Emilio Bouza, M.D., Ph.D.

• Professor
• Clinical Microbiology
• University Complutense of Madrid
• Chief
• Clinical Microbiology and Infectious Diseases
• Hospital General Universitario Gregorio
• Mara?on (HGUGM)
• Madrid, Spain

Venous thromboprophylaxis should be started as soon as feasible once Case Studies Case Study 1 A fit and well 18-year-old primigravida had a forceps delivery in theater under spinal block with a 700-mL measured blood loss antiviral journals order cheapest vermox and vermox. In the recovery room anti viral pneumonia purchase online vermox, she had a small bleed of 300 mL and then 60 minutes later was noted to be hypotensive and tachycardic and a further 1000 mL blood loss from uterine atony noted antiviral warning vermox 100mg generic. She returned to theater and had a small piece of residual placenta removed under the residual spinal block hiv infection from precum generic vermox 100 mg amex. Case Study 2 A multiparous woman with a previous history of placental abruption was admitted to the delivery suite complaining of abdominal pain the infection cycle of hiv includes cheap vermox 100 mg line. Fetal distress was noted on the cardiotocograph and a decision for immediate cesarean section under general anesthetic was made hiv infection rates japan generic vermox 100 mg otc. Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study. Disseminated intravascular coagulation in obstetric disorders and its acute hematological management. Guidance for diagnosis and treatment of disseminated intravascular coagulation from harmonization of the. Pathogenesis and management of peripartum coagulopathic calamities (disseminated intravascular coagulation and amniotic fluid embolism). Platelet count and transfuion requirements during moderate or severe postpartum haemorrhage. Association between fibrinogen level and severity of postpartum hemorrhage: Secondary analysis of a prospective trial. Early fibrinogen as a predictor of red cell requirements during postpartum hemorrhage. Predictive factors of advanced interventional procedures in a multicenter severe postpartum hemorrhage study. Predictive factors for failure of pelvic arterial embolization for postpartum hemorrhage. Hemostatic monitoring during postpartum hemorrhage and implications for management. The use of fibrinogen concentrate to correct hypofibrinogenemia rapidly during obstetric hemorrhage. Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage. Bedside assessment of fibrinogen level in postpartum hemorrhage by thrombelastometry. A prospective longitudinal study on rotation thromboelastometry in women with uncomplicated pregnancies and postpartum. Preemptive treatment with fibrinogen concentrate for postpartum hemorrhage: randomized controlled trial. National audit of the use of fibrinogen concentrate to correct hypofibrinogenemia. Comprehensive maternal hemorrhage protocols improve patient safety and reduce utilization of blood products. Comprehensive maternal hemorrhage protocols reduce the use of blood products and improve patient safety. Acute lung injury complicating blood transfusion in post-partum hemorrhage: Incidence and risk factors. Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of hemostasis in critically ill patients. Efficacy of intravenous tranexamic acid in reducing blood loss after elective cesarean section: A prospective, randomized, double-blind, placebo-controlled study. The focus of management is hence on early identification and instigation of appropriate treatment[3]. Supportive measures initiated include fluid resuscitation (crystalloids and/or blood products) and correction of any coagulation defect. In cases where control of hemorrhage is required, such as in planned cesareans for pre-known or suspected placental abnormalities, and prior to either hysterectomy or uterine embolization, prophylactic balloon occlusion of the internal iliac or the anterior division of the internal iliac arteries is proposed. Abnormal placentation (placenta accreta and placenta previa) is diagnosed on antenatal ultrasound or magnetic resonance imaging[5]. Placenta accreta refers to a morbidly adherent placenta and dependent on the degree of invasion into and then through the myometrium is classified as acreta, increta, and percreta, respectively[6]. Placenta previa is defined as a low-lying placenta that wholly (major) or partially (minor/partial) covers the cervical os. Interventional radiologists familiar with the vascular territory being treated and experienced in use of the various embolic materials are essential. Informed consent should be obtained if feasible following discussion with the patient and family. If, as is more often the case, a bleeding source is not identified, the anterior divisions of the respective internal iliac arteries are cannulated in turn. It is preferable to selectively catheterize the uterine arteries if time permits and it is technically feasible. Sometimes it may prove difficult to cannulate the internal iliac artery on the same side as that of the access common femoral artery. Under these circumstances, the contralateral common femoral artery access would allow straightforward access to the target internal iliac artery[7]. Prophylactic Balloon Occlusion In patients with abnormal placentation and hence considered high risk during delivery, prophylactic balloon occlusion of both internal iliac arteries may help control/reduce postpartum hemorrhage[6]. The placement of the occlusion balloon catheters is ideally carried out prior to advanced labor. The catheters are connected to heparin infusion pumps to prevent surrounding thrombosis. Complications include transient fever, transient buttock ischemia, foot ischemia, iliac artery perforation, and abscess formation[9]. The role of prophylactic balloon occlusion in the management of abnormal placentation remains debatable. The impact appears to be greater in cases of the more invasive placenta percreta[11]. Complications related to prophylactic balloon occlusion are estimated to be approximately 3% and include iliac artery thrombosis and transection[10]. They can reduce transfusion requirement, preserve fertility, and thus have the potential to reduce maternal morbidity and mortality. Case Studies Case Study 1 A 30-year-old woman presented with massive postpartum hemorrhage after forceps vaginal delivery, warranting transfer to the intensive care unit. Despite aggressive resuscitation, the patient showed evidence of hypotensive shock. The Role of Emergency and Elective Interventional Radiology in Postpartum Hemorrhage (Good Practice No. Endovascular therapies for primary postpartum hemorrhage: techniques and outcomes. Primary postpartum hemorrhage: outcome of pelvic arterial embolization in 251 patients at a single institution. Failed pelvic arterial embolization for postpartum hemorrhage: clinical outcomes and predictive factors. Preoperative intravascular balloon catheters and surgical outcomes in pregnancies complicated by placenta accreta: a management paradox. Prophylactic use of intravascular balloon catheters in women with placenta accreta, increta and percreta. This process is usually sufficient to control bleeding at sites of microvascular injury, such as within mucosal tissues like the genitourinary tract. The management of inherited disorders of primary hemostasis during pregnancy, delivery, and the postpartum period can pose particular challenges. Consideration should be given to the inheritance risk to the fetus and the bleeding risk to the mother, with appropriate multidisciplinary management plans to minimize complications for both. Good communication among the hematologists, obstetricians, anesthetists, neonatologists, and labor ward staff is required, as well as full information for the patient. Where possible this should begin prior to conception and be reviewed as pregnancy advances. To address this, attempts have been made in recent years to standardize the bleeding history by developing quantitative bleeding scoring systems. It is recommended that a bleeding assessment tool such as that developed by the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis be used in the assessment of patients for primary hemostatic defects[5]. Second, the likelihood of there being a mutation in the 04:31:11 Inherited Disorders of Primary Hemostasis Table 19. Thus, in addition to clinical features of impaired primary hemostasis, the bleeding pattern resembles that of patients with hemophilia, with the potential for spontaneous joint and muscle bleeds. There is no convincing evidence to show increased risk of early miscarriage but this can be complicated by significant bleeding[12]. The patient should be fully informed of potential bleeding risks and the plan for management of pregnancy, delivery, and the postpartum period. This should begin prior to conception and should be reviewed as pregnancy advances (Table 19. These women can be safely managed in standard obstetric units in collaboration with hemophilia 04:31:11 237 Hemorrhagic Disorders Table 19. If an adequate rise is demonstrated, only a third trimester sample may be necessary for subsequent pregnancies, unless earlier interventions are required. Desmopressin is generally safe both in pregnancy and at delivery[13,14] but should be avoided in preeclampsia. Fluid intake should be restricted to 1 L for the following 24 hours, to prevent maternal hyponatremia. Repeated administration should be avoided in view of the sensitivity of the fetus to the effect of hyponatremia. The advantages of desmopressin are its low cost, unlimited availability, and most importantly, the avoidance of blood products. However, there are many situations where desmopressin may be contraindicated or ineffective and plasma products necessary (Table 19. These concentrates are available as lyophilized powders and, after reconstitution in water, can be administered by slow bolus intravenous injection. During intravenous infusion, hypotension, headache, and facial flushing are common but generally mild. There are anecdotal reports of myocardial and cerebral infarction and desmopressin should be avoided in patients known to have arterial disease or hypertension. It can also be given in conjunction with replacement factor concentrate but is not usually necessary. Spinal anesthesia is preferred to epidural, as it requires a smaller needle and does not involve leaving a catheter in situ. Neonates are at risk of intracranial hemorrhage and cephalhematomas during labor and delivery. For patients with significantly low pre-pregnancy levels, consider desmopressin if known responder. Ensure regular contact with the patient after discharge and encourage them to report excessive or increasing blood loss. Consider use of the combined oral contraceptive pill if excessive bleeding is ongoing despite prophylaxis. In normal pregnancies, the median duration of bleeding after childbirth is 21 to 27 days, with delayed or secondary postpartum hemorrhage occurring in fewer than 1% of cases. In addition, there are multiple cases of postpartum hemorrhage that have occurred despite prophylaxis. If the bleeding risk is prolonged by complicated delivery and delayed recovery or development of sepsis, normal levels should be maintained for longer. It is contraindicated in patients with hematuria and doses should be reduced in renal failure. Tranexamic acid crosses the placenta but has been used to treat antenatal bleeding in a number of cases without reported adverse fetal effects. Traces have been found in breast milk but this has not been associated with changes to fibrinolytic activity in the infant. Prophylactic heparin during these times could have a significant effect on increased bleeding risk. Resulting thrombosis has been reported in these cases but most were perioperative without use of monitoring. Attention should be given to simple thromboprophylactic measures, including mobilization and hydration. The dose is 1 g tds and it is usually prescribed for up to 14 days, which can be continued for a longer period if needed. In addition, at least two separate viral inactivation steps are incorporated into the manufacturing process of pooled plasma concentrates.

Family history reveals consanguinity (parents are first cousins) and a cousin with two stillbirths hiv infection germany buy vermox online pills. Owing to symptoms of anemia hiv infection rate vietnam purchase vermox from india, in addition to starting folic acid 5 mg/day hiv infection quiz order vermox 100 mg visa, the patient is transfused 2 units of blood; however antiviral nasal spray best order vermox, 2 weeks later her hemoglobin is 70 g/L with evidence of ongoing hemolysis over the counter antiviral cream discount vermox online master card. A second transfusion is given and the option of a splenectomy is discussed with the patient antiviral meds for cats purchase vermox 100mg online, with an explanation that this is most safely performed during the second trimester. The patient agrees to this course of action and is vaccinated against meningococcus, pneumococcus, and H. Two weeks later, at 20 weeks, a laparoscopic splenectomy is successfully performed. The rest of the pregnancy is uneventful, with the patient maintaining a hemoglobin level of 85 g/L. At term, a healthy male infant is delivered; however, he is deeply jaundiced, requiring phototherapy, but not exchange transfusion. Hemoglobinopathies affecting maternal-fetal oxygen gradient during pregnancy: molecular, biochemical and clinical studies. High-risk pregnancies in Diamond-Blackfan anemia: a survey of 64 pregnancies from the French and German registries. Diagnosing and treating Diamond Blackfan anemia: results of an international clinical consensus conference. Fetal platelet antigens are expressed on platelets in normal amounts from as early as the 16th week of pregnancy. Neonatal thrombocytopenia has many causes and is the commonest hematological problem in the newborn infant. However, it requires considerable operator expertise in order to ensure maximum sensitivity and specificity, and the selection of appropriate screening cells is critical. In some of these cases, testing against standard donor platelet panels may be negative. There may also be unusual presentations such as isolated fetal hydrocephalus, unexplained fetal anemia, or recurrent miscarriages. Laboratory Diagnosis Detailed laboratory investigations are required for confirmation of a provisional clinical diagnosis, and should be performed by an experienced reference laboratory. It is not appropriate to wait for the laboratory confirmation of the diagnosis in suspected cases. However, in some of the cases, spontaneous recovery of the neonatal platelet count may have been the reason for the apparent response to random donor platelet transfusions. Compatible platelet concentrates were shown in another study to produce a larger increase in platelet count and twice the length of survival of the transfused platelets compared to random donor platelets[9]. The platelet count will usually increase to a level where no further treatment is needed after 1 week. Serial Fetal Platelet Transfusions Early studies with intrauterine fetal transfusions, with compatible platelets, highlighted the short survival of transfused platelets, and the difficulty of maintaining the fetal platelet count at a "safe" level. This was achieved by increasing the dose of platelets, while avoiding an unacceptable increase in the transfused volume, by concentrating the platelet collection by centrifugation and removal of plasma. Later improvements in apheresis technology allowed the preparation of leukocyte-depleted concentrated platelets suitable for fetal transfusion without the need for further processing. The aim was to maintain the fetal platelet count above 30 x 109/L by raising the immediate post-transfusion platelet count to above 300 x 109/L after each transfusion. The fetal platelet count fell below 10 x 109/L on one occasion when there were problems in preparing the fetal platelet concentrate and the dose of platelets was inadequate. Prednisolone has been widely used in pregnancy, and is known to cause fluid overload, high blood pressure, diabetes mellitus, irritability, and osteoporosis. Some studies suggested that the pre-treatment platelet count had predictive value for the response to maternal treatment. However, the ideal effective treatment without significant side effects to the mother or fetus has yet to be determined. There are some basic principles to consider in the management of an individual case[2]: 1. Close collaboration is required between specialists in fetal medicine, obstetrics, hematology/transfusion medicine, and pediatrics. This is based on data describing the effectiveness and safety of maternal treatment. Different centers have different strategies based on their own experience and those of published studies. The strategies for antenatal treatment have included the use of serial platelet transfusions, which, while effective, are invasive and associated with significant morbidity and mortality. Maternal therapy involving the administration of intravenous immunoglobulin and/or steroids is also effective and associated with fewer risks to the fetus. Maternal treatment with intravenous immunoglobulin and steroids was started from 14 weeks in the third pregnancy. The fourth pregnancy was managed by administering weekly intraperitoneal injections of immunoglobulin to the fetus from 12 to 18 weeks. The platelets were unwashed as it was considered to be more important to avoid additional manipulation and possible damage to the maternal platelets than the infusion of maternal antibody and prolongation of the neonatal thrombocytopenia. This case report illustrates the need to monitor responses to postnatal platelet transfusions and to change the management if there are poor responses to standard treatment, i. Incidence and consequences of neonatal alloimmune thrombocytopenia: a systematic review. Screening in pregnancy for fetal or neonatal alloimmune thrombocytopenia: a systematic review. Feto-maternal alloimmune thrombocytopenia: a literature review and statistical analysis. Fetal and neonatal alloimmune thrombocytopenia: lessons learned from animal models. Will it ever be possible to balance the risk of intracranial hemorrhage in fetal or neonatal alloimmune thrombocytopenia against the risk of treatment strategies to prevent it Antenatal screening for fetomaternal alloimmune thrombocytopenia: should we be doing it Parallel randomized trials of risk-based therapy for fetal alloimmune thrombocytopenia. A less invasive treatment strategy to prevent intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia. Fetal and neonatal alloimmune thrombocytopenia: a management algorithm based on risk stratification. A variety of etiologies are recognized; however, this chapter focuses on red cell alloimmunization, i. Pathogenesis Antibodies recognizing red cell surface antigens usually arise secondary to a blood transfusion, or following the birth of a baby with a different blood group to the mother. These red cell antibodies can, in a subsequent pregnancy, reach the fetal circulation and cause immune-mediated destruction of fetal red blood cells. This transplacental transportation of maternal immunoglobulin G begins in the early second trimester and red cell antibodies recognizing certain erythrocyte antigens may bind and bring about premature destruction of the fetal red cells by the reticuloendothelial system. One of the breakdown products of heme is bilirubin, and levels rise within the fetus and amniotic fluid, although placental transfer limits this accumulation. Progressive anemia initially stimulates the bone marrow first but, as its capacity to maintain the hemoglobin levels is exceeded, extramedullary hematopoiesis becomes increasingly important. This hyperactivity of the reticuloendothelial system results in fetal hepatosplenomegaly. A degree of portal hypertension and hypoalbuminemia secondary to liver dysfunction may contribute to extracellular fluid accumulation within the. Fetal anemia induces a high-output cardiac state and a degree of hypoxia may directly impair myocardial contractility. These changes are seen only when fetal hemoglobin levels decline well below the normal range and are a late feature of erythroblastosis fetalis. Intrauterine death will ensue in severe cases if the problem is not treated or the baby delivered. There are numerous etiologies for fetal ascites, but fetal anemia (from any cause) is one of the more common explanations. This results from a combination of high-output cardiac failure and also possible hepatic dysfunction and hypoproteinemia. Athetoid cerebral palsy, other movement disorders, deafness, and impaired eye movements may all be long-term sequelae of kernicterus. Repeated exposure of an isoimmunized woman to the same red cell antigen, as occurs in successive pregnancies, will further stimulate antibody production. Subsequent pregnancies, which express the blood group in question, have a tendency to show more severe hemolysis, and at earlier gestations. The Rhesus D (RhD) antigen was discovered in 1939, but the full complexity of this blood group system has only become evident much more recently with the advent of molecular biology. Sixteen percent of white Europeans, 5% of West Africans, and virtually no Chinese are RhD negative. The Rhesus proteins are coded for by two genes which share a major degree of homology. A slender fetal pericardial effusion and a small left-sided pleural effusion behind the heart can be seen. These features are all consistent with, but are non-specific signs of, fetal anemia. The Rhesus proteins are characterized by 12 intramembranous segments and 6 extracellular "surface" loops. Their function remains unclear, although ammonium ion transportation and gas exchange across the erythrocyte cell membrane have been postulated. The RhD negative phenotype is recognized in the laboratory by failure of red cells to agglutinate with standard anti-D reagents (antibodies). However, in the majority of African individuals typed as RhD negative the genotype is very different. Furthermore, missense mutations causing single amino acid substitutions in the intramembranous or cytoplasmic portions of the RhD protein may impair integration of the protein into the membrane, so bringing about a quantitative reduction in the number of cell-surface antigen sites per red blood cell. This too may reduce the agglutination response of these cells to standard laboratory anti-D antibodies. These "partial D" and "weak D" phenotypes, as they are respectively known, can be important from a clinical perspective and will be discussed in greater detail later. Each allele expresses only C or c, in combination with E or e, and, among Europeans, the Ce haplotype is most common. Prevention of RhD isoimmunization, and improvements in the antenatal and neonatal care of isoimmunized women and their babies, has all but eradicated serious morbidity and mortality associated with this condition. Some of the key landmarks in the evolution of this success story are listed in Table 11. By the early 1960s, Stern had demonstrated that exogenous anti-D given to RhD negative individuals could prevent immunization occurring when RhD positive blood was transfused into them. Exogenous anti-D is produced by exposing RhD negative volunteers to the RhD antigen. They regularly donate their blood, and cold-ethanol precipitation is used to separate the immunoglobulins from their hyperimmune plasma. There were theoretical concerns that passive antiD might itself cause hemolysis within the fetus. A Cochrane review of six eligible trials of routine postpartum anti-D prophylaxis gives a relative risk of 0. Various doses of anti-D have been tried, and indeed protocols still vary around the world today. Occasional bleeds exceeding 4 mL are recognized and a higher dose of anti-D is administered. The anti-D is usually given by intramuscular injection (although intravenous preparations are available) and ideally should be given within 72 hours of delivery (or any other possible sensitizing event). The studies examining the risk of first trimester isoimmunization are old and few in number[3]. The risk probably lies between 0 and 3%, but does seem to be higher when the uterus is instrumented. Crowther subsequently published a systematic review in the Cochrane database, although only two trials were deemed of high enough quality to be included. After treatment, any erythrocytes containing HbF retain their hemoglobin and can be stained and recognized. Unfortunately, some adults have persistent HbF production and this can confuse matters. Flow cytometry: this uses immunofluorescently stained antibodies to recognize fetal erythrocytes, which can then be flow-sorted and quantified. Although the trials varied in design and methodology, they gave remarkably consistent results.

E Opening of ligand-gated Na+ channels would be the signal transduction pathway of activation of nicotinic muscular receptors hiv infection lung 100 mg vermox with amex. Learning objective: Identify the disorder appropriate for the use of lactulose in cirrhotic patients quercetin antiviral discount vermox american express. A Opening of ligand-gated K+ channels would be the mechanism of action of some antihypertensive drugs like minoxidil the hiv infection process safe vermox 100mg. B Increased synthesis of diacylglycerol would be the signal transduction pathway of activation of some autonomic receptors hiv infection symptoms duration purchase vermox line, Eliminating toxic enteric products (mainly fecal ammonia) is a therapeutic goal in hepatic encephalopathy hiv infection breast milk discount 100mg vermox amex. Patients with severe liver disease have an impaired capacity to detoxify ammonia coming from the colon hiv infection rate in kenya best vermox 100mg, where it is produced by bacterial metabolism of fecal urea. Lactulose is an osmotic laxative that, when given in high doses, can lower colonic pH. The low pH converts the ammonia into a polar ammonium ion that, being water-soluble, is poorly absorbed by the intestine. In other words, the decreased ammonia absorption occurs through an ion-trapping mechanism. Current guidelines state that lactulose should be given to all cirrhotic patients with symptoms and signs of hepatic encephalopathy, as in the present case. B Lactulose cannot improve portal hypertension that is a hemodynamic consequence of liver cirrhosis. C, E Both secondary hyperaldosteronism and hypoalbuminemia are signs of cirrhosis, but lactulose cannot improve these signs. The patient denied the use of alcohol or illicit drugs but had been smoking two packs of cigarettes daily for 15 years. Physical examination showed a man in slight distress with the following vital signs: blood pressure 130/80 mm Hg, heart rate 65 bpm, respirations 26/min, body temperature 99. Lung auscultation yielded wheezing in the right upper lobe; the remainder of lung fields were clear. After four cycles of cisplatin and paclitaxel, tumor growth was not effectively controlled. Taking into account the cytogenetic analysis, the oncologist chose to stop the ongoing regimen and to start an erlotinib treatment. Which of the following is the most likely current estimation of the percentage of small-cell cancers due to smoking As a rule, a larger (and older) solid tumor is more difficult to remove by chemotherapy. Which of the following phrases best explains the reason for this chemotherapeutic weakness The inhibition of which of the following pairs of enzymes most likely mediate the antitumor effect of this drug The patient was most likely at increased risk of which of the following adverse effects as a result of paclitaxel therapy Which of the following adverse effects could most likely occur during erlotinib treatment These findings are typical of squamous cell cancer, which can produce keratin in the same way as normal squamous epithelial cells. A Small-cell lung cancer histology usually shows small cells with a high nucleocytoplasmic ratio. B Lung adenocarcinoma histology usually shows glandular tumor cells producing mucus. D Large-cell lung cancer histology usually shows sheets or nests of large polygonal or giant multinuclear cells. E Lung carcinoid histology usually shows medium-sized polygonal cells with round to oval finely granular nuclei and scant vascular stroma. Learning objective: Explain why larger solid tumors are more difficult to eradicate by chemotherapy. Answers and Explanations Learning objective: Identify the percentage of lung cancers that are due to smoking. About 85 to 90% of non-small cell lung cancers are due to smoking, but practically all small-cell lung cancers are caused by smoking. For most other tumors (especially solid tumors), the growth rate is not constant but rather slows as a tumor increases in size. This can be modeled using Gompertzian analysis (a plot of the log of the number of cancer cells in a tumor vs. The slower growth of the tumor is, in part, due to more cells entering the G0 (resting) phase of the cell cycle. One reason for this is related to the increased size of the tumor that is not supplemented by a parallel increase in blood flow. This reduces the delivery of oxygen and nutrients that the rapidly dividing cells need. This can explain why older and larger tumors are more difficult to eradicate by chemotherapy. Moreover, the delivery of anticancer drugs to the tumor is reduced because of the reduced blood flow. B A decreased P-glycoprotein activity would increase responsiveness to the anticancer drug, because this protein normally pumps the drug out of cancer cells. A decreased topoisomerase activity would increase, not decrease, the effectiveness of anticancer drugs (of note some anticancer drugs are topoisomerase inhibitors). E Since the tumor blood flow is lower when the tumor is larger, the tumor metabolic rate will be decreased, not increased. Learning objective: Identify the pairs of enzymes specifically inhibited by gemcitabine. Gemcitabine is phosphorylated to the diphosphate and triphosphate nucleotide forms. These drugs have broad antineoplastic activity and are currently used for treatment of many solid tumors, including lung, ovarian, head and neck, bladder, esophageal, and colon cancer. Platinum analogues are activated inside the cells, yielding positively charged and highly reactive molecules. B Inhibition of microtubule disassembly would be the mechanism of action of taxanes (paclitaxel, docetaxel). D Inhibition of thymidylate synthase would be the mechanism of action of fluorouracil. E Inhibition of de novo pathway of purine biosynthesis would be the mechanism of action of several anticancer antimetabolite drugs. These drugs block specific steps of intermediary metabolism of proliferating cells. Even if these steps are similar for normal and for cancer cells, there are quan- 241 27 Lung Cancer Learning objective: Identify the major adverse effect of cisplatin. Answer: C Peripheral neuropathy is a common adverse effect of taxanes such as paclitaxel, affecting more than 50% of patients under treatment. The exact pathophysiological mechanism of paclitaxel-induced peripheral neuropathy is not well understood, but the inhibition of tubulin depolymerization and the consequent microtubule dysfunction seems the most widely accepted mechanism. Intact microtubules are required for both anterograde and retrograde axonal transport, and neuronal survival and function depend on these transport processes. Increased axonal microtubule stability might alter axonal transport leading to a loss of axonal integrity, or axonal degeneration in more severe cases. This phenomenon begins in the most vulnerable part of the nerve, the distal nerve endings of the longest nerves, where transport problems may manifest most quickly. E, F Paclitaxel causes a profound myelosuppression, which in turn increases the risk of opportunistic infections. Avium-cellulare infection, but urinary tract infection and tuberculosis have not been reported. The routine use of hydration and diuresis has reduced cisplatin-induced nephrotoxicity, but even with these procedures, renal insufficiency occurs in up to 30% of patients treated chronically with the drug. The mechanism of cisplatin-induced nephrotoxicity is most likely related to the concentration of the drug within the kidney, which exceeds that in blood, suggesting an active accumulation of drug by renal parenchymal cells. In vivo administration of nephrotoxic doses of cisplatin produces a large increase in both necrosis and apoptosis of renal cells, and there is a large body of evidence indicating that cisplatin activates the intrinsic mitochondrial pathway of apoptosis. A, C, D, E the risk of all these adverse effects is low or negligible with cisplatin therapy. This prevents the microtubule disassembly and causes a mitotic arrest of cells in metaphase. C Inhibition of purine biosynthesis would be the mechanism of action of several anticancer antimetabolite drugs. Erlotinib is the prototype of the subclass of tyrosine kinase inhibitors approved for the treatment of non-small-cell lung cancers in patients whose tumors have epidermal growth factor exon 19 deletions or exon 21 mutations and are refractory to at least one prior chemotherapy regimen, as in the present case. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by phosphorylation, a step counteracted by tyrosine kinase inhibitors. Disappointingly, their clinical efficacy is limited by the development of resistance, which is caused in more than 50% of the cases by the emergence of a secondary point mutation in the epidermal growth factor receptor. In the majority of cases the rash is mild, although in 8 to 12% of cases the rash is severe enough that the treatment is stopped. A, B, C, D, E All these adverse effects can occur during erlotinib therapy, but their incidence is < 10%. He also noted recently increased forgetfulness, emotional instability, some pain on his tongue, tingling and numbness of the fingers, and alternating constipation and diarrhea, but no weight loss. In spite of the therapy, however, the disease did not improve, and a gastroscopy done 5 years ago indicated an extensive multifocal gastric atrophy. He reported that his diet was balanced and that he was taking two to three glasses of wine daily during meals. Physical examination showed an elderly, pleasant man with the following vital signs: blood pressure 132/80 mm Hg, pulse 84 bpm, respirations 16/min, body temperature 98. Neurological examination disclosed decreased cutaneous pain and vibratory sensation in both the upper and lower extremities. Which of the following pairs of morphological findings would be most likely expected in K. The synthesis of which of the following endogenous compounds is impaired by both folic acid and cobalamin deficiency Which of the following molecular actions most likely mediated the effect of the prescribed drug Which of the following phrases best explains why high doses of oral cobalamin can be absorbed even when gastric intrinsic factor is absent For these reasons, anemic conditions can be classified in terms of the hemoglobin content within red blood cells, just as normochromic or hypochromic. C Macrocytic, hypochromic anemia occurs when macrocytic anemia is associated with iron deficiency anemia. Answers and Explanations Learning objective: Identify the correct classification of megaloblastic anemias. Vitamin B12 (also called cobalamin) is found in most animal products (meat, eggs, dairy products, etc. The patient had been suffering from metaplastic atrophic gastritis, a disease that destroys the gastric parietal cells. When cobalamin absorption is blocked it takes about 4 to 5 years for the appearance of megaloblastic anemia, as in the present case. Because of the size of the cobalamin storage pool and the existence of an enterohepatic cobalamin circulation, a very long time (as long as 20 years) is required for a clinically 1. Answer: E 248 Megaloblastic anemias belong to the group of anemias due to deficient erythropoiesis. Cytoplasm maturity is greater than nuclear maturity, producing megaloblasts in the marrow before they appear in the peripheral blood. Deficient hematopoiesis results in intramedullary cell death, causing indirect hyperbilirubinemia and hyperuricemia. E, F Renal excretion of cobalamin and folic acid is negligible in a normal person. It can be decreased in case of kidney failure and can be increased when in excess. However, both cases are not clinically relevant, due to the negligible overdose toxicity of both drugs. Learning objective: Identify the organ that represent a huge reservoir of cobalamin. However, anemia due to folic acid deficiency lacks the neurological symptoms that are present in anemia due to cobalamin deficiency-namely, decreased vibratory and pain sensation, impaired memory, and emotional instability. A, B, D, E, F All these symptoms and signs can occur in both folic acid and cobalamin deficiency anemias. Learning objective: Explain the most likely reason for anemia-induced loss of pain sensation. Answer: D A megaloblastic anemia associated with loss of pain sensation is most likely due to cobalamin deficiency. The exact mechanism of neurological damage in cobalamin deficiency is still not fully elucidated, but the leading hypothesis is that the impaired methionine synthesis may lead to depletion of S-adenosylmethionine, which is required for the synthesis of myelin phospholipids. The myelin degeneration in the spinal cord can in turn cause an impairment in sensory transmission that explains the loss of pain sensation. A Insufficient blood flow to the extremities usually causes ischemic pain, not loss of pain sensation. B Loss of cortical excitatory neurons usually causes loss of several motor and cognitive functions.

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Past history revealed that hiv infection vaccine buy discount vermox 100 mg on-line, at age 21 hiv infection rates in europe discount vermox 100 mg mastercard, she had had unprotected sexual intercourse with her boyfriend antiviral tincture order genuine vermox on-line, and for the first time she had used an emergency contraceptive pill to prevent an unwanted pregnancy antivirus windows xp discount 100 mg vermox overnight delivery. After that incident she had consulted her physician about starting an appropriate hormonal contraceptive for continuous contraception naproxen antiviral order cheap vermox. She had tried 8 months of different treatments for acne antiviral zidovudine generic vermox 100 mg on-line, including benzoyl peroxide and doxycycline, to which she had not responded well. She was a nonsmoker at that time, and her family history was not significant for any cardiovascular disorder. Her menstrual periods were painful with cramps, for which she would take naproxen, on as-needed basis, during her periods. Her physician had given her appropriate instructions on how to cover for the missed dose so as to continue the contraceptive effect in such cases. Her pregnancy was normal, and she gave birth to a baby boy after a normal vaginal delivery. Because she wanted a contraceptive method immediately after delivery, her gynecologist gave her an appropriate contraceptive. She started smoking to deal with the stress and would smoke more than 15 cigarettes a day. Physical examination revealed a white woman (height 162 cm, weight 55 kg) who looked in normal body shape with no pallor or cyanosis. Her vital signs were as follows: blood pressure 122/86 mm Hg, pulse 72 bpm, respirations 16/min. Which of the following drugs did she most likely take to prevent pregnancy after having unprotected sexual intercourse One of the adverse effects of norethindrone, a progestin that is present in conventional oral combination hormonal contraceptive preparations, is acne. Which of the following receptors does this agent interact with to cause this adverse effect Which of the following is the most likely mechanism of action by which the patch exerts its contraceptive effects What advice did she most likely receive from her physician to cover for the missed dose Which of the following instructions did the patient need to follow while using the progestin-only pill for achieving its best possible contraceptive effect There are some noncontraceptive benefits of using combination hormonal contraceptives. The drug acts by stimulating uterine contractions and facilitates expulsion of uterine contents resulting from conception. D Clomiphene is a partial estrogen receptor agonist and is used for inducing ovulation in patients with polycystic ovary disease. It is used for the treatment of infertility when administered in a pulsatile manner. Learning objective: Describe the mechanism of contraceptive action of combination hormonal contraceptives. The estrogen component also acts to stabilize the endometrial lining, thus preventing breakthrough bleeding. Answer: C Levonorgestrel is a widely recommended agent for an emergency contraception. When a woman is not on any hormonal contraceptive for continuous contraception and the couple is not using any physical barrier method (such as condoms) or when the contraceptive method fails (such as condom rupture), emergency contraceptives are useful in preventing unwanted pregnancy. Plan B-One Step is one of the emergency contraceptive preparations that contains 1. It is recommended that the drug be taken within 72 hours of unprotected sexual intercourse for it to be successful. This is available over the counter, and no age restrictions apply to obtain the drug. This preparation should not be used for regular contraception, because it is not as effective for that purpose, and also it is not an abortifacient for terminating an established pregnancy. Other adverse effects, such as mood changes and water retention, are associated with the progestin component. Inhibition of steroidogenesis is not the cause of inhibition of ovulation; rather it is the result of inhibition of graafian follicle growth. Learning objective: Describe the mechanism by which combination hormonal contraceptives act to show therapeutic effects in acne. Answer: E Acne is the result of overactive sebaceous glands in response to many factors. Therefore, a therapeutic approach used to treat acne is to decrease the androgenic activity in these patients. Suppression of steroidogenesis results in decreased synthesis of both ovarian androgens and estrogens, thus resulting in a decrease in plasma androgen levels. Learning objective: Describe the characteristics of different types of synthetic progestins. A, B, E Of course norgestimate also has negligible estrogenic, glucocorticoid, and mineralocorticoid activities, but these properties do not explain why this drug is an appropriate contraceptive for a patient with acne. Learning objective: Describe different formulations of combined hormonal contraceptives. While all of these agents are "progestins," they have slightly different spectra of activities, which may be considered either adverse effects or advantageous effects, arising from their basic structural differences. These progestins have some androgenic actions that manifest as adverse effects, such as acne, hirsutism, and weight gain. Learning objective: Describe the clinical application of different types of progestin agents. All these formulations are combination hormonal contraceptives that contain an estrogen and a progestin agent. The mechanism of contraceptive action of all these formulations is the same-inhibition of ovulation. It also acts to stabilize the endometrial lining, thus preventing breakthrough bleeding. The fourth week is used as a patch-free week to allow withdrawal bleeding to occur. However, depending on the indication, the patch can be used as an extended-cycle contraceptive when the patch is applied every week for a longer duration of time without providing a patch-free period. A Hormonal contraceptives do not inhibit fertilization of an egg already in the tube. B, C, D All these can be additional mechanisms of the action of hormonal contraceptives, but they are not the primary mechanism. Answer: D Synthetic progestins are derived from either C-21 or 19-nortestosterone substrates. Newer 19-nor derivatives, called gonanes, including norgestimate and levonorgestrel, have less androgenic activity. This method is believed to minimize the confusion about when to take the first pill and has the potential to increase adherence. The method is also believed to provide contraception sooner and prevent unwanted pregnancy. Learning objective: Describe the guidelines for providing backup contraception for a missed dose of an oral combination hormone contraceptive. It is structurally related to spironolactone (a potassium-sparing diuretic) and has antiandrogenic and antimineralocorticoid activities. However, because drospirenone has antiandrogenic activity, it does not cause androgenic adverse effects, such as acne or hirsutism. Drospirenone acts as an aldosterone antagonist, so it would facilitate excretion of sodium in the urine while retaining potassium in exchange. According to the guidelines, no additional contraceptive is needed as a backup in such a scenario. When used as extended-cycle contraceptives, these formulations are used continuously for a longer than usual period (21 days in the 21-day pill pack, 24 days in the 24-day pill pack), and allow less frequent hormonefree periods for withdrawal bleeding to occur. The pill is taken as one pill a day continuously for 84 days, and the following 7 days are pill free (or nonhormonal inactive pills) to allow withdrawal bleeding. A similar approach is used for the transdermal patch and the vaginal ring, in which the patch-free or the vaginal ring-free period is provided less frequently. The extended-cycle contraceptive approach is used for decreasing blood loss in menses, especially in women with menorrhagia and anemia, and is also useful in the treatment of dysmenorrhea and endometriosis. The extended-cycle contraceptive methods are also used purely for lifestyle preferences (useful for women who want convenience for their menstruation, including women who travel, are on deployment in the military, or seek more control regarding the timing of menstruation and wish to have fewer restrictions in their sexual life due to menstruation). It is also used for the management of menorrhagia as well as purely as a preference. A, B, D, E As already explained, all these statements do not define extended-cycle contraception. Learning objective: Describe appropriate contraceptive methods in the immediate postpartum period. Therefore, choice E, progestin-only pill, is the most appropriate choice of hor- 198 Answers and Explanations monal contraceptive for this patient. D Ulipristal is a selective progestin receptor modulator used only as an emergency contraceptive within 5 days of unprotected sexual intercourse. Learning objective: Describe the pharmacokinetics of progestins and its clinical applicability. Learning objective: Identify the disease whose risk is decreased with the use of combination hormonal contraceptives. Studies have suggested that risk is decreased by 10 to 12% after 1 year of use and by approximately 50% after 5 years of use. In these women there is a multifold greater risk of myocardial infarction and stroke. Learning objective: Identify the most appropriate hormonal contraceptive for women who are over the age of 35 and are smokers. Answer: A Due to clearance of progestin agents from the circulation, the contraceptive action of oral progestin agents persists for about 24 hours. It is therefore important to take the next dose exactly at the same time in order to avoid a decline in plasma levels of progestins below the minimal required levels for achieving the contraceptive effects. If a dose is delayed, but not more than 3 hours, the missed dose should be taken immediately, and no backup birth control method is needed. If the pill is taken more than 3 hours later than the usual time, it is advised to exercise abstinence or use a backup birth control method (usually a male condom) for at least 2 days, while continuing taking the remaining pills at the usual time. Mechanisms by which progestin-only contraceptive pills exhibit contraceptive effect include (1) thickening of the cervical mucus, thus making it impermeable to sperms; (2) thinning of endometrial lining, making it unfavorable for implantation; and (3) inhibition of ovulation. Because the patient wanted to take a nonoral contraceptive, this choice is not appropriate for her. Medical history of the patient indicated that he had used heroin in the past, but he stated that he had successfully completed a rehabilitation program and had been "clean" for the last 8 months. Six months ago the patient received a blood transfusion after a trauma due to a car accident. The patient was circumcised ad admitted he had had sexual intercourse (always protected) with different women over the past 6 months. Oral examination disclosed white patches on the tongue and on other areas of the mouth and throat. A diagnosis of oral candidiasis was made, and a local therapy with miconazole mucoadhesive buccal tablets was prescribed. The therapy of oral candidiasis was changed and miconazole was substituted with oral fluconazole. He was also instructed to come back to the clinic every 2 months for routine follow-up. Given the response to date, no changes were required, and the current regimen was confirmed. The antiretroviral therapy was changed, discontinuing emtricitabine and tenofovir and adding raltegravir. He admitted he had recently disregarded the antiviral therapy because he felt quite well. He complained of a low-grade fever, fatigue, cough with blood-streaked sputum, and excessive night sweating over the last month. He also complained of floating spots, light flashes, and difficulty with far vision. A local miconazole therapy and later an oral fluconazole therapy was prescribed to treat F. Which of the following sets of blood cells represents the main target of this virus Both drugs most likely act by inhibiting which of the following enzymes or virion action Which of the following steps of the viral growth cycle is specifically inhibited by emtricitabine and tenofovir Which of the following is a rare but life-threatening adverse effect that can be caused by emtricitabine and tenofovir Which of the following steps of the viral cycle is specifically inhibited by this drug combination Which of the following was most likely the main reason for the association of ritonavir with the other antiretroviral drugs The synthesis of which of the following mycobacterial cell components was most likely inhibited by this drug

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