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C. Nefarius, M.A., M.D.

Program Director, Oklahoma State University Center for Health Sciences College of Osteopathic Medicine

The resulting high levels of Bcl-2 are thought to help transform lymphoid cells into cancerous lymphoma cells by inhibiting the signals that would normally induce apoptotic cell death. Bcl-2 levels have been found to play an important role in regulating the normal life span of various hematopoietic cell lineages, including lymphocytes. A normal adult has about 5 L of blood with about 2000 lymphocytes/mm3 for a total of about 1010 lymphocytes. Because the immune system cannot sustain such a massive increase in cell numbers for an extended period, the system needs a means to eliminate unneeded activated lymphocytes once the antigenic threat has passed. Weissman and colleagues developed a novel way of enriching the concentration of mouse hematopoietic stem cells, which normally constitute less than 0. Their approach relied on the use of antibodies specific for molecules known as differentiation antigens, which are expressed only by particular cell types. They exposed bone-marrow samples to antibodies that had been labeled with a fluorescent compound and were specific for the differentiation antigens expressed on the surface of mature red and white blood cells (Figure 2-6). The labeled cells were then removed by flow cytometry with a fluorescenceactivated cell sorter (see Chapter 6). After each sorting,the remaining cells were assayed to determine the number needed for restoration of hematopoiesis in a lethally x-irradiated mouse. As the pluripotent stem cells were becoming relatively more numerous in the remaining population, fewer and fewer cells were needed to restore hematopoiesis in this system. However, if the lymphocytes continue to be activated by antigen, then the signals received during activation block the apoptotic signal. As antigen levels subside, so does activation of the block and the lymphocytes begin to die by apoptosis (Figure 2-5). Activation of B cells induces increased expression of cytokine receptors and decreased expression of Bcl-2. Because Bcl-2 prevents apoptosis, its reduced level in activated B cells is an important factor in Plasma cell B memory cell making activated B cells more susceptible to programmed cell death than either naive or memory B cells. A reduction in activating signals quickly leads to destruction of excess activated B cells by apoptosis. Treatment of the resulting partly enriched preparation with antibody specific for Sca-1, an early differentiation antigen, removed most of the progenitor cells. M = monocyte; B = basophil; N = neutrophil; Eo = eosinophil; L = lymphocyte; E = erythrocyte. Progressive enrichment of stem cells is indicated by the decrease in the number of injected cells needed to restore hematopoiesis. To further enrich the pluripotent stem cells, the remaining cells were incubated with various antibodies raised against cells likely to be in the early stages of hematopoiesis. One of these antibodies recognized a differentiation antigen called stem-cell antigen 1 (Sca-1). Nakauchi and his colleagues have devised procedures that allow them to show that, in 1 out of 5 lethally irradiated mice, a single hematopoietic cell can give rise to both myeloid and lymphoid lineages (Table 2-3). By exploiting the association of this marker with stem cell populations, it has become possible to routinely enrich preparations of human stem cells. These lymphocytes continually circulate in the blood and lymph and are capable of migrating into the tissue spaces and lymphoid organs, thereby integrating the immune system to a high degree. The lymphocytes can be broadly subdivided into three populations-B cells, T cells, and natural killer cells-on the basis of function and cell-membrane components. Resting B and T lymphocytes are small, motile, nonphagocytic cells, which cannot be distinguished morphologically. B and T lymphocytes that have not interacted with antigen- referred to as naive, or unprimed-are resting cells in the G0 phase of the cell cycle. Known as small lymphocytes, these cells are only about 6 m in diameter; their cytoplasm forms a barely discernible rim around the nucleus. Small lymphocytes have densely packed chromatin, few mitochondria, and a poorly developed endoplasmic reticulum and Golgi apparatus. Interaction of small lymphocytes with antigen, in the presence of certain cytokines discussed later, induces these cells to enter the cell cycle by progressing from G0 into G1 and subsequently into S, G2, and M (Figure 2-7a).

Adverse events following infusion of T cells for adoptive immunotherapy: a 10-year experience. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. End points to establish the efficacy of new agents in the treatment of acute leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Adoptive cell transfer therapy following nonmyeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. Patients with cardiac disease resulting in slight limitation of physical activity. Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain. Patients with cardiac disease resulting in marked limitation of physical activity. Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Liver histology showing aggressive hepatitis, bridging necrosis or cirrhosis Or 3b). Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy specimen Or 3d). Involvement of any other organ this material is the property of the University of Pennsylvania. This endpoint will be evaluated through day 180 post-transplant to account for delayed onset. Downgrade one stage if an additional cause of elevated bilirubin has been Volume of diarrhea applies to adults. Criteria for grading given as minimum degree of organ involvement required to confer that grade. Stage 1-2 Stage 3 or Stage 4 or None Stage 1 or Stage 2-3 or Stage 4 None Stage 1 Stage 2-4 - documented. It enables early identification of selected disorders that, without detection and treatment, can lead to permanent mental and physical damage or death in affected children. The goal of newborn screening is to facilitate prevention of developmental impairments (such as mental disability and neurological deficits), delayed physical growth, severe illness, and death through early detection and intervention. Across the United States, there are variations in the disorders for which each state screens. Although testing is possible for many other disorders, Washington adds tests to the newborn screening panel only after careful consideration of the following criteria set by the State Board of Health: Available Technology: Sensitive, specific and timely tests are available that can be adapted to mass screening. See the Washington State Board of Health Process to Evaluate Conditions for Inclusion in the Required Newborn Screening Panel for more information. The Washington State Newborn Screening Program is within the Department of Health and is located at the State Public Health Laboratories facility in Shoreline. It is a coordinated system of screening services comprised of laboratory, follow-up, and support staff. In October 2019, the Washington State Newborn Screening Program established a contract with the Hawaii Department of Health and began providing newborn screening services for babies born in Hawaii. This specimen (or signed parental refusal) must be received by the Newborn Screening Laboratory within 72 hours of collection. Healthcare providers are to inform parents or guardians about newborn screening prior to collection of the specimen, including the legal requirement for screening and the right to refuse based on valid reasons (see next section). In the instance that the parents/guardians refuse screening for religious reasons, it is the responsibility of the birth hospital or out of hospital birth attendant to document the refusal appropriately. As with a blood specimen, the refusal signature must be obtained within 48 hours of birth, and the card must be received by the Newborn Screening Laboratory within 72 hours of collection. It is important to note that religious reasons are the only valid basis for refusal per State law. Newborn screening statistics indicate that the majority of infants whose parents sign a refusal in the hospital are later tested, suggesting that the refusal was not truly based on religious principles. This dangerous practice could result in a delayed diagnosis for an affected infant and place them at significant risk of permanent damage or possibly death.

A comparative study of infantile autism and specific developmental receptive language disorder. A major susceptibility locus for specific language impairment is located on 13q21. Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy. Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. Prader-Willi syndrome, compulsive and ritualistic behaviors: the first populationbased survey. Epilepsy in young adults with autism: a prospective population based follow-up study of 100 individuals diagnosed in childhood. Molecular basis of hypoxanthine-guanine phosphoribosyltransferase deficiency in ten subjects determined by direct sequencing of amplified transcripts. Tuberous sclerosis complex: clinical features, diagnosis, and prevalence within Northern Ireland. Neurofibromatosis type 1: pathologic substrate of high-signal intensity in the brain. A randomized, double-blind, crossover study of methylphenidate and lithium in adults with attention-deficit/hyperactivity disorder: preliminary findings. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Autism spectrum disorders and symptoms in children with molecularly confirmed 22q11. Anomalous anatomy of speech-language areas in adults with persistent developmental stuttering. A double-blind placebo-controlled study of the efficacy of transdermal clonidine in autism. A double-blind comparison of clomipramine, desipramine and placebo in the treatment of autistic disorder. A double-blind comparison of clomipramine and desipramine in the treatment of developmental stuttering. Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome. The cardinal features of Bardet-Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. Reversible language regression as an adverse effect of topiramate treatment in children. A study and review of developmental dysgraphia in relation to acquired dysgraphia. Attention deficithyperactivity disorder in people with generalized resistance to thyroid hormone. A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism.

In neonates there are widespread signal abnormality- hypointense on T1, and hyperintense on T2. If relapse occurs, re-treat and consider prophylaxis with oral aciclovir or valaciclovir for 90 days. Non-viral causes of infectious encephalitis Viral causes are found in approximately 50% cases of encephalitis. Consider the following if no viral cause is found especially if there is an appropriate travel history or if the child is immunocompromised. Other causes of pyogenic meningitis/abscess: especially if septicaemia and micro-abscesses are possible. Anterior horn cell infection Polio Polio virus is an enterovirus causing biphasic febrile illness with initial prodrome then further fever with acute-onset asymmetrical progressive flaccid paralysis of one or more limbs. Children may develop later onset of weakness >30 yrs after initial illness-post-polio syndrome. Enterovirus 71 Causes outbreaks of hand, foot and mouth disease in the Asia-Pacific region. May develop polio-like neurological manifestations with or without meningitis or encephalitis. Anaerobes such as bacteroides, Streptococcus milleri and Fusobacterium are also commonly found. Direct extension can occur from the ears or sinuses, or abscesses can develop following trauma or meningitis. Antibiotic treatment alone is often insufficient, and surgical drainage needs to be considered. Aspiration and/or excision relieve pressure and enable a microbiological diagnosis. Radiological resolution is frequently slow, with a ring lesion persisting for weeks to months. Other possible treatments include quinidine, artemisan derivatives, or sulphadoxine/pyrimethamine. Complications Mortality is high at around 20%, but in those that survive, the majority (780%) have a normal outcome unless venous infarction occurs. A single lesion may pose diagnostic dilemma as it is difficult radiologically to exclude tuberculoma. Surgical resection is occasionally required after drug treatment for large lesions. Hyperdensities on T2-weighted images are seen in the periventricular frontal, temporal and occipital white matter. Approximately 50% of children will have increased signals on T2-weighted images in the basal ganglia and thalamus. Generalized cerebral atrophy and ventricular dilatation occur with disease progression. They are reports from open trials that combinations of antiviral drugs (ribavirin, inosiplex and interferon A) may be worth considering.

By using antibodies against cell-surface markers conjugated to different fluorescent dyes, it is possible to analyze the relative numbers of cells present in a specific tissue location. As cells pass through the apparatus in a single file, a computer-generated graph is produced, plotting the intensity and color of fluorescence of each cell along the axes. Each dot on the graph reflects the passage of a cell with a certain level and color of fluorescence, so the darkly dotted areas of the graph reflect the presence of many cells of similar attributes. The concept dates back into the 1100s when the Chinese practiced the art of variolation. However, the practice is credited to Edward Jenner in 1798, when he used a strain of cowpox virus to protect a child from smallpox. This chapter will discuss the science behind vaccination as well as a summary of the types of vaccine currently used in medicine. The increased speed of this response is due to the presence of the memory-cell progeny of the primary response throughout the body. The increased amplitude of effector production is due to the fact that activation and cloning begin from a much larger pool of respondents. The goal of passive immunization is transient protection or alleviation of an existing condition, whereas the goal of active immunization is the elicitation of protective immunity and immunologic memory. Active and passive immunization can be achieved by both natural and artificial means. The generation of IgE after infusion with even human gamma globulins is particularly an issue in persons with selective IgA deficiency (1:700 in population) as IgA is a molecule they have not encountered before. Birth 1200 1000 800 600 400 200 150 100 50 0 0 2 4 6 8 0 2 4 Months 6 8 lg (mg/100 ml) Maternal IgG Total antibody lg (percent of adult level) 60% 80% Infant IgG IgM 75% 20% IgA 10 12 Figure I-10-3. Immunoglobulins in Serum of Fetus and Newborn Child 97 98 Part I 1 mo 2nd dose 3rd dose Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger-United States, 2017. For those who fall behind or start late, provide catch-up vaccination at the earliest opportunity as indicated by the green bars. The symptoms of each disease highlight the importance of that aspect of the immune system on protecting the host. Most of these immune disorders are pediatric in nature and begin to appear around age 6 months. This highlights the importance of the protective immunity afforded by maternal IgG, which is nearly depleted by age 6 months and completely depleted by age 12-15 months. Another important aspect of immunodeficiency diseases is that several are X-linked and therefore more common in males than females. Defects of Humoral Immunity Disease Bruton (X-linked) agammaglobulinemia Molecular Defect Deficiency of the Bruton tyrosine kinase (btk) which promotes pre-B cell expansion; faulty B-cell development Symptoms/Signs Increased susceptibility to encapsulated bacteria and bloodborne viruses, low immunoglobulins of all isotypes, absent or low levels of circulating B-cells. B-cell maturation does not progress past the pre-B cell stage while maintaining cell-mediated immunity. High serum titers of IgM without other isotypes, normal B and T-cell numbers, susceptibility to encapsulated bacteria and opportunistic pathogens. Because of the central role of T cells in activation, proliferation, differentiation, and modulation of virtually all naturally occurring immune responses, abnormalities in these cell lines send shock waves throughout the system. It is often a Herculean clinical effort to dissect the cause-and-effect relationships in such inherited diseases, and their diagnosis is often one of trialand-error, which takes years to unravel. The B-cell defect, if any, is usually not detected for the first few months of life because of the passive transfer of immunoglobulins from the mother through the placenta or colostrum. The immune system is so compromised that even attenuated vaccine preparations can cause infection and disease. They may result from uncontrolled or excessive responses against foreign antigens or from a failure of self-tolerance, in which case they are called autoimmune diseases. The 2 principal factors which determine the clinical and pathologic consequences of such conditions are the type of immune response elicited and the nature and location of the inciting antigen.