ECG Case of the Month: ECG in a 20-Year-Old Woman with Dyspnea. Sinus tachycardia (104 beats/minute), slight right axis deviation of the QRS (+92°), an R/S ratio greater than 1 in lead V1 with ST depression and T wave inversion in leads V1 - V4, and a prominent S wave in lead I, Q wave in lead III, and inverted T wave in lead III(S1 Q3 T3). These findings suggest right ventricular hypertrophy or strain and are consistent with pulmonary emboli.

A 20-year-old Hispanic woman presented to the emergency department complaining of six months of progressive dyspnea on exertion associated with intermittent palpitations. Her only past medical history was a stillbirth at 32 weeks gestation about two years ago. Her vital signs in the emergency department were a heart rate of 120 beats/minute, a blood pressure of 145/86 mmHg, and an arterial oxygen saturation of 98 percent with her breathing air. Significant laboratory values included a blood hemoglobin of 14.5 gm/dL, a hematocrit of 49 percent, a brain naturetic peptide (BNP) level of 177 pg/mL, a D-dimer level of 330 ng/ml, a prothrombin time of 12.85 s with an INR of 1.2, and a partial thromboplastin time of 45.7s. Urine pregnancy test was positive, and serum beta-human chorionic gonadotropin level was 81 MIU/mL consistent with a fetus of 3-4 weeks gestational age. An electrocardiogram was recorded.

DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status.

The association of narcolepsy-cataplexy, a sleep disorder caused by the loss of hypocretin/orexin neurons in the hypothalamus, with DQA1*01:02-DQB1*06:02 is one of the tightest known single-allele human leukocyte antigen (HLA) associations. In this study, we explored genome-wide expression in peripheral white blood cells of 50 narcolepsy versus 47 controls (half of whom were DQB1*06:02 positive) and observed the largest differences between the groups in the signal from HLA probes. Further studies of HLA-DQ expression (mRNA and protein in a subset) in 125 controls and 147 narcolepsy cases did not reveal any difference, a result we explain by the lack of proper control of allelic diversity in Affymetrix HLA probes. Rather, a clear effect of DQB1*06:02 allelic dosage on DQB1*06:02 mRNA levels (1.65-fold) and protein (1.59-fold) could be demonstrated independent of disease status. These results indicate that allelic dosage is transmitted into changes in heterodimer availability, a phenomenon that may explain the increased risk for narcolepsy in DQB1*06:02 homozygotes versus heterozygotes.

27-year-old Asian man presenting with chronic nocturnal cough.

With increased globalization, more people are migrating to the United States (US) for higher education and employment. Consequently, more internationally associated infectious diseases are being diagnosed in the United States. Physicians should be aware of the consequences of this global travel and become familiar with parasitic infections and their clinical manifestations. We report a case of tropical pulmonary eosinophilia in a foreign medical resident from India. Tropical pulmonary eosinophilia should always be included in the differential diagnosis of chronic cough with eosinophilia, especially when dealing with immigrants or when there is a history of recent travel to an endemic area.

Kleine-Levin syndrome: a systematic study of 108 patients.

OBJECTIVE: Kleine-Levin syndrome is a rare disorder characterized by relapsing-remitting episodes of hypersomnia, cognitive disturbances, and behavioral disturbances, such as hyperphagia and hypersexuality. METHODS: We collected detailed clinical data and blood samples on 108 patients, 79 parent pairs, and 108 matched control subjects. We measured biological markers and typed human leukocyte antigen genes DR and DQ. RESULTS: Novel predisposing factors were identified including increased birth and developmental problems (odds ratio, 6.5). Jewish heritage was overrepresented, and five multiplex families were identified. Human leukocyte antigen typing was unremarkable. Patients were 78% male (mean age at onset, 15.7 +/- 6.0 years), averaged 19 episodes of 13 days, and were incapacitated 8 months over 14 years. The disease course was longer in men, in patients with hypersexuality, and when onset was after age 20. During episodes, all patients had hypersomnia, cognitive impairment, and derealization; 66% had megaphagia; 53% reported hypersexuality (principally men); and 53% reported a depressed mood (predominantly women). Patients were remarkably similar to control subjects between episodes regarding sleep, mood, and eating attitude, but had increased body mass index. We found marginal efficacy for amantadine and mood stabilizers, but found no increased family history for neuropsychiatric disorders. INTERPRETATION: The similarity of the clinical and demographic features across studies strongly suggests that Kleine-Levin syndrome is a genuine disease entity. Familial clustering and increased prevalence in the Jewish population support a role for a major genetic susceptibility factor. Considering the inefficacy of available treatments, we propose that disease management should primarily be supportive and educational.

DQB1*0301 and DQB1*0601 modulate narcolepsy susceptibility in Koreans.

The association of narcolepsy with HLA-DQB1*0602 is established in Japanese, African-Americans, European, and North American Caucasians. We examined DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 in 163 patients with centrally mediated daytime sleepiness (100 with narcolepsy) and 211 Korean controls. In this population, the DQB1*0602 association was always evident in the context of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. The DQB1*0602 association was highest in cases with hypocretin deficiency (100% vs 13% in controls), most of which had narcolepsy-cataplexy (81%). A weaker DQB1*0602 (45%) association was present in cases without cataplexy. No human leukocyte antigen (HLA) association was present in idiopathic hypersomnia or in cases with normal cerebrospinal fluid (CSF) hypocretin-1. As in other populations, DQB1*0602 homozygosity increased risk in cases with cataplexy and/or hypocretin deficiency (odds ratio = 2.0 vs heterozygotes). Non-DQB1*0602 allelic effects were also observed but could not be interpreted in the context of DQB1*0602 overabundance and linkage disequilibrium. We therefore next analyzed compound heterozygote effects in 77 subjects with either hypocretin deficiency or cataplexy and one copy of DRB1*1501-DQA1*0102-DQB1*0602, a sample constructed to maximize etiologic homogeneity. In this analysis, we found additional predisposing effects of DQB1*0301 and protective effects for DQA1*0103-DQB1*0601. Unexpectedly, the predisposing effects of DQB1*0301 were present in the context of various DQA1-bearing haplotypes. A predisposing effect of DQA1*0303 was also suggested. These results indicate a remarkable consistency in the complex HLA association present in narcolepsy across multiple ethnic groups.

Variable hematopoietic graft rejection and graft-versus-host disease in MHC-matched strains of mice.

MHC typing for human hematopoietic cell transplantation (HCT) from unrelated donors is currently performed by using a combination of serologic and molecular techniques. It has been determined that allelic differences in human MHC molecules, revealed by nucleotide sequencing but not by serologic typing, substantially influence graft rejection and graft-versus-host disease, two serious complications of clinical HCT. We studied transplantation of purified hematopoietic stem cells in a series of mouse strains that were matched at the MHC but had different background genes, and we observed striking differences in engraftment resistance and graft-versus-host disease severity, both factors depending on the donor-recipient strain combination. The individual mouse lines studied here were established nearly a century ago, and their MHC types were determined exclusively by serologic techniques. We considered the possibility that serologically silent MHC polymorphisms could account for our observations and, therefore, we performed DNA sequencing of the class I and II MHC alleles of our mouse strains. At each locus, exact homology was found between serologically MHC-matched strains. Our results likely extend to all serologically MHC-matched mouse strains used in modern research and highlight the profound and variable influence that non-MHC genetic determinants can have in dictating outcome after HCT.