Longitudinal neurological follow-up of a group of HIV-seropositive and HIV-seronegative hemophiliacs: results from the hemophilia growth and development study

BACKGROUND: Boys and young men with hemophilia treated with factor infusions before 1985 had a substantial risk of acquiring the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome. This study was designed to assess the effects of HIV and hemophilia per se on neurological function in a large cohort of subjects with hemophilia, and to investigate the relationships between neurological disease and death during follow-up. METHODS: Three hundred thirty-three boys and young men (207 HIV seropositive and 126 HIV seronegative) were evaluated longitudinally in a multicenter, multidisciplinary study. Neurological history and examination were conducted at baseline and annually for 4 years. The relationship between neurological variables, HIV serostatus, CD4+ cell counts, and vital status at the conclusion of the study was examined using logistic regression models. RESULTS: The risks of nonhemophilia-associated muscle atrophy, behavior change, and gait disturbance increased with time in immune compromised HIV-seropositive subjects compared with HIV seronegative or immunologically stable HIV-seropositive subjects. The risk of behavior change in immune compromised HIV-seropositive hemophiliacs, for example, rose to 60% by year 4 versus 10% to 17% for the other study groups. Forty-five subjects (13.5%), all of whom were HIV seropositive, died by year 4. Subjects who died had had increased risks of hyperreflexia, nonhemophilia-associated muscle atrophy, and behavior change. CONCLUSIONS: These results indicate that immune compromised, HIV-seropositive hemophiliacs have high rates of neurological abnormalities over time and that neurological abnormalities were common among subjects who later died. By contrast, immunologically stable HIV-seropositive subjects did not differ from the HIV-seronegative participants. Hemophilia per se was associated with progressive abnormalities of gait, coordination, and motor function.     

RADIOACTIVE IRON AND ITS EXCRETION IN URINE,BILE, AND FECES

Radioactive iron as ferrous gluconate given by vein enables us to study iron excretion in urine, bile, and feces. There is an initial extra output in urine and feces during a few days (3 to 15 days) following the iron injection and this may total 2 to 8 per cent of the injected iron. Following this initial reaction the urinary excretion of radio-iron drops to traces or even to zero. The feces always contain measurable amounts of radio-iron—in five dogs receiving 100 to 250 mg. of radio-iron the fecal excretion per day settled down to 0.05 to 0.4 mg. per day. Blood destruction (acetyl-phenylhydrazine) causes a definite increase in radio-iron eliminated in the feces (0.1 to 1.0 mg. per day). Probably most of this excess iron comes through the biliary tract (bile fistula). The bile under usual conditions contributes very little iron to the intestine (0.01 mg. radio-iron per day or less). The body controls its iron stores by absorption or lack of it rather than by its capacity to eliminate it. The evidence is overwhelming that the dog excretes iron with difficulty and in small amounts (even in the plethoric state) by means of the biliary and gastro-intestinal tracts.     

RADIOACTIVE IRON AND ITS METABOLISM IN ANEMIA : ITS ABSORPTION,TRANSPORTATION, AND UTILIZATION

Artificially produced radioactive iron is an extremely sensitive agent for use in following iron in the course of its changes in body metabolism, lending itself to studies of absorption, transport, exchange, mobilization, and excretion. The need of the body for iron in some manner determines the absorption of this element. In the normal dog when there is no need for the element, it is absorbed in negligible amounts. In the anemic animal iron is quite promptly assimilated. The plasma is clearly the means of transport of iron from the gastrointestinal tract to its point of mobilization for fabrication into hemoglobin. The speed of absorption and transfer of iron to the red cell is spectacular. The importance of the liver and bone marrow in iron metabolism is confirmed.     

Computed axial tomography-MIBI image fusion for preoperative localization in primary hyperparathyroidism

BACKGROUND: An imaging-guided unilateral surgical approach in patients with primary hyperparathyroidism (HPTH) requires reliable preoperative localization procedures. Using present imaging techniques, 60% to 80% of patients with primary HPTH can be treated successfully with limited surgery. Thus, further improvement of diagnostic accuracy is required. Computed axial tomography (CAT)-MIBI image fusion was introduced as a new technique for localizing enlarged parathyroid glands. We describe the new method and present its first results. METHODS: Six consecutive patients with primary HPTH underwent CAT-MIBI image fusion for preoperative parathyroid localization. CAT and technetium-99m-sestamibi scan were performed separately. The patient's head and neck were fixed with the noninvasive Vogele-Bale-Hohner Head Holder (VBH HeadFIX; Medical Intelligence, Schwabmünchen, Germany) and the BodyFIX (Medical Intelligence) vacuum cushion. Radiographic and scintigraphic markers were mounted at the head holder and the patient. CAT and MIBI images were fused by overlaying radiographic markers using a commercial software and workstation. RESULTS: In 5 patients, localization and dimension of the solitary adenomas were exactly predicted. In 1 patient with multiglandular disease (3 enlarged glands), CAT-MIBI image fusion was not able to predict multiple gland involvement. However, in a retrospective analysis of the localization study, the other two enlarged parathyroid glands could be correctly identified regarding their site and size. CONCLUSIONS: First results of CAT-MIBI image fusion are promising. The new technique provides a higher image resolution and better delimitation of enlarged parathyroid glands and adjacent anatomic structures than conventional scintigraphic methods.     

Transforming growth factor-beta regulation of the insulin-like growth factor binding protein-4 protease system in cultured human osteoblasts.

IGFBP-4 is an inhibitor of IGF-I in bone. We show that TGF-beta regulates IGFBP-4 and enhances IGF-I-stimulated growth of cultured human bone cells through increased expression of an IGFBP-4 protease, PAPP-A. This effect of TGF-beta on IGF-I bioavailability may promote local bone formation. Insulin-like growth factor binding protein (IGFBP-4) proteolysis is implicated in the regulation of local insulin-like growth factor (IGF)-I bioavailability during bone remodeling. The IGFBP-4 protease secreted by normal adult human osteoblastic (hOB) cells in culture is a novel metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). We have recently identified an inhibitor of PAPP-A, the precursor form of major basic protein (proMBP). Very little is known about the molecular regulation of this IGFBP-4 protease system. In the present study, we determined the effect of transforming growth factor (TGF)-beta and IGF-II, the two most abundant growth factors in human bone, on PAPP-A and proMBP expression in primary cultures of hOB cells. Treatment with TGF-beta resulted in time- and dose-dependent increases in PAPP-A mRNA expression, with a maximal 12-fold increase after 24 h of stimulation with 10 ng/ml TGF-beta. Increased PAPP-A levels in hOB cell-conditioned medium paralleled PAPP-A gene expression. In addition, TGF-beta completely suppressed proMBP expression. Treatment of hOB cells with IGF-II had no effect on PAPP-A or proMBP gene expression. However, IGFBP-4 proteolysis in cell-free assay was dependent on IGF-II, and there was increased IGF-II-dependent IGFBP-4 protease activity in conditioned medium from hOB cells that were treated with TGF-beta. IGF-I stimulation of hOB cell proliferation was markedly enhanced by pretreatment with TGF-beta and [Leu27]IGF-II, and this enhancement was prevented with protease-resistant IGFBP-4. In summary, TGF-beta regulates IGFBP-4 proteolysis in hOB cells through increased expression of the protease, PAPP-A, and decreased expression of the inhibitor, proMBP. However, functional activation of the IGFBP-4 protease system is dependent on IGF-II, which acts at a post-translational level. These data support a model whereby local TGF-beta and IGF-II in the bone microenvironment coordinately amplify IGF-I bioavailability through controlled IGFBP-4 proteolysis, which may be a means to promote bone formation.     

Relationship of the clinical response and binding of recombinant interferon alpha in patients with lymphoproliferative diseases

Patients with hairy cell leukemia (HCL) and chronic lymphocytic leukemia (CLL) were treated with recombinant interferon alpha A (rIFN- alpha A). The binding of iodinated recombinant interferon-alpha to baseline samples of peripheral blood mononuclear cells (PBMCs) from the leukemia patients was compared with clinical responsiveness to rIFN- alpha A. HCL patients (8/10) responded to rIFN-alpha A therapy, whereas none (0/10) of the CLL patients studied responded. The PBMCs from the eight responsive HCL patients bound approximately twice as much iodinated interferon as the PBMCs from nonresponsive CLL patients. This difference was due to more high-affinity receptors per cell with no difference in the affinity of the interferon-receptor interaction. However, because PBMCs from HCL patients were larger than PBMCs from CLL patients, the cell surface receptor density was similar. The leukemic cells from one of the two nonresponsive HCL patients bound iodinated interferon similarly to the cells from the responsive HCL patients, whereas the leukemic cells from the other nonresponsive HCL patient bound considerably less. The rapidity of response of the HCL patients did not correlate with the level of binding of iodinated interferon. Our results suggest that the absolute number of interferon receptors per cell may be only one of several important parameters in the response to rIFN-alpha A therapy, and that the responsiveness of a particular lymphoproliferative disease or a particular patient to rIFN- alpha A therapy cannot be predicted or explained solely by the degree of interaction between IFN and its cell surface receptor.     

Intrauterine cytomegalovirus infection and glycoprotein B genotypes

Cytomegalovirus (CMV) strains display polymorphisms for the gene encoding glycoprotein B (gB; gpUL55). Recent data suggest that the gB genotype may influence the outcome of acquired CMV infections. To determine whether the gB genotype also contributes to the outcome of intrauterine infection, CMV strains were studied from 56 infants with culture-confirmed intrauterine CMV infections who were born in Iowa or Texas. CMV gB genotypes were compared with the neonatal clinical features and neurodevelopmental outcomes. Fifty-three strains (95%) could be assigned a gB genotype. The overall distribution of genotypes was as follows: type 1, 50%; type 2, 18%; type 3, 23%; and type 4, 4%. Strains with the gB 3 genotype were more common among the Iowa infants (P=.082). The gB 3 genotype was more common among infants with asymptomatic infections (P=.004), but geographic location and ascertainment biases may have accounted for these differences. The gB genotypes did not correlate with the neurodevelopmental outcome of intrauterine infection.