Frontotemporal dementia progresses to death faster than Alzheimer disease.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a common cause of non-Alzheimer dementia, but its natural history and the factors related to mortality in affected patients are not well understood. METHODS: This retrospective, longitudinal study compared survival in FTLD (n = 177) with Alzheimer disease (AD; n = 395). Hazards analysis investigated the contribution of various demographic, neuropsychiatric, and neuropsychological variables and associated neurologic and neuropathologic findings. RESULTS: The frontotemporal dementia (FTD) subtype of FTLD progressed faster than AD (median survival from retrospectively determined symptom onset, 8.7 +/- 1.2 vs 11.8 +/- 0.6 years, p < 0.0001; median survival from initial clinic presentation, 3.0 +/- 0.5 vs 5.7 +/- 0.1 years, p < 0.0001). Survival was similarly reduced in the related conditions corticobasal degeneration and progressive supranuclear palsy. Survival in the semantic dementia subtype of FTLD (11.9 +/- 0.2 years from onset and 5.3 +/- 0.4 years from presentation), however, was significantly longer than in FTD and did not differ from AD. Hazards analysis to determine factors affecting survival in FTLD showed no effect of age at onset, sex, education, family history, or neuropsychiatric profile. Among neuropsychological measures examined, impaired letter fluency had a significant association with reduced survival. Associated ALS significantly reduced survival in FTLD. The presence of tau-positive inclusions was associated with the slowest progression. CONCLUSIONS: Frontotemporal lobar degeneration progresses more rapidly than Alzheimer disease, and the fastest-progressing cases are those with the frontotemporal dementia clinical subtype, coexisting motor neuron disease, or tau-negative neuropathology.

Skull of Early Eocene Cantius abditus (Primates:Adapiformes) and its phylogenetic implications, with a reevaluation of "Hesperolemur" actius.

A substantially complete skull and mandible of the primitive adapiform Cantius is reported from the Early Eocene Willwood Formation of Wyoming. The mandible contains an almost complete lower dentition in which the lower incisors are strongly inclined and have spatulate crowns, I(2) is larger than I(1), and the canine is large and projecting. The cranium shares many features with those of Notharctus and Smilodectes but differs in having nasals that broaden proximally. Presence of a prominent canine and strong sagittal crest may indicate that it represents a male. The basicranium preserves auditory structures almost identical to those in extant noncheirogaleid lemurs, including a large bony tube for the stapedial artery and a small, open sulcus for the distal portion of the promontorial artery. The dentition is sufficiently primitive to be compatible with a relationship to either strepsirrhines or anthropoids, but the anatomy of the auditory region is more consistent with either specific relationship to lemurs or, more likely, a basal position that approximates the euprimate morphotype. Certain features of the basicranium of "Hesperolemur" actius, described by Gunnell ([1995] Am. J. Phys. Anthropol. 98:447-470) as being unlike that of any other adapiform, were either misinterpreted or are apparently no longer present in the holotype. Reassessment of these and other features indicates that in fact "H." actius differs little from Cantius and should not be separated from the latter at the genus level, although on dental grounds the species appears to be distinct (as C. actius).

Lethal mutagenesis of HIV with mutagenic nucleoside analogs.

The human immunodeficiency virus (HIV) replicates its genome and mutates at exceptionally high rates. As a result, the virus is able to evade immunological and chemical antiviral agents. We tested the hypothesis that a further increase in the mutation rate by promutagenic nucleoside analogs would abolish viral replication. We evaluated deoxynucleoside analogs for lack of toxicity to human cells, incorporation by HIV reverse transcriptase, resistance to repair when incorporated into the DNA strand of an RNA.DNA hybrid, and mispairing at high frequency. Among the candidates tested, 5-hydroxydeoxycytidine (5-OH-dC) fulfilled these criteria. In seven of nine experiments, the presence of this analog resulted in the loss of viral replicative potential after 9-24 sequential passages of HIV in human CEM cells. In contrast, loss of viral replication was not observed in 28 control cultures passaged in the absence of the nucleoside analog, nor with other analogs tested. Sequence analysis of a portion of the HIV reverse transcriptase gene demonstrated a disproportionate increase in G --> A substitutions, mutations predicted to result from misincorporation of 5-OH-dC into the cDNA during reverse transcription. Thus, "lethal mutagenesis" driven by the class of deoxynucleoside analogs represented by 5-OH-dC could provide a new approach to treating HIV infections and, potentially, other viral infections.

Mutagenesis by human immunodeficiency virus reverse transcriptase: incorporation of O6-methyldeoxyguanosine triphosphate.

The high frequency of incorporation of non-complementary nucleotides by HIV-1 reverse transcriptase is likely to be a major factor in the exceptionally rapid accumulation of viral mutations during the course of AIDS infections. To investigate whether this high level of infidelity is also associated with the incorporation of nucleotide analogs, we analyzed O6-methyldeoxyguanosine triphosphate and compared the incorporation of this analog by HIV-1 reverse transcriptase to that catalyzed by other DNA synthesizing enzymes. Our results indicate that O6-methyldeoxyguanosine triphosphate serves as a substrate for DNA synthesized in vitro by HIV-1 RT on both DNA and RNA templates. The product DNA contains the modified purine; it is sensitive to the repair enzyme, O6-methylguanine methyltransferase, which specifically reacts with DNA containing methylated guanines at the O6 position. Using a forward mutation assay we demonstrated that the nucleotide analog incorporated by HIV-1 RT is mutagenic. The mutations produced are single-base substitutions opposite template thymidines and result in A:T --> G:C transitions. The incorporation of a mutagenic nucleotide by HIV-1 RT highlights the possibility of increasing the rate of mutagenesis of HIV by the use of nucleotides that form non-complementary base pairs at high frequency.

On the origin of the order Artiodactyla.

The first known members of the order Artiodactyla appeared suddenly throughout the Holarctic region at the beginning of the Eocene. They are characterized by distinctive cursorial skeletal specializations. Owing to their abrupt appearance and the lack of transitional forms, the origin of the order is problematic. Descent from a "condylarth," specifically the arctocyonid Chriacus, has been suggested based on dental resemblances, but until now postcranial anatomy seemed to preclude close relationship between Arctocyonidae and Artiodactyla. A middle Paleocene specimen of a small arctocyonid (?Chriacus) reported here is much more similar to the oldest artiodactyl, Diacodexis, in the derived condition of the hindlimb, reviving the possibility that Artiodactyla evolved from an arctocyonid.

Mammal extinctions, body size, and paleotemperature.

There is a general inverse relationship between the natural logarithm of tooth area (a body size indicator) of some fossil mammals and paleotemperature during approximately 2.9 million years of the early Eocene in the Bighorn Basin of northwest Wyoming. When mean temperatures became warmer, tooth areas tended to become smaller. During colder times, larger species predominated; these generally became larger or remained the same size. Paleotemperature trends also markedly affected patterns of local (and, perhaps, regional) extinction and immigration. New species appeared as immigrants during or near the hottest (smaller forms) and coldest (larger forms) intervals. Paleotemperature trend reversals commonly resulted in the ultimate extinction of both small forms (during cooling intervals) and larger forms (during warming intervals). These immigrations and extinctions mark faunal turnovers that were also modulated by sharp increases in sediment accumulation rate.

Additional fossil evidence on the differentiation of the earliest euprimates.

Several well-preserved jaws of the rare North American omomyid primate Steinius vespertinus, including the first known antemolar dentitions, have been discovered in 1989 and 1990 in the early Eocene Willwood Formation of the Bighorn Basin, Wyoming. They indicate that its dental formula is as primitive as those in early Eocene Donrussellia (Adapidae) and Teilhardina (Omomyidae)--widely considered to be the most primitive known euprimates--and that in various dental characters Steinius is as primitive or more so than Teilhardina. Therefore, despite its occurrence at least 2 million years later than Teilhardina, S. vespertinus is the most primitive known omomyid and one of the most primitive known euprimates. Its primitive morphology further diminishes the dental distinctions between Omomyidae and Adapidae at the beginning of the euprimate radiation

Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: a case report.

The authors report a case of spontaneous spinal epidural hematoma causing paraplegia secondary to a qualitative platelet disorder from excessive garlic ingestion. The case also demonstrates satisfactory recovery from thoracic spinal epidural hematoma in a nonagenarian. Recovery from severe spinal cord compression can occur even in the very elderly.

Climbing adaptations in the early eocene mammal Chriacus and the origin of artiodactyla.

A virtually complete articulated skeleton of the arctocyonid Chriacus, recently found in northern Wyoming, is one of the most intact early Eocene mammal skeletons ever found. It exhibits numerous adaptations characteristic of mammals that climb, including strong bony crests and processes (reflecting powerful musculature), ability for considerable forearm supination, a highly mobile ankle joint, plantigrade feet, curved and transversely compressed claws, and a long, possibly semiprehensile tail. These features contrast sharply with those of the oldest artiodactyls and indicate that Chriacus or a similar arctocyonid was not ancestral to the Artiodactyla, as has been proposed.

The skeleton of early Eocene Cantius, oldest lemuriform primate.

A recently discovered partial skeleton of the adapid Cantius trigonodus from the early Eocene Willwood Formation of the Bighorn Basin, Wyoming, documents substantial new information about the anatomy of the oldest lemuriform primates. It is very similar in all features to its descendant, middle Eocene Notharctus, and both exhibit numerous resemblances to certain extant Malagasy lemurs, particularly Lepilemur, Propithecus, Lemur, and Hapalemur griseus. Like these forms, Cantius had relatively long hind limbs and short forelimbs. Forelimb traits (prominent brachialis flange of the humerus, well-developed olecranon process of the ulna, and strong shafts of the ulna and radius) suggest active use of the forelimbs in progression. Specializations in the hind limb (e.g., expanded articular surface of the femoral head, narrow and elevated patellar trochlea and prominent lateral trochlear ridge, posteriorly oriented femoral and tibial condyles, narrow and elongate talus, and hallucal metatarsal with prominent peroneal tubercle) indicate capabilities for leaping and for powerful grasping with an opposable hallux. Cantius was presumably primitive in having a relatively long ischium and much more distal inferior tibial tuberosity than most extant lemurs--traits suggesting that powerful extension of the thigh and flexion at the knee were important in its locomotion and posture. We interpret Cantius as an active arboreal quadruped with a propensity for leaping. The existence of this skeletal structure in one of the oldest primates of modern aspect suggests that it represents the primitive lemuriform morphology.

Transdermal administration of nicotine.

The physiological response to nicotine topically applied to the skin was measured in an adult male volunteer. Nicotine base (9 mg) was applied in a 30% aqueous solution to intact skin on the underside of the forearm. Salivary nicotine, heart rate and blood pressure were monitored for 12 h after application of the nicotine. Within 30 min a significant level of nicotine was detected in the saliva (50 ng/ml), pulse had risen by 15 beats/min and systolic blood pressure had risen 10 mmHg. Nicotine levels remained elevated for 2 h and were comparable to levels of nicotine produced by cigarette smoking. Because previous research has shown nicotine to suppress smoking behavior, it may be fruitful to examine transdermal administration of nicotine as a smoking reduction and cessation aid.

Skeleton of diacodexis, oldest known artiodactyl.

A nearly complete skeleton of early Eocene Diacodexis, the oldest known member of the mammalian order Artiodactyla, is described. Its slender, elongate limb elements indicate that Diacodexis was highly cursorial and closer in postcranial adaptations to tragulids and other primitive ruminants than to living or extinct nonruminant artiodactyls. Its skeletal specializations call into question the widespread notion that Diacodexis was the ancestor of all later artiodactyls.

Function of the mandibular tooth comb in living and extinct mammals.

Among the most interesting mammalian dental specialization is the mandibular 'tooth comb' or 'tooth scraper' that evolved independently in certain primates and other mammals. Its occurrence is most widely known in lemurs and lorises, where it is comprised of the long, slender, procumbent incisors (one or two pairs) and incisiform canines (Fig. 1). In non-primates to canines are not incorporated into the comb. Some tree shrews (Tupaiidae) possess a tooth comb consisting of the four central incisors, and some early Tertiary arctocyonid condylarths had a similar structure composed of all six lower incisors. The extant flying lemurs (Dermoptera: Cynocephalus) also have a dental 'comb' but it is very different from the ones already mentioned, consisting of two pairs of pectinate incisors, each tooth modified into a comb with as many as 15 tines. This condition, although sometimes said to be similar to that in lemurs, is unique to Cynocephalus. One of the principal functions of the tooth comb in primates is to comb the fur, and we present here indirect evidence that condylarths used this structure in the same way, millions of years before tooth combs evolved in prosimians. We also show that the comb-like incisors of Cynocephalus, contrary to popular belief, probably do not function to comb the fur.

Clarkforkian land-mammal age: revised definition, zonation, and tentative intercontinental correlations.

New faunal and stratigraphic evidence documents the validity of the North American Clarkforkian Land-Mammal Age. Its limits are defined by the initial appearances of immigrant taxa. In the type area (northwestern Wyoming), the Clarkforkian is subdivided into three zones. Clarkforkian faunas are approximately correlative with latest Paleocene-earliest Eocene faunas of the Paris Basin of Europe and in part with the Gashato-Naran Bulak faunas of Mongolia.

Differentiated perceptions of exertion: part I. mode of integration of regional signals.

The mode of sensory integration of differentiated perceptions of exertion from the legs and chest was determined during sub-maximal cycle ergometer exercise. 50 male subjects performed three separate cycle ergometer tests. Power output was held constant at 840 kpm/min., while pedalling rate was randomly set at 40, 60, or 80 rpm. The over-all rating of perceived exertion was significantly lower than the rating for the legs and higher than that for the chest at each pedalling rate. Local signals from the legs dominated the sensory process. Central signals were less pronounced. The mean of the ratings for the legs and chest was slightly but significantly higher than the over-all rating at each pedalling rate. Therefore, the integration process at the superordinate level of sensory processing appeared as a weighted average of the involved regional signals.

Differentiated perceptions of exertion: part II. relationship to local and central physiological responses.

Differentiated ratings of perceived exertion in the legs and chest were compared to local and central physiological adjustments during submaximal cycle ergometer exercise. 50 male subjects performed three separate cycle ergometer tests. Power output was held constant at 840 kpm/min., while pedalling rate was randomly set at 40, 60, or 80 rpm. Differentiated reports of exertion from the legs were considered to be local signals and reports from the chest to be central signals. Ratings of exertion for the legs, chest and over-all body were each significantly higher at 40 rpm than 60 or 80 rpm. Heart rate, oxygen uptake, ventilation and respiratory rate were also higher at 40 rpm. Lactic acid, pH, and pCO2 were similar between pedalling rates. Lactic acid did not operate differentially to influence local perceptual signals from the legs. Central measures of respiratory and aerobic metabolic adjustments were consistent with the more intense regional report of chest exertion at 40 rpm.

Perceived exertion and the field-independence--dependence dimension.

Perceived exertion responses were compared between field-independent and field-dependent perceivers at three cycle-ergometer pedalling rates. 50 male subjects were classified according to mode of field approach on the basis of their performance on an embedded-figures test. Power output was held constant at 840 kpm/min., while pedalling rate was randomly set at 40, 60, or 80 rpm. Significant differences between the field-independent and -dependent groups were not found at the three pedalling rates for any of the physiological variables or for over-all, legs and chest ratings of perceived exertion. The extent of differentiated psychological functioning did not account for individual differences in perceptual reactance during muscular exertion.

Perceived exertion and stimulus intensity modulation.

Perceptual augmentation and reduction were considered contrasting styles of Stimulus Intensity Modulation. Differences in perceived exertion between augmenters and reducers were determined for three cycle ergometer work loads. Subjects were 20 males having similar physiological characteristics. Stimulus Intensity Modulation was determined by kinesthetic figural aftereffect. Augmenters rated their perceptions of physical exertion to be more intense than reducers at 450, 750 and 1050 kpm/min. Differences in physiological responses between augmenters and reducers were not significant at the three work loads. Style of Stimulus Intensity Modulation appeared differentially to influence perceived exertion at the work levels studied.