1 year to >10 years) according to particular subtype and disease features such as proportion of marrow blasts, karyotyping results, and the severity of cytopenias. Most patients who do not die of unrelated conditions die as a result of either bleeding or infection, but in some, transformation to leukaemia proves fatal. These syndromes result from malignant transformation and clonal expansion of a mutated multipotent myeloid progenitor or stem cell. The advent of next-generation sequencing technology has led to advances in our understanding of the disease, but treatment options remain limited and clinical outcomes unsatisfactory. This article sets out to describe our current understanding of the pathophysiology, epidemiology, clinical features, and therapeutic options for this heterogeneous group of bone marrow failure syndromes. Isolated cytopenias, especially mild anaemia, are often underinvestigated in the elderly. Diagnosis in those younger than 50 years is rare (unless exposed to the risk factors outlined previously) and diagnosis in children is extremely rare, with an estimated annual incidence of one per million. However, there is a worldwide variation in age at diagnosis, with a lower average age documented in patients in Asia and Eastern Europe. The exact cause of this is unknown, but may be attributable to differing environmental exposures or genetic background. The subsequent domination of the bone marrow by one or several mutated progenitor cells is known as clonal haematopoiesis. The size of the 5q deletion is variable; the two commonly deleted regions are 5q31. As most patients with del(5q) retain a normal 5q arm, haploinsufficiency is enough to cause the phenotype, and a number of genes on 5q- have been identified as relevant. Del(5q) may also occur together with other abnormalities, in which case it bears a more adverse prognosis with poor response to lenalidomide. Monosomy 7 occurs most frequently after alkylating agent exposure and is a poor prognostic marker.

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Fibrosis and scaring from surgery further impair speech and swallowing as time progresses requiring a relationship with speech-language pathology to decrease or avoid gastric tube dependence birth control lose weight effective mircette 15mcg, recurrent aspiration birth control 45 discount mircette 15mcg online, and difficulties with communication. Management consists of early mobilization using exercise or mouth opening assisting devices; however, if not employed early, limited improvement may be gained by such therapies. Peri-incisional numbness is frequent after neck dissection and tumors involving the mandible or lip may result in damage to the inferior alveolar or mental nerves. Anesthesia from a mental nerve injury will improve, but not completely, in these patients if the lip was not sacrificed. While these injuries are not directly related to oral cavity function, care must be taken during the surgical procedure and postoperatively to limit sequelae of injury or sacrifice. Injury or sacrifice can lead to impaired taste, poor food bolus preparation, accidental tongue biting, and dysarthria. In the case of bilateral hypoglossal injury, the airway can be compromised through posterior positioning of the tongue in the supine position. Long-term management involves speech and language therapy rehabilitation for patients with unilateral, clinical injury and potentially surgical airway management with bilateral hypoglossal injury. Injury to this nerve can impair oral liquid consumption, contribute to drooling, and may result in impaired cosmesis of the lower lip. Rehabilitation may consist of contralateral chemical denervation if cosmetic or lip wedge resection functional concerns are present. Patients who undergo radiation therapy have significantly decreased salivary gland function and subsequent xerostomia making them increasingly susceptible to dental caries. Educating health care professionals to provide institutional changes in cancer survivorship care. Is routine follow-up useful after combined-modality therapy for advanced head and neck cancer Costs of posttreatment surveillance for patients with upper aerodigestive tract cancer. The recurrence and survival of oral squamous cell carcinoma: a report of 275 cases. Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor. Treatment results on advanced neck metastasis (N3) from head and neck squamous carcinoma. Predictive factors for distant metastasis from oral and oropharyngeal squamous cell carcinoma. Squamous cancer of the head and neck: surgical treatment of local and regional recurrence. Oral squamous cell carcinoma: clinicopathological features in patients with and without recurrence. Patterns of recurrence and second primary tumors in oral squamous cell carcinoma treated with surgery alone. Site specific dependency of second primary cancer in early stage head and neck squamous cell carcinoma. Smoking cessation interventions and cessation rates in the oncology population: an updated systematic review and meta-analysis. Squamous cell carcinoma of the oral cavity in ever smokers: a matched-pair analysis of survival. Clinical examination and assessment of functional outcomes is necessary at each visit. Posttreatment imaging is useful to establish a baseline after treatment and for monitoring distant metastasis overtime. Patients who undergo radiation therapy should have thyroid function checked at least annually and have biannual dental evaluations. Alcohol and tobacco use prediagnosis and postdiagnosis, and survival in a cohort of patients with early stage cancers of the oral cavity, pharynx, and larynx.

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The modality sensitivity of a receptor neuron also determines the diameter of its axon and the patterns of connections it makes in the central nervous system birth control for women 00 buy cheap mircette. Most mechanoreceptors have a large-diameter axon covered by a thick myelin sheath birth control essay cheap mircette 15 mcg with visa. The mechanoreceptors are the fastest conducting sensory receptor neurons in the somatic sensory system. The dorsal column-medial lemniscal system receives sensory input principally from these fast conducting mechanoreceptors with large-diameter axons. By contrast, dorsal root ganglion neurons that are sensitive to noxious stimuli, temperature, and itch have small-diameter axons that are either thinly myelinated or unmyelinated. Table 4-1 lists the functional categories of primary sensory fibers, including the two fiber nomenclatures based on axonal diameter: A-a (group 1), A-~ (group 2), A-15 (group 3), and C (group 4). The spinal cord has a rostrocaudal segmental organization, which forms early during development. These somitesfrom which the muscles, bones, and other structures of the neck, limbs, and trunk develop-have a rostrocaudal organization. Importantly, for each of these somites, there is a corresponding vertebra and spinal cord segment, with associated dorsal and ventral roots. Dorsal view of the brain stem without the rerebellum, lllustratlng the course of the dorsal column-medlal lemnlscal system. A2 shows the dorsal root gangllon neuron and the organization of the primary afferent flber. The sensory receptOr Illustrated In A2 ls a mechanoreceptOr, a Paclnlan corpuscle. The dorsal column-medial lemniscal pathway, as viewed by a series of transverse slices through the brain stem and a coronal slice through the thalamus and cerebral cortex. It receives an efferent innervation from the spinal cord that maintains receptor sensitivity during muscle contraction. The synapse between the gamma motor neuron and the intrafusal fiber is termed ttie gamma motor ending. The Golgi tendon organ, located within tendons, is most sensitive to active force generated by contracting muscle. The position of the developing nervous system In the embryo Is Illustrated as well as the segmentil organlmtlon of rhombomeres and somltes. The two mesencephallc segments and the segment between the metacephalon and mesencephalon are not shown. Note that me spinal nerves exit from me vertebral canal through lntervertebral fcramlna. In the mature spinal cord, segmentation is apparent as the series of dorsal and ventral roots emerging from its surface. The area of skin innervated by the axons in a single dorsal root is termed a dermatome. This is because the primary sensory fibers have extensive rostro-caudal branches in the spinal cord. This explains the common clinical observation that, when a physician probes sensory capacity after injury to a single dorsal root, typically no anesthetic area is observed. Single dorsal root injury commonly produces radlcular pain, which is localized to the dennatome of the injured root. The dorsal half becomes the donal hom, which mediates sensory functions; many dorsal horn neurons project to the brain stem or diencephalon; others are intemeurons. BecaU$e the spinal cord has a longitudinal organization, the dorsal and ventral horns form columns of neurons that run rostroc:a. Dorsal root ganglion neurons that are sensitive to mechanical stimuli synapse in a different part of the dorsal horn than neurons sensitive to pain, temperature, and itch. We will see in later chapters that somatic motor neurons controlling striated muscle are located in different parts of the ventral horn than are neurons controlling visceral structures.

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Some patients with rapidly developing megaloblastic anaemia birth control pills 892 purchase mircette 15mcg with visa, particularly due to folate deficiency birth control pills bad for you order mircette 15 mcg on line, may develop almost complete aplasia of the red cell series, and the peripheral blood and bone marrow may resemble that of acute myeloid leukaemia. In the elderly, low serum vitamin B12 concentrations usually in the range 100 to 200ng/litre may occur in the absence of anaemia or macrocytosis. Raised haptocorrin also occur in association with some tumours, especially hepatoma and fibrolamellar tumour of the liver. In active liver diseases, vitamin B12 leaks from the liver with saturation of the serum vitamin B12 binders. Rare cases of congenital methylmalonic aciduria have been described, due to a variety of enzyme defects. Randomized trials are needed to assess the value of preventing or treating putative vitamin B12 deficiency in these subjects. Raised levels occur after folate therapy and also in vitamin B12 deficiency and in the stagnant-loop syndrome. Red cell folate is not now recommended for routine diagnostics but may be useful in some patients with probable folate deficiency in whom the serum folate is found to be normal. It is low in a proportion of patients with megaloblastic anaemia solely due to vitamin B12 deficiency. Serum homocysteine levels are usually raised in folate and vitamin B12 deficiency and many other situations. Diagnosis of vitamin B12 or folate deficiency the peripheral blood and bone marrow appearances are identical in folate or vitamin B12 deficiency. Vitamin B12 deficiency the assay of serum vitamin B12 content of serum is by competitive binding of intrinsic factor and immunochemiluminescencebased assays. The reference range, depending on the assay, is from 160 to 200 mg/litre to 960 to 1200ng/litre. It is difficult to determine a normal range and each laboratory should establish this independently. The concentrations are low in vitamin B12 deficiency, being extremely low in patients with neurological disease. Unfortunately, using competitive-binding assays, false-normal results have been reported in some patients with untreated pernicious anaemia and intrinsic factor antibodies in serum, which interfere with the test. A brief dietary history will rapidly establish whether or not the patient is a vegan or takes a very inadequate diet. Endoscopy and gastric biopsy will show features of gastric atrophy and help to exclude gastric carcinoma. Followthrough radiographic examination of the small intestine will help to exclude a small-intestinal lesion. Diagnosis of the cause of folate deficiency An inadequate diet is usually at least partly implicated, but an exact estimate of dietary intake from the clinical history is impossible because of variation in folate content of foods, losses in cooking, and size of portions. Many underlying inflammatory or malignant diseases may exaggerate the tendency to folate deficiency in patients with inadequate diets. The main cause of malabsorption of folate is gluteninduced enteropathy; in patients with severe folate deficiency, tests for transglutaminase and endomysial antibodies and a duodenal biopsy are usually necessary. In certain tropical countries, sprue may cause a generalized malabsorption syndrome in which folate deficiency commonly occurs. Prophylaxis Vitamin B12 therapy should be given from the time of operation after total gastrectomy or ileal resection. Routine endoscopy is not warranted but these diseases must be particularly borne in mind if relevant symptoms or signs develop. It is unclear whether vitamin B12 should be given orally or parenterally to those with biochemical (subclinical) vitamin B12 deficiency without anaemia or macrocytosis or clinical symptoms. Treatment of megaloblastic anaemia Therapy is aimed at correcting the anaemia, completely replenishing the body of whichever vitamin is deficient, treatment of the underlying disorder, and prevention of relapse. In most cases, it is possible to diagnose which deficiency is present before starting therapy. It is essential to first exclude vitamin B12 deficiency so that precipitation of a neuropathy is avoided. It is usual to continue for at least 4 months until there is a completely new set of red cells, although body stores will theoretically be normal within a few days of therapy.

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Bleeding time and platelet aggregation studies are frequently birth control pills insurance coverage cheap mircette 15 mcg on line, but not always birth control the patch mircette 15mcg free shipping, abnormal. Prolongation of prothrombin and partial thromboplastin times are frequently encountered, usually reflecting a laboratory artefact due to erythrocytosis (the volume of plasma in the collection tube might be too small relative to the amount of citrate anticoagulant present in these tubes). Low levels persist in two-thirds of patients after normalization of the haematocrit. Elevations in leucocyte alkaline phosphatase (70%), serum vitamin B12 levels (40%), and serum vitamin B12 binding proteins (70%) are common, as are hyperuricaemia and increased histamine levels. Bone marrow examination reveals a hypercellular marrow with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes. Reticulin is often seen, but is not predictive of evolution into the myelofibrotic phase. Cytogenetic abnormalities have been observed in 25% of patients, but none is characteristic. A recent study using fluorescence in situ hybridization analyses has shown that abnormalities involving chromosome 9 rearrangements are common, being present in up to 53% of patients with polycythaemia vera. Other chromosomal abnormalities involving chromosomes 1, 5, 7, 8, 12, and 13 have been associated with disease progression. Approach to the patient with polycythaemia It is wise to avoid the temptation of diagnosing polycythaemia on the basis of a single blood count unless extremely high haematocrit levels are observed. Heavy smokers with mild polycythaemia should be asked to stop smoking and their counts repeated after a few weeks. Once a genuine elevation of haemoglobin or haematocrit has been established, the next step is to decide whether this represents an absolute increase in total red cell mass, or merely a relative phenomenon. A blood volume study with direct quantitation of both red cell mass and plasma volume can be helpful in making this distinction if available. In patients with extreme degrees of erythrocytosis (haematocrit >55% in men and >49. If absolute polycythaemia is confirmed, it is essential to elucidate whether it is the consequence of a primary myeloproliferative disorder such as polycythaemia vera or a secondary condition. The presence of leucocytosis, thrombocytosis, or splenomegaly is suggestive of polycythaemia vera as the cause for the elevated red cell mass. Arterial blood gases and the direct determination of oxygen saturation in arterial blood, if decreased, may aid in the recognition of a chronic pulmonary or congenital cardiovascular abnormality. Otherwise, causes for a physiologically inappropriate polycythaemia should be sought. There is a small but definite group of patients in whom a specific cause for polycythaemia remains elusive, despite appropriate diagnostic testing. Regular, continued surveillance is recommended for all noncategorized patients, as some of them develop polycythaemia vera in the future. Management of polycythaemia vera the two main goals in the management of patients with polycythaemia vera involve the confirmation of the diagnosis and reduction of the red cell mass. The untoward effects of an increased red cell mass on tissue blood flow occur independently from the specific cause of the polycythaemia. It is thus reasonable to recommend that all patients with uncorrectable erythrocytosis be offered phlebotomy. The main therapeutic goals are the maintenance of well-being and the prevention of complications for as long as possible. Several therapeutic strategies have resulted in dramatic increases in the survival of patients. Historical evidence suggests a median survival of approximately 18 months in untreated patients with polycythaemia vera whereas with appropriate management, survival of over 10 years is now common. The main therapeutic objective is the reduction of the haematocrit to a normal level. Every possible effort should be made to discourage patients with polycythaemia vera from smoking. A regimen of phlebotomies should be prescribed as soon as the diagnosis has been clearly established. It is often feasible to remove between 350 and 500ml of blood every other day until the desired haematocrit level is attained. Many haematologists still target 42% for women, though this is not based on prospective data. Once the target haematocrit level is achieved, a maintenance regimen should be instituted.

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Initial concerns about the possible leukaemogenicity of hydroxycarbamide have not been borne out by long-term studies of its safety birth control used to treat acne order mircette in india. If hydroxycarbamide is not tolerated or ineffective birth control pills estradiol order 15mcg mircette amex, long-term elective red cell exchange programmes may be used, with good effect. Although this may be a significant burden for the patient and pose a risk of red cell alloimmunization, it may free patients with especially severe clinical phenotypes from frequent and disabling crises. Regular top-up transfusions are avoided where possible to avoid iron overload (with the exception of transfusion in the light of Doppler studies suggesting an increased risk of stroke in children-mentioned previously). The increased viscosity of the blood in patients with sickle cell disease means that over-transfusion (>100 g/litre) should also be avoided. Crizanlizumab, monoconal antibody targeted against the adhesion molecule P-selectin, has been shown in randomized studies to reduce the rate of sickle-related painful crises relative to placebo, by disrupting the cell-cell interactions which are thought to be central to development of such exacerbations. Whether these agents will have an impact on the long term outcomes of patients with sickling disorders remains to be seen. Towards a cure for the sickling disorders the management of sickle cell anaemia remains largely supportive, with hydroxycarbamide being the only widely available effective treatment to date. As with thalassaemia major, allogeneic bone marrow transplant programmes exist which offer the possibility of cure to patients who have sustained only minimal end-organ damage and who can therefore tolerate the procedure. Efforts to understand the normal control of globin transcription, and thus to reverse its silencing in adult life, remain the focus of many translational research groups. The unstable haemoglobin disorders the unstable haemoglobin disorders are a rare group of inherited haemolytic anaemias which result from structural changes in the haemoglobin molecule that cause intracellular precipitation with the formation of Heinz bodies. There have been several well-documented families in which patients with one of these haemoglobin variants have had no affected relatives, suggesting that the condition has arisen by a new mutation. Aetiology and pathogenesis Most of the unstable haemoglobin variants result from single amino acid substitutions at critical areas of the molecule. For example, substitutions in or around the haem pocket can disrupt the normal structure and allow in water, with subsequent oxidative damage to haem which leads to precipitation of the haemoglobin. Some substitutions, such as those involving proline residues, cause a marked disruption of the secondary structure of a globin chain. A few of these variants result from deletions of either single or several amino acid residues. For example, in haemoglobin Gun Hill, five amino acids are missing including the haem binding site. The degradation products of the precipitated haemoglobin, notably haem and iron, cause oxidative damage to the red cell membrane proteins in much the same way as the excess and chains produced in the thalassaemias. Clinical features All these conditions are characterized by a haemolytic anaemia of varying severity and splenomegaly. There may be a history of the passage of dark urine, particularly during episodes of infection. As in all chronic haemolytic anaemias, there is an increased incidence of pigment gallstones. In the more severe forms, such episodes are associated with life-threatening anaemia. Patients with unstable haemoglobins are at particular risk of haemolytic episodes following Haemolysis due to common haemoglobin variants other than haemoglobin S After haemoglobin S, the second commonest variant in West Africa is haemoglobin C. Because of its relatively low solubility haemoglobin C appears to exist in a precrystalline state in red cells, causing their rigidity and premature destruction in the microcirculation. The homozygous state, haemoglobin C disease, is characterized by a mild haemolytic anaemia with splenomegaly, and 100% target cells on the blood film. The commonest haemoglobin variant throughout South-East Asia and the Indian subcontinent is haemoglobin E. The homozygous state for this variant, haemoglobin E disease, is characterized by a very mild degree of anaemia with a slight reticulocytosis. The blood film shows mild morphological changes of the red cells which are hypochromic and microcytic, resembling the changes seen in thalassaemia. Haemoglobin variants which migrate in the position of haemoglobin S on electrophoresis but which do not sickle have been given the general title of haemoglobin D. There are several different molecular varieties of this variant; the commonest is haemoglobin D Los Angeles. The homozygous state is associated with moderate anaemia, splenomegaly, and a mild degree of haemolysis. The compound heterozygous state with haemoglobin S produces a disorder very similar to sickle cell anaemia.