Novel endotheliotropic herpesviruses fatal for Asian and African elephants.

A highly fatal hemorrhagic disease has been identified in 10 young Asian and African elephants at North American zoos. In the affected animals there was ultrastructural evidence for herpesvirus-like particles in endothelial cells of the heart, liver, and tongue. Consensus primer polymerase chain reaction combined with sequencing yielded molecular evidence that confirmed the presence of two novel but related herpesviruses associated with the disease, one in Asian elephants and another in African elephants. Otherwise healthy African elephants with external herpetic lesions yielded herpesvirus sequences identical to that found in Asian elephants with endothelial disease. This finding suggests that the Asian elephant deaths were caused by cross-species infection with a herpesvirus that is naturally latent in, but normally not lethal to, African elephants. A reciprocal relationship may exist for the African elephant disease.

Cyclin E2: a novel CDK2 partner in the late G1 and S phases of the mammalian cell cycle.

We report here the cloning and characterization of human and mouse cyclin E2, which define a new subfamily within the vertebrate E-type cyclins, while all previously identified family-members belong to the cyclin El subfamily. Cyclin E2/CKD2 and cyclin E/CDK2 complexes phosphorylate histone H1 in vitro with similar specific activities and both are inhibited by p27Kip1. Cyclin E2 mRNA levels in human cells oscillate throughout the cell cycle and peak at the G1/S boundary, in parallel with the cyclin E mRNA. In cells, cyclin E2 is complexed with CDK2, p27 and p21. Like cyclin E, cyclin E2 is an unstable protein in vivo and is stabilized by proteasome inhibitors. Cyclin E2-associated kinase activity rises in late G1 and peaks very close to cyclin E activity. In two malignantly transformed cell lines, cyclin E2 activity is sustained throughout S phase, while cyclin E activity has already declined and cyclin A activity is only beginning to rise. We speculate that cyclin E2 is not simply redundant with cyclin E, but may regulate distinct rate-limiting pathway(s) in G1-S control.

A chromatographic assay for heme oxygenase activity in cultured human cells: application to artificial heme oxygenase overexpression.

Heme oxygenase (HO) activity oxidizes heme, releasing carbon monoxide; heme iron; and biliverdin, which is converted to bilirubin by biliverdin reductase. Inducible HO-I expression is a marker of oxidative stress in mammalian cells, while noninducible HO-II contributes to basal HO activity. HO-I and HO-II activities are implicated in cellular antioxidant defense mechanisms. We describe a microassay for HO activity in cultured human cells, using high-performance liquid chromatography of biliverdin and bilirubin. The assay is sufficiently sensitive to quantify basal and inducible HO activity in various human cell types. We have established human cell lines overexpressing heme oxygenase-II activity in microsomes using a metallothionein promoter-regulated expression system. Stable transformants treated with ZnCl2 express up to ninefold induction of HO activity. We have constructed human cell lines overexpressing HO-II protein and activity (5-15-fold) in the absence of tetracycline, using the HtTA-1 cell line transfected with tetracycline-regulated expression vectors (Gossen et al., Proc. Natl. Acad. Sci. USA 89, 1992). Functional HO-II overexpressing clones will be useful in investigating anti- or pro-oxidant effects of HO activity during cellular oxidative stress.

Psychological screening of children for participation in nontherapeutic invasive research.

BACKGROUND: The need for children to participate in research has raised concerns about ethical issues surrounding their participation. OBJECTIVES: To describe a protocol of preresearch psychological screening and postresearch outcomes and to present the results of the screening process for a nontherapeutic, invasive research study. DESIGN AND SETTING: Descriptive study carried out at The University of Iowa Hospitals and Clinics, Iowa City. PARTICIPANTS: Twenty-eight children (mean age, 10.6 years) were screened, with 4 not completing the research study and another 4 unavailable for psychological follow-up. MAIN OUTCOME MEASURES: Prescreening interviews with parent and child and screening measures of appropriate child cognitive abilities and behavior; postscreening parent and child questionnaires. RESULTS: Of the 4 children who did not complete the research study, 3 were identified with increased anxiety during the screening and were advised to not participate in the study. The primary motivator for participation was monetary reimbursement (14 parents [82%]; 15 children [75%]), followed by altruistic reasons (10 parents [59%]; 4 children [20%]). Before participating, none of the children reported concerns related to participating in the study. However, on follow-up, 9 (45%) of the children reported that they had had concerns before participating. Follow-up assessment showed that parents underestimated their children's concerns related to sexual development assessment and intravenous insertion. CONCLUSIONS: Children with increased anxiety may not be appropriate participants in potentially anxiety-provoking research. Children's reports of concerns may change from preparticipation to postparticipation, and discrepancies may exist between parent and child reports of concerns with research participation. Further research is needed to ensure children's safe participation in research.

Increased incidence of a midline brain anomaly in patients with nonsyndromic clefts of the lip and/or palate.

BACKGROUND AND PURPOSE: Nonsyndromic clefts of the lip and palate (CLP) are developmental craniofacial abnormalities that are often associated with cognitive dysfunction. This study was designed to evaluate, in patients with CLP, the presence of a specific midline brain anomaly (enlarged cavum septi pellucidi [CSP]) that has been shown in other developmental syndromes to be related to poor cognitive function. METHODS: Brain images were obtained using magnetic resonance imaging on 49 adult men with CLP and 75 healthy controls. Size of CSP was measured using consecutive coronal images. RESULTS: The incidence of large CSP in the CLP group was 8% (4 of 49), significantly higher than that found in the control group. In 2 of these 4 subjects, the anomaly was complete nonfusion of the septal leaflets, known as a combined CSP and cavum vergae. Furthermore, there was a significant inverse relationship of IQ and CSP in CLP patients that was not present in controls. That is, in individuals with CLP, the larger the CSP, the lower the IQ. CONCLUSIONS: Adult men with CLP have an increased prevalence of enlarged CSP. Moreover, this anomaly is directly related to cognitive deficits. This study provides further evidence that the development of the face and the development of the brain are intimately related and that defects in craniofacial development are most likely associated with defects in brain development.

A variant of the endotheliotropic herpesvirus in Asian elephants (Elephas maximus) in European zoos.

Newly discovered, lethal elephant endotheliotropic herpesviruses (EEHV) have been identified in both Asian (Elephas maximus) and African (Loxodonta africana) elephants. Carried by otherwise healthy African elephants they can be fatal mainly for young Asian elephants. Since zoos often harbour both elephant species, we conducted a survey on the presence of EEHV in Asian elephants from 12 European zoos, 3 circuses and 1 Israeli zoo. Here, we demonstrate that all EEHV that have affected Asian elephants so far belong to the EEHV1 group. We also describe the detection and the partial sequencing of an endotheliotropic herpesvirus variant (named EEHV1b) in Asian elephants, being either an EEHV endogenous to Asian elephants or indicating different sources (African elephants) of infection.

Comparison of glycoprotein B (gB) variants of the elephant endotheliotropic herpesvirus (EEHV) isolated from Asian elephants (Elephas maximus).

The recently described elephant endotheliotropic herpesviruses (EEHV) have been associated with the deaths of numerous captive elephants. A proposed tool for the detection of EEHV infection in elephants is the PCR-based screening for EEHV-DNA in whole blood samples. Unfortunately, this detection method has only been successful in post-mortem analyses or in animals already displaying clinical signs of EEHV disease, thus rendering this method unsuitable for identification of carrier elephants. Here, we focus on glycoprotein B (gB) for serologic assay development, since gB is an envelope protein known to induce a neutralising antibody response in other herpesvirus infections. We sequenced the entire gB gene from five Asian elephants with EEHV, representing four different gB variants. Computer-aided methods were used to predict functionally important regions within EEHVgB. An extra-cytoplasmic region of 153 amino acids was predicted to be under positive selection and may potentially contain antigenic determinants that will be useful for future serologic assay development.

Immediate memory functions in reading disability subtypes.

This study examined immediate memory processes in specific reading disability subtypes. Three subgroups (n = 15 in each subgroup) of reading disabled children were examined: (a) perceptual-motor disorder, (b) verbal disorder-general, and (c) verbal disorder-specific (memory). The three groups were matched for age and full scale IQ. All children received a memory-for-colors task (Color Span Test) designed to evaluate intra- and intermodal serial memory functioning. Comparison of memory profiles for the three reading disability subtypes revealed that patterns varied depending on mode of stimulus presentation or response. Although all three groups performed considerably below normative levels on each of the four subtests of the Color Span Test, all subjects performed significantly better on verbally presented items than on visually presented items. The findings were interpreted to suggest that these reading disabled children may not consistently utilize verbal strategies for coding or retrieval of information when stimuli are visually presented.

School adjustment of children with observable disabilities.

This study investigated school behavior and achievement of children with mild degrees of observable physical disability. Children from two different disability types (cleft palate and cerebral palsy) were compared with each other and to a control group in order to determine potential similarities across disability types. Children (N = 78) from each of the two disability groups were individually matched to each other and to a normal control group (N = 39) by sex, IQ, socioeconomic status, age, and grade. They were compared on the basis of teachers' behavioral ratings and achievement test scores. All children attended regular public school classrooms. The two disability groups displayed significantly greater inhibition of impulse and lower educational achievement than did the controls. The implication of similar school adjustment across mild but observable subtypes is discussed.

Patterns of intellectual ability in children with verbal deficits.

Patterns of intellectual ability were examined in 81 children with verbal deficits identified by a Low Verbal/High Performance WISC profile. The results of verbal and nonverbal tests of intellectual functioning were factor-analyzed, and three groups of children were defined based on patterns of factor scores. Group 1 consisted of children with a Specific Language Disability (SLD) but good Abstract Reasoning ability, while Group 2 included SLD children with good Sequencing-Memory skills. Group 3 children displayed a General Language Disability (GLD) with deficits in both abstract reasoning and sequencing memory. The intellectual patterns were related to cognitive interpretations and found to have educational implications, with Group 1 children reading adequately, Group 2 children showing somewhat poorer reading skills, and Group 3 children reading very poorly. These findings emphasize the importance of identifying subgroups of children with verbal deficits and demonstrate the feasibility of extracting relatively specific cognitive information from global measures of intelligence. The results question the appropriateness of applying traditional assumptions regarding cognitive organization derived from studies of normal children to atypical groups of children.

Cognitive profiles of children with insulin-dependent diabetes.

Intellectual and reading skills were evaluated and related to disease variables in 42 children with Type I (insulin-dependent) diabetes. A significant interaction revealed lower Wechsler Intelligence Scale for Children-Revised (WISC-R) Performance IQ for children with early disease onset (less than 7 years) and long disease duration (greater than or equal to 5 years). IQ scores were nevertheless in the average range. Although there was no specific pattern of visual spatial impairment, functioning on the Performance subtests was uniformly lower for this group. Slower responding to the timed tasks of the Performance scale may account for generally lower scores. Children with early onset-long duration also evidenced higher rates of reading and memory impairment. These results indicate the importance of ascertaining educational skills in diabetic children before planning diabetic treatment regimens, especially for children with disease of early onset and long duration, who may be especially vulnerable to skill deficits.

Psychological effects of idiopathic adolescent scoliosis.

This article reviews the literature concerning psychological characteristics of adolescents with idiopathic scoliosis. Although much has been written on the topic, it is largely based on clinical judgment rather than empirical data. In spite of methodological flaws, the few empirical studies available raise questions regarding the following issues: maladjustment occurs in a significant number of adolescents with scoliosis; there are sex and age differences in response to scoliosis diagnosis and treatment; and noncompliance is a major factor in treatment. Implications for further research are discussed.

Clinical and pathological findings of a newly recognized disease of elephants caused by endotheliotropic herpesviruses.

The unique clinical and pathological findings in nine Asian (Elephas maximus) and two African (Loxodonta africana) elephants from North American Zoos with a highly fatal disease caused by novel endotheliotropic herpesviruses are described. Identification of the viruses by molecular techniques and some epidemiological aspects of the disease were previously reported. Consensus primer polymerase chain reaction (PCR) combined with sequencing yielded molecular evidence that confirmed the presence of two novel but related herpesviruses associated with the disease, one in Asian elephants and the second in African elephants. Disease onset was acute, with lethargy, edema of the head and thoracic limbs, oral ulceration and cyanosis of the tongue followed by death of most animals in 1 to 7 days. Pertinent laboratory findings in two of three clinically evaluated animals included lymphocytopenia and thrombocytopenia. Two affected young Asian elephants recovered after a 3 to 4 wk course of therapy with the anti-herpesvirus drug famciclovir. Necropsy findings in the fatal cases included pericardial effusion and extensive petechial hemorrhages in the heart and throughout the peritoneal cavity, hepatomegaly, cyanosis of the tongue, intestinal hemorrhage, and ulceration. Histologically, there were extensive microhemorrhages and edema throughout the myocardium and mild, subacute myocarditis. Similar hemorrhagic lesions with inflammation were evident in the tongue, liver, and large intestine. Lesions in these target organs were accompanied by amphophilic to basophilic intranuclear viral inclusion bodies in capillary endothelial cells. Transmission electron microscopy of the endothelial inclusion bodies revealed 80 to 92 nm diameter viral capsids consistent with herpesvirus morphology. The short course of the herpesvirus infections, with sudden deaths in all but the two surviving elephants, was ascribed to acute cardiac failure attributed to herpesvirus-induced capillary injury with extensive myocardial hemorrhage and edema.

Patellar tendon rupture in five deer.

Acute unilateral or bilateral rupture of the patellar tendon was diagnosed in 5 aged obese female Pere David's deer housed at a zoological park. Rupture occurred after an episode of sudden exertion in 4 of 5 deer. Fragmentation, degeneration, necrosis, and mineralization of ruptured patellar tendon fibers were found on histologic examination. Similar changes were often seen in intact contralateral tendons that did not have gross lesions. Patellar tendon rupture in humans is associated with concurrent systemic disease, such as systemic lupus erythematosus, rheumatoid arthritis, or chronic renal failure. Without evidence of underlying systemic disease, spontaneous patellar tendon rupture in deer can be considered a sequela to age-related tendinous degeneration compounded by sudden exertion and chronic overload attributable to obesity.

Comparison of visual-spatial performance strategy training in children with Turner syndrome and learning disabilities.

This study examined the effects of a verbal mediation strategy on three groups of subjects who had visual-spatial deficits. Thirteen females with Turner syndrome, 13 females with nonverbal learning disabilities, and 14 males with nonverbal learning disabilities, who ranged in age from 7 to 14 years, were taught via a cognitive behavioral modification approach to verbally mediate a spatial matching task. Pretest and posttest performance differences on parallel forms of a visual-spatial orientation task were examined. All three groups showed significant improvement in visual-spatial task performance after the training. There were no significant differences in the degree of improvement among the three groups. The results suggest that children with Turner syndrome may benefit from problem-solving strategy training in a manner similar to children with nonverbal learning disabilities.

The dynamics of vertical eye movements in normal human subjects.

We studied the dynamics of horizontal and vertical slow eye movements (vestibular, optokinetic, pursuit, and visual-vestibular) in 10 normal human subjects. Several differences between horizontal and vertical eye movements were found. The time constant (time required for the slow-phase eye velocity to decay to 37% of the peak value) of vertical postrotatory nystagmus (PRN) was, on average, 50% as long as the time constant of horizontal PRN; the mean phase lead of per-rotatory nystagmus during low-frequency sinusoidal rotation in the vertical plane was approximately twice the mean phase lead of per-rotatory nystagmus at the same frequency in the horizontal plane. Vertical optokinetic after-nystagmus (OKAN) was minimal compared to horizontal OKAN. Asymmetries in the dynamics of vertical eye movements were also noted. The mean time constant of PRN with upward slow phases was consistently longer than the mean time constant of PRN with downward slow phases and vertical OKAN only occurred when the optokinetic stimulus moved upward. Upward pursuit was better than downward pursuit and upward slow phases of vestibular nystagmus were poorly inhibited with fixation while downward slow phases were normally inhibited.

Use of famciclovir for the treatment of endotheliotrophic herpesvirus infections in Asian elephants (Elephas maximus).

Two juvenile Asian elephants (Elephas maximus) presented with an acute onset of facial edema and lethargy. Examination of the oral cavity of each animal revealed cyanosis of the tip and distal margins of the tongue suggestive of endothelial inclusion body disease (EIBD) of elephants. Whole-blood samples were obtained, and polymerase chain reaction tests confirmed the presence of elephant herpesvirus. The animals were administered famciclovir (Famvir, SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania 19101, USA), a potent human anti-herpesvirus drug, in the course of their disease, and recovery followed a treatment regime of 3-4 wk. These are the first known cases of elephants surviving EIBD.

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