BACKGROUND

Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts.

METHODS
We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotypespecific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs).

RESULTS
The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels ofORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific.

CONCLUSIONS
Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.)

BACKGROUND
Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamicpituitaryadrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.

METHODS
In a total of 158 patients in the intensive care unit and 64 matched controls, we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol; plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; plasma clearance of 100 mg of hydrocortisone; levels of urinary cortisol metabolites; and levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes.

RESULTS
Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P0.03 f or both comparisons). All these

factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liverbiopsy samples (P0.004 for all comparisons).

CONCLUSIONS
During critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisolmetabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression. The diagnostic and therapeutic implications for critically ill patients are unknown. (Funded by the Belgian Fund for Scientific Research and others; ClinicalTrials.gov numbers, NCT00512122 andNCT00115479; and Current Controlled Trials numbers,

A 59-year-old man presented with a 6-week history of pain in the thumb. He also reported having a cough, weight loss, and a history of heavy smoking. Physical examination revealed swelling, redness, and tenderness over the first right metacarpal and a mass (10 cm in diameter) fixed to the thorax. Laboratory tests revealed a C-reactive protein level of 123 mg per liter and a leukocyte count of 34109 per liter. A radiograph of the hand showed osteolysis of the first metacarpal (Panel A, arrow), and a chest radiograph showed a solid mass of the thoracic wall expanding into the subpleural space (Panel B, long arrow) and a tumor in the hilus of the right lung (Panel B, short arrow). A specimen of the metacarpal lesion obtained through needle aspiration was negative for bacteria. The final diagnosis was lung adenocarcinoma with osseous lesions of the hand and ribs. The patient received palliative care.

In a recent study that analyzed data from the GeoSentinel Surveillance Network (which consists of 42 specialized travel or tropical-medicine sites located around the world) on 25,867 returned travelers over a 9-year period (from 1996 to 2005), of the 2902 clinically significant pathogens that were isolated, approximately 65% were parasitic, 31% bacterial, and 3% viral. Six organisms (giardia, campylobacter, Entamoeba histolytica, shigella, strongyloides, and salmonella species) accounted for 70% of the gastrointestinal burden.

Clinical Pearls - What are the clinical manifestations of Giardia lamblia infection? Giardia lamblia (also called Giardia intestinalis or Giardia duodenalis) is highly contagious (ingestion of as few as 10 to 25 cysts may cause disease), with persons becoming infected through the ingestion of cysts in contaminated food or water. However, person-to-person transmission is possible. The clinical manifestations range from mild intestinal problems that resolve spontaneously to complex symptoms that last up to several weeks, such

as protein-losing enteropathy, postinfectious fatigue, chronic diarrhea, abdominal pain, nausea, and weight loss. In children, the disease can cause growth and cognitive impairment as a result of iron and micronutrient deficiencies. - What is the natural history, typical clinical course, and methods to diagnose amebiasis? E. histolytica and E. moshkovskii are pathogenic in humans, causing amebiasis. The parasite is acquired through the ingestion of food or water contaminated with fecal cysts. After it has been ingested, the cyst emerges in the terminal ileum as an active trophozoite, which migrates to the colon where it colonizes the mucus layer. Invasion may take days to years after the initial infection and is characterized by fever, abdominal pain, and bloody dark-brown diarrhea. However, 90% of cases are asymptomatic and self-limiting. Symptomatic disease occurs when trophozoites invade the mucosa and submucosa, and some trophozoites enter the portal circulation and disperse to the liver and other soft organs. Disease of the right colon is common and is associated with the following serious complications: strictures, rectovaginal fistulas, bowel obstruction, toxic megacolon, perforation, peritonitis, and death. Only 1% of clinical cases of amebiasis involve the liver. Several stool antigen assays specific for E. histolytica are commercially available to make an accurate diagnosis of intestinal or hepatic amebiasis on the basis of the Gal/GalNAc lectin. Microscopic examination of the stool is no longer performed for amebiasis because of its low sensitivity and specificity; with microscopy, it is easy to confuse E. histolytica with the identically appearing and much more common nonpathogenic parasite E. dispar.

Morning Report Questions Q: What are the manifestations of strongyloides infection? A: Strongyloides stercoralis (threadworm) is the most dominant species causing infection in humans. Third-stage filariform larvae penetrate the skin (usually the foot) of the human host, reach the lungs via the blood circulation, and enter respiratory pathways. From there, they migrate upward through the trachea, are swallowed, and finally reach the small intestine, where they mature into adult egg-laying female worms. Female worms embed in the submucosa of the duodenum, where they produce dozens of eggs per day. These hatch in the gut lumen, and the first-stage rhabditiform larvae either are passed out in the feces and develop into infective third-stage larvae or remain in the gastrointestinal tract of the human host and start a new infection cycle (autoinfection). Autoinfection can result in persistent infection for decades. More than 50% of patients with a chronic infection are asymptomatic. For a subset of patients with disease, the symptoms include erythematous pruritus, skin eruptions, larva currens, abdominal pain, diarrhea, and weight loss. In travelers presenting with eosinophilia or elevated IgE levels,

strongyloides should be considered in the differential diagnosis. In immunocompromised persons, strongyloidiasis can cause a hyperinfection syndrome owing to the reproductive capacity of the parasite inside the host. In cases of disseminated disease, the hyperinfection syndrome can be associated with a mortality rate of close to 90%. Q: What is the natural history and clinical presentation of schistosomiasis? A: Schistosomiasis is a common chronic helminth disease caused by intravascular parasitic schistosoma trematode worms. The three most important species in humans are Schistosoma hematobium, S. mansoni, and S. japonicum. Schistosome transmission requires the contamination of water by egg-containing feces or urine, a specific freshwater snail as intermediate host, and human contact with water inhabited by the intermediate host snails. Schistosome larvae (cercariae) emerge from the snails and penetrate human skin, thereby instigating infection. A maculopapular eruption consisting of discrete erythematous, raised lesions that vary in size from 1 to 3 cm may arise at the site of percutaneous penetration by the cercariae. Patients with acute schistosomiasis, or Katayama fever, which usually begins with the deposition of schistosome eggs into host tissues, can present with fever, malaise, myalgia, fatigue, nonproductive cough, diarrhea (with or without blood), hematuria (S. hematobium), and right-upper-quadrant pain. A skin reaction may develop within a few hours after infection in migrants or tourists infected for the first time, although a rash may appear as much as a week later. In cases of infection with S. mansoni and S. japonicum, a T-cell-mediated granulomatous reaction to schistosome eggs leads to fibrosis and chronic disease of the human liver, resulting in the development of severe hepatosplenic schistosomiasis; in cases of S. hematobium, this reaction leads to fibrosis and calcification of the bladder and ureters, which can result in bladder cancer.

TEACHING TOPIC Vaginal Bleeding CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL, Case 14-2013: A 70-Year-Old Woman with Vaginal Bleeding, (https://www.nejm.org/action/doSecureKeyLogin?uuid=7676846&dateTime=2013051 80000&key=0rSCw5hWJYFuQ6MwpDd%2FHHb9duCvOf9ptOHi%2FlfDIO0%3D&uri=/doi/full/ 10.1056/NEJMcpc1209276?query=BUL) R.T. Penson and Others CME Exam

The underlying cause of abnormal vaginal bleeding is age-dependent. Ten percent of premenopausal women with abnormal bleeding have a malignant tumor. In contrast, 75% of women over 70 years of age with postmenopausal bleeding have cancer, and the risk rises with age in postmenopausal women.

Clinical Pearls - What is the typical presentation of carcinosarcoma of the uterus? Postmenopausal vaginal bleeding is the most common manifestation of carcinosarcoma. Patients with carcinosarcoma also frequently present with the classic triad of painful postmenopausal bleeding, an enlarged uterus, and prolapsed tumor visible at the cervical os. - Under what circumstances is surgery not the primary treatment for uterine cancer? In only a few circumstances is surgery not the primary treatment for uterine cancer -- when there is a desire to preserve fertility, high operative risk, and unresectable disease. The goals of surgical treatment are excision of all disease with at least a 1-cm margin and staging of the tumor. The initial spread is to regional lymph nodes; therefore, standard treatment is a radical total abdominal hysterectomy and bilateral salpingo-oophorectomy with lymphadenectomy. Endometrial cancers have several potential patterns of spread: direct invasion and expansion of the primary tumor, lymphatic invasion, hematogenous spread, and intraperitoneal dissemination. Because metastasis is common, preoperative combination positron-emission tomography and computed tomography (PET-CT) and a meticulous exploratory laparotomy are standard practice.

Morning Report Questions Q: What features affect the overall prognosis of patients with carcinosarcoma? A: Diagnostic features of malignant mixed mullerian tumor (carcinosarcoma) include the finding of a biphasic malignant tumor that is composed of high-grade carcinoma (most commonly endometrioid or serous) and sarcoma and is typically homologous (arising from mesenchymal tissue normally found in the uterus), although in up to 50% of cases, the tumor has a heterologous component (most commonly rhabdomyosarcoma or chondrosarcoma). There is no transition between the two components. Tumor stage is the most important prognostic factor in these tumors, although histologic features also affect outcome. The finding of serous or clear-cell carcinoma is associated with a more aggressive course. Sarcomatous components adversely affect the overall prognosis of patients with stage I tumors (5-year survival is 30% among patients with heterologous elements as compared with 80% among patients with homologous elements); myometrial and lymphovascular invasion are also associated with a poor prognosis. Q: What are the treatment options for carcinosarcoma? A: Carcinosarcoma is thought to require multiple methods of treatment.

Radiation therapy has been shown to reduce the rates of local recurrence in the pelvis but does not increase the survival benefit among patients with carcinosarcoma. Adjuvant chemotherapy has not been shown to have an effect on recurrence rates or progression-free or overall survival among patients with carcinosarcoma. Hormonal therapy is of no use, since estrogen and progesterone receptors do not control tumor growth, even though they are typically present in patients with carcinosarcoma.

QUOTE OF THE WEEK "In our study, more bleeding events of WHO grade 2, 3, or 4 occurred in the no-prophylaxis group than in the prophylaxis group, with a significant increase in the number of days with bleeding events of WHO grade 2, 3, or 4 and a decreased time to the first bleeding event of WHO grade 2, 3, or 4. Virtually all these bleeding episodes were WHO grade 2; only 7 of the 600 patients in the study had a bleeding event of WHO grade 3 or 4. More patients in the no-prophylaxis group had bleeding events of WHO grade 3 or 4, but this difference was not significant. The results of our study support the need for the continued use of prophylaxis . . . ." S.J. Stanworth and Others, Original Article, "A No-Prophylaxis