Effect of age at menarche on microvascular complications among women with Type 1 diabetes.

AIM: To test the hypothesis that delayed menarche is associated with an increased microvascular complication risk among women with Type 1 diabetes. METHODS: We studied the female participants of an ongoing prospective study of childhood-onset Type 1 diabetes diagnosed during the period 1950-1980. Of 325 women, we included data from 315 who had reached menarche by the study baseline (1986-1988) and who self-reported their age at menarche. Both cross-sectional and prospective analyses over the 25-year follow-up were used to assess the relationship of age at menarche with the prevalence, incidence and cumulative incidence of microvascular complications, comprising overt nephropathy, proliferative retinopathy and confirmed distal symmetric polyneuropathy. RESULTS: In cross-sectional analyses at baseline, the odds of overt nephropathy increased 1.24 times (P=0.02) with each annual increase in age at menarche, and 3.2 times (P=0.009) in those with delayed menarche compared with women with normal menarche onset, after adjustment. Similarly, the cumulative incidence of overt nephropathy increased 1.16 times (P=0.01) with each older year of menarche and women with delayed menarche were at twofold increased risk of overt nephropathy (hazard ratio 2.30, P=0.001) compared with women with normal menarche onset. However, age at menarche was not significantly associated with either proliferative retinopathy or confirmed distal symmetric polyneuropathy after adjusting for covariates. CONCLUSIONS: Age at menarche was significantly associated with the prevalence and cumulative incidence of overt nephropathy, but not with proliferative retinopathy or confirmed distal symmetric polyneuropathy in Type 1 diabetes. Women with delayed menarche may therefore be targeted for early screening and timely interventions to prevent the development of nephropathy.

Suprasellar cavernous malformation presenting with extensive subarachnoid hemorrhage.

Cavernous malformations are usually intraparenchymal, extra-axial lesions being uncommon. They have very rarely been reported as the cause of subarachnoid hemorrhage. We present a case of hemorrhage related to a cavernous malformation, unusual in two ways. First, it is rare for an intracranial cavernous malformation to present with massive subarachnoid hemorrhage. Secondly, this cavernous malformation lay in the chiasmatic cistern.

Short note: a novel approach for treating early-stage acute leukemias.

A novel approach to treating acute leukemias is suggested by hypothesizing a focal unique origin in a focal area of bone marrow and this area can be localized (and ablated) before the leukemia stem cells have seeded other bone marrows.

The prevalence and CT appearance of the levator claviculae muscle: a normal variant not to be mistaken for an abnormality.

BACKGROUND AND PURPOSE: The levator claviculae muscle is an infrequently recognized variant in humans, occurring in 2% to 3% of the population, and has rarely been reported in the radiologic or anatomic literature. The importance of this muscle to radiologists is in distinguishing it from an abnormality; most commonly, cervical adenopathy. After discovering this muscle on the CT scans of two patients during routine clinical examinations, we conducted a study to determine the prevalence and appearance of the muscle on CT studies. METHODS: We evaluated 300 CT scans that adequately depicted the expected location of the muscle. The most superior level in which the muscle could be identified and the apparent location of insertion on the clavicle were recorded for all subjects in whom the muscle was detected. RESULTS: Seven levator claviculae muscles were identified in six subjects (2%). It was bilateral in one, on the left in four, and on the right in one. It was identified up to the level of the transverse process of C3 in all cases. The insertion was the middle third of the clavicle for two muscles and the lateral third of the clavicle for the remaining five muscles. CONCLUSION: Because the levator claviculae muscle will most likely be encountered during a radiologist's career, it is important to recognize this muscle as a variant and not as an abnormality.

Targeting retroviral vectors to CD34-expressing cells: binding to CD34 does not catalyze virus-cell fusion.

We have attempted to engineer murine leukemia virus (MuLV)-based retroviral vectors to specifically transduce cells expressing human CD34, an antigen present on the surface of undifferentiated hematopoietic stem cells. A number of chimeric ecotropic MuLV envelope (Env) proteins were constructed that contained anti-CD34 single-chain antibody variable fragments (scFvs). The scFv-Env proteins were generated either by replacing the receptor-binding domain of Env with the scFv or by inserting the scFv into the N terminus of the Env protein. Only chimeric Env proteins with scFv insertions between amino acids 6 and 7 were incorporated into viral particles, and coexpression of native MuLV Env did not rescue incorporation-defective proteins. In addition, the efficiency of incorporation varied with the specific anti-CD34 scFv that was used. Retroviral vectors containing the scFv-Env proteins bound to CD34+ cells and transduced NIH 3T3 cells expressing human CD34 (3T3-CD34 cells) at approximately twice the efficiency of the parental NIH 3T3 cells. However, the introduction of the mutation D84K, which prevents binding to the ecotropic MuLV receptor mcat-1, prevented transduction of both NIH 3T3 and 3T3-CD34 cells. Complementation cell-cell fusion assays [Zhao et al. (1997). J. Virol. 71, 6967-6972] in 3T3-CD34 cells revealed that although the scFv-Env proteins could contribute postbinding entry functions when bound to mcat-1, they were unable to do so when bound to CD34. Taken together, these data suggest that although the interaction with CD34 effectively increased the concentration of virus on 3T3-CD34 cells, entry could occur only through an interaction with mcat-1; CD34 alone was not capable of triggering the appropriate postbinding changes that lead to viral entry.

Autoantibodies to leukocyte alphaMbeta2 integrin glycoproteins in HIV infection.

HIV infection is often associated with polyclonal B-cell activation, autoantibodies, and clinically evident autoimmune disease. Because neutropenia and anti-neutrophil autoantibodies are common clinical features of HIV disease, we studied a series of HIV+ patients to determine whether anti-alphaMbeta2 integrin (MAC-1) specific anti-neutrophil autoantibodies occur in HIV disease, as we have shown to occur in patients with immune neutropenia not associated with HIV. Two new assays specific for anti-alphaMbeta2 IgG were developed to carry out these studies: an ELISA method using affinity-purified alphaMbeta2 integrin protein, and a flow cytometry method using subclones of the 293 human fetal kidney cell line, stably transfected with cDNAs for the alphaM and/or beta2 integrin subunits. In studies of the sera of 20 untreated HIV+ individuals, anti-alphaMbeta2 activity was detected in 9 (45%) by one or the other of these assays and in 5 (25%) by both assays. Seven of the 20 HIV+ study subjects had unexplained neutropenia, and of these, 6 (86%) were positive for anti-alphaMbeta2 autoantibodies. Our findings indicate that anti-alphaMbeta2 integrin autoantibodies are frequent in HIV+ individuals, particularly when unexplained neutropenia is also present, and raise the possibility that these autoantibodies may have a role in the acquired neutrophil dysfunction and increased risk of nonopportunistic bacterial infections observed in HIV disease.

Autologous peripheral blood stem cell transplantation for lung cancer.

Lung carcinoma, the most frequent cause of cancer-related death in both men and women, remains a difficult therapeutic problem. Small-cell lung carcinoma, despite its high response rate to chemotherapy, is associated with a rapid recurrence and ultimately limited overall survival. In attempts to exploit tumour chemosensitivity, high-dose chemotherapy (HDC) combining several active drugs has been studied to improve outcome. In addition, haematopoietic stem cell support has been used to allow dose escalation without major myelosuppression. In contrast to small-cell carcinoma, non-small-cell carcinoma of the lung is generally not very responsive to chemotherapy, and results with dose intensity in unresectable tumour have so far been very disappointing. We review the results of HDC in terms of response and survival, and discuss potential strategies to improve the effectiveness of dose intensity.

Immunological recovery and tumour-specific immunotherapeutic approaches to post-autologous haematopoietic stem cell transplantation.

Haematological recovery following autologous peripheral blood stem cell treatment is very rapid. Immune recovery is a more prolonged process requiring a year or more for full reconstitution. Because high-dose chemotherapy followed by autologous peripheral blood stem cell treatment results in (or is presumed to result in) minimal burden of residual malignant disease it provides a potentially ideal setting for immune-mediated anti-tumour therapy. The slow immune reconstitution following transplantation may however hamper the development of effective immunotherapy. Among different approaches proposed, we focus on the potential use of tumour antigens in conjunction with cellular therapy in an attempt to eliminate residual tumour following autologous transplantation.

Interobserver reliability of detecting lumbar intervertebral disc high-intensity zone on magnetic resonance imaging and association of high-intensity zone with pain and anular disruption.

STUDY DESIGN: Retrospective analysis of a spine imaging center's records of patients with chronic low back pain referred by tertiary care facilities. OBJECTIVES: 1) To assess the interobserver reliability of detecting lumbar intervertebral disc high-intensity zone on T2-weighted magnetic resonance imaging, and 2) to assess the relation between high-intensity zone and discography or post-computed tomography in symptomatic patients with low back pain. SUMMARY OF BACKGROUND DATA: Two of the three previous studies on this subject found an association between high-intensity zone and the presence of Grade 4 anular disruption with discographic reproduction of patients' exact low back pain. METHODS: Records of patients with low back pain who had undergone lumbar spine discography injection and post-computed tomography from June 1995 to August 1996 were reviewed. Two independent observers were asked to identify the presence of an high-intensity zone from the T12-L1 disc to L5-S1 on T2-weighted magnetic resonance images. With this data, interobserver reliability was assessed with the kappa statistic. Concordant high-intensity zone results were then compared with the Dallas Discogram rating for anular disruption and to patients' subjective pain response to discography injection. With this data, the sensitivity, specificity, and predictive values of high-intensity zone for detecting disc disruption and pain response were calculated. RESULTS: The interobserver reliability for detecting a high-intensity zone in a given disc was fair to good (kappa = 0.57; 95% confidence interval = 0.44, 0.70). The sensitivity of high-intensity zone for detecting Grade 4 anular disruption and exact pain was poor (31%) but its specificity was relatively high (90%). The positive predictive value of a high-intensity zone was low (40%) for a severely disrupted and exactly painful disc. CONCLUSIONS: The interobserver reliability of detecting a high-intensity zone and the positive predictive value of the presence of a high-intensity zone for detecting a severely disrupted and exactly painful disc were much lower than previous studies have shown. The relatively low positive predictive value may be attributable to differences in sample characteristics or procedural variations, or suggest that a high-intensity zone is not indicative of exactly painful internal intervertebral disc disruption.

Integral and shell-MIP display algorithms in MR and CT three-dimensional models of the brain surface.

BACKGROUND AND PURPOSE: Our purpose was to demonstrate the use of integral and shell maximum intensity projection (shell-MIP) display algorithms in the 3-D CT and MR depiction of cerebral gyral and surface venous anatomy and disorders. These new algorithms are compared against MIP and shaded-surface-display (SSD) algorithms. METHODS: Integral and shell-MIP displays were generated from a specified number of proximal surface voxel layers in a 3-D model. Algorithmic models were compared on nine contrast-enhanced spoiled gradient-recalled acquisition in a steady state (SPGR) MR venograms for brain surface anatomic identification and detail. Seven CT venograms were compared for conspicuity of filling defects. Twelve contrast-enhanced preoperative planning 3-D MR models were rated for neurosurgical utility. RESULTS: A shell-MIP score of 7.00 and an integral score of 6.78 represented the highest mean subjective MR gyral quality (1-10 scale) followed by an SSD score of 3.89 and an MIP score of 1.06. Mean confidence scores for MR central sulcus identification (1-10 scale) were shell-MIP, 7.67; integral, 7.00; SSD, 3.22; and MIP, 1.00. Mean superficial venous quality MR ratings (1-10 scale) were shell-MIP, 8.22; MIP, 7.39; integral, 7.00; and SSD, 3.72. The mean number of cortical veins draining into each side of the superior sagittal sinus on MR was as follows: MIP, 6.19; integral, 6.06; shell-MIP, 5.94; and SSD, 3.81. Mean confidence scores for filling defect identification on CT venograms (1-5 scale) revealed a shell-MIP score of 4.36 and an integral score of 4.29 to be superior to a MIP score of 3.00. In selected cases, 3-D presurgical planning, prior to tumor resection, was clinically useful. CONCLUSION: Integral and shell-MIP are useful 3-D display algorithms for simultaneous display of superficial cerebral veins and gyri on MR images and of thrombosis on CT venograms.

Anti-CD34+ Fabs generated against hematopoietic stem cells in HIV-derived combinatorial immunoglobulin library suggest antigen-selected autoantibodies.

Bone marrow suppression associated with HIV infection does not appear to be solely due to direct viral cytopathic effects. Autoantibodies may play a role in myelosuppression, however it is unclear whether autoantibodies produced in HIV infection represent a primary pathogenic process or merely reflect polyclonal B cell activation. To address these questions, we generated combinatorial immunoglobulin libraries using the pComb3 phagemid from an HIV+ individual with evidence of circulating autoantibodies. From one library, three anti-CD34 Fabs were identified using fresh CD34+ cells as antigenic targets by a method of phage subtraction. The anti-CD34 Fabs are specific by immunoblotting and Elisa and are of high affinity, with calculated Kds in the range of 10(-7) -10(-8) M. Nucleic acid sequencing revealed all three to be of the VH3 family and to have lambda light chains with some gene segments expressing little somatic mutation, while other segments were somatically mutated in patterns suggestive of antigen selection. These findings indicate that (1) A subset of HIV-associated anti-CD34 autoantibodies are monospecific and antigen-selected and are not merely a consequence of polyclonal B cell activation and elevated Ig levels in HIV. Autoreactivity in HIV therefore includes both polyspecific, low affinity antibodies as well as monospecific antigen-selected high affinity antibodies. (2) Although bone marrow suppression in HIV is likely to be multifactorial, autoantibodies to hematopoietic stem cells may contribute to its pathogenesis. (3) Library sampling of VH gene family rearrangements shows no evidence for under-representation of the VH3 family in the immune dysregulation of HIV infection. Phage subtraction is corroborated to be an effective means of identifying, cloning, and characterizing antibodies to hematopoietic differentiation antigens.

T2-weighted three-dimensional turbo spin-echo MR of intracranial aneurysms.

A T2-weighted three-dimensional turbo spin-echo sequence is described that accurately depicted the anatomy of 18 intracranial aneurysms in 10 patients.

MR enhancing brain lesions in methanol intoxication.

Methanol intoxication can cause necrosis of the putamen and subcortical white matter that is evident on neuroimaging. We report a 47-year-old man with significant methanol intoxication who had enhancing lesions in the caudate nuclei, putamina, hypothalamus, and subcortical white matter by MRI. This case demonstrates that contrast enhancement of brain lesions can be observed after methanol poisoning.

Asymptomatic pontine lesions found by magnetic resonance imaging: are they central pontine myelinolysis?

Clinicians occasionally receive radiographic reports noting pontine lesions in their patients who have undergone magnetic resonance imaging (MRI) for symptoms not referable to the pons. Based on these relatively isolated lesions, patients may receive the presumptive radiographic diagnosis of central pontine myelinolysis (CPM). Review of our MRI database from the last five years identified twelve such patients with hyperintense pontine lesions on T2-weighted scans which were out of proportion to supratentorial white matter disease processes and unexplained by the remainder of their radiographic studies. In an attempt to further clarify whether these findings were more consistent with CPM or some other process, we reviewed these patients' clinical records with particular attention to electrolyte disturbances, alcoholism, liver disease and hypertension. We also compared the MRI studies from these twelve patients with four MRI scans from patients with clinically diagnosed CPM and with eight post-mortem MRI scans on autopsy-proven asymptomatic CPM. By comparing pre- and post-mortem scans, five of the twelve unknown pontine lesions were felt to be too large to represent asymptomatic CPM. Five were thought to be incompatible with CPM based on shape and/or discohesiveness; one of these came to autopsy and showed cerebral and pontine ischemic rarefaction, not CPM. Only two of these twelve cases were felt to be asymptomatic or mildly symptomatic CPM, but have not come to autopsy. We conclude that pontine lesions found incidentally on MRI scans are a heterogeneous group, many of which are more consistent with pontine ischemic rarefaction than with asymptomatic CPM.

The development of the corpus callosum in semilobar and lobar holoprosencephaly.

OBJECTIVE: The objective of this study was to determine whether and how a true corpus callosum develops in milder cases of holoprosencephaly. MATERIALS AND METHODS: The MR scans of seven patients with holoprosencephaly and a callosum-like structure were reviewed. The anatomy of the callosum-like structure and the pericallosal anatomy were evaluated. RESULTS: Six of the seven cases had a posterior corpus callosum. The seventh case was indeterminate because lack of myelination prevented confirmation that the callosum-like structure consisted only of white matter. In each case the posterior corpus callosum formed posterior to white matter which spanned the interhemispheric fissure beneath a layer of cortical gray matter. CONCLUSION: A posterior corpus callosum can develop in holoprosencephaly because the first callosal axons use the white matter of the undivided hemispheres as a bridge to cross the interhemispheric fissure.

Peripheral blood mononuclear cells from autologous hematopoietic stem cell transplantation recipients produce and respond to IL-12.

Autologous hematopoietic stem cell transplantation effectively results in restoration of hematopoiesis, but induces an often prolonged period of T cell dysfunction including redistribution of T cell subsets and defective T cell proliferation. Because IL-2 production is markedly decreased following autologous stem cell engraftment, and because IL-12 has direct stimulatory effects on TH1 cells, a major source of IL-2, we investigated the production and responsiveness of IL-12 of peripheral blood mononuclear cells (PBMC) of autologous stem cell recipients in the first 6 months following engraftment. When stimulated with S. aureus Cowan I (SAC), PBMC from autologous hematopoietic transplant recipients in the early months following engraftment show no decrease in production of IL-12 as compared to control PBMC. Furthermore, transplant-derived PBMC appear to be functionally responsive to exogenously provided IL-12 as indicated by several criteria. In vitro proliferation of total PBMC and of isolated CD4+ T cells from transplanted recipients to PHA (1 microgram/ml) + IL-12 (20 U/ml) was comparable to controls, excluding the possibility that only NK or CD8+ cells respond to IL-12. Culture of both control and transplant-derived PBMC in PHA + IL-12 (20 U/ml) or IL-2 (100 U/ml) + IL-12 (20 U/ml) combinations yielded comparable production of IFN-gamma, one of the major biological effects of IL-12 in vivo, as well as equal production of TNF-alpha, a costimulatory factor of IL-12-mediated induction of IFN-gamma by NK cells. Taken together, this in vitro evidence suggests that following autologous transplantation, PBMC do not appear to have either decreased production of endogenous IL-12 or defective functional responsiveness to exogenously provided IL-12.