Sensitivity to a metabolite of diclofenac as a cause of acute immune hemolytic anemia

A 75-year-old woman taking the nonsteroidal anti-inflammatory drug diclofenac (DCF) presented with acute Coombs-positive hemolytic anemia and subsequently developed renal failure. A drug-dependent antibody specific for red blood cells (RBCs) could not be demonstrated by in vitro testing with DCF. However, her serum was found to contain an IgM antibody that reacted strongly with RBCs in the presence of urine from any of four subjects who had ingested DCF. The active substance in urine was isolated, subjected to high-performance liquid chromatographic (HPLC) analysis, and found to be a glucuronide conjugate of a known DCF metabolite, 4'-hydroxydiclofenac (4'-OH DCF). Negative results were obtained with four other DCF metabolites. Two 4'-OH DCF glucuronides were synthesized in vitro using a liver microsomal system. One promoted agglutination of normal RBCs by the patient's serum and was identified as the glucuronide ester of 4'-OH DCF by proton nuclear magnetic resonance (NMR) analysis. Studies with a panel of RBCs showed that the patient's antibody reacted preferentially with the e antigen of the Rh system. Acute immune hemolytic anemia in this patient appears to have been caused by sensitization to DCF modified by 4' hydroxylation and glucuronidation. This is the first reported example of immune cytopenia caused by sensitivity to a glucuronide conjugate of a drug metabolite. Since glucuronidation is a common pathway of drug metabolism, studies of the frequency with which glucuronide derivatives of primary medications cause immune cytopenia seem warranted.     

Magnetoencephalography in partial epilepsy: clinical yield and localization accuracy

The goals of this study were to determine (1) the yield of magnetoencephalography (MEG) according to epilepsy type, (2) if MEG spike sources colocalize with focal epileptogenic pathology, and (3) if MEG can identify the epileptogenic zone when scalp ictal electroencephalogram (EEG) or magnetic resonance imaging (MRI) fail to localize it. Twenty-two patients with mesial temporal (10 patients), neocortical temporal (3 patients), and extratemporal lobe epilepsy (9 patients) were studied. A 37-channel biomagnetometer was used for simultaneously recording MEG with EEG. During the typical 2-3-hour MEG recording session, interictal epileptiform activity was observed in 16 of 22 patients. MEG localization yield was greater in patients with neocortical epilepsy (92%) than in those with mesial temporal lobe epilepsy (50%). In 5 of 6 patients with focal epileptogenic pathology, MEG spike sources were colocalized with the lesions. In 11 of 12 patients with nonlocalizing (ambiguous abnormalities or normal) MRI, MEG spike sources were localized in the region of the epileptogenic zone as ultimately defined by all clinical and EEG information (including intracranial EEG). In conclusion, MEG can reliably localize sources of spike discharges in patients with temporal and extratemporal lobe epilepsy. MEG sometimes provides noninvasive localization data that are not otherwise available with MRI or conventional scalp ictal EEG.     

The orientation of a T cell receptor to its MHC class II:peptide ligands

The TCR found on CD4 T cells recognizes peptides bound to self MHC class II molecules as well as non-self MHC class II molecules. We have used the receptor on a cloned T cell line called D10.G4.1 (D10) to perform a structure-function analysis of this interaction. The D10 T cell clone recognizes not only a peptide from conalbumin (CA-wt) bound to syngeneic I-Ak against which it was raised, but also the allogeneic MHC molecules I-A(b,v,p,q,d). In the present study, we show that residue 30 in complementarity-determining region 1 (CDR1) of the TCR alpha-chain interacts with the I-A alpha-chain at hvr2 (residues 52, 53, and 55). We also show that residue 51 in CDR2 of the TCR alpha-chain interacts with the peptide at peptide residue 2. Finally, we show that residue 29 in CDR1 of the TCR beta-chain affects recognition of the glutamic acid at residue 66 in the I-A beta-chain. These data suggest an orientation of TCR relative to its peptide:MHC class II ligands. We argue that this orientation will be shared by all CD4 TCRs, and that it is only subtly different from the common orientation proposed for receptors binding to MHC class I.     

Disease ecology and a reformist alternative: the case of infant mortality

This paper attempts to shed some light on the recent debate between those who advocate a reformed medical geography and those who respond that reform is not necessary. We show that disease ecology and a reformist alternative display certain tendencies in the ways in which they address issues of health and disease. We use the example of geographic variations in infant mortality rates to show how two non-positivist perspectives from social theory, political economy and humanism, support a reformist viewpoint, while also acknowledging the value of a complementary disease ecology approach. Two concepts, the social construction of health and illness and social relevance, are used to portray the political economy approach; humanism is described in terms of the meaning of individual experience and the importance of place. The paper concludes with a discussion of the respective roles of disease ecology and a reformist approach in models of infant mortality and a summary of the main differences between the two perspectives.     

Hemoperitoneum caused by spontaneous rupture of a true splenic cyst

A 34 year-old man presented with hemoperitoneum from a spontaneously ruptured spleen. At laparotomy, a 5-cm diameter splenic cyst was found to be ruptured. Histological examination confirmed the diagnosis of a true splenic cyst of the mesothelial type. Spontaneous rupture with hemoperitoneum is a rare but potentially lethal complication of a true splenic cyst.     

The surgical management of giant cervicofacial lymphatic malformations

Giant cervicofacial lymphatic malformation, a potentially life-threatening congenital malformation, historically has been removed in staged resections. However, complete surgical extirpation is desirable and can be achieved with the aid of a multidisciplinary team. The authors present the case of a 12-year-old girl who had an extensively enlarged cervicofacial lymphatic malformation. Effective treatment involved aggressive surgical excision, facilitated by mandibular osteotomies to provide access to the floor of the mouth, the tongue, and the pharyngeal wall. In addition, total removal of involved facial and neck skin was performed. The remaining soft tissue defect was reconstructed primarily with an abdominal musculocutaneous free flap. In the 5 years since the procedure, there has been no recurrence. Based on this experience, excision of involved skin and mandibular access osteotomies are important techniques to help completely remove cervicofacial lymphatic malformations with oral involvement, thus potentially reducing the number of recurrences. In addition, these cases require the best efforts of a multidisciplinary team to achieve a successful result so that complete and radical excision can be performed with the hope of avoiding the pitfalls of multiple resections.     

Purification and partial characterization of (6-4) photoproduct DNA photolyase from Xenopus laevis

Liposarcomas of the head and neck are exceedingly rare, and fewer than 90 cases have been reported in the literature. Liposarcoma of the oral cavity is an even less common entity, and to our knowledge only nine cases have been reported to date. We report the clinical and pathologic findings of a case of well-differentiated liposarcoma of the base of tongue and tonsillar fossa. The patient is a 76-year-old white man with a long-standing history of a mass in the oral cavity and hypopharynx. The mass had been resected several times over the span of 23 years, and diagnoses of lipoma, neurofibroma, mesenchymoma, and angiofibrolipoma have been rendered on different occasions. At the last admission, a polypoid mass of the left tonsillar fossa and base of tongue was resected. The tumor was multinodular and measured 2.5 cm in greatest diameter. Histologically the tumor was ill-defined with infiltrating borders and was composed predominantly of mature adipose tissue with occasional lipoblasts. A small proportion of the tumor consisted of clusters of spindle cells and pleomorphic lipoblasts. Mitotic activity was not seen. The pleomorphic cells were positive for S100 protein and negative for muscle-specific markers. Ultrastructural analysis confirmed the nature of the lipoblasts. Our case depicts the typical natural history and histologic features of liposarcoma of the oral cavity. This tumor is usually well differentiated and has a high recurrence rate and almost no tendency for metastasis. Based on our case and review of the literature, it appears that well-differentiated liposarcoma of the oral cavity can occasionally be underdiagnosed because of the low mitotic activity and long latent period between the original diagnosis and first recurrence.