Seth Shay Martin, M.D., M.H.S.

• Director, Advanced Lipid Disorders Program of the Ciccarone Center
• Associate Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/10000548/seth-martin

American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer medicine 834 best 100 mg epitol. American Society of Hematology/ American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer medicine bag buy generic epitol 100mg on line. Recombinant human erythropoiesisstimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials symptoms 2 weeks after conception epitol 100 mg with amex. A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates medications 2016 generic 100 mg epitol free shipping. Impact of pretreatment factors on adverse events: a pooled analysis of North Central Cancer Treatment Group advanced stage non-small cell lung cancer trials symptoms 9 days after iui purchase epitol amex. Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count medications 7 rights purchase epitol 100 mg visa. Paraneoplastic acanthosis nigricans: the importance of exhaustive and repeated malignancy screening. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trelat, and multiple acrochordons. A possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. Hypertrophic osteoarthropathy: what a rheumatologist should know about this uncommon condition. Treatment of hypertrophic osteoarthropathy with zoledronic acid: case report and review of the literature. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Malignancies associated with dermatomyositis and polymyositis in Taiwan: a nationwide population-based study. Hari Many decades ago, researchers determined that bone marrow cells transplanted from one animal to another could restore blood production. Cure or effective disease control depends on delivering intensive doses of chemotherapy and/or radiation therapy. This intensity often exceeds the tolerance of bone marrow, necessitating restoration of hematopoietic marrow function in such patients to prevent irreversible and fatal marrow aplasia. This is accomplished by restoring blood production using either autologous ("self") cells. Patients with poor performance status (Karnofsky performance score 60) or significant comorbidities. Similarly heavily pretreated and chemotherapy-refractory patients are unlikely to benefit from this procedure, underscoring the need for timely transplant evaluation for suitable patients. This procedure usually takes 2 to 3 hours and processes three to four blood volumes. Prior chemotherapy or radiation therapy can impair mobilization, which may affect mobilization or collection strategy. Breakdown of the normal mucosal barriers in the gastrointestinal tract leading to oral mucositis, pain, diarrhea, and increased susceptibility to infectious complications is common. Red blood cell and platelet transfusions are essential to prevent or treat complications and symptoms of profound cytopenias. All blood products must be irradiated to prevent inadvertent engraftment of "contaminating" allogeneic lymphocytes from the transfused unit that may cause lethal transfusion-associated graft-versus-host disease. Rare but serious problems include hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, idiopathic pneumonia syndrome, and diffuse alveolar hemorrhage. Advanced renal impairment is frequent (20% to 30%) in patients with myeloma, with up to 8% requiring long-term renal replacement therapy. A two- to three-fold increase in second primary malignancies was seen in both studies associated with the lenalidomide maintenance. Similar randomized trials in the rituximab-era after first-line chemoimmunotherapy are not available. Hematopoietic Cell Transplantation for Diffuse Large B-Cell Lymphoma Hematopoietic Cell Transplantation for Diffuse Large B-Cell Lymphoma: In First Remission for High-Risk Disease? Hematopoietic Cell Transplantation for Diffuse Large B-Cell Lymphoma: In Relapsed Disease. Several registry140­143 and prospective studies in the rituximab era74 (see Table 130. Fortunately, the grim prognosis for the patient with relapsed/refractory Burkitt lymphoma is uncommon. Hematopoietic Cell Transplantation for Hodgkin Lymphoma Hematopoietic Cell Transplantation for Relapsed Hodgkin Lymphoma. Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Monoclonal antibodies in conditioning regimens for hematopoietic cell transplantation. Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. Autologous and allogeneic stem-cell transplantation for transformed follicular lymphoma: a report of the Canadian blood and marrow transplant group. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. Patient-controlled analgesia provides superior patient satisfaction for mucositis pain and results in lower cumulative doses of narcotics. Regimens that include high-dose Cy can result in acute hemorrhagic cystitis, which can usually be prevented by the sulfhydryl compound mercaptoethanesulfonate (mesna). The Bu/Cy regimen was associated with a high incidence of sinusoidal obstruction syndrome in early studies; however, this complication has been reduced by the use of ursodiol prophylaxis. Current use and outcome of hemaotpoietic stem cell transplantation: Center for International Blood and Marrow Transplant Research Summary Slides, 2012. Strategies to improving homing of the infused stem cells to hematopoietic niches are also being explored to improve engraftment. Minor H antigen-specific T cells exhibit potent antileukemic activity both in vitro78 and in vivo,79,80 and specifically eliminate the leukemic stem cells that establish human leukemia in immune-deficient mice. Laboratory signs include eosinophilia, thrombocytopenia, and hypo- or, less commonly, hypergammaglobulinemia. Anti­T-cell antibody preparations such as antithymocyte globulin of equine or lapine origin, and monoclonal anti­ T-cell antibodies such as daclizumab are commonly used in this setting, but there is no agent that has been shown to be effective in a randomized, double-blind, placebo-controlled fashion. Candida and Aspergillus are the most common fungal pathogens; however, other organisms may be observed. Patients that develop a fever should be evaluated by physical exam for potential portals of entry, blood and urine cultures, and a chest X-ray or other imaging studies informed by the clinical presentation. Empiric antibiotic therapy should be initiated promptly and modified depending on the results of cultures. The choice of antibiotics for empiric therapy of febrile neutropenia depends on clinical presentation, results of prior surveillance cultures, local susceptibility patterns, toxicity of individual agents, and allergic history. Typically, a third- or fourth-generation cephalosporin, carbapenem alone or in combination with an aminoglycoside, to provide coverage for pseudomonas and other gram-negative pathogens, are considered in seriously ill patients with neutropenic fever, with adjustment of the antibiotic regimen as culture data becomes available. Nocardia, Legionella, and Mycobacterium infections are uncommon but should be considered in patients with pulmonary infiltrates. Such patients are at risk from serious sinopulmonary infections and systemic infections with encapsulated organisms, and should be treated with daily prophylaxis with penicillin, trimethoprim-sulfamethoxazole, or a suitable alternative. Historically, herpes simplex virus type 1 or 2 infection occurred in approximately 80% of seropositive patients, but is now nearly universally prevented by the administration of acyclovir beginning with conditioning. There are no antiviral drugs with proven efficacy for adenovirus; however, this infection may be susceptible to adoptive T-cell therapy with donor-derived adenovirus-specific T cells. Bacterial pneumonia in the neutropenic phase can be reduced by the use of prophylactic antibiotics. This syndrome is thought to result from release of proinflammatory cytokines and influx of neutrophils into the lung, and responds to high-dose corticosteroids. Failure of the graft usually is the result of the persistence of host immune cells that reject the donor marrow, a phenomenon that is termed graft rejection. Retransplantation from another donor or the same donor with more immunosuppressive conditioning is sometimes successful for patients with primary graft failure or acute graft rejection. In this situation, a search for infectious causes of pancytopenia, or drugs that suppress graft function should be undertaken. These patients sometimes respond to treatment with a hematopoietic growth factor with an increase in the granulocyte count that may be sustained even after discontinuation of the growth factor. Imaging studies of the liver are useful to demonstrate hepatomegaly, ascites, and attenuated hepatic venous flow, and exclude other causes. The etiology of cholestasis may be evident after clinical evaluation and imaging studies, and therapy should be directed at the causative factors. The frequency of cholestasis has been reduced by the use of prophylactic ursodeoxycholic acid, which has reduced nonrelapse mortality. It is the only therapy with curative potential for patients with primary refractory or relapsed disease, and is increasingly utilized as consolidation therapy for patients in first remission whose disease characteristics are associated with significant risk for relapse. Consequently, patients who would have been classified a decade ago as being in remission on the basis of <5% marrow blasts could potentially be considered to have persistent or recurrent disease today if the marrow contained 0. One consequence of this evolution in diagnostic criteria is the likely inclusion in older transplant studies of patients erroneously classified as being in remission due to the use of the <5% marrow blast criterion. Current use and outcome of hematopoietic stem cell transplantation: Center for International Blood and Marrow Transplant Research Summary Slides, 2012. Registry data show a 2-year survival probability increasing from 39% for transplants performed in the period 1999 to 2003 to 47% for patients transplanted in 2008 to 2010. Nonetheless, transplant continues to have therapeutic utility, with 1,197 transplants performed in the United States from 2008 to 2012. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. Graft-versus-host disease and graftversus-tumor effects after allogeneic hematopoietic cell transplantation. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Similar overall survival using sibling, unrelated donor, and cord blood grafts after reduced-intensity conditioning for older patients with acute myelogenous leukemia. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Human proT-cells generated in vitro facilitate hematopoietic stem cell-derived T-lymphopoiesis in vivo and restore thymic architecture. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisonesparing therapy for gastrointestinal graft-versus-host disease. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. An international comparison of current strategies to prevent herpesvirus and fungal infections in hematopoietic cell transplant recipients. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Monitoring and preemptive rituximab therapy for Epstein-Barr virus reactivation after antithymocyte globulin containing nonmyeloablative conditioning for umbilical cord blood transplantation. Improved survival with ursodeoxycholic acid prophylaxis in allogeneic stem cell transplantation: long-term follow-up of a randomized study. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission. Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation. Outcomes of allogeneic hematopoietic cell transplantation for adolescent and young adults compared with children and older adults with acute myeloid leukemia. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. Outcomes in patients age 70 or older undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.

Facial fasciculation along with fasciculation of tongue and limbs seen-Kennedy syndrome medications prolonged qt discount 100mg epitol with amex. The ganglion of this neuron situated at Rosenthal canal at the base of bony spiral lamina called spiral ganglion of cochlear nerve medicinenetcom symptoms cheap epitol 100mg mastercard. The efferent of this ganglion enters the brainstem at the level of ventral cochlear nuclei as cochlear nerve medicine 02 generic epitol 100 mg amex. Dorsal aspect of all three nuclei receives high frequency sound Ventral aspect of all three nuclei receives low frequency (apical hair cells) sounds medications heart disease proven epitol 100 mg. From these nuclei, 2nd order of neurons arise and give rise to several projections symptoms electrolyte imbalance 100mg epitol overnight delivery. Some fibers from ventral nuclei projects to contralateral superior olivary nucleus medicine ball chair order 100mg epitol. Some fibers from ventral nucleus pass through superior salivary nucleus uninterrupted and end at inferior collicular nucleus of contralateral side passing along contralateral lateral lemniscus. The fibers, those terminated in superior olivary nuclei pass along the lateral lemnisci end in inferior colliculus. Fibers from interior colliculus end in medial geniculate body ipsilaterally in a tonotopic manner: Fibers containing high frequency sounds terminate in apical and lateral areas of medial geniculate body. Fibers containing low frequency sounds terminate in medial part of medial geniculate body. Following are the connection areas: In case of unilateral brainstem lesion-bilateral distribution of cochlear nerve are of immense significance. The connection between two cochlear nuclei the connection between two dorsal nuclei of lateral lemniscus through commissure of probst. The connection between colliculus inferior on each side through commissure of inferior colliculus. The connections between central nucleus of inferior colliculus and contralateral medial geniculate body through inferior cerebellar peduncle From inferior colliculus upwards there are two important projection system: Core system: the connection between portions of inferior colliculus, portions of medial geniculate body and primary auditory cortex direct auditory pathway. Neurology 1043 Bell projection: the connection between pericentral inferior colliculus, nonlaminated portion of medial geniculate body and secondary auditory cortex. The descending auditory pathways are: Corticogenicular fibers Geniculocollicular fibers Corticocollicular fibers Collicular efferents Efferent cochlear nerves from superior olivary nucleus end in cochlear hair cells of organ of Corti. The special organ is: Membranous labyrinth: It consists of: Otolith organ-utricle and saccule Three semicircular canals. Linear acceleration is monitored by specialized receptors, macules of utricle and saccule. Angular acceleration is maintained by specialized receptors, cristae of ampullae of three semicircular canals. Semicircular canals are three in number-arranged at right angles to one another to detect movement of head. Utricle and Saccule They are arranged at right angle to one another Utricle is parallel to base of skull and is stimulated with linear motion Saccule is parallel to sagittal plane and stimulated with angular motion. Mode of Transmission of Stimulation Transmission from membranous labyrinth is transmitted in two different components of vestibular system: 1. Superior portion of nerve carries input from: Horizontal semicircular canal Anterior or superior semicircular canal Utricle. Interior portion of nerve carries input from: Posterior semicircular canal Saccule. Neurology 1045 Vestibular Nuclei Initiate Contralateral vestibulo-ocular responses. Semicircular canals relate preferentially to superior and medial vestibular nuclei. Medial vestibulospinal tract (project to contralateral spinal cord): this tract receives fibers from: Medial vestibular nuclei Inferior vestibular nuclei-to some extent Lateral vestibular nuclei-to some extent. Through this tract, medial vestibular nuclei exert the excitatory or inhibitory effect on cervical cord or upper thoracic level of contralateral spinal cord. Lateral vestibule spinal tract (project to ipsilateral spinal cord): this tract receives fibers from: Lateral vestibular nucleus Inferior vestibular nucleus. This tract is responsible for extensor trunk muscle tone and action of antigravity muscles. Cerebellum: erent fibers through vestibulocerebellar tract connect Aff inferior and medial vestibular nuclei with ipsilateral flocculonodular lobe, uvula and fastigial nucleus of cerebellum. Reticular formation: rough cerebellar projection vestibular nuclei influence Th reticular formation. Vestibular nuclei also projects fibers back to hair cells in membranous labyrinth-to serve modulating function. Cortical representation of vestibular function is present in: Postcentral gyrus near areas 2 and 5 of cerebral cortex Frontal lobe (area 6) Superior temporal gyrus. Thalamic Representation of Vestibular Function Posterior nuclear group of thalamus. Vertigo: this can be described as sensation of motion, which may be subjective (he/she is spinning) or objective (surrounding environment is moving). Vertigo may be associated with-nausea with or without vomiting (related to lesion of peripheral vestibular apparatus) pallor, presence or absence of sweating. Paroxysmal or continuous-pulsatile or nonpulsatile tinnitus associated without vertigo-mainly due to peripheral lesions. Unilateral, pulsatile, fluctuating tinnitus or tinnitus associated with vertigo-It may be due to central or peripheral serious lesions. Pulsatile tinnitus due to all above causes except idiopathic intracranial hypertension may be decreased by rotating head to ipsilateral side. Gaze-evoked Tinnitus this type of tinnitus associated with saccades, vestibulo-ocular eye movements may occur due to aberrant connection between vestibular and cochlear nerve,atheterization and irrigation with a somewhat alkaline solution. These agents induce both single-gene and chromosomal mutations in germ cells of animals,196 both of which cause genetic disease in the offspring. Mutations induced in stem spermatogonia cause the continued production of mutation-carrying sperm for the lifetime of the male, whereas those induced in later stages of spermatogenesis result in the production of mutation-carrying sperm for only a few months. Radiation and several alkylating agents produce single-gene mutations in murine spermatogonia, whereas other tested chemotherapeutic drugs do not. Clinical reports of outcomes of pregnancies in which conception occurred while the man was undergoing cytotoxic therapy are too limited to evaluate the risks, but animal experiments and gamete genetic analyses show a higher risk. Most of these processes are controlled by trunks of nerve fibers forming the hypogastric plexus overlying the aorta and sacrum below the origin of the inferior mesenteric artery. However, improvements in surgical techniques have reduced these adverse outcomes without diminishing the efficacy of treating the cancer. A penile prosthesis is usually not offered to patients until 2 years after a radical prostatectomy to allow for tissue healing and adequate monitoring of cancer control. Feinberg for their assistance with the writing of the prior revision of this chapter. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. Birth outcomes among offspring of adult cancer survivors: a population-based study. Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Effects of oncological treatments on semen quality in patients with testicular neoplasia or lymphoproliferative disorders. Long-term recovery of spermatogenesis after radiotherapy in patients with testicular cancer. Testicular function in patients with testicular cancer treated with orchiectomy alone or orchiectomy plus cisplatin-based chemotherapy. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Sphingolipids, apoptosis, cancer treatments and the ovary: investigating a crime against female fertility. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers. Anti-Mьllerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. However, the power of these studies can only rule out twofold or higher increases in abnormalities; the possibility remains of a small genetic risk that would increase genetic abnormalities less than twofold over background levels. Also, these long-term studies do not include as many patients receiving the newer chemotherapeutic agents. There are significant teratogenic risks from cytotoxic therapy given to a woman during pregnancy. Methotrexate, which is a documented teratogen in the first trimester, was excluded from the combination. Such analyses are used only in the male because harvesting female gametes is impractical. Chromosomal abnormalities are measured by sperm karyotyping after fusion with hamster eggs or by fluorescence in situ hybridization. Cancer patients should be informed by their physicians about the possibilities of sterility and genetic risk from their disease and its treatment. The probability that sterility will result from the planned cytotoxic therapy should be calculated from the cumulative doses of agents and combinations that cause prolonged azoospermia, ovarian failure, or pituitary damage (see Tables 141. They should also be told about psychological and physical effects on sexual desire, erectile function, and the ability to achieve orgasm. Now that a large percentage of reproductive-aged patients are surviving cancer, different methods of fertility preservation (see Table 141. Pretreatment gonadal function testing and referral to a reproductive endocrinologist should be considered. Ovarian transposition for patients with cervical carcinoma treated by radiosurgical combination. Ovarian recovery after total body irradiation and allogeneic bone marrow transplantation: long-term follow up of 79 females. Risk factors for endocrine testicular dysfunction in adolescent and adult males who have survived malignancies in childhood. Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. Factors of importance for implantation and problems after treatment for childhood cancer. Neuroendocrine function in survivors of childhood acute lymphocytic leukemia and non-Hodgkins lymphoma: a study of pulsatile growth hormone and gonadotropin secretions. Spermatogonial stem cell preservation and transplantation: from research to clinic. Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. Practice Committees of American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. Assisted reproductive technology and birth defects: a systematic review and meta-analysis. Autotransplantation of cryopreserved ovarian tissue in cancer survivors and the risk of reintroducing malignancy: a systematic review. Restoration of fertility to oophorectomized sheep by ovarian autografts stored at -196 degrees C. First reported clinical pregnancy following heterotopic grafting of cryopreserved ovarian tissue in a woman after a bilateral oophorectomy. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Fertility preservation and management of gonadal failure associated with lymphoma therapy. Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis. Gonadatrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial. Benefits and risks of hormone replacement therapy in young adult cancer survivors with gonadal failure. Genetic disease in offspring of long-term survivors of childhood and adolescent cancer treated with potentially mutagenic therapies. Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm. Berger Fatigue is recognized as one of the most common symptoms in patients receiving treatment for cancer, often persisting beyond the conclusion of active treatment and at the end of life. An inherently subjective condition, fatigue may be experienced and reported differently by each individual. Qualitative studies of fatigue underscore the fact that the cancer fatigue experience is unlike any other fatigue patients have previously experienced,30 and patients emphasize that its unpredictability and refractoriness to self-management strategies that were previously effective make fatigue a particularly distressing symptom. Conceptual models can be organized into four thematic groups: (1) energy balance/ energy analysis models, (2) fatigue as a stress response models, (3) neuroendocrine-based regulatory fatigue models, and (4) hybrid models. Significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level A2. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. There is evidence from the history, physical examination, or laboratory findings that the symptoms are a consequence of cancer or cancer therapy. The symptoms are not primarily a consequence of comorbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium. Although a single-item measure may provide for a rapid assessment of general fatigue or serve as a screening tool, evidence suggests that single-item measures do not fully capture all the dimensions of fatigue.

Even in the latter groups the number needed to treat to obtain an effect was quite high shinee symptoms buy epitol 100 mg lowest price. Thus symptoms xanax addiction order 100 mg epitol amex, it was not surprising that diuretic therapy became popular with the introduction of chlorothiazide in the 1960s symptoms diarrhea best order for epitol. Those given diuretics had a decreased incidence of edema and hypertension medicine quotes doctor buy cheap epitol 100mg on-line, but not of preeclampsia 714x treatment order epitol 100 mg otc. According to most studies treatment skin cancer cheap epitol 100 mg on-line, women with preexisting chronic hypertension are at significantly high risk of preeclampsia compared with normotensive women. For example, lipid peroxides and free radicals contribute to endothelial cell injury. Thus, supplementation with these two vitamins was proposed to improve the oxidative capability of women at risk of preeclampsia. In the largest of these, conducted at 25 clinical sites in the United Kingdom, Poston et al. Of note, there were significantly more low-birthweight infants, fetal deaths, and low Apgar scores among babies born to mothers in the supplemented group, although small-for-gestational age infants did not differ between groups. Among participants who became preeclamptic, those in the antioxidant group developed it earlier. This trial failed to demonstrate a benefit of antioxidant supplementation in reducing the rate of preeclampsia among patients with chronic hypertension and/or prior preeclampsia. Subsequent meta-analyses and systematic reviews also concluded that there are no salutary protective effects of these antioxidant vitamins on the incidence of preeclampsia. As discussed thoughout this fourth edition of Chesley, the preeclampsia syndrome is characterized by vasospasm, endothelial cell activation and dysfunction, and activation of the coagulation cascade. As discussed in Chapter 17, enhanced platelet activation and thromboxane production appear to play an important role in some of these pathophysiological abnormalities. Indeed, evidence suggests that thromboxane A production is markedly increased while that of prostacyclin is reduced even in women prior to the onset of clinical preeclampsia. Putative sequelae are placental infarction and spiral artery thrombosis, notably in pregnancies with severe fetal-growth restriction, fetal death, or both. In doses of 50­150 mg daily during pregnancy, aspirin effectively inhibits platelet thromboxane A biosynthesis with minimal effects on vascular prostacyclin reduction. In 21 women given low-dose aspirin, there was a significant reduction in the incidence of preeclampsia. As also shown, however, lowdose aspirin failed to reduce the incidence of preeclampsia in any of these groups of extremely high-risk women. The Paris Collaborative Group more recently performed a meta-analysis of the efficacy and safety of antiplatelet agents ­ predominantly aspirin ­ in preventing preeclampsia. When these latter data were included in the Roberge meta-analysis, however, they supported the concept of lowdose aspirin reducing the risk of preeclampsia in women at high risk. One problem with all the approaches described above, and apparently neglected or not discussed in the recommendations of the various national and international working groups summarized below, is the problem inherent in subgroup analysis, especially when such analysis was not included in the original study design. Those treated with low-molecular-weight heparin and low-dose aspirin had an 8% recurrence rate for preeclampsia and a 6% rate for recurrent fetal-growth restriction. They compared pregnancy outcomes in 23 women given low-dose aspirin alone with those in 31 women given low-molecular-weight heparin plus low-dose aspirin. The incidence of recurrent preeclampsia in women given lowdose aspirin was 30% compared with only 3% in those given the combination (p < 0. Furthermore, the group given low-dose aspirin plus heparin had a greater mean gestational age at delivery (p < 0. Despite these findings providing further evidence of benefit, current guidelines advise against the use of lowmolecular heparin to prevent hypertensive disorders in pregnancy. The rationale is that statins stimulate hemoxygenase-1 expression and inhibit sFlt-1 release in vivo and in vitro, which may ameliorate the progression of early-onset preeclampsia. Primary eclampsia prevention can be achieved by preventing worsening of preeclampsia; secondary prevention can be accomplished by using agents to prevent convulsions in women with established preeclampsia; and tertiary prevention targets recurrent convulsions in women with eclampsia. The decision to use secondary prophylaxis is based on the likelihood of eclamptic convulsions in women with preeclampsia. This in turn is dependent on a number of factors, some of which are discussed in further detail in Chapter 20. Because seizure prophylaxis is recommended only during labor and for 12 to 24 hours postpartum, it can prevent only about 40% of eclampsia cases because 40% occur before labor, and 20% develop >24 hours postpartum. Other benefits Observational Studies of the Incidence of Eclampsia in Hypertensive Women Not Given Seizure Prophylaxis Inclusion Classification Patients No. Studies that support this conclusion include two large prospective observational studies from the same medical center in South Africa that describe the rate of eclampsia in women with severe preeclampsia who did not receive prophylactic magnesium sulfate. Odendaal and Hall75 reported 1001 such women, of whom 510 received magnesium sulfate prophylaxis based upon the clinical impression of impending eclampsia, while 491 women did not. Interestingly, two of the three postpartum seizures occurred beyond 48 hours and thus would not have been eligible for their standard magnesium sulfate regimen. In a subsequent report, Hall and associates76 enrolled 318 women with preeclampsia ­ mostly severe and remote from term and not in labor ­ who were managed expectantly with antihypertensive drugs and without magnesium sulfate. Of these, 26 subsequently received magnesium sulfate during labor or because of antepartum seizures (n = 4). Therefore, only two would have been prevented by their standard magnesium sulfate prophylaxis regimen. The authors of these studies therefore questioned the need for magnesium sulfate prophylaxis in patients with severe preeclampsia. Thus, clinical characteristics, obstetrical care, and availability of maternal and neonatal intensive care units differed widely. Many aspects of clinical characteristics or management were poorly defined or controlled. Some of these women received study medications antepartum during expectant management for 24 hours only with no magnesium sulfate with subsequent labor or postpartum, some were discharged, some received drug during labor and delivery, and some were not randomized until postpartum. Half of the women received antihypertensive agents before randomization and 75% received antihypertensive medications afterwards. Finally, 9% received anticonvulsants before randomization to magnesium sulfate, 6% received magnesium sulfate or other anticonvulsants after randomization, and 17 women had eclampsia before randomization. In addition, in women with mild preeclampsia, a secondary benefit might include a decreased rate of progression to severe preeclampsia. There have been four randomized trials that compared magnesium sulfate with phenytoin for women with various pregnancy hypertensive disorders Table 12. These findings suggest that the rate of seizures in women with mild hypertension or mild preeclampsia receiving phenytoin is 0. Importantly, the trial indicates that magnesium sulfate is superior to phenytoin for seizure prophylaxis in such women. There are no randomized trials with sufficient power to allow comparison of magnesium sulfate with placebo to prevent seizures in women with mild preeclampsia. The only two double-blind placebo-controlled trials that we could locate did, however, permit comparison for the percentage of women who progressed to severe preeclampsia, as shown in Table 12. In fact there were higher rates of postpartum hemorrhage and two instances of magnesium toxicity in one of the trials. Trial showed a significant reduction in the rate of eclampsia in women assigned to magnesium sulfate. These investigators enrolled women at 14 sites in eight countries who were given the study drugs during labor and for 24 hours postpartum. Most of this difference was due to the lower eclampsia rate postpartum among women assigned to magnesium sulfate. The overall results of these two studies, along with the other two, are listed in Table 12. In aggregate, they demonstrate that magnesium sulfate prophylaxis in severe preeclampsia is associated with a significantly lower rate of eclampsia compared with either nimodipine or no treatment. Effects of Magnesium Sulfate on Maternal Mortality and Morbidity the trials cited above provided information regarding maternal mortality and some morbidities. There were no maternal deaths reported in two of the trials,77­80 and in another there was one death from pelvic sepsis among 340 women assigned to placebo. In the placebo group, three deaths were due to renal failure, three from pulmonary embolism, and two women died from sepsis. The rate of cesarean delivery was similar in the two groups: 50% magnesium compared with 48% placebo. While the numbers are too small to draw certain conclusions, the studies did not demonstrate a decided benefit of magnesium sulfate on maternal mortality. Importantly, the frequency of ventilatory support was similar in the magnesium and control groups-59 versus 69%. Finally, the frequency of cerebrovascular accidents was similar in the magnesium and control groups ­ three versus six women. In the United States, magnesium sulfate has been used for this purpose for over 60 years. Until relatively recently, this was criticized as empirical and dogmatic because it had never been tested in randomized trials. The results of four large observational studies that address this are shown in Table 12. This in part stimulated the design of randomized trials to compare magnesium sulfate with traditional anticonvulsants. In apparently only one multicenter trial was there an adequate sample size to compute a significant difference between magnesium sulfate and the comparative drugs. The Collaborative Eclampsia Trial85 was conducted in several centers in South Africa and South America. The trial included 1680 eclamptic women who were randomized to magnesium sulfate, phenytoin, or diazepam in two different randomization schemes. The protective effects of magnesium sulfate to decrease maternal mortality with eclampsia are shown in Table 12. Overall, magnesium sulfate therapy was associated with significantly lower maternal mortality ­ 3. Effects of Magnesium Sulfate on Perinatal Mortality and Morbidity the three trials that provided adequate information regarding perinatal mortality are shown in Table 12. That said, maternal deaths or "near misses" from magnesium overdose have been reported from the United States and require vigilance to prevent. In all trials except in some women enrolled in the Magpie Trial,79 magnesium sulfate was started once the decision for delivery was made. In some trials, magnesium sulfate was given during labor and delivery, and for up to 24 hours postpartum. In the Magpie Trial,79 some women did not receive the drug during labor, delivery, or postpartum. In the trial by Moodley and Moodley,77 the loading dose was given intravenously and the maintenance dose intramuscularly. This variation in the route of administration and the total amount of magnesium sulfate used in the various trials possibly explains the differences in seizure rates and side effects among those assigned to magnesium sulfate. Because of these protocol variations, investigators from the University of Mississippi Medical Center have suggested an individualized postpartum magnesium sulfate protocol based on clinical parameters in women with preeclampsia. Postpartum women with mild disease received a minimum of 6 hours of intravenous magnesium sulfate, and those with severe preeclampsia received a minimum of 12 hours infusion. This protocol was based on blood pressure levels, need for antihypertensive therapy, onset of diuresis, and presence of symptoms. Women with mild preeclampsia required an average duration of magnesium sulfate therapy of 9. Although there were no cases of eclampsia, the sample size is inadequate to evaluate efficacy for convulsions. Like the first study, this protocol also was based on blood pressure levels, onset of use of antihypertensive drugs, diuresis, and symptoms. Magnesium sulfate was given for 2 to 72 hours in those with mild disease and up to 77 hours postpartum in those with severe disease. Magnesium sulfate therapy which had been discontinued was reinstituted based on clinical parameters in 6. Again, there were no cases of eclampsia, but the number of women included in this study ­ most had mild disease ­ is inadequate to draw any conclusions regarding efficacy. Because such a protocol requires intensive postpartum monitoring, it is impractical compared with an empirical protocol and is not used in the United States. One group of 50 were given 24 hours of therapy, whereas the other group of 48 were given therapy until the onset of diuresis. Women in the latter group had a shorter duration of therapy compared with those treated empirically for 24 hours ­ 507 ± 480 versus 1442 ± 158 minutes, respectively. There were no cases of eclampsia, and the postpartum hospital stays were not significantly different ­ 3. Ehrenberg and Mercer96 performed a randomized trial comparing a 12-hour to a 24-hour course of postpartum magnesium sulfate for women with mild preeclampsia. In the 107 women assigned to the 12-hour regimen, magnesium sulfate therapy was extended in seven for progression to severe disease compared with only one in the 24-hour group (p = 0. There were no seizures, but women with chronic hypertension and insulin-requiring diabetes were at risk of progression to severe disease. Again, the small number of subjects in this study hampers the generaliziblity of these regimens. Serum magnesium levels were obtained within the first 2 hours, and every 6 hours in the subsequent 42 hours. In addition, serum creatinine levels and creatinine clearances were also studied to correlate with magnesium levels.

The Thompson systematic review8 highlighted 2 decision rules which were able to rule out meningitis and meningococcal disease treatment questionnaire generic epitol 100mg on line. The first12 was able to identify 35 % who did not require a lumbar puncture despite signs of meningitis (see Table 27 medicine 773 purchase genuine epitol. In one prospective study4 of 264 infants with fever and skin haemorrhages medicine 0552 buy generic epitol pills, 5 clinical variables were found to distinguish between meningococcal disease and other condition (see Table 27 symptoms 7dpiui best buy for epitol. The presence of two or more features gives a 97 % probability of identifying a patient with meningococcal disease and a false positive rate of 12 % symptoms upper respiratory infection purchase 100 mg epitol free shipping. Whilst this suggests that large symptoms nausea dizziness cheap epitol 100mg amex, widely distributed lesions are of greatest concern, any petechial rash must be considered to be a potential marker of serious infection. In such cases it is difficult to decipher retrospectively if these children were misdiagnosed or had a coexisting infection or an infection which progressed to meningitis. The prior use of antibiotics poses a number of diagnostic challenges as it may affect the way in which a child presents and/or the results of investigations. The fever interval (time from onset of fever to the diagnosis of meningitis) is thought to vary between causative organisms. The longer the duration of fever preceding diagnosis, the higher the probability that a child would have made contact with a clinician and antibiotics commenced. Doctors should also be aware that pre-treated children may present differently or more subtly than those who have not received prior antibiotics. In 1 retrospective case14 series of 258 children aged 24 months or younger significantly less fever > 38. On the one hand, the course of the disease may be tempered by the antibiotic administration and therefore the child demonstrates less features of severe disease; on the other, admission and further antibiotics may be unnecessary if in fact the child does not have serious bacterial infection. Whilst blood tests are still of use in these children, it is often the case that if they remain well then a more prolonged period of observation may be required, with or without antibiotics. If there is any doubt a senior paediatric review should be obtained and any child discharged must have adequate safety netting advice which may include a face-to-face review within 24 hours to ensure they remain well. In view of the progressing rash the child is referred to the paediatric team for admission and observation. The paediatric team state they are reassured by the blood results and the distribution of the rash and advise the patient be observed in the clinical decision unit. Evidence base Duration of observation in a child with a petechiae rash Klinkhammer et al. Their aim was to identify risk factors predicative of significant bacterial sepsis. Expert comment Observation of 4 hours is recommended in all cases where diagnosis is uncertain. Always wake a child to assess him/her fully so you are confident that he/she is well and watch him/her play and interact. It is important to not behave in a manner which may deter parents from re-presenting. The safety net should be one or more of the following: Provide the parent with verbal and/or written information on warning signs on how further healthcare can be accessed. Liaise with other healthcare professionals, including out-of-hours providers, to ensure the parent/ carer has direct access to further assessment for their child. A Final Word from the Expert Petechial rashes in children can be frightening both for parents and clinicians. It is important to remember that although they may indicate serious illness, often they are simply a feature of more mild, self-limiting conditions. In well children you can afford to take a little longer to assess and observe, but always be prepared to step in rapidly if the child deteriorates. Many departments have a written advice sheet when discharging children with fever or rash and parents should always be advised what features to look for to prompt them to seek further medical attention. Systematic review and validation of predictaion rules for identifying children with serious infections in emergency departments and urgent access primary care. Procalcitonin to detect invasive bacterial infection in non-toxic-appearing infants with fever without apparent source in the emergency department. Comparison of the test characteristics of procalcitonin to C-reactive protein and leukocytosis for the detection of serious bacterial infections in children presenting with fever without source: a systematic review and meta-analysis. Prediction of bacterial meningitis in children with meningeal signs: reduction of lumbar punctures. Fever interval before diagnosis, prior antibiotic treatment, and clinical outcomes for young children with bacterial meningitis. Pediatric bacterial meningitis: Is prior antibiotic therapy associated with an altered clinical presentation? Does prior antibiotics treatment hamper the diagnosis of acute bacterial meningitis? Feverish illness in children: Assessment and initial management in children younger than 5 years. Two days ago she complained of vague earache on the right side of her head that subsided, but today her husband has noticed her face looks odd. She reports that she has been dribbling from the right side of her mouth and has found it hard to blink for a couple of days. She has no other past medical history of note, but has a family history of hypertension. Inflammation, ischaemia, oedema, autoimmune, and infectious causes have all been suggested with a focus on Herpes simplex type I and Herpes zoster virus reactivation. The onset is fairly rapid (<72 hours) with the peripheral lower motor neuron lesion of the 7th cranial nerve often preceded by an ache beneath the ipsilateral ear. It may be accompanied by decreased taste sensation, decreased lacrimation, and hyperacusis. Challenging Concepts in Emergency Medicine Expert comment Facial palsy is acutely concerning to patients and may occur from a multitude of causes. Rapid early assessment to identify reversible pathology such as acute ischaemic stroke is critical. It is very important for the first emergency care provider to find out and document the time that the patient was last completely normal, and the suddenness of onset of any neurological deficit, as this will help the emergency physician and the stroke team to determine the likelihood of stroke and the appropriateness of acute treatment. It is also important to perform a detailed history and examination of the patient to ensure that subtle, sinister pathologies are not missed. A confident diagnosis is critical as prognosis can be time-dependent and can be improved by the early initiation of treatment. Without the need for immediate stroke team activation, you embark on a detailed history and examination. On review, you find a female patient who is able to mobilize and fully alert and orientated. The right eye cannot be closed and the patient is unable to elevate her right eyebrow. The mouth is drooping and the movements of the mouth are paralysed with drawing up of the lips on the left. Eye movements are full in all directions and the retina appears normal with no signs of papilloedema. There is no neck stiffness and power, tone, sensation are normal in the upper and lower limbs with symmetrical reflexes. Vesicles in the external auditory meatus or on the pinna suggest the diagnosis of Ramsey-Hunt syndrome. Infection within the geniculate ganglion causes loss of taste to the anterior two-thirds of the tongue on the affected side. Ramsay-Hunt syndrome is theoretically a contraindication to steroid therapy, although this is very controversial and rational guidance on treatment is impossible due to the lack of evidence. A bluish red nodule on the earlobe or nose may represent Borrelial lymphocytoma which is associated with Lyme disease, an important cause of facial palsy. If the forehead is unaffected and the paralysis is present on voluntary but not involuntary movements of expression, then it suggests an upper motor neurone lesion. Deviation of the tongue is frequently observed in patients with facial nerve palsy but does not represent additional involvement of the hypoglossal nerve. A unilateral lower motor neurone lesion of the 12th cranial nerve would make the tongue curve to that side and would have wasting and possible fasciculation. The early prescription of steroids should help to reverse the swelling and lead to more rapid and complete recovery. Primary outcome was time to complete recovery of facial function, assessed with Sunnybrook scale score of 100 points. Early treatment with prednisolone significantly improves the chance of complete recovery at 3 and 9 months. It should be prescribed within the first 3 days and works best if given within 24 hours. Typical trial doses of prednisolone were 50­60 mg daily (in single or divided doses) for 5 days, then reducing by 10 mg per day over 5­6 days. Two major randomized controlled trials, each with more than 500 randomized patients, showed that early prednisolone treatment improved the proportion of patients who recovered within 9­12 months. Crucially, both of these trials recruited patients who presented within 72 hours of onset, thus making initiation of this therapy an important decision for the emergency physician. The subsequent Cochrane review14 and an evidence-based emergency medicine review16 supported early high-dose prednisolone therapy based mostly on these 2 landmark studies. The House-Brackman grading system17 is an accepted scheme to describe the degree of facial paralysis and it is the standard method of assessing response in facial palsy trials. The blood glucose, blood pressure, and temperature should be checked in all patients as gross abnormalities in these may suggest an alternative diagnosis. Lacrimation can be assessed by performing Schirmers test; a small strip of filter paper is placed in the lower conjunctival fold, the eye is closed and the length of wet filter paper is measured after 5 minutes. There is no statistically significant difference observed with acyclovir Quant et al. Review of 3 multicentre randomized controlled trials Recovery using validated measures of facial nerve function. Studies have been hampered by poor design, inadequate numbers, lack of standardized end points, and heterogeneity. Outcomes need to be standardized and the timing of the primary outcome needs to be long enough to show any possible benefit of an antiviral agent, probably 12 months. Finally, the bioavailability of valacyclovir is greater than that of acyclovir, so there may be improved outcomes with valacyclovir; however, previous studies using both agents have not shown any difference in efficacy or outcomes. Future studies should compare valacyclovir with prednisolone against prednisolone alone. The patient is most distressed about her inability to close her eye; you therefore consider what management options there are and what advice to provide. As the surface of the eye is insensate and the eyelid does not fully close, it is vulnerable to trauma which might go undetected. On discharging the patient, most emergency physicians provide some advice on this, explaining that at the first signs of trauma. What evidence is there for effectiveness of any interventions offered at the time of diagnosis? There are no specific studies which have considered ocular interventions in Bells palsy, therefore conclusions must be inferred from studies which have looked at other disorders. At night, lubricating ophthalmic ointment can be applied to prevent exposure keratopathy. Full paralysis indicates nerve Case 28 Facial palsy 283 degeneration at a point along its pathway. Regeneration is slow and after 6­12 months, 10­15 % of patients have incomplete recovery. A common complaint amongst this cohort of patients is lacrimation when they eat or other synkinesias. These patients need follow-up with a maxillofacial or plastic surgery specialist to consider further treatment. Important differentials include Ramsey-Hunt syndrome, meningitis, Guillain-Barre syndrome, or Lyme disease. An occult neoplasm is always a concern, but pointers in the history like slowly progressive paralysis, headache, or other cranial nerve abnormalities would suggest more sinister pathology. Corticosteroids as adjuvant to antiviral treatment in Ramsay Hunt syndrome (herpes zoster oticus with facial palsy) in adults. He had initially attempted to continue working but within minutes realised that he would need to stop. It has been increasing through the day and is not improving with simple analgesia. He has opened his bowels as normal earlier in the day and has reported no difficulties with passing urine. There was no leg weakness or sensory disturbance on examination but he complains of occasional shooting pains down the back of his right leg. Classification can be acute (< 6 weeks), sub-acute (6­12 weeks) or chronic (> 12 weeks) It remains a significant cause of lost work days with the demographic now shifting from manual labourers to office / desk workers. As per your usual practice, you explain that you do not feel that a fracture is likely in his case and that an X-ray will not diagnose any other significant pathology. The patient nonetheless remains adamant, stating that both he and his colleagues have previously been given X-rays after identical accidents, and that his work will demand proof of the injury sustained. Clinical tip Sciatica Sciatica is a commonly used lay term for any pain radiating into the buttock, knee, calf, and heel. Risk factors for this include increasing height, age between 45­64 years, smoking, and occupations with strenuous activities of lifting and twisting. A crossed straight leg test where the contralateral leg is raised and pain is elicited in the affected leg is shown to have a higher specificity of 88 % but a sensitivity of 29 %. Clinical question: Is there a role for plain film imaging in any-age patient with acute low back pain? Public perception still remains that all forms of back pain necessitates plain film imaging in the first instance. This may hold true for direct trauma or specifically axial compression trauma; however, atraumatic back pain must be considered as a distinct clinical presentation.

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