Treatment of HCV positive individuals with normal serum ALT levels

A substantial number of cases of chronic hepatitis C infection can be shown to have normal or near normal serum ALT levels. Major questions that arise when such cases are seen are: should such patients be treated; if so for how long; and what is the end point of therapy. The reported experience of such patients treated by IFN is reviewed.     

Risk factors in the pathogenesis of coronary artery disease

In men, plaque rupture is strongly correlated with total cholesterol, and smoking is a predictor of acute thrombosis. In women younger than 50, plaque erosion correlates with smoking, whereas in women older than 50, thrombosis is secondary to plaque rupture and correlates with total cholesterol.     

Radiological assessment of a new bone densitometer--the Lunar EXPERT

Dual energy X-ray absorptiometry (DXA) is one of the most widely used techniques in the management of osteoporosis and other skeletal diseases. Although patient doses from DXA are generally low, it is still necessary to measure them to assess the risk of radiation injury. We report on a study to estimate the effective dose (ED) to patients and staff from a new DXA scanner--the Lunar EXPERT, and make a comparison with a similar study carried out on a Lunar DPX-L. The entrance surface doses were measured to be 895 microGy and 10.25 microGy for the EXPERT and DPX-L, respectively. The EXPERT maximum EDs were calculated to be 74.7 microSv and 44.9 microSv for the anteroposterior (AP) lumbar spine and the proximal femur, respectively. More than 50% reduction in ED could be achieved by using a smaller scanning width. The maximum EDs for the DPX-L were calculated to be 0.21 microSv and 0.15 microSv for the AP lumbar spine and the proximal femur, respectively. The scattered dose rates (ambient dose equivalent) were measured to be less than 2 and less than 1 microSv h-1 at 50 cm and 100 cm, respectively, for the DPX-L, and the equivalent values for the EXPERT were 240 and 64 microSv h-1. Although both the patient dose and scattered dose rates are quite low relative to other radiological examinations, good practice aimed at dose reduction should still be implemented. Whilst protection for the operator is not needed for the DPX-L system, it may be (depending on the size of the room) for the EXPERT system.     

Regional distribution of neurotrophin receptors in the developing auditory brainstem

Neuron survival and axonal regeneration become severely limited during early postnatal development. In conjunction with our recent organotypic analysis of regeneration in the auditory midbrain, we wished to determine whether neurotrophins could serve as a trophic substance during the postnatal period. Therefore, the current study examines the development of three neurotrophin receptor tyrosine kinases (TrkA, TrkB, and TrkC) in the gerbil auditory brainstem. Immunoreactivity to TrkA, the nerve growth-factor receptor, was observed in nonneuronal cells during the first two postnatal weeks. In the cochlear nucleus of mature animals, however, there was a TrkA-positive neuronal subpopulation. In contrast, immunoreactivity to TrkB and TrkC (the receptors for brain-derived neurotrophic factor and neurotrophin-3, respectively) displayed a widespread distribution in the auditory brainstem. At postnatal day 0, TrkB and TrkC staining was virtually absent from auditory nuclei, although immunopositive neurons were present in the mesencephalic trigeminal nucleus. By postnatal day 7, TrkB- and TrkC-positive neurons were present in most brainstem auditory nuclei. At postnatal day 15, TrkB immunoreactivity was observed throughout the inferior colliculus (IC), the cochlear nucleus, the medial and lateral nuclei of the trapezoid body, and the lateral superior olive, whereas TrkC labeled only a subpopulation of neurons within the central nucleus of the IC. The TrkB immunoreactivity was present on both neuronal somata and dendrites, whereas TrkC was generally restricted to cell bodies. At postnatal day 30, TrkB immunostaining was observed on most neurons of the IC. The medial and lateral nuclei of the trapezoid body displayed extremely strong TrkB staining, followed by the cochlear nucleus. In contrast, the TrkC immunostaining was decreased dramatically by postnatal day 21. Observations at the ultrastructural level confirmed a neuronal localization of TrkB and TrkC. Immunostaining for both receptors was restricted largely to the postsynaptic density of synaptic profiles in both dendrites and somata. In summary, this study illustrates a differential pattern of immunoreactivity between three neurotrophin receptors during development. The general increase of TrkB expression is well correlated with the onset of sound-evoked activity in this system, and its synaptic localization suggests that it may be involved in the modulation or maintenance of postsynaptic physiology.     

An isoleucine to valine substitution in Escherichia coli acyl carrier protein results in a functional protein of decreased molecular radius at elevated pH

Escherichia coli acyl carrier protein (ACP) has been reported to exist in at least two distinct conformers in solution. A novel form of ACP having an increased electrophoretic mobility on polyacrylamide gel electrophoresis was noted previously during work on beta-ketoacyl-acyl carrier protein synthase II (fabF) mutants of E. coli (Jackowski, S., and Rock, C. O.(1987) J. Bacteriol. 169, 1469-1473). These workers reported that the increased electrophoretic mobility of the ACP from fabF strains occurred irrespective of prosthetic group attachment or the state of acylation of the prosthetic group. Since these workers were unable to detect a difference between the amino acid sequence of the ACP from the fabF mutants and that of wild type ACP, they suggested that the increased electrophoretic mobility was due to an unknown post-translational modification of the polypeptide chain. We have reinvestigated these mutants and report that the increased electrophoretic mobility is due to a mutation within the gene (acpP) that encodes ACP. This mutation results in substitution of isoleucine for valine 43 of ACP. Site-directed mutagenesis of a synthetic ACP gene demonstrated that the amino acid substitution at residue 43 is the cause of the increased electrophoretic mobility. Gel filtration experiments indicated that the increased electrophoretic mobility results from the more compact structure of V43I ACP at high pH. The altered residue lies within the ACP region of greatest conformational lability, and thus the V43I substitution may shift the equilibrium toward the more compact conformation(s). The disulfide-linked dimer of V43I ACP was readily formed and had an electrophoretic migration greater than the dimer of wild type ACP, suggesting that formation of ACP.ACP dimers does not require structural deformation of the protein.     

Fluorescence studies of the location and membrane accessibility of the palmitoylation sites of rhodopsin

Fluorescent fatty acid labels have been incorporated into the palmitoylation sites of rhodopsin and used to probe the membrane accessibility and location of these sites. The fluorescence properties of anthroyloxy and pyrenyl fatty acids bound to rhodopsin were investigated in a reconstituted vesicle system. Collisional quenching of fluorescence by stearic acid (DSA) labeled with doxyls in the 16, 12, and 5 positions was used to determine the membrane accessibility and disposition of the modifying fatty acids. To properly determine the membrane concentration of these quenchers, the dependence of the Stern-Volmer parameters on both quencher and vesicle concentration was determined. An analysis of these dependences provided a correction for partitioning of the quencher between the aqueous phase and the membrane. After this correction, the relative effectiveness of doxyl quenchers was 16-DSA > 12-DSA > 5-DSA. Parallel studies on free anthroyloxy and pyrenyl fatty acids incorporated into the reconstituted system showed the same dependence on quencher position. These results indicate that the labels at the palmitoylation sites of rhodopsin are situated in the membrane much as a free fatty acid. This anchoring of the palmitates in the membrane results in the formation of a fourth cytoplasmic loop.     

Growth hormone treatment of children with neural tube defects: results from 6 months to 6 years

OBJECTIVE: Patients with neural tube defects (myelomeningocele) have severe growth retardation, and treatment with recombinant human growth hormone (rHGH) for 6 months accelerates growth velocity. We examined patients treated for longer periods to determine whether accelerated growth persists, and whether patients demonstrated to be growth hormone deficient have a greater response to rHGH therapy. METHODS: We retrospectively evaluated the growth rate and length standard deviation score (SDS) of 22 patients in response to treatment with 0.3 mg/kg per week of rHGH for 7 to 72 months. Nine of 22 patients were growth hormone deficient (nocturnal and provocative growth hormone responses < 7 ng/ml). Treatment success was defined as an increase of length SDS of > 0.2 SD per year. RESULTS: Fourteen patients (64%) had treatment successes, and eight had treatment failures. Length SDS improved from a pretreatment value of -2.9 (+/- 1.2) to the most recent length SDS of -1.9 (+/- 1.4) (p < 0.001). The growth rate was significantly increased through year 4 of treatment. The annualized growth rate after 6 months of rHGH treatment was significantly different for the success and failure groups (11.0 +/- 2.6 cm/yr vs 5.1 +/- 3 cm/yr, p < 0.001). The annualized 6-month growth rate during treatment was related to the probability of treatment success. CONCLUSION: Treatment with rHGH significantly improves the growth rate and length SDS of children with neural tube defects. The 6-month annualized growth velocity during treatment was predictive of long-term treatment response. The effect on adult stature is unknown.