31P magnetic resonance spectroscopy is sensitive to tumor hypoxia: perfusion and oxygenation of rat 9L gliosarcoma after treatment with BCNU

The mechanism behind the relative increase in high-energy phosphates observed by MRS in many tumors following chemotherapy is poorly understood. To test the hypothesis that this metabolic activation is associated with a decrease in tumor hypoxia, tumor blood flow and oxygenation were measured in tumors that were also analyzed by MRS. 31P MR spectra were acquired with a GE 2T CSI spectrometer from subcutaneous 9L tumors in rats 4 days following treatment with BCNU (10 mg/kg) and from age-matched sham-treated control tumors. BCNU-treated tumors (n = 13) underwent a significant improvement in bioenergetic state compared to control tumors (n = 14), showing a relative increase in high-energy phosphate (Pi/phosphocreatine) (p less than 0.01), and a relative decrease in Pi (Pi/alpha nucleoside biphosphate) (p less than 0.01). Gamma camera imaging of 133Xe washout, following injection of 133Xe in saline into control and treated 9L tumors 4 days after treatment, was used to measure tumor perfusion. Sham-treated control tumors (n = 21) were perfused at a rate of 35.4 (+/- 6.4 SE) mL/100 g/min, while BCNU-treated tumors (n = 20) were perfused at a rate of 55.1 (+/- 7.5 SE) mL/100 g/min (T = 1.96; p less than 0.05). The partial pressure of oxygen (pO2), measured with a polarographic electrode was found to be significantly higher in treated 9L than in sham-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human ocular counterroll: assessment of static and dynamic properties from electromagnetic scleral coil recordings

Summary Static and dynamic components of ocular counterroll as well as cyclorotatory optokinetic nystagmus were measured with a scleral search coil technique. Static counterroll compensated for about 10% of head roll when the head was tilted to steady positions up to 20 deg from the upright position. The dynamic component of counterroll, which occurs only while the head is moving, is much larger. It consists of smooth compensatory cyclorotation opposite to the head rotation, interrupted frequently by saccades moving in the same direction as the head. During voluntary sinusoidal head roll, cyclorotation compensated from 40% to more than 70% of the head motion. In the range 0.16 to 1.33 Hz, gain increased with frequency and with the amount of visual information. The lowest values were found in darkness. The gain increased in the presence of a visual fixation point and a further rise was induced by a structured visual pattern. Resetting saccades were made more frequently in the dark than in the light. These saccades were somewhat slower than typical horizontal saccades. Cyclorotatory optokinetic nystagmus could be induced by a patterned disk rotating around the visual axis. It was highly variable even within a same subject and had in general a very low gain (mean value about 0.03 for stimulus velocities up to 30 deg/s). It is concluded that cyclorotational slip velocity on the retina is considerably reduced by counterroll during roll of the head, although the residual cyclorotation after the head has reached a steady position is very small.     

Optokinetic nystagmus in the rabbit and its modulation by bilateral microinjection of carbachol in the cerebellar flocculus

Summary 1. In the alert, pigmented rabbit, eye movements were recorded during optokinetic nystagmus (OKN) and during optokinetic afternystagmus (OKAN). These responses were elicited by steps in surround-velocity ranging from 5–110°/s during binocular as well as monocular viewing. 2. In the baseline condition, OKN showed an approximately linear build-up of eye velocity to a steady-state, followed by a linear decay of eye velocity during OKAN after the lights were turned off. Build-up during binocular viewing was characterized by a constant, maximum eye-acceleration (about 1°/s²) for stimulus velocities up to 60°/s. OKAN, instead, was characterized by a fixed duration (about 10 s) for stimulus velocities up to 20°/s. Steady-state eye velocity saturated at about 50°/s. 3. Monocular stimulation in the preferred (nasal) direction elicited a build-up that was on average twice as slow as during binocular stimulation. Steady-state velocity during monocular stimulation saturated at about 20°/s. OKAN was of equal duration as during binocular stimulation. In the non-preferred direction, a very irregular nystagmus was elicited without velocity build-up. The stronger response to binocular stimulation, compared to the responses under monocular viewing condition in either nasal and temporal direction suggests potentiation of the signals of either eye during binocular viewing. 4. OKN and OKAN were re-assessed after intra-floccular microinjection of the nonselective cholinergic agonist carbachol. In the binocular viewing condition, eye-acceleration during build-up was strongly enhanced from 1°/s² before to 2.5°/s² after injection. The saturation level of steady-state eye velocity was also increased, from 50°/s before to more than 60°/s after carbachol. The duration of OKAN, however, was shortened from 10 s before to 6 s after injection. The response to monocular stimulation in the preferred direction revealed similar changes. 5. The flocculus appears to be involved in the control of the dynamics of OKN in the rabbit. Cholinergic mechanisms affect the floccular control of the rate at which slow-phase velocity can be built up and the rate of decay of eye velocity during OKAN. Cholinergic stimulation of the flocculus enhances the dynamics of OKN, while velocity storage is shortened.     

Injections of beta-noradrenergic substances in the flocculus of rabbits affect adaptation of the VOR gain

Noradrenaline (NA) has been implicated as a neuromodulator in plasticity, presumably facilitating adaptive processes. Recent experiments by others have suggested a modulatory role of NA in adaptive changes in the vestibulo-ocular reflex (VOR). These experiments showed that general depletion of brain NA resulted in a decreased ability to produce adaptive changes in the VOR gain. In order to identify the specific brain region responsible for these effects, as well as the nature of the adrenoceptors involved, we injected beta-adrenergic substances bilaterally into the flocculus of rabbits. The flocculus is known to receive noradrenergic afferents and, moreover, ablation of the flocculus interferes strongly with the normal adaptive changes in the VOR gain. We injected the beta-agonist isoproterenol and the beta-antagonist sotalol, and compared the adaptive capacity of the rabbits after these injections to that in a situation without injection. The rabbit was oscillated in a direction opposite to the direction of motion of the platform on which the rabbit was mounted, a condition which normally results in an increase in the VOR gain, measured either in light or in darkness. Injection of the beta-agonist did not greatly affect the adaptation of the VOR measured in the light. In darkness, the increase in gain after the injection of isoproterenol was larger than in the non-injection experiments in 9 out of 10 rabbits. The beta-antagonist sotalol reduced the adaptation of the VOR gain significantly in the light, as well as in darkness. In a control condition without pressure for adaptation (only intermittent testing of the VOR gain over a period of 2.5 h), the gain of the VOR either remained unaffected or was only slightly affected by similar injections of beta-adrenergic agents in individual rabbits. For the group as a whole, these effects were insignificant. We conclude from these results that noradrenergic systems facilitate the adaptation of the VOR gain to retinal slip in rabbits, without affecting the VOR gain directly. At least part of this influence is exerted through beta-receptors located in the cerebellar flocculus.     

Neutralizing antibodies in gene-defective hosts

In a host with a normal immune system and a complete gene defect, the nondefective gene product will be immunogenic. Consequently, neutralizing antibodies against the respective protein can arise either 'spontaneously' or after immunization, as shown in patients and in animal models, such as knockout mice. Accordingly, patients with X-linked or homozygous autosomal gene defects are at risk of developing neutralizing antibodies, in particular after protein substitution or gene therapy. This Review compares and exemplifies the various genetic and immunological contexts that lead to 'neutralizing and generated by gene defect' or 'nagged' antibodies, and outlines implications and solutions for therapeutic strategies.     

Ultrastructure of the Kidney in Acute Interstitial Nephritis

Fifteen percutaneous renal biopsies from patients with acute renal failure due to acute interstitial nephritis (AIN), in almost all cases due to drugs, were studied by electron microscopy. Differential counting of interstitial cells showed an average of 69% lymphocytes (small and large) and 11 % macrophages. Plasma cells and eosinophils were comparatively rare. The infiltrate resembled that of acute rejection, suggesting a cellular hypersensitivity reaction. Proximal and distal tubules were severely affected focally. Migration of lymphocytes through the tubular basement membrane of otherwise well-preserved tubules was considered to be the first phase. Other tubules showed extreme thinning of the tubular basement membrane, with still intact cellular walls. Rupture of the tubular basement membrane and necrotic disintegration of tubular epithelial cells are probably late phenomena. The non-necrotic tubules displayed severe reduction of proximal brush border and proximal as well as distal tubular basolateral infoldings. Focal tubular disintegration leading to tubular block and/or backleak as well as decrease of proximal tubular sodium resorption leading to a decreased glomerular filtration (a mechanism probably also acting in ischemic acute renal failure) may all be factors responsible for the acute renal failure in AIN.     

Sexual Contact as Risk Factor for Campylobacter Infection,Denmark

Campylobacteriosis is a disease of worldwide importance, but aspects of its transmission dynamics, particularly risk factors, are still poorly understood. We used data from a matched case-control study of 4,269 men who have sex with men (MSM) and 26,215 controls, combined with national surveillance data on Campylobacter spp., Salmonella spp., and Shigella spp., to calculate matched odds ratios (mORs) for infection among MSM and controls. MSM had higher odds of Campylobacter (mOR 14, 95% CI 10–21) and Shigella (mOR 74, 95% CI 27–203) infections, but not Salmonella (mOR 0.2, 95% CI 0–13), and were less likely than controls to have acquired Campylobacter infection abroad (χ² = 21; p<0.001). Our results confirm that sexual contact is a risk factor for campylobacteriosis and also suggest explanations for unique features of Campylobacter epidemiology. These findings provide a baseline for updating infection risk guidelines to the general population.