Human brain metabolic response to caffeine and the effects of tolerance

OBJECTIVE: Since there is limited information concerning caffeine's metabolic effects on the human brain, the authors applied a rapid proton echo-planar spectroscopic imaging technique to dynamically measure regional brain metabolic responses to caffeine ingestion. They specifically measured changes in brain lactate due to the combined effects of caffeine's stimulation of glycolysis and reduction of cerebral blood flow. METHOD: Nine heavy caffeine users and nine caffeine-intolerant individuals, who had previously discontinued or substantially curtailed use of caffeinated products because of associated anxiety and discomforting physiological arousal, were studied at baseline and then during 1 hour following ingestion of caffeine citrate (10 mg/kg). To assess state-trait contributions and the effects of caffeine tolerance, five of the caffeine users were restudied after a 1- to 2-month caffeine holiday. RESULTS: The caffeine-intolerant individuals, but not the regular caffeine users, experienced substantial psychological and physiological distress in response to caffeine ingestion. Significant increases in global and regionally specific brain lactate were observed only among the caffeine-intolerant subjects. Reexposure of the regular caffeine users to caffeine after a caffeine holiday resulted in little or no adverse clinical reaction but significant rises in brain lactate which were of a magnitude similar to that observed for the caffeine-intolerant group. CONCLUSIONS: These results provide direct evidence for the loss of caffeine tolerance in the human brain subsequent to caffeine discontinuation and suggest mechanisms for the phenomenon of caffeine intolerance other than its metabolic effects on elevating brain lactate.     

Idiopathic thrombocytopenic purpura in a liver transplant recipient with previous primary biliary cirrhosis

The loss of immunotolerance has been implicated in the pathogenesis of both primary biliary cirrhosis (PBC) and idiopathic, immune-mediated thrombocytopenic purpura (ITP). An association between these two autoimmune diseases has been well described. We describe a 41-year-old woman in whom ITP developed 457 days after liver transplantation for PBC while receiving immunosuppressive medications sufficient to maintain allograft function. Our case report, the first to describe post-transplant ITP in association with PBC, demonstrates the persistence of the underlying immune dysregulation of PBC after transplantation. The practice of decreasing the dosage of immunosuppressive medication to maintenance levels after transplantation may unmask the effects of this defect in immunotolerance.     

Mode of chemotherapy does not affect complications with an implantable venous access device

BACKGROUND: Few reports have been made regarding the long term safety of implantable venous access devices used for the delivery of chemotherapeutic agents. The authors' goals were to determine the frequency of complications in patients receiving chemotherapy with these devices; to determine whether complications were associated with the mode of chemotherapy delivery (push/bolus or infusional regimens); and to evaluate the influence of other risk factors, including home-based versus hospital-based administration. METHODS: A total of 152 oncology patients at the John L. McClellan Memorial Veterans Administration Medical Center in Little Rock, Arkansas (ages 26-81 years; mean age, 62 years), who underwent surgical placement of an Infus-a-Port (Strato, Inc., Beverly, MA) between May 1, 1992 and May 31, 1994, were evaluated retrospectively for postplacement device complications, such as infection, thrombosis, and mechanical failure. RESULTS: Twenty-seven patients experienced 1 complication each: 17 episodes of device-related sepsis, cellulitis, or fever of unknown origin; 8 episodes of thrombosis or catheter occlusion; 1 episode of drug extravasation; and 1 mechanical failure. Patient age, frequency of port accession, mode of chemotherapy delivery, tumor type, and neutropenia were evaluated as risk factors, but none was statistically significant. Complications were more frequent during the first 90 days after implantation, but they continued to occur throughout the observation period. CONCLUSIONS: Complications attributable to an implantable venous access device were infrequent in this patient population. No differences in complications for patients receiving home-based versus hospital-based chemotherapy administration were noted, opening the possibility of significant time and cost savings with home treatment.     

Heterogeneity of glomerular perfusion and filtration induced by epinephrine and norepinephrine

The role of catecholamines in the distribution of intrarenal blood flow and in single-nephron glomerular filtration rate (SNGFR) was evaluated in anesthetized Wistar rats by the Hanssen technique. Epinephrine (EPI) and norepinephrine (NOR) were infused to produce elevations of 20-30 mmHg in mean arterial pressure. Superficial and juxtamedullary nephron perfusion and filtration were determined by the presence of Prussian blue dye. In the control group, 100% of the nephrons presented a homogeneous pattern of perfusion and filtration. In contrast, a heterogeneous distribution of the dye was found even in the larger arteries (arciform and radial), indicating variable perfusion and filtration in both superficial and juxtamedullary nephrons. The effects of EPI and NOR were also evaluated in the superficial cortex by the micropuncture technique in two additional groups of Munich-Wistar rats. Mean SNGFR was 27% and 54% lower in the EPI- and NOR-treated groups, respectively. No change in mean intraglomerular hydraulic pressure was observed after EPI or NOR infusion in spite of a highly scattered pattern, indicating an important variability in perfusion along the superficial cortex, and/or different sensitivity of the pre- and post-glomerular arterioles. The present data suggest that EPI and NOR may affect intrarenal hemodynamics by modifying perfusion and filtration in both superficial and juxtamedullary glomeruli and not by shifting blood flow from superficial to juxtamedullary nephrons. The heterogeneous pattern of perfusion was a consequence of differential vasoconstriction along the intrarenal arteries, probably due to different density and/or sensitivity of the adrenergic receptor subtypes present in the intrarenal vascular tree.     

A paradigm of experimentally induced mild hyperthyroidism: effects on nitrogen balance, body composition, and energy expenditure in healthy young men

OBJECTIVE: To conceptualize, with fine needle aspiration cytology (FNAC), the early cellular events occurring in and around fresh autogenous and allogenic bone grafts during the first 40 postimplantation days. STUDY DESIGN: Forty-eight cases of bone grafts were studied by FNAC at serial intervals of 10, 20, 30 and 40 postimplantation days. Twenty patients were recipients of autogenous grafts, 16 received 0.6N HCI partially decalcified allogenic bone implants, and 4 received combined autogenous and allogenic bone grafts (included in the allograft group). There were eight control cases of closed fracture shaft femur, which were managed conservatively. RESULTS: The initial cellular responses in autogenous grafts, allografts and controls appear to be a part of the nonspecific reparative process followed by a more specific phase, with a steady increase in relative lymphocyte count from the 20th day onwards. Osteogenesis, as judged by osteoblasts and osteoclasts, was also comparable. CONCLUSION: Partially decalcified allografts appear to be a good substitute for autogenous bone grafts in clinical practice when adequate autogenous material is not available. FNAC is a good technique for studying bone graft responses without interfering with graft uptake. It is helpful in the early detection of subclinical infection or any other pathology at the graft site.     

Amino-terminal charge affects the periplasmic accumulation of recombinant heregulin/EGF hybrids exported using the Escherichia coli alkaline phosphatase signal sequence

An Escherichia coli expression system that exploits the bacterial alkaline phosphatase (PhoA) signal sequence to translocate recombinant human epidermal growth factor (hEGF) to the periplasm was used to evaluate how changes in the composition and sequence of amino acids near the PhoA-hEGF junction influence the periplasmic accumulation of recombinant protein. A series of chimeric structural genes was generated by in vitro replacement of hEGF sequence with analogous segments from the EGF-like domain of human heregulin (HRG), significantly altering the electrostatic character of the amino-terminal region of the mature protein. Quantitation of HRG/EGF protein in E. coli periplasmic extracts, by RP-HPLC, showed a fourfold decrease after one of two acidic residues located in the amino-terminal region of the mature hEGF, near the PhoA junction, was replaced. An additional threefold decrease was observed when the second acidic residue was replaced with a positively charged lysine. Further extension of the amino-terminal HRG sequence, beyond the first six residues, resulted in net neutralization of a more distant EGF acidic residue with no additional effect on protein yield. The importance of having a negatively charged group in the amino-terminal region of the mature protein was confirmed when insertion of an aspartic acid near the amino-terminus of two poorly expressed hybrid protein sequences resulted in a five- to eightfold increase in their recovery from the periplasm. This study demonstrates the importance of having negatively charged residues near the fusion junction of recombinant proteins expressed in E. coli using the PhoA signal sequence for protein export.