Endocrine profile of children with intrauterine growth retardation

BACKGROUND: Intrauterine growth retardation (IUGR) is a major cause of short stature in childhood. Most but not all children experience catch-up growth by 2 years of age. METHODS: We investigated the endocrine profile (thyroid function, prolactin, cortisol, C-peptide and insulin-like growth factor-I [IGF-IJ levels) of 57 children with IUGR, aged 2-10 years, and compared it with 30 controls whose birth weight was appropriate-for-gestational-age. RESULTS: The hormonal profile for both groups was similar for thyroid hormones, prolactin, C-peptide and IGF-I. Cortisol levels were significantly lower in the IUGR group compared to controls (p <0,05). When the IUGR group was divided into 'catch-up' growth and 'non-catch-up' subgroups, the latter had significantly lower IGF-I levels (p <0.001). CONCLUSIONS: Lower cortisol levels in children born with IUGR may reflect impaired function of the hypothalamic-pituitary-adrenal axis associated with this condition. The significantly lower IGF-I levels of the 'non-catch-up' subgroup may be involved in their failure to grow.     

Cognitive patterns and progression in multiple sclerosis: construction and validation of percentile curves

BACKGROUND AND OBJECTIVES: Rate and pattern of progression of cognitive decline in multiple sclerosis (MS) has not been clearly identified. The present study aimed to identify correlations between cognitive tests and disease duration, construct longitudinal cognitive curves, and assess pattern of change over time. METHODS: The Neuropsychological Screening Battery for Multiple Sclerosis was administered in 150 consecutive MS patients, and tests that correlated with disease duration were identified. Percentile curves were constructed and the pattern of cognitive decline over time explored. The cognitive curves were validated in an additional group of 83 patients with MS. RESULTS: Three of four measures of the spatial recall test (SPART 7/24), and the paced auditory serial addition task for two seconds (PASAT 2'), correlated with disease duration. These tests were used to construct cross-sectional curves identifying the pattern of cognitive decline over time in the MS population. On the basis of this cross-sectional analysis, the earliest cognitive decline occurred in the SPART 7/24 trials 1-5 between one and three years from onset, followed by decline in the SPART delayed recall between three and seven years, and then by decline in the PASAT 2' after seven years from onset. CONCLUSIONS: Verbal fluency and verbal memory appear to be affected earliest in MS. The pattern of cognitive decline is further characterised by a decrease in visuospatial learning, followed by delayed recall, and then by attention and information processing speed. Cognitive percentile curves can be used to evaluate the pattern of progression and identify patients at increased risk.     

Second hepatitis C replication compartment indicated by viral dynamics during liver transplantation

BACKGROUND/AIMS: The existence of an extrahepatic hepatitis C virus replication compartment is an important question for optimizing therapy and preventing the infection of liver grafts. An extraheptic replication compartment could be indicated if viral decline during the anhepatic phase is not a single exponential. However, the duration of the anhepatic phase is too short (0.5-2h) to allow such analysis. Here we mathematically analyze viral decline during liver transplantation beyond the period of the anhepatic phase and examine the possibility of viral compartmentalization. METHODS: Viral load of 30 patients undergoing liver transplantation was frequently measured. Simulation and non-linear fitting of differential equation models were used to test different compartmentalization hypotheses. RESULTS: In 16 of the patients (56%), a bi-phasic viral decline was observed which is explained by the existence of a second replication compartment. This extrahepatic compartment is responsible for about 3.1% of virus in circulation and the mean half-life of its infected cells is 2.6 days. The remaining patients, with a single exponential decline, have either a second compartment with relatively low contribution or no second compartment. CONCLUSIONS: These results provide a first quantitative picture of the extrahepatic hepatitis C viral contribution and may suggest new approaches for viral clearance.     

Lower dose intraventricular T-PA fibrinolysis: case report

BACKGROUND: Recombinant tissue plasminogen activator (rtPA) intraventricular fibrinolysis has been demonstrated to be efficacious in clearing blood from the ventricular system. Preliminary studies indicate it may improve survival. There have also been reports of adverse affects from intraventricular fibrinolysis. Optimal dosing of rtPA has not been established. METHODS: A 40-year-old patient with intraventricular hemorrhage extension secondary to a ruptured aneurysm was treated with a one-time infusion of 1 mg of rtPA through a right ventriculostomy. RESULTS: Computed tomography scans demonstrated excellent resolution of intraventricular blood and improvement in cerebral spinal fluid flow after fibrinolysis. Fibrinolysis was most marked in the third and fourth ventricles. There were no adverse effects noted. CONCLUSIONS: Intraventricular fibrinolysis is effective at a lower dose than previously used. Lower doses may have fewer adverse affects.     

Semaphorin-3F is an inhibitor of tumor angiogenesis

The neuropilin-1 (np1) and neuropilin-2 (np2) receptors form complexes with type-A plexins. These complexes serve as signaling receptors for specific class-3 semaphorins. Np1 and np2 function in addition as receptors for heparin-binding forms of vascular endothelial growth factor (VEGF), such as VEGF(165). Human umbilical vein endothelial cells (HUVEC) express tyrosine-kinase receptors for VEGF and basic fibroblast growth factor (bFGF), as well as np1, np2, and several type-A plexins. We have found that semaphorin-3F (s3f), a semaphorin which signals through the np2 receptor, was able to inhibit VEGF(165), as well as bFGF-induced proliferation of HUVECs. Furthermore, s3f inhibited VEGF as well as bFGF-induced phosphorylation of extracellular signal-regulated kinase-1/2. Our experiments indicate that bFGF does not bind to neuropilins, nor does s3f inhibit the binding of bFGF to FGF receptors. It is therefore possible that s3f inhibits the activity of bFGF by a mechanism that requires active s3f signal transduction rather than by inhibition of bFGF binding to FGF receptors. s3f also inhibited VEGF(165), as well as bFGF-induced in vivo angiogenesis as determined by the alginate micro-encapsulation and Matrigel plug assays. Overexpression of s3f in tumorigenic human HEK293 cells inhibited their tumor-forming ability but not their proliferation in cell culture. The tumors that did develop from s3f-expressing HEK293 cells developed at a much slower rate and had a significantly lower concentration of tumor-associated blood vessels, indicating that s3f is an inhibitor of tumor angiogenesis.     

CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 participate in the retention of normal hematopoietic stem cells within the bone marrow (BM) and their release into the circulation. Homing and engraftment of human stem cells in immunodeficient mice are dependent on cell surface CXCR4 expression and the production of BM SDF-1, which acts also as a survival factor for both human and murine stem cells. However, the role of SDF-1/CXCR4 interactions in the control of human acute myelogenous leukemia (AML) cell trafficking and disease progression is poorly understood. In this study, we report that although some AML cells do not express surface CXCR4, all AML cells tested express internal CXCR4 and SDF-1. Culture of AML cells with SDF-1 promoted their survival, whereas addition of neutralizing CXCR4 antibodies, SDF-1 antibodies, or AMD3100 significantly decreased it. Pretreatment of primary human AML cells with neutralizing CXCR4 antibodies blocked their homing into the BM and spleen of transplanted NOD/SCID/B2m(null) mice. Furthermore, weekly administrations of antihuman CXCR4 to mice previously engrafted with primary AML cells led to a dramatic decrease in the levels of human AML cells in the BM, blood, and spleen in a dose- and time-dependent manner. Interestingly, the same treatment did not affect significantly the levels of normal human progenitors engrafted into NOD/SCID mice. Taken together, our findings demonstrated the importance of the SDF-1/CXCR4 axis in the regulation of in vivo motility and development of human AML stem cells and identified CXCR4 neutralization as a potential treatment for AML.