Abnormalities in Monocyte Recruitment and Cytokine Expression in Monocyte Chemoattractant Protein 1–deficient Mice

Monocyte chemoattractant protein 1 (MCP-1) is a CC chemokine that attracts monocytes, memory T lymphocytes, and natural killer cells. Because other chemokines have similar target cell specificities and because CCR2, a cloned MCP-1 receptor, binds other ligands, it has been uncertain whether MCP-1 plays a unique role in recruiting mononuclear cells in vivo. To address this question, we disrupted SCYA2 (the gene encoding MCP-1) and tested MCP-1–deficient mice in models of inflammation. Despite normal numbers of circulating leukocytes and resident macrophages, MCP-1^−/− mice were specifically unable to recruit monocytes 72 h after intraperitoneal thioglycollate administration. Similarly, accumulation of F4/80+ monocytes in delayed-type hypersensitivity lesions was impaired, although the swelling response was normal. Development of secondary pulmonary granulomata in response to Schistosoma mansoni eggs was blunted in MCP-1^−/− mice, as was expression of IL-4, IL-5, and interferon γ in splenocytes. In contrast, MCP-1^−/− mice were indistinguishable from wild-type mice in their ability to clear Mycobacterium tuberculosis. Our data indicate that MCP-1 is uniquely essential for monocyte recruitment in several inflammatory models in vivo and influences expression of cytokines related to T helper responses.     

Imaging apolipoprotein AI in vivo

Coronary disease risk increases inversely with high-density lipoprotein (HDL) level. The measurement of the biodistribution and clearance of HDL in vivo, however, has posed a technical challenge. This study presents an approach to the development of a lipoprotein MRI agent by linking gadolinium methanethiosulfonate (Gd[MTS-ADO3A]) to a selective cysteine mutation in position 55 of apo AI, the major protein of HDL. The contrast agent targets both liver and kidney, the sites of HDL catabolism, whereas the standard MRI contrast agent, gadolinium-diethylenetriaminepentaacetic acid-bismethylamide (GdDTPA-BMA, gadodiamide), enhances only the kidney image. Using a modified apolipoprotein AI to create an HDL contrast agent provides a new approach to investigate HDL biodistribution, metabolism and regulation in vivo.     

Abnormal white matter in a neurologically intact child with incontinentia pigmenti

Incontinentia pigmenti is an X-linked neurocutaneous disorder which is often lethal in males. Ectodermal tissues are involved, and affected females often have abnormalities of skin, teeth, hair, eyes, and the central nervous system. Central nervous system involvement ranges from none to multiple strokes, seizures, and mental retardation. Deletions in the nuclear factor kappa beta essential modulator gene at Xq28 are present in 70-80% of patients with incontinentia pigmenti. White matter abnormalities have been reported in females with significant neurologic involvement. This report describes a neurologically intact child with deletion positive incontinentia pigmenti with significant white matter involvement, broadening the scope of this finding in incontinentia pigmenti.     

The hemoglobin glycation index is not an independent predictor of the risk of microvascular complications in the Diabetes Control and Complications Trial

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy aimed at improved glucose control markedly reduced the risk of diabetes complications compared with conventional therapy. The principal determinant of risk was the history of glycemia. Recently, McCarter et al. (Diabetes Care 27:1259-1264, 2004) have presented analyses of the publicly available DCCT data using their hemoglobin glycation index (HGI), which is computed as the difference between the observed HbA1c (A1C) and that predicted from the level of blood glucose. In their analyses, the HGI level was a significant predictor of progression of retinopathy and nephropathy in the DCCT, which the authors claimed to support the hypothesis that the biological propensity for glycation, so-called biological variation in glycation, is another mechanism that determines risk of complications. However, we have criticized these analyses and conclusions because, from statistical principles, the glycation index must be positively correlated with the A1C level and thus may simply be a surrogate for A1C. Herein, we present the statistical properties of the glycation index to document its high correlation with A1C. We then replicate the analyses of McCarter et al. using both the HGI and the A1C together. Analyses show conclusively that the glycation index is not an independent risk factor for microvascular complications and that the effect of the glycation index on risk is wholly explained by the associated level of A1C. The HGI should not be used to estimate risk of complications or to guide therapy.     

Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia

To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity.     

Chiari I malformation and neurofibromatosis type 1

Single case reports exist in the medical literature of patients with tonsillar ectopia, i.e., the Chiari I malformation and neurofibromatosis type 1. However, large series of patients with either of these entities have not been examined for the presence of both defects. We have retrospectively examined two large groups of pediatric patients: Group I, with the primary diagnosis of Chiari I malformation, who have undergone posterior fossa decompression for symptomatology; and Group II patients, who have been observed in our hospital's neurofibromatosis clinic for evaluation. Of 130 surgically addressed Chiari I malformations (Group I), we determined that 5.4% of these patients had the additional diagnosis of neurofibromatosis type 1. Of Group II patients (198) who underwent imaging of the brain, 8.6% were found to have a concomitant Chiari I malformation. These data suggest that Chiari I malformation and neurofibromatosis type 1 are not spurious findings but rather true associations. We hypothesize that the same early dysgenesis of mesoderm that is widely accepted as a culprit in the genesis of many Chiari I malformations is the same pathology affecting primitive development of tissues involved in many patients with neurofibromatosis type 1. Perhaps these data will aid in the determination of a genetic locus for the Chiari I malformation.