STUDIES ON TUBERCULIN FEVER : II. OBSERVATIONS ON THE ROLE OF ENDOGENOUS PYROGEN IN TOLERANCE

Certain characteristics of tolerance which develops to the pyrogenic effects of old tuberculin (OT) in BCG-vaccinated rabbits have been described. Rabbits made tolerant by several injections of OT lost their ability to produce detectable amounts of endogenous pyrogen (EP) in response to the specific agent (OT) but mobilized normal amounts of EP when given a small unrelated stimulus. On the other hand, when this stimulus followed shortly after an initial tuberculin fever of sufficient magnitude, release of additional EP was suppressed, presumably due to an inhibitory effect of the EP previously mobilized by tuberculin. Similarly, a single large dose of endotoxin almost completely suppressed the response of sensitized rabbits to OT given several hours later. Since several spaced injections of the same dosage were ineffective, this phenomenon does not appear to be attributable to the known mechanisms by which endotoxins promote non-specific resistance to toxicity and infection. Tolerance to tuberculin could not be definitely shown following an injection of Newcastle disease virus which also produces a circulating EP, and it has been inferred that endotoxin blocks the pyrogenic action of antigen on host tissues directly rather than through mobilizing EP. On the basis of these observations, the relationship of specific to non-specific tolerance to tuberculin fever has been compared in terms of the ability of such tolerant animals to mobilize EP to heterologous stimuli and it is concluded that the two forms of tolerance are different. Furthermore, the fact that a number of unrelated agents produce tolerance non-specifically supports the concept that there may be a common source of EP released by a number of stimuli, including endotoxins and myxoviruses, as well as antigen in specifically sensitized hosts.     

Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations

Arylsulfatase A (ASA) knockout mice represent an animal model for the lysosomal storage disease metachromatic leukodystrophy (MLD). Stem cell gene therapy with bone marrow overexpressing the human ASA cDNA from a retroviral vector resulted in the expression of high enzyme levels in various tissues. Treatment partially reduces sulfatide storage in livers exceeding 18 ng ASA/mg tissue, while complete reduction was observed in livers exceeding 50 ng ASA/mg tissue. This corresponds to about 80% and 200% of normal enzyme activity. Similar values seem to apply for kidney. A partial correction of the lipid metabolism was detectable in the brain where the galactoerebroside/sulfatide ratio, which is diminished in ASA-deficient mice, increased upon treatment. This partial correction was accompanied by amelioration of neuropathology; axonal cross-sectional areas, which are reduced in deficient mice, were significantly increased in the saphenic and sciatic nerve but not in the optic nerve. Behavioral tests suggest some improvement of neuromotor abilities. The gene transfer did not delay the degeneration occurring in the acoustic ganglion of ASA-deficient animals. The limited success of the therapy appears to be due to the requirement of unexpected high levels of ASA for correction of the metabolic defect.     

Reversible oxidative modification: implications for cardiovascular physiology and pathophysiology

Reminiscent of phosphorylation, cellular signaling can induce reversible forms of oxidative modification of proteins with an impact on their function. Redox signaling can be coupled to cell membrane receptors for hormones and be a physiologic means of regulating protein function, whereas pathologic increases in oxidative stress may induce disease processes. Here we review the role of reversible oxidative modification of proteins in the regulation of their function with particular emphasis on the cardiac Na(+)-K(+) pump. We describe how protein-kinase-dependent activation of redox signaling, mediated by angiotensin receptors and β adrenergic receptors, induces glutathionylation of an identified cysteine residue in the β(1) subunit of the α/β pump heterodimer; and we discuss how this may link neurohormonal abnormalities, increased oxidative stress, and cardiac myocyte Na(+) dysregulation and heart failure with important implications for treatment.     

Transcranial Magnetic Stimulation at M1 disrupts cognitive networks in schizophrenia

Transcranial Magnetic Stimulation (TMS) is rapidly gaining acceptance as a non-invasive probe into brain functionality. We utilize TMS to study the connectivity of a simple motor network in patients of schizophrenia (N=19), and in healthy control subjects (N=9). TMS was used in an externally paced finger tapping task, perturbing the internal network oscillations invoked by the finger motion as it keeps pace with a metronome. TMS perturbations were synchronized to the metronome and applied to the network at the level of the primary motor cortex (M1). Contrary to initial expectations, TMS did not affect the sensorimotor synchronization of subjects with schizophrenia or their tapping accuracy. TMS did cause extreme deviations in the finger's trajectory, and altered the timing perceptions of subjects with schizophrenia. Additionally, it invoked high-level deficiencies related to attention and volition in the form of lapses, implying that the connectivity between modules in the brain that underlie motor control, sensorimotor synchronization, timing perception and awareness of action, can be disrupted by TMS in subjects with schizophrenia, but not in healthy subjects. The ability to disrupt high level network functions with perturbations to the lower level of M1 supports models describing deficits in connectivity of distributed networks in the brains of schizophrenia patients. It also demonstrates the use of TMS to probe connectivity between components of such networks.     

Civilian and detainee orthopaedic surgical care at an Air Force theater hospital

This study is a retrospective analysis of the orthopaedic care rendered to Iraqi citizens, both military and civilian, and detainees in Balad, Iraq, at an Air Force theater hospital. Defining the scope of care for this patient group and emphasizing the differences in care provided for the endemic population in contrast to the rapidly air-evacuated Coalition injured combatant are the primary focus of the study. Approximately 50% of more than 1600 trauma/combat-related injury admissions to Air Force Theater Hospital in Balad, Iraq, from the period of September 2, 2005 through January 18, 2006, were Iraqi citizens and detainees. The care rendered to this population differed from the care given to a rapidly air-evacuated patient in that definitive care of all combat wounds, including fracture care and soft tissue management, was the responsibility of the deployed surgeons. Open reduction and internal fixation, definitive debridement, Wound VAC placement (Vacuum-Assisted Closure Device; KCI International, San Antonio, Tex), and final soft tissue management were performed at Air Force Theater Hospital. All patients were treated according to their injuries, including detainees, who received the same level of care as any other injured patient. This article will depict examples of the civilian and detainee orthopaedic care available and performed in a war zone and how that care differed from that rendered to a rapidly evacuated American combatant. Injured Coalition combatants received high-level damage control orthopaedic care and initial debridements, with external fixation as the single most common means of long-bone fracture stabilization. Civilians and detainees seen at Balad received the same high-level care and much, if not all, of their definitive care while at Air Force Theater Hospital. The care rendered to Iraqi citizens and detainees at an Air Force theater hospital is described, with multiple case examples that reflect a high level of definitive care offered in a war zone.