Age-dependent neurodegeneration and organelle transport deficiencies in mutant TDP43 patient-derived neurons are independent of TDP43 aggregation.

TAR DNA-binding protein 43 (TDP43) plays a significant role in familiar and sporadic amyotrophic lateral sclerosis (ALS). The diverse postulated mechanisms by which TDP43 mutations cause the disease are not fully understood. Human wildtype and TDP43 S393L and G294V mutant spinal motor neuron cultures were differentiated from patient-derived iPSCs. Mutant hTDP43 and wildtype motor neuron cultures did not differ in neuron differentiation capacity during early maturation stage. During aging we detected a dramatic neurodegeneration including neuron loss and pathological neurofilament abnormalities only in TDP43 mutant cultures. Additionally mitochondria and lysosomes of aging spinal motor neurons revealed robust TDP43 mutation dependent abnormal phenotypes in size, shape, speed and motility which all appeared without TDP43 mislocalization or aggregation formation. Furthermore, D-sorbitol - known to induce stress granules and cytoplasmic mislocalization of TDP43 - rescued axonal trafficking phenotypes without signs of TDP43 mislocalization or aggregation formation. Our data indicate TDP43 mutation-dependent but cytosolic aggregation-independent mechanisms of motor neuron degeneration in TDP43 ALS.

Vesicular fast axonal transport rates in young and old rat axons.

An isolated sciatic nerve preparation was used to measure the transport rates of more than 18,000 vesicles in 72 axons from young (3-4 months of age) and old (24-26 months of age) rats from two strains (Harlan Sprague-Dawley and Fisher-344). Average anterograde and retrograde vesicle transport rates were significantly slower in the older animals. The amount of slowing of anterograde vesicles was twice as great as the slowing of retrograde vesicles. Age-related slowing of vesicle transport was inversely proportional to vesicle speed, with the result that transport of the slowest and largest vesicles may essentially be blocked in older axons. One possible explanation for these data is that long-lived axonal cytoskeletal proteins are subject to age-related changes that impede vesicle transport.

A national survey of drug testing policies for college athletes.

This study examined current and proposed drug testing policies from a stratified random sample of colleges and universities in the United States. Two-hundred forty-five of the 288 athletic directors surveyed responded, and 29% reported drug testing of their student athletes. Testing was most commonly conducted on a random basis, with cocaine and amphetamines the most frequently screened drugs, 85% and 83%, respectively. Only 56% tested for other specific performance-enhancing drugs such as steroids. Referral for treatment was the most common consequence of testing positive. Among schools conducting testing, the majority of students supported the program, whereas in schools without a testing program, it was anticipated that the majority of students would be opposed. It is suspected that more schools will initiate testing over the short term.

Silhouettes elicit alarm calls from captive vervet monkeys (Cercopithecus aethiops).

In Part 1, we analyzed alarm calls produced by captive vervets (Cercopithecus aethiops) in response to naturally occurring stimuli. Females and juveniles regularly alarm called to airplanes, birds, and barking dogs. Juvenile females accounted for 60% of these alarm calls. In Part 2, we isolated several monkeys from the colony and presented them with life-sized silhouettes of a leopard, snake, eagle, baboon, vervet, and goose. Adult monkeys alarm called more than did juveniles. Alarm calls were elicited by leopard, snake, baboon, and vervet silhouettes, but none were elicited by eagle or goose silhouettes. Some leopard and snake alarm calls matched those recorded in the wild in the context of the vervets' natural predators. Results indicate that silhouette stimuli are a useful technique for eliciting monkey vocalizations in the laboratory.

An examination of current and proposed drug-testing policies at US colleges and universities.

Administrators at 400 colleges and universities were surveyed for information regarding their schools' current or proposed policies for the urine drug testing of faculty, nonfaculty employees, and students. Three hundred seven schools (77%) responded regarding their testing policies for employees and applicants for employment, including faculty and nonfaculty; 332 (83%) responded with respect to students. Twenty-five schools reported testing one or more of these groups. None of the schools reported randomly testing applicants for either faculty or nonfaculty positions, and none tested all applicants for all positions. Fewer than 7% of the colleges and universities surveyed reported that they tested urine of employees and applicants for employment to detect drug use. In those institutions that carried out tests, the tests were most often directed toward particular types of workers. Student testing was limited to approximately 2% of the 332 responding institutions.

Differential sensitivity to vowel continua in Old World monkeys (Macaca) and humans.

Previous studies indicate that monkey pure tone frequency discrimination is quantitatively and qualitatively very different from that of humans: Monkey DLs at 1.0 and 2.0 kHz are up to 20 times larger than human DLs, and monkeys DLs increase as sensation level increases, in contrast to human DLs [Sinnott et al., J. Acoust. Soc. Am. 78, 1977-1985 (1985); Sinnott et al., J. Comp. Psychol. 101, 126-131 (1987)]. These results led to an hypothesis that monkey frequency discrimination is more dependent upon "rate" coding than is that of humans. The present study compared monkey and human DLs for formant frequency changes along three synthetic vowel continua /I-i/, /ae-epsilon/, and /a-v/. Here, monkey DLs for formants near 1.0 and 2.0 kHz (32-48 Hz) were only about two to three times larger than human DLs (11-21 Hz), and both monkeys and humans exhibited relatively similar, flat sensation level functions. Taken together, these data indicate that monkey and human frequency discrimination is more similar in the case of a complex vowel stimulus than in the case of a simple pure tone stimulus. Results are discussed in relation to "rate" versus "temporal" coding of tones and vowels in the auditory system.

Effects of combined fluoxetine and counseling in the outpatient treatment of cocaine abusers.

Three methods of analysis were used to determine the effects of the combination of counseling with fluoxetine (20, 40, or 60 mg) and "active" placebo (diphenhydramine, 12.5 mg) randomly assigned. Forty-five cocaine-only dependent subjects were treated as outpatients with "interpersonal" counseling, medication, and drug use monitoring three times per week for up to 12 weeks. Treatment effects were analyzed: first, by comparing the three original assignments and placebo; second, by comparing the placebo group to fluoxetine subjects with detectable fluoxetine/norfluoxetine blood levels and those with no detectable medication blood level; third, by examining relapse prevention versus use cessation through stratifying the subjects into four groups according to fluoxetine or placebo assignment and initial urine cocaine positivity or negativity. All three analyses showed improvement on some measures over time regardless of group assignment. The 60-mg fluoxetine group showed least effectiveness, the group with detectable blood levels had less cravings, and the fluoxetine subjects who were abstinent at the start of treatment were somewhat less likely to avoid relapse than those on placebo.

Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls.

The assay of plasma very long chain fatty acids (VLCFAs), developed in our laboratory in 1981, has become the most widely used procedure for the diagnosis of X-linked adrenoleukodystrophy (X-ALD) and other peroxisomal disorders. We present here our 17 years' experience with this assay. Three VLCFA parameters, the level of hexacosanoic acid (C26:0), the ratio of C26:0 to tetracosanoic acid (C24:0), and of C26:0 to docosanoic acid (C22:0), were measured in 1,097 males (hemizygotes) with X-ALD, 1,282 women heterozygous for this disorder, including 379 obligate heterozygotes, 797 patients with other peroxisomal disorders, and 29,600 control subjects. All X-ALD hemizygotes who had not previously received Lorenzo's oil or a diet with a high erucic acid content had increased VLCFA levels, but the application of a discriminant function based on all three measurements is required to avoid the serious consequences of a false-negative result. VLCFA levels are increased at day of birth, thus providing the potential for neonatal mass screening, are identical in the childhood and adult forms, and do not change with age. Eighty-five percent of obligate heterozygotes had abnormally high VLCFA levels, but a normal result does not exclude carrier status. VLCFA levels were increased in all patients homozygous for Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease, and in patients with deficiencies of peroxisomal acyl-coenzyme A oxidase, bifunctional enzyme, and 3-oxoacyl-coenzyme A thiolase. In these patients the degree of VLCFA excess correlated with clinical severity.