Retinal degeneration but not obesity is observed in null mutants of the tubby-like protein 1 gene.

The tub gene is a member of a small, well conserved neuronal gene family of unknown function. Mutations within this gene lead to early-onset blindness and deafness, as well as late-onset obesity and insulin resistance. To test the hypothesis that mutations within other members of this gene family would lead to similar phenotypes as observed in tubby mice, and hence have similar functional properties, we have generated null mutants of the tubby-like protein ( Tulp ) 1 gene by homologous recombination. Similarly to tubby mice, Tulp1 (-/-)mice exhibit an early-onset retinal degeneration with a progressive, rapid loss of photoreceptors, further supporting the notion that previously identified mutations within the human TULP1 gene are indeed causative of retinitis pigmentosa. However, in contrast to tubby mice, Tulp1 (-/-)mice exhibited normal hearing ability and, surprisingly, normal body weight despite the fact that both TUB and TULP1 are expressed in the same neurons within the hypothalamus in areas known to be involved in feeding behavior and energy homeo stasis. However, TUB and TULP1 show a distinctly different staining pattern in the nucleus of these neurons, perhaps explaining the difference in body weight between the Tulp1 (-/-)and tubby mutant mice.

Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice.

PURPOSE: To characterize ocular abnormalities associated with iris atrophy in DBA/2J mice and to determine whether mice of this strain develop elevated intraocular pressure (IOP) and glaucoma. METHODS: Different approaches, including slit-lamp biomicroscopy, ophthalmoscopic examination, ultrasound backscatter microscopy, and histology were used to examine the eyes of DBA/2J mice ranging from 2 to 30 months old. IOP was measured in DBA/2J mice of different ages. RESULTS: DBA/2J mice were found to develop pigment dispersion, iris transillumination, iris atrophy, anterior synechias, and elevated IOP. IOP was elevated in most mice by the age of 9 months. These changes were followed by the death of retinal ganglion cells, optic nerve atrophy, and optic nerve cupping. The prevalence and severity of these lesions increased with age. Optic nerve atrophy and optic nerve cupping was present in the majority of mice by the age of 22 months. CONCLUSIONS: DBA/2J mice develop a progressive form of secondary angle-closure glaucoma that appears to be initiated by iris atrophy and the associated formation of synechias. This mouse strain represents a useful model to evaluate mechanisms of pressure-related ganglion cell death and optic nerve atrophy, and to evaluate strategies for neuroprotection.

Auditory ERPs to non-target stimuli in schizophrenia: relationship to probability, task-demands, and target ERPs.

The effects of task demands and stimulus probability on the N1 and P2 components of the auditory event-related potential (ERP) to non-target stimuli were investigated in normal and medicated schizophrenic subjects. Subjects either read a book while tones were presented, or counted the rare (low probability) tones in an auditory oddball paradigm. The mismatch negativity to rare tones in the reading condition was present, and did not differ between groups. N1 amplitude was smaller in schizophrenic patients in all conditions. When subjects counted the rare tones, the amplitude and latency of P2 increased. This task-related effect on P2 was much greater in control than in schizophrenic subjects. Difference ERPs were used to better characterize the effect of task demands by subtracting the ERP in the reading condition from the ERP in the counting condition. The difference ERP consisted of a negative deflection at 182 ms, and a positive deflection at 276 ms, which were both reduced in schizophrenic subjects. N2 and P3 amplitude to target stimuli were reduced in patients as well, but these abnormalities were uncorrelated with N1 and P2 abnormalities to non-target stimuli. Despite automatic registration of stimulus mismatch, and normal processing speed, patients showed deficient task-related modulation of processing to both non-target and target stimuli. Reduction of N1 amplitude in schizophrenia occurs regardless of task demands, and may reflect a chronic, early-stage disturbance in information processing.

Parametric manipulations of auditory stimuli differentially affect P3 amplitude in schizophrenics and controls.

Schizophrenics show P3 amplitude reduction and topographic asymmetries. It is unclear whether the underlying cause of these deficits is primarily functional or structural. This study examined the effect of stimulus discriminability and task instruction on behavioral performance and P3 in schizophrenics and normal control subjects. Stimulus discriminability was manipulated by varying the overall loudness and pitch disparity of the two tones in an auditory oddball paradigm. Instructions emphasized either speed or accuracy of response. Instructions had no significant effects on reaction time, perceptual sensitivity, response bias, or P3. With increased discriminability, however, both groups improved in mean reaction time to targets and perceptual sensitivity. In controls, P3 became earlier and larger with increased stimulus discriminability and was consistently larger over left temporal areas than over right temporal areas. In schizophrenics, P3 latency was related to stimulus discriminability, but amplitude was not; P3 amplitude did not increase with improvement of perceptual sensitivity and reaction time. Unlike normal controls, schizophrenics had a P3 asymmetry at temporal sites, with reduced left-sided voltages. The results are not consistent with a primarily functional cause of P3 aberrations in schizophrenia and are compatible with the hypothesis that P3 amplitude deficits in schizophrenia are related to underlying pathophysiology of temporal lobe generator sites.

Laparoscopically guided blood salvage and autotransfusion in splenic trauma: a case report.

Salvage of intraperitoneal blood with autotransfusion is a well-accepted practice. Laparoscopic examination is gaining popularity and holds diagnostic promise for the evaluation of trauma patients. We describe herein the successful combination of these techniques in a patient who sustained blunt abdominal trauma, facilitating splenic salvage, autotransfusion, and avoidance of laparotomy.

Modification of liver fatty acid metabolism in mice by n-3 and n-6 delta 6-desaturase substrates and products.

The effects of dietary supplementation of either alpha-linolenic acid (18:3(n-3)) or stearidonic acid (18:4(n-3)) in combination with either linoleic acid (18:2(n-6)) or gamma-linolenic acid (18:3(n-6)) on liver fatty acid composition in mice were examined. Essential fatty acid deficient male C57BL/6 mice were separated into four groups of seven each and were fed a fat-free semi-purified diet supplemented with 1% (w/w) fatty acid methyl ester mixture (1:1), 18:2(n-6)/18:3(n-3), 18:2(n-6)/18:4(n-3), 18:3(n-6)/18:3(n-3), or 18:3(n-6)/18:4(n-3). After 7 days on the diets, fatty acid compositions in liver phosphatidylcholine and phosphatidylethanolamine fractions were analyzed. In groups fed 18:4(n-3) (18:2(n-6)/18:4(n-3) or 18:3(n-6)/18:4(n-3)) as compared to those fed 18:3(n-3) (18:2(n-6)/18:3(n-3) or 18:3(n-6)/18:3(n-3)), the levels of 20:4(n-3), 20:5(n-3) and 22:5(n-3) were increased, whereas those of 20:3(n-6) and 20:4(n-6) were decreased. When 18:3(n-6) replaced 18:2(n-6) as the source of n-6 acids, the levels of 18:3(n-6), 20:3(n-6), 20:4(n-6) and 22:5(n-6) were increased, whereas those of 20:4(n-3) and 20:5(n-3) were reduced. Replacing 18:3(n-3) by 18:4(n-3) reduced the (n-6)/(n-3) ratio by approx. 30%, whereas replacing 18:2(n-6) by 18:3(n-6) increased the (n-6)/(n-3) ratio by approx. 2-fold. These findings indicated that delta 6-desaturase products were metabolized more readily than their precursors. Both products also competed for the subsequent metabolic enzymes. However, the n-6 fatty acids derived from 18:3(n-6) were incorporated more favourably into liver phospholipids than n-3 fatty acids derived from 18:4(n-3).

Organelle dynamics in lobster axons: anterograde and retrograde particulate organelles.

Particulate organelles in isolated axons from the walking legs of the lobster were detected with differential interference contrast optics and video microscopic techniques. The motion of the organelles was studied in normal axons, in axons whose surface membrane was rendered permeable with saponin, and in axoplasm extruded from the axons. In normal axons at 20-22 degrees C, organelles moved more rapidly in the anterograde direction than in the retrograde direction (respective mean velocities 1.73 micron/s and 0.63 micron/s). The instantaneous velocities of both sets of organelles were variable: those of the anterograde organelles varied less than those of retrograde organelles. The variation in instantaneous velocity was patterned; all organelles studied had velocities that fluctuated slowly with a major frequency at about 0.1 Hz. Some organelles oscillated about a fixed position at a similar major frequency. In axons with a permeabilized surface membrane there was no organelle motion unless adenosine 5'-triphosphate (ATP) was present in the bathing medium. Organelle motion reactivated with ATP was patterned in a way similar to that in normal intact axons. In extruded axoplasm in the presence of ATP, organelles moved along transport filaments that were assumed to be microtubules. Movement of organelles from one transport filament to another was not accompanied by changes in motion that could explain the normal fluctuation in velocity. The evidence indicates that the variable, or oscillatory, character of organelle motion in lobster axons is caused by an active component of the mechanisms of axonal transport.

Organelle dynamics in lobster axons: anterograde, retrograde and stationary mitochondria.

Mitochondria in isolated motor axons from the walking legs of lobster were observed with differential interference contrast optics and video microscopic techniques. Movements of the mitochondria were analyzed in time-lapse videotape records. The mean velocity of transport in the retrograde direction (1.33 +/- 0.64 micron/s) was greater than the mean velocity of transport in the anterograde direction (0.72 +/- 0.26 micron/s). The mean lengths of the mitochondria moving in the retrograde and anterograde directions were only slightly different (6.9 microns and 5.5 microns, respectively). No correlation was found between mitochondrial length and average velocity or reciprocal velocity. The instantaneous velocities of mitochondria were distributed over a range of approximately 3 micron/s; both the anterograde and retrograde distributions contained a small proportion of values whose sign was opposite to the modal value. The variation in instantaneous velocity took place at frequencies close to 0.1 Hz. Some mitochondria displayed longitudinally oriented oscillatory movements of a similar low frequency. While the movement of most mitochondria was parallel to the axis of the axon, transverse deviations and complex circular paths were sometimes observed. Some mitochondria reversed their orientation and continued in the same direction, so that the end which had been the leading end became the trailing end. Many mitochondria immediately beneath the plasma membrane were stationary and adhered strongly to the plasma membrane when the axoplasmic structure was disrupted. In electron micrographs, fine strands connected peripheral mitochondria and the plasma membrane. These strands may anchor the stationary mitochondria to the plasma membrane.

Axonal inclusions in the crab Hemigrapsus nudus.

Light microscopic examination of living giant axons from the walking legs of Hemigrapsus nudus revealed intra-axonal inclusions which were usually several tens of micrometers long and about 5 micron wide. The inclusions were filled with small light-scattering particles. The inclusions were shown, by thin section electron microscopy, to be composed largely 68% by volume) of mitochondria. Each inclusion was surrounded by membrane bounded spaces which are presumed to represent a part of the smooth endoplasmic reticulum. Similar inclusions were not found in the leg axons of a variety of other decapod crustaceans.